1. Azu MA, Han GT, Wolf JM, Naples AJ, Chawarska K, Dawson G, Bernier RA, Jeste SS, Dziura JD, Webb SJ, Sugar CA, Shic F, McPartland JC. Clinician-caregiver informant discrepancy is associated with sex, diagnosis age, and intervention use among autistic children. Autism;2024 (Sep 30):13623613241279999.

In some cases, a clinician’s perceptions of a child’s autism-related behaviors are not the same as the child’s caregiver’s perceptions. Identifying how these discrepancies relate to the characteristics of the child is critical for ensuring that diagnosis procedures are unbiased and suitable for all children. This study examined whether discrepancies between clinician and caregiver reports of autism features related to the child’s sex at birth. We also explored how the discrepancies related to the age at which the child received their autism diagnosis and how much intervention they received. We found that clinicians rated autism features higher than caregivers for boys and rated autism features lower than caregivers for girls. In addition, lower clinician relative to parent ratings was related to being diagnosed at an older age and receiving less intervention. These findings suggest that there is more to learn about the presentation of autism-related behaviors in girls. When caregiver and clinician ratings of autism features do not align, it may be important to consider caregivers’ ratings to obtain a more accurate picture of the child’s autism features and the support they may need.

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2. Bazbaz W, Kartawy M, Hamoudi W, Ojha SK, Khaliulin I, Amal H. The Role of Thioredoxin System in Shank3 Mouse Model of Autism. J Mol Neurosci;2024 (Sep 30);74(4):90.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by difficulties in social interaction and communication, repetitive behaviors, and restricted interests. Unfortunately, the underlying molecular mechanism behind ASD remains unknown. It has been reported that oxidative and nitrosative stress are strongly linked to ASD. We have recently found that nitric oxide (NO•) and its products play an important role in this disorder. One of the key proteins associated with NO• is thioredoxin (Trx). We hypothesize that the Trx system is altered in the Shank3 KO mouse model of autism, which may lead to a decreased activity of the nuclear factor erythroid 2-related factor 2 (Nrf2), resulting in oxidative stress, and thus, contributing to ASD-related phenotypes. To test this hypothesis, we conducted in vivo behavioral studies and used primary cortical neurons derived from the Shank3 KO mice and human SH-SY5Y cells with SHANK3 mutation. We showed significant changes in the levels and activity of Trx redox proteins in the Shank3 KO mice. A Trx1 inhibitor PX-12 decreased Trx1 and Nrf2 expression in wild-type mice, causing abnormal alterations in the levels of synaptic proteins and neurotransmission markers, and an elevation of nitrosative stress. Trx inhibition resulted in an ASD-like behavioral phenotype, similar to that of Shank3 KO mice. Taken together, our findings confirm the strong link between the Trx system and ASD pathology, including the increased oxidative/nitrosative stress, and synaptic and behavioral deficits. The results of this study may pave the way for identifying novel drug targets for ASD.

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3. Casey MR, Sall S, Parsons G, Raveendran K, Zaheri A. Misdiagnosis in an Autistic Adolescent. Cureus;2024 (Aug);16(8):e68129.

With the increase in autism diagnoses in recent years due to improved public and clinical awareness, the association between autism and mental health has emerged as an important issue for patients and their caregivers. Although many with autism spectrum disorder also have coexisting mental health conditions, there exist differences in the presentation and etiology of these symptoms. This case report explains an interaction with a 17-year-old adolescent autistic male with a history of mild depression who was found non-responsive in the shower at home. Although the emergency medical team interpreted the scene as an attempted suicide, after lengthy interviews with the patient and the patient’s family, the psychiatry team revealed a pre-existing condition, subdural empyema, that caused him seizures. This case highlights how autism characteristics can mask other relevant clinical details and delay proper diagnosis and treatment, especially when patients are non-responsive or exhibiting atypical behavior. It also underscores the importance of investigating all relevant clinical diagnoses, including those not related to psychiatric conditions. It is vital that healthcare providers learn how to effectively communicate with autistic patients to ensure proper treatment and improve patient outcomes.

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4. Chen M, Guo L, Li Q, Yang S, Li W, Lai Y, Lv Z. Research progress on hippocampal neurogenesis in autism spectrum disorder. Pediatr Investig;2024 (Sep);8(3):215-223.

