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Italian Journal of Pediatrics Jun 2024Researches have found that alteration of intestinal flora may be closely related to the development of autism spectrum disorder (ASD). However, whether probiotics... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Researches have found that alteration of intestinal flora may be closely related to the development of autism spectrum disorder (ASD). However, whether probiotics supplementation has a protective effect on ASD remains controversial. This meta-analysis aimed to analyze the outcome of probiotics in the treatment of ASD children.
METHODS
The Pubmed, Cochrane Library, Web of Science and Embase were searched until Sep 2022. Randomized controlled trials (RCTs) relevant to the probiotics and placebo treatment on ASD children were screened. Quality assessment of the included RCTs was evaluated by the Cochrane collaboration's tool. The primary outcomes were ASD assessment scales, including ABC (aberrant behavior checklist) and CBCL (child behavior checklist) for evaluating the behavior improvement, SRS (social responsiveness scale) for social assessment, DQ (developmental quotient) for physical and mental development and CGI-I (clinical global impression improvement) for overall improvement. The secondary outcome was total 6-GSI (gastrointestinal severity index).
RESULTS
In total, 6 RCTs from 6 studies with 302 children were included in the systemic review. Total 6-GSI (MD=-0.59, 95%CI [-1.02,-0.17], P < 0.05) decreased significantly after oral administration of probiotics. Whereas, there was no statistical difference in ABC, CBCL, SRS, DQ and CGI-I between probiotics and placebo groups in ASD children.
CONCLUSION
Probiotics treatment could improve gastrointestinal symptoms, but there was no significant improvement in ASD.
Topics: Humans; Probiotics; Autism Spectrum Disorder; Child; Randomized Controlled Trials as Topic; Treatment Outcome; Gastrointestinal Microbiome
PubMed: 38902804
DOI: 10.1186/s13052-024-01692-z -
Psychiatry Research Jun 2024Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a wide range of symptoms that include deficits in social cognition and difficulties with social...
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a wide range of symptoms that include deficits in social cognition and difficulties with social interactions. Neural oscillations in the EEG gamma band have been proposed as an important candidate neurobiological marker of higher order cognitive processes and social interactions. We investigated resting-state gamma-activity of patients with ASD (n=23) in order to delineate alterations as compared to typically developing (TD) subjects (n=24). EEG absolute power was examined in the gamma (30-100Hz) frequency band. We found significantly reduced spectral power across the entire gamma range in the ASD group. The decrease was most pronounced over the inferior-frontal and temporo-parietal junction areas. We also found a significant decrease in gamma-activity over the dorsolateral prefrontal cortex, especially in the left side. Since these brain areas have been associated with social functioning, the reduced gamma-activity in ASD may represent a cortical dysfunction that could underlie a diminished capacity to interpret socially important information, thereby interfering with social functioning. The alterations we found may lend support for an improved diagnosis. Furthermore, they can lead to focused therapies, by targeting the dysfunctional brain activity to improve social cognitive and interaction abilities that are compromised in ASD.
PubMed: 38901364
DOI: 10.1016/j.psychres.2024.116040 -
Cell Reports Jun 2024Precision of transcription is critical because transcriptional dysregulation is disease causing. Traditional methods of transcriptional profiling are inadequate to...
Precision of transcription is critical because transcriptional dysregulation is disease causing. Traditional methods of transcriptional profiling are inadequate to elucidate the full spectrum of the transcriptome, particularly for longer and less abundant mRNAs. SHANK3 is one of the most common autism causative genes. Twenty-four Shank3-mutant animal lines have been developed for autism modeling. However, their preclinical validity has been questioned due to incomplete Shank3 transcript structure. We apply an integrative approach combining cDNA-capture and long-read sequencing to profile the SHANK3 transcriptome in humans and mice. We unexpectedly discover an extremely complex SHANK3 transcriptome. Specific SHANK3 transcripts are altered in Shank3-mutant mice and postmortem brain tissues from individuals with autism spectrum disorder. The enhanced SHANK3 transcriptome significantly improves the detection rate for potential deleterious variants from genomics studies of neuropsychiatric disorders. Our findings suggest that both deterministic and stochastic transcription of the genome is associated with SHANK family genes.
PubMed: 38900637
DOI: 10.1016/j.celrep.2024.114376 -
Behavioral and Brain Functions : BBF Jun 2024Autism Spectrum Disorder (ASD) is a group of neurodevelopmental disorders with higher incidence in males and is characterized by atypical verbal/nonverbal communication,...
