1. Editorial for January ASD (Volume 72). Arthropod Struct Dev;2023 (Jan 28):101233.

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2. Ahmadvand M, Eghbalian F, Nasrolahi S, Jenabi E. The Association between Threatened Abortion and the Risk of Autism Spectrum Disorders among Children: A Meta-Analysis. Biomed Res Int;2023;2023:5249585.

BACKGROUND: The current study is aimed at updating the observational studies on the relationship between threatened abortion and the risk of ASD. METHODS: The search keywords were covered in three electronic databases PubMed, Web of Science, and Scopus up to April 2022. The modified Newcastle-Ottawa scale (NOS) was applied to detect the quality of epidemiological studies. We used the chi-square test and the I (2) statistic to show the heterogeneity among articles. I (2) more than 50% was considered high heterogeneity. Egger’s and Begg’s line regression tests were used for evaluating the publication bias. The random-effects model was applied for the analysis of the findings. The Stata 13.0 software package was applied for analysis and indicated p value less than 0.05 as a significant level. RESULTS: The pooled analysis reported significant differences between threatened abortion and the risk of ASD in adjusted studies (OR = 1.93; 95% CI: 1.12, 2.73; I (2) = 59.5.0%) and in crude studies (OR = 2.17; 95% CI: 1.46, 2.88; I (2) = 39.5%). The evidence of publication bias was not found. CONCLUSIONS: The findings suggest that threatened abortion is a risk factor for ASD. As a result, screening tools to detect are necessary in mothers facing a threatened abortion.

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3. Åkerlund S, Håkansson A, Claesdotter-Knutsson E. An auditory processing advantage enables communication in less complex social settings: Signs of an extreme female brain in children and adolescents being assessed for Autism Spectrum Disorders. Front Psychol;2022;13:1068001.

BACKGROUND: The underlying factors of the male predominance in Autism Spectrum Disorders (ASD) are largely unknown, although a female advantage in social communication has been pointed out as a potential factor. Recently, attention has been given to ASD as a sensory processing disorder, focusing on the audio-visual temporal processing paramount for the development of communication. In ASD, a deviant audio-visual processing has been noted, resulting in difficulties interpreting multisensory information. Typically Developed (TD) females have shown an enhanced language processing in unisensory situations compared to multisensory situations. We aim to find out whether such an advantage also can be seen in girls within the ASD population, and if so, is it related to social communication skills? METHOD: Forty children (IQ > 85), 20 females (mean age = 13.90 years, SD = 2.34) and 20 males (mean age = 12.15 years, SD = 2.83) triaged for an ASD assessment were recruited from a child and youth psychiatric clinic in Sweden. Using The Social Responsiveness Scale (SRS) we looked at associations with child performance on the Integrated Visual and Auditory Continuous Performance Test (IVA-2). RESULTS: An auditory advantage in the female group was associated with less rated problems in social communications in unisensory processing whereas in multisensory processing an auditory dominance was associated with more rated problems in Social Awareness. In the male group, a visual dominance was associated with more rated problems in Social Rigidity. CONCLUSION: A female unisensory processing advantage in ASD could very well be explaining the male domination in ASD. However, the social difficulties related to multisensory processing indicate that ASD females might be struggling as hard as males in more complex settings. Implications on the assessment procedure are discussed.

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4. Baghdadli A, Audras-Torrent L, Rattaz C, Gonnier V, Ferrando L, Michelon C, Odoyer R, Maffre T, Picot MC. Multistage screening process for neurodevelopmental disorders in siblings of children with autism: the FRATSA protocol study. BMJ Open;2023 (Jan 30);13(1):e066520.