Autism spectrum disorder (ASD) is a group of severe neurodevelopmental disorders with unclear etiology and significant heterogeneity that is emerging as a global public health concern. Increasing research suggests the involvement of hippocampal neurogenesis defects in the onset and development of ASD, drawing increasing amounts of attention to hippocampal neurogenesis issues in ASD. In this paper, we analyze relevant international studies on hippocampal neurogenesis in ASD, discuss the role of neurobiology in the pathogenesis of ASD, and explore the potential of improving hippocampal neurogenesis as a therapeutic approach for ASD. This review aims to provide new treatment perspectives and theoretical foundations for clinical practice.

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5. Choueiri R, DeMeo M, Tokatli V, Zhu G, Zhang B. Demographic and socioeconomic characteristics of patients diagnosed with autism through the Rapid Interactive screening Test for Autism in Toddlers. Pediatr Investig;2024 (Sep);8(3):209-214.

We evaluated the integration of the Rapid Interactive screening Test for Autism in Toddlers (RITA-T) model in a community, comparing autism spectrum disorder (ASD) toddlers’ demographic and socioeconomic characteristics. Of 394 ASD toddlers, 323 were screened with RITA-T. Those screened were from more deprived areas, traveled farther and were diagnosed earlier. The model improved the diagnosis of ASD in underserved areas.

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6. Farrag EAE, Askar MH, Abdallah Z, Mahmoud SM, Abdulhai EA, Abdelrazik E, Nashar EME, Alasiri FM, Alqahtani ANS, Eldesoqui M, Eldib AM, Magdy A. Comparative effect of atorvastatin and risperidone on modulation of TLR4/NF-κB/NOX-2 in a rat model of valproic acid-induced autism. Behav Brain Funct;2024 (Sep 30);20(1):26.

BACKGROUND: Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that is significantly increasing, resulting in severe distress. The approved treatment for ASD only partially improves the sympoms, but it does not entirely reverse the symptoms. Developing novel disease-modifying drugs is essential for the continuous improvement of ASD. Because of its pleiotropic effect, atorvastatin has been garnered attention for treating neuronal degeneration. The present study aimed to investigate the therapeutic effects of atorvastatin in autism and compare it with an approved autism drug (risperidone) through the impact of these drugs on TLR4/NF-κB/NOX-2 and the apoptotic pathway in a valproic acid (VPA) induced rat model of autism. METHODS: On gestational day 12.5, pregnant rats received a single IP injection of VPA (500 mg/kg), for VPA induced autism, risperidone and atorvastatin groups, or saline for control normal group. At postnatal day 21, male offsprings were randomly divided into four groups (n = 6): control, VPA induced autism, risperidone, and atorvastatin. Risperidone and atorvastatin were administered from postnatal day 21 to day 51. The study evaluated autism-like behaviors using the three-chamber test, the dark light test, and the open field test at the end of the study. Biochemical analysis of TLR4, NF-κB, NOX-2, and ROS using ELISA, RT-PCR, WB, histological examination with hematoxylin and eosin and immunohistochemical study of CAS-3 were performed. RESULTS: Male offspring of prenatal VPA-exposed female rats exhibited significant autism-like behaviors and elevated TLR4, NF-κB, NOX-2, ROS, and caspase-3 expression. Histological analysis revealed structural alterations. Both risperidone and atorvastatin effectively mitigated the behavioral, biochemical, and structural changes associated with VPA-induced rat model of autism. Notably, atorvastatin group showed a more significant improvement than risperidone group. CONCLUSIONS: The research results unequivocally demonstrated that atorvastatin can modulate VPA-induced autism by suppressing inflammation, oxidative stress, and apoptosis through TLR4/NF-κB/NOX-2 signaling pathway. Atorvastatin could be a potential treatment for ASD.

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7. Frumer MH, Napel HT, Yuste-Sánchez MJ, Rodríguez-Costa I. Design and validation of AQUA CHILD-Pre-aquatic questionnaire assessing child development. Brain Behav;2024 (Oct);14(10):e70033.