BACKGROUND
Autism Spectrum Disorder (ASD) is a group of neurodevelopmental disorders with higher incidence in males and is characterized by atypical verbal/nonverbal communication, restricted interests that can be accompanied by repetitive behavior, and disturbances in social behavior. This study investigated brain mechanisms that contribute to sociability deficits and sex differences in an ASD animal model.
METHODS
Sociability was measured in C58/J and C57BL/6J mice using the 3-chamber social choice test. Bulk RNA-Seq and snRNA-Seq identified transcriptional changes in C58/J and C57BL/6J amygdala within which DMRseq was used to measure differentially methylated regions in amygdala.
RESULTS
C58/J mice displayed divergent social strata in the 3-chamber test. Transcriptional and pathway signatures revealed immune-related biological processes differ between C58/J and C57BL/6J amygdala. Hypermethylated and hypomethylated genes were identified in C58/J versus C57BL/6J amygdala. snRNA-Seq data in C58/J amygdala identified differential transcriptional signatures within oligodendrocytes and microglia characterized by increased ASD risk gene expression and predicted impaired myelination that was dependent on sex and sociability. RNA velocity, gene regulatory network, and cell communication analysis showed diminished oligodendrocyte/microglia differentiation. Findings were verified using Bulk RNA-Seq and demonstrated oxytocin's beneficial effects on myelin gene expression.
LIMITATIONS
Our findings are significant. However, limitations can be noted. The cellular mechanisms linking reduced oligodendrocyte differentiation and reduced myelination to an ASD phenotype in C58/J mice need further investigation. Additional snRNA-Seq and spatial studies would determine if effects in oligodendrocytes/microglia are unique to amygdala or if this occurs in other brain regions. Oxytocin's effects need further examination to understand its' potential as an ASD therapeutic.
CONCLUSIONS
Our work demonstrates the C58/J mouse model's utility in evaluating the influence of sex and sociability on the transcriptome in concomitant brain regions involved in ASD. Our single-nucleus transcriptome analysis elucidates potential pathological roles of oligodendrocytes and microglia in ASD. This investigation provides details regarding regulatory features disrupted in these cell types, including transcriptional gene dysregulation, aberrant cell differentiation, altered gene regulatory networks, and changes to key pathways that promote microglia/oligodendrocyte differentiation. Our studies provide insight into interactions between genetic risk and epigenetic processes associated with divergent affiliative behavior and lack of positive sociability.
Topics: Animals; Male; Microglia; Mice; Amygdala; Female; Oligodendroglia; Autism Spectrum Disorder; Mice, Inbred C57BL; Social Behavior; Gene Expression Profiling; Phenotype; Sex Characteristics; Transcriptome; Disease Models, Animal; Oxytocin
PubMed: 38898502
DOI: 10.1186/s12993-024-00240-3 -
Bioscience Trends Jun 2024The brain-gut axis intricately links gut microbiota (GM) dysbiosis to the development or worsening of autism spectrum disorder (ASD). However, the precise GM composition...
The brain-gut axis intricately links gut microbiota (GM) dysbiosis to the development or worsening of autism spectrum disorder (ASD). However, the precise GM composition in ASD and the effectiveness of probiotics are unclear. To address this, we performed a thorough meta-analysis of 28 studies spanning PubMed, PsycINFO, Web of Science, Scopus, and MEDLINE, involving 1,256 children with ASD and 1042 neurotypical children, up to February 2024. Using Revman 5.3, we analyzed the relative abundance of 8 phyla and 64 genera. While individuals with ASD did not exhibit significant differences in included phyla, they exhibited elevated levels of Parabacteroides, Anaerostipes, Faecalibacterium, Clostridium, Dorea, Phascolarctobacterium, Lachnoclostridium, Catenibacterium, and Collinsella along with reduced percentages of Barnesiella, Odoribacter, Paraprevotella, Blautia, Turicibacter, Lachnospira, Pseudomonas, Parasutterella, Haemophilus, and Bifidobacterium. Notably, discrepancies in Faecalibacterium, Clostridium, Dorea, Phascolarctobacterium, Catenibacterium, Odoribacter, and Bifidobacterium persisted even upon systematic exclusion of individual studies. Consequently, the GM of individuals with ASD demonstrates an imbalance, with potential increases or decreases in both beneficial and harmful bacteria. Therefore, personalized probiotic interventions tailored to ASD specifics are imperative, rather than a one-size-fits-all approach.
PubMed: 38897955
DOI: 10.5582/bst.2024.01123 -
BMJ Paediatrics Open Jun 2024The UK National Health Service (NHS) Long Term Plan aims to reduce waiting times for childhood autism diagnostic assessment and improve parent and child satisfaction....
