1. Bitsika V, Sharpley CF, Evans ID, Vessey KA. Neurological Validation of ASD Diagnostic Criteria Using Frontal Alpha and Theta Asymmetry. J Clin Med;2024 (Aug 18);13(16)

Background/Objectives: Diagnosis of Autism Spectrum Disorder (ASD) relies on the observation of difficulties in social communication and interaction, plus the presence of repetitive and restrictive behaviors. The identification of neurological correlates of these symptoms remains a high priority for clinical research, and has the potential to increase the validity of diagnosis of ASD as well as provide greater understanding of how the autistic brain functions. This study focused on two neurological phenomena that have been previously associated with psychiatric disorders (alpha- and theta-wave asymmetry across the frontal region of the brain), and tested for their association with the major diagnostic criteria for ASD. Methods: A total of 41 male autistic youth underwent assessment with the Autism Diagnostic Observation Schedule (ADOS-2) and 3 min of eyes-closed resting EEG to collect alpha- and theta-wave data from right and left frontal brain sites. Results: Different associations were found for theta versus alpha asymmetry and the ADOS-2 subscales, across different brain regions responsible for a varying range of cognitive functions. In general, theta asymmetry was associated with conversation with others, sharing of enjoyment, and making social overtures, whereas alpha asymmetry was linked with making eye contact, reporting events to others, and engaging in reciprocal social communication. Specific brain regions involved are identified, as well as implications for clinical practice. Conclusions: Specific autism symptoms may be associated with selected brain region activity, providing a neurological basis for diagnosis and treatment.

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2. Gaziel-Guttman M, Anaki D, Mashal N. The effect of reappraisal on the emotional regulation of shame in young adults with ASD and typical peers. Sci Rep;2024 (Aug 18);14(1):19116.

Young adults with ASD experience shame in social interactions, and if poorly mishandled, it may interfere with their attempts to participate in their social environment. One strategy to reduce shame is cognitive reappraisal, yet the efficacy of this strategy was not examined in ASD. Here, we investigated the effect of reappraisal in reducing feelings of shame in ASD and the thematic contents used. Young adults with high-functioning ASD and typical participants were shown shame-arousing pictures. They imagined themselves as the primary character in each scenario and rated their feelings of shame. Then, they were trained to reappraise shame-arousing pictures less negatively. Finally, they viewed other shame-arousing photos, reappraised them, stated aloud their new interpretations, and rated their feelings. We found lower shame ratings in participants with ASD than in typical participants. In addition, we found a similar reduction in shame ratings after reappraising these pictures in both groups. Qualitative analysis revealed that participants with ASD used fewer positive narratives and more neutral and unrealistic descriptions than their typical peers. These findings highlight shame-regulation abilities in individuals with ASD while pointing to their unique narratives. We recommend that clinical interventions in ASD emphasize generating positive reappraisals of social situations.

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3. Gehdu BK, Gray KL, Cook R. Poor face recognition predicts social anxiety in autism: A short report. Autism;2024 (Aug 18):13623613241272031.

Research has shown that some autistic people have severe difficulties in recognising other people’s faces. However, little is understood about how these difficulties impact the daily life and the mental well-being of autistic people. In this study, we asked 60 autistic adults with varying degrees of face recognition ability to complete two tests of face recognition, a questionnaire about social anxiety and a bespoke survey which asked participants about their experiences of face recognition and social interaction. We found that participants who had poor face recognition reported experiencing higher levels of social anxiety compared to those with average or better face recognition skills. More than half felt that their face recognition difficulties affected their social interactions, and over a third believed it hindered their ability to make friends. These findings suggest that face recognition difficulties may contribute to social anxiety among autistic individuals.

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4. K CR, Patel NR, Thurmon AN, Lorino MG, Tiemroth AS, Kulstad I, Morrison V, Akumuo M, Shenoy A, Meadows SM, Galazo MJ. Loss of Zmiz1 in mice leads to impaired cortical development and autistic-like behaviors. bioRxiv;2024 (Aug 18)