PURPOSE: We developed a proxy questionnaire for parents of children with Developmental Delay (DD) to provide comprehensive information for instructors about the child’s functioning before participating in aquatic activities. This dedicated information will enable a high-quality treatment plan to promote the child’s functioning in everyday life. METHODS: Based on the International Classification of Functioning, Disability, and Health (ICF) Coreset development and linking rules method, a set of questions was constructed in a preliminary process. A draft version was sent to instructors and parents in Israel. Seventy-five questionnaires from instructors and 25 from parents returned to the statistical analysis procedure. Reliability and face validity were analyzed by experts. RESULTS AND CONCLUSIONS: The questionnaire showed high validity and reliability for its purposes and allowed self-completion by the parents.

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8. George SS, Elenjickal MG, Naik S, Thomas NG, Vellappally S, Varghese N, Mathew A, Narayan V, Varughese RP, Anil S. Oral health status and dental treatment needs in children with autism spectrum disorder. Heliyon;2024 (Sep 30);10(18):e37728.

OBJECTIVE: To evaluate oral health care practices, health status, and dental treatment needs in children with Autism Spectrum Disorder (ASD). METHODS: This cross-sectional study included 96 children diagnosed with ASD per the DSM-V criteria and 96 typically developing healthy children. The WHO form assessed oral health status and dental treatment needs. RESULTS: Over 50 % of ASD children had mild/moderate autism, 35.4 % had severe autism, and 13.5 % had autistic traits. ASD children experienced more toothbrushing difficulties compared to non-ASD children. Based on Nyvad’s criteria and decayed/filled teeth (dft) index, non-ASD children had higher caries prevalence than ASD children, indicating less need for restorative treatments in the ASD group. However, ASD children had poorer plaque scores than non-ASD children. A significantly higher percentage of ASD children exhibited harmful oral behaviors, including mouth breathing, lip biting, bruxism, nail biting, object biting, and self-injury (p < 0.001). ASD children also showed increased traumatic dental injuries compared to non-ASD children. CONCLUSION: Compared to non-ASD peers, children with ASD have lower dental caries prevalence and less need for restorations, yet poorer plaque control. They also demonstrate more frequent oral self-injuries. ASD status appears related to toothbrushing difficulties. These findings highlight the need for tailored oral health interventions for children with ASD.

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9. Hou Y, Wang Y, Deng J, Song X. Effects of different exercise interventions on executive function in children with autism spectrum disorder: a network meta-analysis. Front Psychiatry;2024;15:1440123.

BACKGROUND: A large body of research has identified the positive effects of physical activity on children with autism spectrum disorders (ASD). However, the specific benefits of different types of sports on executive functioning in children with ASD remain unclear. The aim of this study was to further analyze the effects of different sports on executive functioning in children with ASD using reticulated meta-analysis and to establish their effectiveness ranking. METHODS: This study conducted a comprehensive online search in Web of Science, PubMed, Cochrane, Embase, and CNKI databases. It included randomized controlled trials and quasi-experimental studies, and synthesized the data using a Bayesian framework. RESULTS: Several relevant studies were included. The results showed that physical activity significantly improved all three dimensions of executive functioning (inhibitory control, cognitive flexibility, and working memory) in children with ASD. The improvement in cognitive flexibility and inhibitory control both reached a medium effect size. However, the improvement in inhibitory control was better than that in cognitive flexibility, while the improvement in working memory did not reach the level of a medium effect. Mini Basketball was effective in improving inhibitory control and cognitive flexibility, but not working memory. Ping Pong was more effective in cognitive flexibility and working memory, but weaker in inhibitory control. Fixed Bicycle was less effective in all three dimensions. Among other interventions, Learning Bicycles, Animal-assisted therapy, and Exergaming performed better in cognitive flexibility. SPARK, Neiyang Gong, and Martial Arts were also effective in improving inhibitory control. However, SPARK and Fixed Bicycle were not significant in improving working memory. CONCLUSION: Physical activity as an intervention can significantly improve the executive function of children with ASD. The intervention effects of different sports on different dimensions of executive function vary. Mini Basketball was outstanding in improving inhibitory control and cognitive flexibility. Ping Pong was effective in improving cognitive flexibility and working memory. Fixed Bicycle was not effective in any dimension.

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10. Martinez S, Stoyanov K, Carcache L. Unraveling the spectrum: overlap, distinctions, and nuances of ADHD and ASD in children. Front Psychiatry;2024;15:1387179.

