1. Ahirwar LK, Blackburn SL, McBride DW, T PK. Reviewing vascular influences on neuronal migration, cortical development, and neurodevelopmental disorders: focus on autism, ADHD and schizophrenia. Mol Psychiatry;2025 (Sep 2)

During cortical development, newly born neurons migrate radially or tangentially from their origin to expand the cortex. Simultaneously, neuron-derived factors support angiogenesis, and an elaborate network of blood cerebral vessels develops in the cortex. Traditionally, blood cerebral vessels were considered to support the growing cortex or migrating neurons by providing nutrients and oxygen. However, recent studies have shed light on Endothelial cells’ influence on cortical development; they guide neuronal migration by providing molecular cues and structural support. Here, we review the current understanding of how CNS cerebral vessels support neurogenesis, neuronal migration, and the formation of the six-layer cortical structure during development. Additionally, we explore current knowledge regarding the vascular role in neurodevelopmental disorders, including autism spectrum disorder, attention deficit hyperactivity disorder, and schizophrenia.

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2. Al Futaisi ND, Schuller BW, Ringeval F, Pantic M. The Noor Project: fair transformer transfer learning for autism spectrum disorder recognition from speech. Front Digit Health;2025;7:1274675.

Early detection is crucial for managing incurable disorders, particularly autism spectrum disorder (ASD). Unfortunately, a considerable number of individuals with ASD receive a late diagnosis or remain undiagnosed. Speech holds a critical role in ASD, as a significant number of affected individuals experience speech impairments or remain non-verbal. To address this, we use speech analysis for automatic ASD recognition in children by classifying their speech as either autistic or typically developing. However, due to the lack of large labelled datasets, we leverage two smaller datasets to explore deep transfer learning methods. We investigate two fine-tuning approaches: (1) Discriminative Fine-Tuning (D-FT), which is pre-trained on a related dataset before being tuned on a similar task, and (2) Wav2Vec 2.0 Fine-Tuning (W2V2-FT), which leverages self-supervised speech representations pre-trained on a larger, unrelated dataset. We perform two distinct classification tasks: (a) a binary task to determine typicality, classifying speech as either that of a typically developing (TD) child or an atypically developing (AD) child; and (b) a four-class diagnosis task, which further classifies atypical cases into ASD, dysphasia (DYS), or pervasive developmental disorder-not otherwise specified (NOS), alongside TD. This research aims to improve early recognition strategies, particularly for individuals with ASD. The findings suggest that transfer learning methods can be a valuable tool for autism recognition from speech. For the typicality classification task (TD vs. AD), the D-FT model achieved the highest test UAR (94.8%), outperforming W2V2-FT (91.5%). In the diagnosis task (TD, ASD, DYS, NOS), D-FT also demonstrated superior performance (60.9% UAR) compared to W2V2-FT (54.3%). These results highlight the potential of transfer learning for speech-based ASD recognition and underscore the challenges of multi-class classification with limited labeled data.

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3. Bickel J, Hatoun J, Fry M, Prock L, Vernacchio L, Patane LB, Coop A, Weitzman C. Bridging the Gap in Autism Diagnosis: An Evaluation of a Novel Primary Care Training Model. J Dev Behav Pediatr;2025 (Sep 3)