De novo mutations in transcriptional regulators are emerging as key risk factors contributing to the etiology of neurodevelopmental disorders. Human genetic studies have recently identified ZMIZ1 and its de novo mutations as causal of a neurodevelopmental syndrome strongly associated with intellectual disability, autism, ADHD, microcephaly, and other developmental anomalies. However, the role of ZMIZ in brain development or how ZMIZ1 mutations cause neurological phenotypes is unknown. Here, we generated a forebrain-specific Zmiz1 mutant mouse model that develops brain abnormalities, including cortical microcephaly, corpus callosum dysgenesis, and abnormal differentiation of upper-layer cortical neurons. Behaviorally, Zmiz1 mutant mice show alterations in motor activity, anxiety, communication, and social interactions with strong sex differences, resembling phenotypes associated with autism. Molecularly, Zmiz1 deficiency leads to transcriptomic changes disrupting neurogenesis, neuron differentiation programs, and synaptic signaling. We identified Zmiz1-mediated downstream regulation of key neurodevelopmental factors, including Lhx2, Auts2, and EfnB2. Importantly, reactivation of the EfnB2 pathway by exogenous EFNB2 recombinant protein rescues the dendritic outgrowth deficits in Zmiz1 mutant cortical neurons. Overall, our in vivo findings provide insight into Zmiz1 function in cortical development and reveal mechanistic underpinnings of ZMIZ1 syndrome, thereby providing valuable information relevant to future studies on this neurodevelopmental disorder.

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5. Megagiannis P, Mei Y, Yan RE, Yuan L, Wilde JJ, Eckersberg H, Suresh R, Tan X, Chen H, Farmer WT, Cha K, Le PU, Catoire H, Rochefort D, Kwan T, Yee BA, Dion P, Krishnaswamy A, Cloutier JF, Stifani S, Petrecca K, Yeo GW, Murai KK, Feng G, Rouleau GA, Ideker T, Sanjana NE, Zhou Y. Autism-associated CHD8 controls reactive gliosis and neuroinflammation via remodeling chromatin in astrocytes. Cell Rep;2024 (Aug 27);43(8):114637.

Reactive changes of glial cells during neuroinflammation impact brain disorders and disease progression. Elucidating the mechanisms that control reactive gliosis may help us to understand brain pathophysiology and improve outcomes. Here, we report that adult ablation of autism spectrum disorder (ASD)-associated CHD8 in astrocytes attenuates reactive gliosis via remodeling chromatin accessibility, changing gene expression. Conditional Chd8 deletion in astrocytes, but not microglia, suppresses reactive gliosis by impeding astrocyte proliferation and morphological elaboration. Astrocyte Chd8 ablation alleviates lipopolysaccharide-induced neuroinflammation and septic-associated hypothermia in mice. Astrocytic CHD8 plays an important role in neuroinflammation by altering the chromatin landscape, regulating metabolic and lipid-associated pathways, and astrocyte-microglia crosstalk. Moreover, we show that reactive gliosis can be directly mitigated in vivo using an adeno-associated virus (AAV)-mediated Chd8 gene editing strategy. These findings uncover a role of ASD-associated CHD8 in the adult brain, which may warrant future exploration of targeting chromatin remodelers in reactive gliosis and neuroinflammation in injury and neurological diseases.

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6. Moreno RJ, Rose DR, Tancredi DJ, Schmidt RJ, Ozonoff SJ, Ashwood P. Cord blood cytokine profiles in children later diagnosed with autism spectrum disorder: Results from the prospective MARBLES study. Brain Behav Immun;2024 (Aug 18);122:339-344.

In studies investigating the etiology and pathophysiology of autism spectrum disorder (ASD), immune dysregulation is commonly observed, with elevated levels of inflammatory cytokines frequently found in gestational tissues. However, studies investigating the relationship between early immune dysregulation within the umbilical cord blood (CB) compartment and neurodevelopmental outcomes remains limited. In this exploratory study, we utilized data from the prospective Markers for Autism Risk in Babies – Learning Early Signs (MARBLES) study to examine cytokine levels in the plasma fraction of CB in infants later diagnosed with ASD (n = 38) compared to infants typically developing (TD) at age 3 years (n = 103), using multiplex cytokine assays. Our findings reveal altered levels of several inflammatory cytokines in children later diagnosed with ASD, including increased granulocyte colony-stimulating factor (G-CSF) and decreased interleukin-1α (IL-1α), IL-1β, and IL-4 in CB. Furthermore, we identified several associations between behaviors and levels of cytokines, chemokines and growth factors. IL-1α, IL-17A, interferon γ-induced protein 10 (IP-10), and epidermal growth factor (EGF) were associated with worse scores on Autism Diagnostic Observation Schedule (ADOS) and the Mullen Scales of Early Learning (MSEL) assessments. In summary, our study demonstrates dysregulated levels of inflammatory cytokine mediators in the CB of children later diagnosed with ASD and that inflammatory mediators were associated with ASD severity, comorbid behaviors, and neurodevelopmental measures. These findings have important implications for the possible predictive value of early cytokine measures in neurodevelopmental outcomes and subsequent behavioral manifestations.