INTRODUCTION: The elevated rates of neurodevelopmental disorders (NDDs) among siblings of children with autism spectrum disorder (ASD) raise concerns about their developmental monitoring and development. The main aim of this study is to assess the feasibility and acceptability of a standardised screening process on a large sample of siblings. METHODS AND ANALYSIS: This prospective study will assess the feasibility of a selective and multi-stage screening process for NDD performed on 384 siblings of children with confirmed ASD. Stage 1 will consist of the screening of NDD performed using online parental questionnaires (Social Responsiveness Scale, IdentiDys scale, DCDQ, parental concerns) through a web platform. In cases of a positive result, the second stage, consisting of a clinical semi-structured interview with a psychologist, will be proposed to the sibling before referral for diagnosis and treatment, if necessary. Approximately 12 months after stage 2, parents will be contacted by telephone to collect the diagnosis established following the referrals and their level of satisfaction concerning the screening process. Based on an expected participation rate of 50%, to estimate this rate with an accuracy of 5%, it is necessary to screen 384 subjects. ETHICS AND DISSEMINATION: The Ethics Committee on the Research of Human Subjects of Paris (Ile de France VII) approved this study in March 2022 (number: 2021-A02241-40). Express consent is required from all participants. Findings from the cohort study will be disseminated by publication of peer-reviewed manuscripts, presentations at scientific meetings and conferences with associated teams. TRIAL REGISTRATION NUMBER: NCT05512637.

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5. Carpita B, Stagnari R, Palego L, Baroni D, Massimetti G, Nardi B, Cremone IM, Betti L, Giannaccini G, Dell’Osso L. Circulating levels of 5-HT and BDNF in Adults with Autism Spectrum Conditions: an Investigation in a Sample of Subjects with Autism Spectrum Disorder, their first-degree Relatives and Controls. Curr Med Chem;2023 (Jan 31)

BACKGROUND: Several studies investigated circulating levels of serotonin (5-HT) and brain-derived neurotrophic factor (BDNF) in children with Autism spectrum disorder (ASD). More limited literature focused on ASD adults or on populations with subthreshold autism spectrum manifestations, such as relatives of ASD probands. This study aimed to investigate 5-HT and BDNF levels in adults with autism spectrum conditions. Correlations between levels of biochemical variables and ASD symptoms were also evaluated. METHOD: a sample of ASD adults, their first-degree relatives (Broad autism phenotype, BAP group), and controls were recruited and assessed with psychometric scales. Blood samples were collected from all participants. 5-HT and BDNF levels were measured by means of ELISA kits. RESULTS: ASD adults showed significantly lower platelet-poor plasma (PPP) 5-HT levels than BAP and control groups. No significant difference was found among groups for PPP BDNF levels and intra-platelet 5-HT levels. 5-HT levels were reported to be specifically correlated with some autism symptoms. CONCLUSION: This work highlighted the presence in ASD adults of reduced PPP 5-HT levels than in other groups, without significant differences with respect to BDNF levels, supporting the hypothesis that biochemical correlates of ASD in adults may be different from those typically reported in children.

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6. Cerda N, Brinster M, Turner C, Shahidullah JD, Augustyn M. Challenging Case: Leveraging Community Partnerships to Address Barriers to Care for Students with Autism. J Dev Behav Pediatr;2023 (Jan 26)

Sam is an 11-year-old young boy with autism spectrum disorder (ASD), unspecified anxiety disorder, and attention-deficit/hyperactivity disorder, combined presentation. He was initially diagnosed with ASD at 6 years of age after evaluation by a developmental-behavioral (DB) pediatrician. He presents to the DB pediatrics clinic to reestablish care. He established care with psychiatry 5 months ago after his school referred him to a hospital-school-community telepartnership bridge program following statements of self-harm and numerous concerns with his behavior, including elopement.Sam currently receives special education support under the classifications of « Emotional Disturbance » and « Speech Impairment. » His parents report significant challenges with having his medical diagnosis of autism recognized by the school, which has impeded him receiving educational support as a student with autism. This has resulted in Sam being penalized for challenging behaviors related to his neurodevelopmental disorder. He is not currently making meaningful progress in the school setting. Sam currently demonstrates avoidance, physical and verbal aggression, and difficulty adapting to change across settings. In addition to difficulties advocating for more individualized support at school, Sam has never received applied behavior analysis (ABA) therapy because of challenges obtaining insurance approval. There are no additional barriers to accessing care, such as language, geographic, or socioeconomic factors.Sam’s visit to reestablish care with DB pediatrics consisted of an individual clinician evaluation model. The Childhood Autism Rating Scale, Second Edition, (CARS-2) and Vineland Adaptive Behavior Scales, Third Edition (Vineland-3), were administered, and Sam continued to meet DSM-5 criteria for ASD following re-evaluation. A new referral for ABA therapy was submitted. Shortly afterward, his family received an insurance denial letter specifying that additional developmental testing was needed before ABA therapy would be approved. His clinician called the insurance company to appeal this decision but was unsuccessful. Sam was then seen by the DB pediatrics embedded psychologist, who completed additional testing, including assessment of cognitive functioning, administration of the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2), and autism-specific rating scales. This process led to further delays in access to ABA services. Throughout this process, the parents reported feeling helpless and frustrated given the barriers faced in receiving appropriate services. What are your next steps to advocate for supports through the school and insurance company?