OBJECTIVE: The current study assesses the impact of an educational program designed to train primary care clinicians (PCCs) to diagnose children between age 18 and 36 months at high risk for autism spectrum disorder (ASD). METHODS: Two cohorts of PCCs completed an 8-session training over a 9-month period. Clinicians were surveyed at baseline and 3 months after training completion. Information was collected regarding PCCs knowledge of ASD, their diagnostic beliefs, and perceived comfort and competence regarding all aspects of an ASD diagnostic evaluation. RESULTS: A total of 35 participants completed training, and 29 (82%) completed presurvey and postsurvey. At baseline, 89% of PCCs reported no additional training in developmental behavioral pediatrics or diagnosing children with ASD, although 31% had diagnosed a child with ASD in the past year. After training, PCCs reported significantly greater comfort diagnosing ASD in children between age 18 and 36 months with mild ASD (2.31 vs 3.02, p < 0.0001), moderate ASD (3.03 vs 3.83, p < 0.001), and severe ASD (3.45 vs 4.34, p < 0.0001). PCCs also reported a significant increase in their knowledge and perceived competence in completing an autism evaluation, including taking an autism history, completing a structured observation, scoring the Childhood Autism Rating Scale-Second Edition, writing a letter of medical necessity, and discussing findings with families. CONCLUSION: After training, PCCs reported a significant improvement in their knowledge, comfort, and competence regarding all aspects of diagnosing young children 18 to 36 months of age at high risk of ASD. PCCs can help to improve access to services for young children at risk for ASD.

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4. Boeri S, Piai M, Russo S, Alari V, Cogliati F, Simonetta D, Benke TA, Nobili L, Prato G. Clinical differences in monozygotic twins with Rett syndrome: case report and systematic review. Orphanet J Rare Dis;2025 (Sep 2);20(1):473.

BACKGROUND: Rett Syndrome (RTT) is a rare, and severe neurodevelopmental disorder that primarily affects females and is primarily (> 96%) due to pathogenic loss-of-function genetic variants of methyl-CpG-binding protein 2 (MECP2). Despite the rarity of the syndrome, sporadic twin cases have been reported. The descriptions have often focused on the phenotype, emphasizing differences or similarities. We report the case of monozygotic (MZ) twins with RTT carrying the same MECP2 mutation and perform a systematic review of the cases of MZ twins. METHOD: We searched PubMed and Embase for articles reporting MZ twins with RTT who met Neul criteria and carried mutations in the MECP2 gene. We focused on phenotypic discordance and X chromosome inactivation (XCI). RESULTS: Our search yielded 115 results, 18 of which were included in our systematic review. We identified 17 pairs of twins, with 11 showing a discordant phenotype. Data on XCI were reported for only six pairs. We describe MZ twins with typical RTT syndrome who shared the same p.Thr158Met pathogenic variant on the MECP2 gene but exhibited different severity of clinical phenotype, especially regarding epilepsy. The XCI pattern and expression of the wild-type allele in blood were similar in both twins, suggesting that XCI differences assessed in blood may not account for the phenotypic variability. Mononucleate cells were isolated from both twins to generate induced pluripotent stem cells (iPSCs). The patient with more mutated clones presented a more severe phenotype. DISCUSSION: Cases of MZ twins with RTT are few, and the phenotypic difference described in our case and presented in the literature does not seem to be explained by different XCI patterns. Therefore, more detailed genetic investigations are necessary.

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5. Brosnan M, Marikar S, Punter M, Ashwin C. Intolerance of Uncertainty Mediates the Relationship Between Autistic Traits and a Propensity for Deliberation. J Autism Dev Disord;2025 (Sep 3)

The Dual Process Theory of Autism proposes that those high in autistic traits, including autistic individuals, have both a reduced propensity for intuition and an enhanced propensity for deliberation. Whilst intuition is rapid and autonomous, many factors impact upon deliberation, and an intolerance of uncertainty may mediate the relationship between autistic traits and propensity for deliberation (but not intuition). Two studies were conducted to explore this hypothesis. In Study 1, 266 non-autistic participants completed an online self-report assessment of autistic traits, propensity for deliberation and intuition and intolerance of uncertainty. Mediation analyses explored the extent to which intolerance of uncertainty mediated the relationship between autistic traits and propensity for deliberation and intuition. Study 2 was a replication of Study 1 with 258 autistic participants. Results from both studies showed that, while higher autistic traits had no direct relationship with propensity for deliberation, this relationship was fully mediated by intolerance of uncertainty. Prospective intolerance of uncertainty (a desire for predictability) specifically was the significant mediator. In addition, higher autistic traits directly related to reduced propensity for intuition. Comparison of Studies 1 and 2 confirmed greater propensity for deliberation and reduced propensity for intuition in the autistic group compared to the non-autistic group, consistent with the Dual Process Theory of Autism. The findings extend the Dual Process Theory of Autism to suggest that a desire for predictability is a key mechanism underpinning enhanced propensity for deliberation in individuals with higher level of autistic traits, including autism.