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7. Santiago CFG, Lelis DF, Ferreira GFS, Pinto AL, Caldeira IP, Ribeiro NG, Forechi L, Baldo TOF, Baldo MP. Mental health in mothers of children with autism spectrum disorder: a cross-sectional study. Women Health;2024 (Sep);64(8):636-647.

The increased prevalence of autism spectrum disorder (ASD) has placed a significant emotional and psychological burden on mothers. We explored the association between the severity of ASD symptoms in children and the mental health of their mothers during the COVID-19 pandemic. Our study included 1,924 mothers of children with ASD, enrolled in a web-based cross-sectional survey over 85 consecutive days to gather clinical and sociodemographic data. The severity of ASD symptoms was obtained according to the children’s age. Using the Depression, Anxiety, and Stress Scales (DASS-21) scale, we found that 35.8 percent of mothers experienced both anxiety and depression. A high education level and a high family income reduced the chance of concurrent anxiety and depression. Conversely, unemployment, a child using psychiatric medication, and higher severity of ASD symptoms increased the chance. Notably, the severity of the ASD symptom was the sole predictor of maternal co-occurring anxiety and depression across all age groups (<3 years aOR = 2.04, 95%CI 1.07-3.89; 3-5 years aOR = 2.76, 95%CI 1.67-4.56; ≥ 6 years aOR = 1.61, 95%CI 1.04-2.50). Recognizing the challenges associated with ASD leads to greater acceptance and tailored interventions, ultimately improving the overall well-being of both individuals with ASD and their mothers.

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8. Singh Y, Sodhi RK, Kumar H, Bishnoi M, Bhandari R, Kuhad A. Repurposing of niclosamide, an anthelmintic, by targeting ERK/MAPK signaling pathway in the experimental paradigm of autism spectrum disorders. Eur J Pharmacol;2024 (Aug 15);982:176902.

AIM: The current study explores niclosamide’s neuroprotective potential in an animal model of autism spectrum disorder (ASD) and goes further to understand how the ERK/MAPK signaling pathway is thought to contribute to this activity. METHODS: In order to create an autism-like phenotype in rats, 4 μl of 1 M PPA was infused intracerebroventricularly. The oral treatment with niclosamide (50 and 100 mg/kg) and risperidone (1 mg/kg) (used as standard) was given from 3rd to 30th day. Between the 14th and 28th day, behavioral assessments were made for sociability, stereotypy, anxiety, depression, novelty preference, repetitive behavior, and perseverative behavior. The animals were euthanized on the 29th day, and oxidative stress markers were assessed in the brain homogenate. The levels of neuroinflammatory cytokines such as TNF-α, IL-6, NF-κB, IFN-γ and glutamate were estimated using ELISA kits. To assess the involvement of the ERK/MAPK signaling pathway, levels of Nrf2 and ERK2 were also measured. KEY FINDINGS: Niclosamide therapy significantly restored behavioral, biochemical, neurological, and molecular impairments. Hence, niclosamide could be a potential neurotherapeutic candidate for further studies for use in ASD.

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9. Tang K, Hill E, Pellicano E, Thompson C, Myers B. Barriers to and enablers of the transition from child and adolescent to adult mental health services for autistic young people and/or those with attention deficit hyperactivity disorder: protocol for a scoping review. BMJ Open;2024 (Aug 17);14(8):e083373.