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7. Chang JC, Lai MC, Chien YL, Cheng CY, Wu YY, Gau SS. Psychometric properties of the Mandarin version of the autism diagnostic observation Schedule-Generic. J Formos Med Assoc;2023 (Jan 31)

BACKGROUND/PURPOSE: The diagnosis of autism spectrum disorder (ASD), involving multiple components of clinical assessments, is challenging. The Autism Diagnostic Observation Schedule-Generic (ADOS-G), one of the standardized and validated instruments for ASD diagnostic evaluation, has been widely used in many countries. With the preparation of the Mandarin version of the ADOS-G (Mandarin-ADOS-G), this study aims to examine its psychometric properties, including reliability and validity. METHODS: The sample included 554 individuals clinically diagnosed with ASD (477 males, 86.1%) and 50 typically developing (TD) individuals (29 males, 58.0%) who were assessed with different modules of the Mandarin-ADOS-G between 4.1 and 34.0 years old with a mean age of 13.0 years (Module 1, n = 40; Module 2, n = 46; Module 3, n = 275; Module 4, n = 243). We evaluated the inter-rater reliability, test-retest reliability, internal consistency, and concurrent validity with the Chinese Autism Diagnostic Interview-Revised (ADI-R) and Social Responsiveness Scale (SRS) caregiver-report and self-report forms. The discriminative validity of Mandarin-ADOS-G was also examined. RESULTS: The Mandarin-ADOS-G demonstrated good inter-rater reliability (agreement of ADOS classification 0.91), good test-retest reliability (intraclass correlations 0.55-0.73), and low to high good internal consistency (Cronbach’s alpha 0.27-0.86). The concurrent validity showed significant correlations with ADI-R (Pearson correlations 0.22-0.37) and the SRS caregiver-report form (Pearson correlations 0.15-0.23). Moreover, all Mandarin-ADOS-G domains successfully differentiated autistic individuals from TD individuals (all p-values <0.001). CONCLUSION: The Mandarin-ADOS-G is a reliable and valid instrument for assisting the diagnosis of ASD in the Mandarin-speaking population.

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8. Chari T, Hernandez A, Portera-Cailliau C. A novel head-fixed assay for social touch in mice uncovers aversive responses in two autism models. bioRxiv;2023 (Jan 13)

Social touch, an important aspect of social interaction and communication, is essential to kinship across animal species. How animals experience and respond to social touch has not been thoroughly investigated, in part due to the lack of appropriate assays. Previous studies that examined social touch in freely moving rodents lacked the necessary temporal and spatial control over individual touch interactions. We designed a novel head-fixed assay for social touch in mice, in which the experimenter has complete control to elicit highly stereotyped bouts of social touch between two animals. The user determines the number, duration, context, and type of social touch interactions, while monitoring with high frame rate cameras an array of complex behavioral responses. We focused on social touch to the face because of their high translational relevance to humans. We validated this assay in two different models of autism spectrum disorder (ASD), the Fmr1 knockout model of Fragile X Syndrome and maternal immune activation mice. We observed increased avoidance, hyperarousal, and more aversive facial expressions to social touch, but not to object touch, in both ASD models compared to controls. Because this new social touch assay for head-fixed mice can be used to record neural activity during repeated bouts of social touch it should be of interest to neuroscientists interested in uncovering the underlying circuits.