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6. Brown JAR, Ling MYM, Ausió J, Howe LJ. Human MeCP2 binds to promoters and inhibits transcription in an unmethylated yeast genome. Genetics;2025 (Sep 3);231(1)

MeCP2 is a DNA-binding transcriptional regulator that is present at near-histone levels in mammalian cortical neurons. Originally identified as a DNA methylation reader, MeCP2 has been proposed to repress transcription by recruiting corepressors to methylated DNA. While some genome-wide occupancy studies support a preference for methylated DNA, others suggest that MeCP2 binding is more influenced by DNA sequence and accessibility than methylation status. Moreover, multiple studies also suggest a role for MeCP2 in gene activation. To clarify its function, we expressed MeCP2 in Saccharomyces cerevisiae, which lacks DNA methylation and known MeCP2 corepressors. We find that MeCP2 is toxic to yeast and globally inhibits transcription, indicating that MeCP2 can have significant functional impacts without DNA methylation or mammalian corepressors. A subset of MeCP2 mutations that cause the neurodevelopmental disorder Rett syndrome, particularly those that map to the DNA-binding domain, alleviate the toxicity of MeCP2 in yeast. Consistent with the importance of DNA binding for growth inhibition, we show that MeCP2 binds to the yeast genome, with increased occupancy at GC-rich, nucleosome-depleted sequences. These findings present yeast as a useful tool for analyzing MeCP2 and reveal MeCP2 properties that are not strictly dependent on DNA methylation or mammalian corepressors.

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7. Çalışkan G, Lacalle SE, Kul E, Del Ángel M, Zambrano AL, Hukema R, Santos M, Stork O. Modelling fragile X-associated neuropsychiatric disorders in young inducible 90CGG premutation mice. Brain;2025 (Sep 3);148(9):3266-3279.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by a preCGG repeat expansion in FMR1. Individuals with the FMR1 premutation often exhibit neuropsychiatric symptoms before FXTAS onset, leading to the identification of fragile X-associated neuropsychiatric disorders. Rodent models of FXTAS show motor impairments, pathological intranuclear inclusions and heightened anxiety. However, the early onset of neuropsychiatric features and underlying mechanisms remain poorly understood. To address the above issues, we used the doxycycline-inducible 90CGG mouse model, with transgene activation at two developmental stages: adolescence and young adulthood. Mice were evaluated in a behavioural battery to assess anxiety-like behaviour, exploration, and motor coordination and learning. Next, we conducted a combination of ex vivo extracellular local field potential recordings to measure synaptic physiology and oscillatory activity in the limbic system, particularly in the basolateral amygdala (BLA) and ventral hippocampus (vH) regions. Parvalbumin interneurons and intranuclear inclusions in the amygdala and hippocampus were investigated by immunofluorescence, and mass spectrometry and gene set enrichment were used to identify differentially expressed protein molecular pathways. Adolescent 90CGG mice displayed early-onset hyperactivity, transitioning to heightened anxiety in young adulthood, coinciding with the accumulation of intranuclear inclusions in the BLA and vH. Electrophysiological analysis revealed augmented gamma oscillations in the vH, emerging during adolescence and persisting in young adulthood. These changes were correlated with a reduction in parvalbumin interneurons in these regions, and together probably contribute to enhanced BLA excitability and impaired vH plasticity. Finally, proteomic analysis of the vH revealed altered proteins linked to attention deficit hyperactivity disorder in adolescence and anxiety/depression in adulthood, aligning well with behavioural findings. Importantly, these behavioural, electrophysiological and cellular alterations were reversible upon transgene inactivation. This study reveals a temporal progression of CGG premutation effects on behaviour, from hyperactivity to heightened anxiety to late-onset motor dysfunction. Moreover, these findings provide altered network activity in the limbic system as a putative mechanism in neuropsychiatric features of premutation carriers.