INTRODUCTION: Autistic young people and/or those with attention deficit hyperactivity disorder (ADHD) who have co-occurring mental health conditions experience significant challenges when transitioning from child and adolescent mental health services (CAMHS) to adult mental health services (AMHS). However, barriers and facilitators to this service transition are poorly understood for this population. This scoping review aims to synthesise the available evidence on barriers and enablers to the transition from CAMHS to AMHS for autistic young people and/or those with ADHD. METHODS AND ANALYSIS: Arksey and O’Malley’s six-step framework for scoping reviews will be used. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews checklist will guide the reporting of this review. Electronic databases of Medline, PsycINFO, CINAHL, Scopus, ProQuest Central and Google Scholar will be searched for relevant articles published in English with no date limitations. Title, abstract and full-text screening will be completed by two independent reviewers. Studies will be eligible for inclusion if the article focuses on (1) adolescents and/or young people (aged 18-24) with a primary diagnosis of autism spectrum disorder and/or ADHD (population) and (2) describes factors associated with service or care transitions (concept) (3) from CAMHS to AMHS (context). Study quality will be evaluated using the Standard Quality Assessment Criteria for Evaluating Primary Research Papers from a Variety of Fields. Data describing the factors that enable or inhibit the transition from CAMHS to AMHS will be extracted and synthesised using the Bronfenbrenner’s social ecological model as a framework for organising and reporting results. ETHICS AND DISSEMINATION: Ethics approval is not required. Findings will be disseminated via peer-reviewed publications and presented at conferences. TRIAL REGISTRATION NUMBER: https://doi.org/10.17605/OSF.IO/BZPQF.

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10. Washington AM, Mercer AH, Burrows CA, Dager SR, Elison JT, Estes AM, Grzadzinski R, Lee C, Piven J, Pruett JR, Jr., Shen MD, Wilfond B, Wolff J, Zwaigenbaum L, MacDuffie KE. Parent attitudes towards predictive testing for autism in the first year of life. J Neurodev Disord;2024 (Aug 17);16(1):47.

BACKGROUND: Emerging biomarker technologies (e.g., MRI, EEG, digital phenotyping, eye-tracking) have potential to move the identification of autism into the first year of life. We investigated the perspectives of parents about the anticipated utility and impact of predicting later autism diagnosis from a biomarker-based test in infancy. METHODS: Parents of infants were interviewed to ascertain receptiveness and perspectives on early (6-12 months) prediction of autism using emerging biomarker technologies. One group had experience parenting an older autistic child (n=30), and the other had no prior autism parenting experience (n=25). Parent responses were analyzed using inductive qualitative coding methods. RESULTS: Almost all parents in both groups were interested in predictive testing for autism, with some stating they would seek testing only if concerned about their infant’s development. The primary anticipated advantage of testing was to enable access to earlier intervention. Parents also described the anticipated emotions they would feel in response to test results, actions they might take upon learning their infant was likely to develop autism, attitudes towards predicting a child’s future support needs, and the potential impacts of inaccurate prediction. CONCLUSION: In qualitative interviews, parents of infants with and without prior autism experience shared their anticipated motivations and concerns about predictive testing for autism in the first year of life. The primary reported motivators for testing-to have more time to prepare and intervene early-could be constrained by familial resources and service availability. Implications for ethical communication of results, equitable early intervention, and future research are discussed.

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11. Yi YJ, Heidari Matin N, Brannan D, Johnson M, Nguyen A. Design Considerations for Virtual Reality Intervention for People with Intellectual and Developmental Disabilities: A Systematic Review. Herd;2024 (Aug 18):19375867241271434.

OBJECTIVES: This systematic review aims to explore virtual reality (VR) applications for rehabilitation purposes among people with intellectual and developmental disabilities (IDD), identify their effects on rehabilitation outcomes, explore themes to consider in VR intervention design, and provide guidance for designers and researchers in creating therapeutic environments using VR technology. BACKGROUND: VR has gained increasing attention in healthcare settings to assist in achieving rehabilitation goals for people with IDD. VR is particularly advantageous since it simulates the real world while providing controllable, safe, and versatile environments. It is necessary to expand the current body of knowledge on VR intervention’s outcomes by synthesizing further information on VR application characteristics as well as identifying design considerations regarding feasibility, usability, safety, and other aspects that will benefit future VR intervention design and research. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framed the current review. Multiple databases were searched to identify studies published between 2001 and 2023. The review qualitatively organized VR environment design considerations according to three themes: feasibility, usability, and safety. RESULTS: This review included 27 articles and included 868 participants. The overall findings indicated that VR interventions are promising in enhancing rehabilitation outcomes among people with IDD, such as physical, cognitive, emotional, and functional independence domains. CONCLUSION: This review provides design recommendations to create effective, usable, and safe VR interventions for individuals with IDD. The suggested design implications should be applied with the awareness that VR is a relatively emerging technology with rapidly evolving features.

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