This review explores the clinical presentation of similarities and differences in Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD). This paper investigates the deficits in executive function, social function, and emotional intelligence that are seen in both conditions and how the presence of both conditions can exacerbate these deficiencies. Understanding the clinical presentations in these domains is critical to refine diagnostic methods and treatments and improve outcomes for those affected by these neurodevelopmental disorders. The similarities in clinical presentation between ADHD and ASD present a significant diagnostic challenge, with individuals often exhibiting similar behaviors and difficulty navigating the complexities that encompass reacting to their environment. Further research is paramount in gaining more knowledge of the disorders and challenges faced by these individuals, especially those with the presence of both conditions.

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11. Methods In Medicine CAM. RETRACTION: Evaluation and Analysis of the Intervention Effect of Systematic Parent Training Based on Computational Intelligence on Child Autism. Comput Math Methods Med;2024;2024:9761804.

[This retracts the article DOI: 10.1155/2022/7746374.].

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12. Persichetti AS, Shao J, Gotts SJ, Martin A. A functional parcellation of the whole brain in high-functioning individuals with autism spectrum disorder reveals atypical patterns of network organization. Mol Psychiatry;2024 (Sep 30)

Researchers studying autism spectrum disorder (ASD) lack a comprehensive map of the functional network topography in the ASD brain. We used high-quality resting state functional MRI (rs-fMRI) connectivity data and a robust parcellation routine to provide a whole-brain map of functional networks in a group of seventy high-functioning individuals with ASD and a group of seventy typically developing (TD) individuals. The rs-fMRI data were collected using an imaging sequence optimized to achieve high temporal signal-to-noise ratio (tSNR) across the whole-brain. We identified functional networks using a parcellation routine that intrinsically incorporates internal consistency and repeatability of the networks by keeping only network distinctions that agree across halves of the data over multiple random iterations in each group. The groups were tightly matched on tSNR, in-scanner motion, age, and IQ. We compared the maps from each group and found that functional networks in the ASD group are atypical in three seemingly related ways: (1) whole-brain connectivity patterns are less stable across voxels within multiple functional networks, (2) the cerebellum, subcortex, and hippocampus show weaker differentiation of functional subnetworks, and (3) subcortical structures and the hippocampus are atypically integrated with the neocortex. These results were statistically robust and suggest that patterns of network connectivity between the neocortex and the cerebellum, subcortical structures, and hippocampus are atypical in ASD individuals.

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13. Regev O, Shil A, Bronshtein T, Hadar A, Meiri G, Zigdon D, Michaelovski A, Hershkovitz R, Menashe I. Association between rare, genetic variants linked to autism and ultrasonography fetal anomalies in children with autism spectrum disorder. J Neurodev Disord;2024 (Sep 30);16(1):55.

BACKGROUND: Recent evidence suggests that certain fetal anomalies detected upon prenatal ultrasound screenings are associated with autism spectrum disorder (ASD). In this cross-sectional study, we aimed to identify genetic variants associated with fetal ultrasound anomalies (UFAs) in children with ASD. METHODS: The study included all children with ASD who are registered in the database of the Azrieli National Center of Autism and Neurodevelopment and for whom both prenatal ultrasound and whole exome sequencing (WES) data were available. We applied our in-house integrative bioinformatics pipeline, AutScore, to these WES data to prioritize rare, gene-disrupting variants (GDVs) probably contributing to ASD susceptibily. Univariate statistics and multivariable regression were used to assess the associations between UFAs and GDVs identified in these children. RESULTS: The study sample comprised 126 children, of whom 43 (34.1%) had at least one UFA detected in the prenatal ultrasound scan. A total of 87 candidate ASD genetic variants were detected in 60 children, with 24 (40%) children carrying multiple variants. Children with UFAs were more likely to have loss-of-function (LoF) mutations (aOR = 2.55, 95%CI: 1.13-5.80). This association was particularly noticeable when children with structural anomalies or children with UFAs in their head and brain scans were compared to children without UFAs (any mutation: aOR = 8.28, 95%CI: 2.29-30.01; LoF: aOR = 5.72, 95%CI: 2.08-15.71 and any mutation: aOR = 6.39, 95%CI: 1.34-30.47; LoF: aOR = 4.50, 95%CI: 1.32-15.35, respectively). GDVs associated with UFAs were enriched in genes highly expressed across all tissues (aOR = 2.76, 95%CI: 1.14-6.68). There was a weak, but significant, correlation between the number of mutations and the number of abnormalities detected in the same children (r = 0.21, P = 0.016). CONCLUSIONS: The results provide valuable insights into the potential genetic basis of prenatal organogenesis abnormalities associated with ASD and shed light on the complex interplay between genetic factors and fetal development.