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8. Chen E, Schmitt J, McIntosh G, Young BP, Lian T, Liu J, Chen KK, Liston JB, MacDonald L, Wang B, Medina Giro S, Boehme B, Das M, Indran S, Chao JT, Rogic S, Pavlidis P, Allan DW, Loewen CJR. Revealing function-altering MECP2 mutations in individuals with autism spectrum disorder using yeast and Drosophila. Genetics;2025 (Sep 3);231(1)

Pathogenic variants in MECP2 commonly lead to Rett syndrome, where MECP2’s function as a DNA cytosine methylation reader is believed critical. MECP2 variants are also cataloged in individuals with autism spectrum disorder (ASD), including nine missense variants which had no known clinical significance at the start of this study. To assess these nine variants as risk alleles for ASD, we developed MECP2 variant functional assays using budding yeast and Drosophila. We calibrated these assays with known pathogenic and benign variants. Our data predict that four ASD variants are loss of function and five are functional. Protein destabilization offers insight into the altered function of some of these variants. Notably, yeast and Drosophila lack DNA methylation, yet all Rett pathogenic and ASD variants located in the methyl DNA-binding domain that we analyzed proved to be loss of function, suggesting a clinically relevant role for non-methyl DNA-binding by MECP2.

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9. Clarke N, Urchs S, Nguyen HD, Moreau C, Dansereau C, Tam A, Evans AC, Bellec L. High-precision machine learning identifies a reproducible functional connectivity signature of autism spectrum diagnosis in a subset of individuals. Gigascience;2025 (Jan 6);14

BACKGROUND: Discovery of predictive biomarkers is essential for understanding the neurobiological underpinnings of autism spectrum diagnosis (ASD) and improving identification. Resting-state functional connectivity analyses of individuals with ASD have established sensitivity of brain connectivity at the group level. However, the extensive heterogeneity in ASD limits the translation of these findings into reliable individual-level biomarkers. We analyzed the Autism Brain Imaging Data Exchange 1 and 2 datasets, calculating Pearson’s correlation-based functional connectivity across 18 brain networks. Using transductive conformal prediction, a machine learning approach that assigns confidence scores to predictions based on conformality to known classes, we classified individuals with ASD and neurotypical controls. RESULTS: By combining predictors into an ensemble using hierarchical agglomerative clustering, we identified a signature that confers a more than 7-fold increase in individual risk of ASD, yet is still identified in an estimated 1 in 200 individuals in the general population. The individual risk conferred by the model is increased 4-fold over that of previously published imaging models and outperforms the current state of the art in precision for ASD classification. The high-risk signature was characterized by underconnectivity of transmodal brain networks, including the frontoparietal and basal ganglia network, and subcomponents of the limbic and default mode networks. CONCLUSIONS: A highly targeted prediction model can identify a subset of functional connectivity alterations that confer high risk for ASD at the individual level, which may be masked by traditional machine learning models due to ASD heterogeneity. Results could help disentangle the multitude of etiological pathways and behavioral symptoms that challenge our understanding of ASD by focusing on highly penetrant connectivity signatures.

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10. Dali-Sahi M, Benguella-Benamnsour M, Amraoui N, Harek Y, Salmi T, Berrahoui S, Benosman C, Dennouni-Medjati N. Selenium deficiency and altered Cu/Se, Zn/Se and Cu/Zn ratios associated with GPx1 activity: non-invasive biomarkers of oxidative stress in autism spectrum disorders. Free Radic Biol Med;2025 (Sep 3)