BACKGROUND
The UK National Health Service (NHS) Long Term Plan aims to reduce waiting times for childhood autism diagnostic assessment and improve parent and child satisfaction. This empirical research investigated current childhood diagnostic practice provision, and changes made by teams to address challenges faced.
METHODS
Data were collected using an online semi-structured research questionnaire. UK childhood autism diagnostic assessment services (for children aged 1-18 years) were invited to participate through multidisciplinary clinical networks, special interest groups and professionals mailing lists. The study was on the National Institute for Health Research Clinical Research Network portfolio.
RESULTS
128 clinicians from diverse NHS services responded including: 10 (8%) integrated services, 46 (36%) Child and Adolescent Mental Health Services (CAMHS) and 72 (56%) paediatric services. A minority of services (23, 17.9%) reported always meeting the National Institute for Health and Care Excellence guidance for assessment. Referrals rose 115% between 2015 and 2019. Clinicians described increased child and family complexity compared with previously; children had more co-occurring physical, mental health and neurodevelopmental conditions and there were more frequent family health problems and safeguarding concerns. Most services (97, 75.8%) reported recent funding stayed constant/decreased. Incomplete multidisciplinary teams (MDTs) were frequently reported; a minority of services reported increased availability of professionals, and some experienced reductions in key professionals. Many teams were unable to undertake assessments or make recommendations for associated neurodevelopmental and co-existing conditions. Teams described improvement strategies implemented (eg, adapting professionals' roles, supporting parents).
CONCLUSIONS
Most UK autism paediatric and CAMHS diagnostic teams experience significant challenges affecting the assessment of children with possible autism, and recommendations regarding treatment/intervention. Where CAMHS or paediatric services work in isolation, there are often competency gaps in MDTs and ability to deliver full neurodevelopmental and mental health assessments. Teams identified service improvement strategies; however, investment in MDT expertise is required to enable services to implement changes to meet the needs of children and families.
Topics: Humans; United Kingdom; Child; Child, Preschool; Adolescent; Autistic Disorder; Infant; Male; Female; Surveys and Questionnaires; Child Health Services; State Medicine; Referral and Consultation; Health Care Surveys
PubMed: 38897620
DOI: 10.1136/bmjpo-2024-002496 -
Brain, Behavior, and Immunity Jun 2024Rodent models of maternal immune activation (MIA) are increasingly used as experimental tools in preclinical research of immune-mediated neurodevelopmental disorders and...
Rodent models of maternal immune activation (MIA) are increasingly used as experimental tools in preclinical research of immune-mediated neurodevelopmental disorders and mental illnesses. Using a viral-like MIA model that is based on prenatal poly(I:C) exposure in mice, we have recently identified the existence of subgroups of MIA-exposed offspring that show dissociable behavioral, transcriptional, brain network and inflammatory profiles even under conditions of genetic homogeneity and identical MIA. Here, we tested the hypothesis that the intrauterine positions of fetuses, which are known to shape individual variability in litter-bearing mammals through variations in fetal hormone exposure, may contribute to the variable outcomes of MIA in mice. MIA was induced by maternal administration of poly(I:C) on gestation day 12 in C57BL/6N mice. Determining intrauterine positions using delivery by Cesarean section (C-section), we found that MIA-exposed offspring developing between female fetuses only (0M-MIA offspring) displayed significant deficits in sociability and sensorimotor gating at adult age, whereas MIA-exposed offspring developing between one or two males in utero (1/2M-MIA offspring) did not show the same deficits. These intrauterine position effects similarly emerged in male and female offspring. Furthermore, while MIA elevated fetal brain levels of pro- and anti-inflammatory cytokines independently of the precise intrauterine position and sex of adjacent fetuses during the acute phase, fetal brain levels of TNF-α remained elevated in 0M-MIA but not 1/2M-MIA offspring until the post-acute phase in late gestation. As expected, 1/2M offspring generally showed higher testosterone levels in the fetal brain during late gestation as compared to 0M offspring, confirming the transfer of testosterone from male fetuses to adjacent male or female fetuses. Taken together, our findings identify a novel source of within-litter variability contributing to heterogeneous outcomes of short- and long-term effects in a mouse model of MIA. In broader context, our findings highlight that individual differences in fetal exposure to hormonal and inflammatory signals may be a perinatal factor that shapes risk and resilience to MIA.
PubMed: 38897330
DOI: 10.1016/j.bbi.2024.06.015 -
Stem Cell Research Jun 2024Autism spectrum disorder (ASD) is a complex developmental disorder characterized by challenges with social interactions and restricted/repetitive behaviors. Here, we...