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14. Reid M, Delgado D, Heinly J, Kiernan B, Shapiro S, Morgan L, Maddox B, Jager-Hyman S. Suicidal Thoughts and Behaviors in People on the Autism Spectrum. Curr Psychiatry Rep;2024 (Sep 30)

PURPOSE OF REVIEW: This review synthesizes recent research on suicidal thoughts and behaviors among autistic individuals. We present literature on risk and protective factors, risk assessment, intervention, and crisis services, and recommendations for future research. RECENT FINDINGS: Literature on this topic has grown substantially in recent years. Areas of advancement include improved understanding of risk factors (e.g., Interpersonal Theory of Suicide constructs, autistic burnout, mental health conditions, cognitive factors, diagnosis timing, emotion dysregulation), screening, assessment, acute-care services, and suicide-specific psychosocial treatments (e.g., safety planning, dialectical behavior therapy). Gaps include protective factors, impact of intersectional identities, and tailored approaches to screening, assessment, and intervention. Heightened awareness of suicide risk in autistic individuals has led to increased understanding of why autistic individuals think about and attempt suicide and the strategies used to identify and reduce suicide risk. We recommend community-partnered, multi-faceted, and strength-based approaches to inform tailored prevention and intervention efforts.

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15. Shi YR, Sin KFK. Exploring the effects of web-based psychological capitals training on teachers’ PsyCap development, emotional stability, and support: Evidence from Chinese inclusive education. PLoS One;2024;19(9):e0306453.

Inclusive education for students with autism spectrum disorders (ASD) has increasingly received attention nationwide in China. Schools realize that teachers are under stress and lack the skills to handle daily interactions with these students. So far, few studies have directed efforts to provide a remedy for teachers to improve their daily work. This study aimed to design and implement a 2-hour web-based training on psychological capital (PsyCap) to protect their well-being and foster their supportive behavior for ASD students in the inclusive class. A total of 120 targeted teachers were invited to participate in the training and were randomly divided into control and treatment groups. Pre-, post-, and follow-up surveys were distributed before, after, and one week after the training. ANOVA results suggested that teachers showed a significant increase in their PsyCap scores after completing the training, although the training effect slightly decreased after one week. Moreover, higher levels of PsyCap showed a positive influence on teachers’ emotional stability and supportive behavior in class. The results highlighted the effectiveness of web-based PsyCap training in boosting teacher positivity, which enhances teacher support for students in inclusive education.

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16. Tamai K, Matsumoto N, Yorifuji T, Takeuchi A, Nakamura M, Kageyama M. Postnatal weight loss and neurodevelopmental outcomes at age 3 years in extremely preterm infants: a cohort study. BMC Pediatr;2024 (Sep 30);24(1):618.

BACKGROUND: Previous research has suggested a correlation between postnatal maximum weight loss (MWL) and both neonatal mortality and morbidities in extremely preterm infants. However, the relationship between MWL and neurodevelopmental outcomes remains underexplored. METHODS: In a single-center, retrospective cohort study at Okayama Medical Center, we evaluated data from extremely preterm infants admitted to the neonatal intensive care unit from 2010 to 2020. Infants who died within the first 10 days of life were excluded. MWL in the first 10 days was the main exposure, categorized into three groups: >15%, 5-15%, and < 5%. The primary outcome evaluated was the occurrence of death or neurodevelopmental impairment (NDI) at age 3 years, defined as developmental impairments (developmental quotient [DQ] < 85), cerebral palsy, hearing impairments, or visual impairments. Data analysis involved robust Poisson regression, adjusted for perinatal confounders, with a restricted cubic spline function to examine the dose-response relationship. We also conducted a sensitivity analysis using a DQ of < 70 to define developmental impairment. RESULTS: Among 135 infants assessed for neurodevelopmental outcomes, 40 were in the > 15% MWL group, 71 in the 5-15% group, and 24 in the < 5% group. Median gestational ages and birth weights were 25.9 weeks and 821 g for > 15% MWL; 26.1 weeks and 818 g for 5-15% MWL; and 26.0 weeks and 734 g for < 5% MWL. Compared with the 5-15% MWL group, the < 5% group exhibited a higher risk of death or NDI at age 3 years (62.8% vs. 80.8%, risk ratio [RR] 1.36, 95% confidence interval [CI] 1.04-1.79) and NDI alone (59.2% vs. 79.2%, RR 1.43, 95% CI 1.06-1.94). Furthermore, higher risks of developmental impairment were also noted in the > 15% (RR 1.32, 95% CI 1.00-1.75) and < 5% (RR 1.46, 95% CI 1.08-1.98) groups. These associations were confirmed by spline analyses. In contrast, the associations between MWL and neurodevelopmental outcomes using a DQ of < 70 were not apparent. CONCLUSIONS: MWL within the first 10 days of life may be associated with increased risks of NDI and developmental impairments by age 3 years in extremely preterm infants.