Metal micronutrient dyshomeostasis appears to be involved in the risk of autism spectrum disorders (ASD). Selenium (Se), copper (Cu) and zinc (Zn) are essential for the defence against oxidative stress (OS), a key factor in the maintenance of synaptogenesis and neurogenesis. This study assessed plasma concentrations of Se, Cu, and Zn, along with their ratios, malondialdehyde (MDA) levels, and erythrocyte glutathione peroxidase (GPx1) activity in Algerian children with ASD. A total of 30 subjects diagnosed with ASD and 32 neurotypically developing (ND) children participated in this study. Trace element levels were measured using a polarographic analyzer. Plasma MDA was determined by UV spectrophotometry and erythrocyte GPx1 activity using a SPECORD® 210 plus dual beam spectrophotometer (Analytik Jena German). The Cu/Zn ratio was significantly lower in children with ASD (p<0.001), while no significant difference was found for MDA between the two study groups. However, in children with ASD, a positive correlation was found between MDA and the plasma Cu/Zn ratio (r = 0.6874, p = 0.005). Se levels and GPx1 erythrocyte activity were significantly lower in children with ASD compared with the ND children (p<0.001; p<0.05). Cu/Se and Zn/Se ratios were significantly higher in children with ASD (p<0.001). Sex-stratified analysis indicated a specific vulnerability to OS among boys with ASD, while no significant age-related differences were observed in children with ASD. These findings suggest that imbalances in micronutrient ratios and a decrease in GPx1 activity favor OS, potentially contributing to ASD pathogenesis in extreme western Algeria.

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11. Hagerman R. Bringing fragile X-associated neuropsychiatric disorders into the phenotypic fold of premutation conditions. Brain;2025 (Sep 3);148(9):3029-3031.

This scientific commentary refers to ‘Modelling fragile X-associated neuropsychiatric disorders in young inducible 90CGG premutation mice’ by Çalışkan et al. (https://doi.org/10/109/brain/awaf203).

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12. Meng S, Qi K, Shen P, Guo S, Tong W. The relationship between fear of negative evaluation and social anxiety in parents of children with ASD: The chain mediating role of perceived social support and coping styles. Comput Biol Chem;2025 (Sep 3);120(Pt 1):108670.

Parents of children with ASD face significantly greater parenting challenges than those raising typically developing children due to prolonged exposure to their children’s developmental disorders, emotional distress, and atypical behaviors, underscoring the urgency of addressing their mental health concerns. This study examined the relationship between fear of negative evaluation (FNE) and social anxiety in parents of children with ASD, with a focus on the mediating roles of perceived social support and coping styles. A cross-sectional survey was conducted among 585 parents of children with ASD using validated instruments: the Brief Fear of Negative Evaluation Scale (BFNE), the Social Anxiety Scale, the Perceived Social Support Scale, and the Simple Coping Style Questionnaire. Data were analyzed through SPSS 29.0 and AMOS 25.0 for structural equation modeling. Key findings revealed: (1) FNE directly predicted social anxiety, with significant standardized direct effects of 0.179 and 0.159 across tested models (p < 0.001); (2) Perceived social support, positive coping styles, and negative coping styles each partially mediated the FNE-social anxiety relationship, with indirect effects of 0.035 (95 % CI [0.025, 0.066]), 0.096 (95 % CI [0.181, 0.242]), and 0.110 (95 % CI [0.115, 0.126]), respectively; (3) Significant chain mediation pathways emerged through perceived social support → positive coping styles (effect = 0.008, 95 % CI [0.012, 0.016]) and perceived social support → negative coping styles (effect = 0.014, 95 % CI [0.031, 0.033]). These findings elucidate the mechanisms linking FNE to social anxiety in this population and provide theoretical foundations for targeted interventions to mitigate parental distress.

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13. Rammos A, Blakey R, Dennison CA, Lewis SJ, Ali N, Davies A, Wren Y, Humphries K, Sandy J, Rees E, Kendall KM, Sharp GC, Owen MJ, van den Bree MBM, Stergiakouli E. Copy number variants and their implications for developmental and behavioural problems in cleft lip and/or palate. Hum Mol Genet;2025 (Sep 3);34(18):1563-1574.