Generation of nine induced pluripotent stem cell lines from six young children with autism spectrum disorder and three matched control subjects from the Qatari population.
Autism spectrum disorder (ASD) is a complex developmental disorder characterized by challenges with social interactions and restricted/repetitive behaviors. Here, we recruited nine Qatari children of Arab ethnicity (males, aged 2-4 years), including six ASD subjects (n = 3 mild-to-moderate ASD and n = 3 severe ASD) and three control subjects. We generated induced pluripotent stem cell (iPSC) lines from PBMC samples of these subjects using non-integrating Sendai viral vectors. These iPSC lines were fully characterized and exhibited pluripotency characteristics, normal karyotypes, and trilineage differentiation potential. These iPSC lines provide valuable cell models for understanding ASD pathophysiology and developing new therapeutics for ASD.
PubMed: 38896970
DOI: 10.1016/j.scr.2024.103470 -
Frontiers in Veterinary Science 2024Given the rising interest in complementary therapeutic strategies for autism spectrum disorder (ASD), this research aims to provide a comprehensive analysis of the...
BACKGROUND
Given the rising interest in complementary therapeutic strategies for autism spectrum disorder (ASD), this research aims to provide a comprehensive analysis of the impact of animal-assisted activities and therapies (AAAT) on various ASD symptoms.
METHODS
A meticulous search of databases, including Scopus and PubMed, was conducted to gather relevant research on AAAT for ASD. This process led to the selection of 45 studies encompassing 1,212 participants. The chosen studies were then subjected to a meta-analysis to evaluate the efficacy of AAAT in alleviating core ASD symptoms.
RESULTS
The meta-analysis revealed significant improvements in several core ASD symptoms due to AAAT. Notably, there were improvements in social communication (MD = -4.96, 95% CI [-7.49, -2.44]), irritability (MD = -2.38, 95% CI [-4.06, -0.71]), hyperactivity (MD = -4.03, 95% CI [-6.17, -1.89]), and different word usage skills (MD = 20.48, 95% CI [7.41, 33.55]). However, social awareness (MD = -1.63, 95% CI [-4.07, 0.81]), social cognition (MD = -3.60, 95% CI [-9.36, 2.17]), social mannerisms (MD = -0.73, 95% CI [-2.55, 1.09]), social motivation (MD = -1.21, 95% CI [-2.56, 0.13]), lethargy (MD = -1.12, 95% CI [-3.92, 1.68]), and stereotypical behaviors (MD = -0.23, 95% CI [-1.27, 0.80]) did not significantly improve.
CONCLUSION
The study demonstrates the potential of AAAT in improving certain core symptoms of ASD, such as social communication, irritability, hyperactivity, and word usage skills. However, the effectiveness of AAAT in other ASD symptom domains remains uncertain. The research is limited by the absence of long-term follow-up data and a high risk of bias in existing studies. Therefore, while the findings indicate the promise of AAAT in specific areas, caution is advised in generalizing its efficacy across all ASD symptoms.
PubMed: 38895710
DOI: 10.3389/fvets.2024.1403527 -
BioRxiv : the Preprint Server For... Jun 2024It is estimated that 1 in 36 children are affected by autism spectrum disorder (ASD) in the United States, which is nearly a twofold increase from a decade ago. Recent...
UNLABELLED
It is estimated that 1 in 36 children are affected by autism spectrum disorder (ASD) in the United States, which is nearly a twofold increase from a decade ago. Recent genetic studies have identified loss-of-function (dnLoF) mutations in the as a strong risk factor for ASD. Previous research has shown that ablation confers social interaction deficits and perseverative behaviors in mouse models. However, it remains unknown to what extent underexpression captures the full range of behaviors, specifically cognitive phenotypes, presented in ASD. Here, we conducted a comprehensive cognitive behavioral phenotyping which revealed that loss of one copy of , as in the +/- mice, displayed hyperactivity, increased anxiety, and motor coordination impairments. Additionally, hippocampal-dependent learning and memory was affected, including working memory, long-term memory, and contextual fear learning. Interestingly, implicit learning processes remained intact. Therefore, LoF produces autistic-like behaviors that are similar to human cases of ASD. These findings further support a role for dnLoF mutations in ASD and suggest +/- as a suitable model for ASD research.
SUMMARY STATEMENT
Autism spectrum disorder represents a growing patient population. Loss of one copy of the gene provides a promising mouse model that reproduces autistic-like behaviors for research and therapeutic testing.
PubMed: 38895491
DOI: 10.1101/2024.06.03.597158