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17. Trudler D, Ghatak S, Bula M, Parker J, Talantova M, Luevanos M, Labra S, Grabauskas T, Noveral SM, Teranaka M, Schahrer E, Dolatabadi N, Bakker C, Lopez K, Sultan A, Patel P, Chan A, Choi Y, Kawaguchi R, Stankiewicz P, Garcia-Bassets I, Kozbial P, Rosenfeld MG, Nakanishi N, Geschwind DH, Chan SF, Lin W, Schork NJ, Ambasudhan R, Lipton SA. Dysregulation of miRNA expression and excitation in MEF2C autism patient hiPSC-neurons and cerebral organoids. Mol Psychiatry;2024 (Sep 30)

MEF2C is a critical transcription factor in neurodevelopment, whose loss-of-function mutation in humans results in MEF2C haploinsufficiency syndrome (MHS), a severe form of autism spectrum disorder (ASD)/intellectual disability (ID). Despite prior animal studies of MEF2C heterozygosity to mimic MHS, MHS-specific mutations have not been investigated previously, particularly in a human context as hiPSCs afford. Here, for the first time, we use patient hiPSC-derived cerebrocortical neurons and cerebral organoids to characterize MHS deficits. Unexpectedly, we found that decreased neurogenesis was accompanied by activation of a micro-(mi)RNA-mediated gliogenesis pathway. We also demonstrate network-level hyperexcitability in MHS neurons, as evidenced by excessive synaptic and extrasynaptic activity contributing to excitatory/inhibitory (E/I) imbalance. Notably, the predominantly extrasynaptic (e)NMDA receptor antagonist, NitroSynapsin, corrects this aberrant electrical activity associated with abnormal phenotypes. During neurodevelopment, MEF2C regulates many ASD-associated gene networks, suggesting that treatment of MHS deficits may possibly help other forms of ASD as well.

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18. Wang HB, Smale NE, Brown SH, Zhou D, Mulji A, Villanueva SAM, Nguyen-Ngo K, Harvey JR, Ghiani CA, Colwell CS. Scheduled feeding improves behavioral outcomes and reduces inflammation in a mouse model of Fragile X syndrome. bioRxiv;2024 (Sep 16)

Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by the abnormal expansion of CGG repeats in the fragile X mental retardation 1 (FMR1) gene. Many FXS patients experience sleep disruptions, and we sought to explore these symptoms along with the possible benefits of a scheduled feeding intervention using the Fmr1 knockout (KO) mouse model. These mutants displayed clear evidence for sleep and circadian disturbances including delay in the onset of sleep and fragmented activity rhythms with increases in cycle-to-cycle variability. The Fmr1 KO mice exhibited deficits in their circadian behavioral response to light with reduced masking, longer time to resetting to shifts in the LD cycle, altered synchronization to a skeleton photoperiod and lower magnitude light-induced phase shifts of activity rhythms. Investigation of the retinal input to the surprachiasmatic nucleus (SCN) with the neurotracer cholera toxin (β subunit) and quantification of the light-evoked cFos expression in the SCN revealed an abnormal retinal innervation of the SCN in the Fmr1 KO, providing a possible mechanistic explanation for the observed behavioral deficits. Interestingly, disruptions in social and repetitive behavior correlated with sleep duration and fragmentation. Understanding the nature of the deficits, we decided to apply a scheduled feeding regimen (6-hr/18-hr feed/fast cycle) as a circadian-based strategy to boast circadian rhythms independently of light. This intervention significantly improved the activity rhythms and sleep in the mutants. Strikingly, the scheduled feeding ameliorated social interactions and reduced repetitive behaviors as well as the levels of Interferon-gamma and Interleukin-12 in the Fmr1 KO mutants, suggesting that timed eating may be an effective way to reduce inflammation. Collectively, this work adds support to efforts to develop circadian based interventions to help with symptoms of neurodevelopmental disorders.