Cleft lip and/or palate (CL/P) is the most common craniofacial congenital anomaly and has been associated with higher risk of neurodevelopmental and behavioural problems indicating potential shared genetic factors between CL/P and neurodevelopmental disorders. In this study, we aimed to determine the prevalence of neurodevelopmental copy number variants (CNV) in children with CL/P and their link to early developmental and behavioural problems. Using data from the Cleft Collective, the largest UK-based national cohort study of children with CL/P, we determined the rates of neurodevelopmental CNVs in children with CL/P comparing them to the general population, explored differences by cleft type and investigated risk of developmental delays and behavioural problems among those with CL/P and neurodevelopmental CNVs. Children with CL/P had a higher prevalence of neurodevelopmental CNVs than participants in four population-based samples (3.7% vs 2.3% in the Avon Longitudinal Study of Parents and Children (ALSPAC), 2.0% in Born in Bradford (BiB), 2.3% in Millenium Cohort Study (MCS), 1.7% in UK Biobank, ORs(95%CIs): ALSPAC = 1.56(1.18-2.06), BiB = 1.84(1.37-2.45), MCS = 1.59(1.19-2.11), UK Biobank = 2.15(1.68-2.71). Children with cleft palate only were 3 times more likely to have a neurodevelopmental CNV (95%CIs1.50-6.59, p = 0.03) than children with cleft lip only. Furthermore, children with CL/P and neurodevelopmental CNVs were more likely to experience early developmental delays and behavioural problems by age 5 compared to children with CL/P and without neurodevelopmental CNVs. These findings highlight that genetic testing ascertaining the presence of neurodevelopmental CNVs might be helpful in early identification of developmental needs in children with CL/P.

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14. Thomas KE, Raghuram K, Banihani R, Church PT, Mbuagbaw L, Penner M. Screening for Autism in Preterm Children: A Systematic Review. Pediatrics;2025 (Sep 3)

OBJECTIVE: Preterm children exhibit a higher prevalence of autism spectrum disorder (ASD) than the general population. The unique neurodevelopmental characteristics of preterm children present challenges in screening for and diagnosing ASD. To date, a systematic review of screening tools for ASD in this population has not been completed. This systematic review and meta-analysis evaluates the diagnostic performance of currently used ASD screening tools in the preterm population. METHODS: The database search was conducted by using MEDLINE, PsycINFO, PubMed, Embase, and CINAHL in July 2024. Articles that quantified the diagnostic accuracy of ASD screening tools in the preterm population were included. Nine studies were included in this review, and only 4 studies in the meta-analyses. All studies were assessed for risk of bias, applicability, and certainty. RESULTS: Sensitivity of screening tools for ASD in preterm children ranged from 0% to 100%, whereas specificity ranged from 38% to 98%. Pooled data were available for the Modified Checklist for Autism in Toddlers (2 studies) and Social Communication Questionnaire. (2 studies), with pooled sensitivities of 55% and 53% and specificities 85% and 90%, respectively. CONCLUSIONS: There was significant study heterogeneity, limiting the number of studies from which to pool diagnostic accuracy data. Screening tools vary in their ability to identify ASD in the preterm population, underscoring how overlapping behavioral phenotypes may confound early identification. There is a critical need to refine and assess ASD screening tools in preterm children, facilitating timely interventions in this cohort.

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15. Yan W, Zhai T, Li Y, Chen J, Sun Z, Lin Y, Zhang X, Du Y. Effects of immersive virtual reality training on the adaptive skills of children and adolescents with high functioning autism spectrum disorder: a mixed-methods pre-post study. Front Psychiatry;2025;16:1570437.

BACKGROUND: Autism Spectrum Disorder (ASD) is characterized by social deficits and restricted, repetitive behaviors, with fewer than 10% achieving independent adulthood. Immersive virtual reality (IVR) provides a novel training approach through interactive and realistic environments. This study developed an IVR system to enhance adaptive skills in children and adolescents with high-functioning ASD. METHODS: Thirty-three individuals with high-functioning ASD (ages 8-18) were enrolled based on clinical diagnoses confirmed by Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) and Autism Diagnostic Interview-Revised (ADI-R), with an intelligence quotient ≥ 80. The study employed a single-arm, within-subject pre-post design. Participants received weekly one-hour IVR training sessions, requiring 6-10 sessions to complete 36 tasks twice. Primary outcomes included changes in IVR task scores and completion times, while secondary outcomes assessed parent-reported questionnaires – Adaptive Behavior Assessment System-Second Edition (ABAS-II), Autism Behavior Checklist (ABC), and Behavior Rating Inventory of Executive Function (BRIEF) – neuropsychological tests (Go/No-Go, 0-back, 1-back, and emotional face recognition tasks), and semi-structured interviews. Usability was evaluated via self-reported comfort levels, willingness to continue and device-related questions. Generalized Estimating Equation models analyzed changes across all measures. RESULTS: The IVR training demonstrated high usability, with an 87.9% completion rate and no severe adverse effects. Some participants reported mild discomforts, including dizziness (28.6%) and fatigue (25.0%), as well as device-related issues such as unsteady walking (34.5%) and headset discomfort (31.0%). However, comfort levels increased over time (adjusted P = 0.026), indicating gradual adaptation to the system. IVR task scores improved by 5.5% (adjusted P = 0.034), and completion times decreased by 29.59% (adjusted P < 0.001). Parent-reported measures showed a 43.22% reduction in ABC Relating subscale scores (adjusted P = 0.006) and moderate reductions in BRIEF Behavioral Regulation and Metacognition indices (adjusted P = 0.020, 0.019). Reaction times for the 1-back and emotional face recognition tasks decreased by 14.81% and 14.14% respectively (adjusted P = 0.012, 0.014). Qualitative feedback indicated improvements in social interaction, emotional regulation, repetitive behaviors, attention, and daily living skills. CONCLUSION: This pilot study supports IVR training as a feasible and potentially effective training method for improving adaptive skills in children and adolescents with high functioning ASD.

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16. Zheng Q, Zhao Y, Cheng Q, Wang H, Liu F, Lai J, Liu Y, Zhang X, Kang Y, Li Z, Cao B, Wei C, Qian Z, Fan J, Ren W, Tian Y. Potentiation of Nigra-Striatal Dopaminergic Projection Underpins Core Autism-Like Behaviors in Valproate-Exposed Mice. J Neurosci;2025 (Sep 3);45(36)

Autism is characterized by two key diagnostic criteria including social deficits and repetitive behaviors. However, the underlying neural circuit dysfunction that accounts for these coexisting symptoms in autism remains poorly understood. Here we revealed that prenatal valproate exposure induced functional alterations of dopaminergic projections from substantia nigra pars compacta (SNc) to dorsomedial striatum (DMS). Specifically, we observed enhanced excitatory input and increased excitability in SNc→DMS dopamine (DA) neurons, resulting in a basal state of potentiation. This potentiated baseline activity blunted the phasic responses of SNc→DMS projections, as evidenced by reduction of transient Ca(2+) and DA signaling during social interaction and expression of repetitive behaviors in valproate-exposed male mice. We then utilized chronic chemogenetic and optogenetic approaches to selectively manipulate the abnormal basal activity of SNc→DMS dopaminergic signaling. This targeted intervention successfully rectified the dysfunction in D1R-expressed medium spiny neurons (D1-MSNs) associated with social deficits, while simultaneously restoring the functionality of D2-MSNs linked to repetitive behaviors. Collectively, our findings support the hypothesis that prenatal valproate exposure disrupts SNc→DMS dopaminergic signaling, which mediates the coexistence of two core autism-like behaviors by reshaping the dynamics of direct and indirect pathway MSNs. Moreover, these results highlight potential therapeutic targets for developing interventions for both core symptoms of autism.

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