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19. Wang T, Ma Y, Du X, Li C, Peng Z, Wang Y, Zhou H. Digital interventions for autism spectrum disorders: A systematic review and meta-analysis. Pediatr Investig;2024 (Sep);8(3):224-236.

IMPORTANCE: Digital technology is now widely available for the interventions of autism, but its validity and feasibility remain to be proved. OBJECTIVE: This study aimed to investigate the effectiveness of digital health interventions (DHIs) in improving core symptoms or intelligence quotient in patients with autism spectrum disorder (ASD). METHODS: Three databases including PubMed, Cochrane, and Scopus, were searched on November 15, 2022. Randomized clinical trials that enrolled patients with ASD who received DHIs and a control group without DHI treatment were included. Cochrane risk of bias tool (RoB 2) was applied to assess the risk of bias. RESULTS: A total of 33 studies, involving 1285 participants (658 [51.2%] in DHI groups and 627 [48.8%] in control groups), were analyzed to investigate the differences between DHI groups and control groups. Significantly greater improvements in the overall performance of ASD were observed in the DHI groups compared to the control groups (including active, waitlist, treatment-as-usual, and no treatment) with an effect size of 1.89 (Cohen’s d 95% confidence interval [CI]: 1.26-2.52). Studies with treatment-as-usual, waitlist, and no treatment control demonstrated large effect sizes of Cohen’s d 3.41 (95% CI: 0.84-5.97), Cohen’s d 4.27 (95% CI: 1.95-6.59), and Cohen’s d 4.52 (95% CI: 2.98-6.06) respectively. In contrast, studies with active control revealed insignificant effect sizes (Cohen’s d 0.73, 95% CI: 0.12-1.33). INTERPRETATION: This meta-analysis found significantly greater improvements in core symptoms or intelligence quotient in ASD patients receiving DHIs compared to those in control conditions. ASD patients may benefit from the DHIs and reduce the economic burden.

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20. Yang Y, Chen J, Li T, Dai Y. PX-478 Alleviated the Autism Spectrum Disorder Progression of Offspring Rats Induced by Prenatal Hypoxia. J Integr Neurosci;2024 (Sep 14);23(9):165.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social interaction, communication, repetitive behaviors, and narrow interests. This study aimed to investigate the impact of the Hypoxia-inducible factor-1 alpha (HIF-1α) inhibitor (PX-478) on ASD-like behaviors in rat offspring exposed to prenatal hypoxia (PH). METHODS: Pregnant rats were randomly assigned to control or PH groups, with the latter experiencing six hours of hypoxia on the 17th day of gestation. Offspring were further treated with PX-478 treatment initiated at one week (+1 w) or three weeks (+3 w) after birth. Hippocampal histology was assessed using hematoxylin and eosin (HE) staining, while protein levels of HIF-1α and phosphatase and tensin homolog (PTEN) were analyzed via western blotting. The concentration of vascular endothelial growth factor (VEGF) was measured using an Enzyme-Linked Immunosorbent Assay (ELISA) kit. RESULTS: PX-478 treatment significantly improved spatial memory, learning, and social ability, while reducing anxiety-like behavior in PH-exposed offspring rats. HE staining revealed that PX-478 treatment decreased the number of hippocampal neurons necrosis in offspring. However, PX-478 treatment at one week post-birth led to decreased body weight and elevated levels of alkaline phosphatase (ALP) and Alanine aminotransferase (ALT) in offspring rats, whereas no significant effect was observed after three weeks of treatment. Additionally, PX-478 treatment resulted in reduced HIF-1α protein levels in the hippocampus and VEGF concentration in the serum of PH-exposed offspring rats, along with elevated PTEN protein levels. CONCLUSIONS: The findings suggest that PX-478 treatment attenuated autism-like behavior in offspring. HIF-1α might play an important role in autism-like behavior induced by prenatal hypoxia, which may be realized by inhibiting PTEN activity.

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