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9. Dhanasekara CS, Ancona D, Cortes L, Hu A, Rimu AH, Robohm-Leavitt C, Payne D, Wakefield SM, Mastergeorge AM, Kahathuduwa CN. Association Between Autism Spectrum Disorders and Cardiometabolic Diseases: A Systematic Review and Meta-analysis. JAMA Pediatr;2023 (Jan 30)

IMPORTANCE: Although the increased risk of obesity among individuals with autism has been well established, evidence on the association between autism, cardiometabolic disorders, and obesity remains inconclusive. OBJECTIVE: To examine the association between autism spectrum disorders and cardiometabolic diseases in a systematic review and meta-analysis. DATA SOURCES: PubMed, Scopus, Web of Science, ProQuest, Embase, and Ovid databases were searched from inception through July 31, 2022, without restrictions on date of publication or language. STUDY SELECTION: Observational or baseline data of interventional studies reporting the prevalence of cardiometabolic risk factors (ie, diabetes, hypertension, dyslipidemia, atherosclerotic macrovascular disease) among children and/or adults with autism and matched with participants without autism were included. DATA EXTRACTION AND SYNTHESIS: Screening, data extraction, and quality assessment were performed independently by at least 2 researchers. DerSimonian-Laird random-effects meta-analyses were performed using the meta package in R. MAIN OUTCOMES AND MEASURES: Relative risks (RRs) of diabetes, hypertension, dyslipidemia, and atherosclerotic macrovascular disease among individuals with autism were the primary outcomes. Secondary outcomes included the RR of type 1 and type 2 diabetes, heart disease, stroke, and peripheral vascular disease. RESULTS: A total of 34 studies were evaluated and included 276 173 participants with autism and 7 733 306 participants without autism (mean [range] age, 31.2 [3.8-72.8] years; pooled proportion [range] of female individuals, 47% [0-66%]). Autism was associated with greater risks of developing diabetes overall (RR, 1.57; 95% CI, 1.23-2.01; 20 studies), type 1 diabetes (RR, 1.64; 95% CI, 1.06-2.54; 6 studies), and type 2 diabetes (RR, 2.47; 95% CI, 1.30-4.70; 3 studies). Autism was also associated with increased risks of dyslipidemia (RR, 1.69; 95% CI, 1.20-2.40; 7 studies) and heart disease (RR, 1.46; 95% CI, 1.42-1.50; 3 studies). Yet, there was no significantly associated increased risk of hypertension and stroke with autism (RR, 1.22; 95% CI, 0.98-1.52; 12 studies; and RR, 1.19; 95% CI, 0.63-2.24; 4 studies, respectively). Meta-regression analyses revealed that children with autism were at a greater associated risk of developing diabetes and hypertension compared with adults. High between-study heterogeneity was a concern for several meta-analyses. CONCLUSIONS AND RELEVANCE: Results suggest that the associated increased risk of cardiometabolic diseases should prompt clinicians to vigilantly monitor individuals with autism for potential contributors, signs of cardiometabolic disease, and their complications.

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10. Fittipaldi S, Armony JL, García AM, Migeot J, Cadaveira M, Ibáñez A, Baez S. Emotional descriptions increase accidental harm punishment and its cortico-limbic signatures during moral judgment in autism. Sci Rep;2023 (Jan 31);13(1):1745.

Individuals with autism spectrum disorder (ASD) present difficulties in integrating mental state information in complex moral tasks. Yet, ASD research has not examined whether this process is influenced by emotions, let alone while capturing its neural bases. We investigated how language-induced emotions modulate intent-based moral judgment in ASD. In a fMRI task, 30 adults with ASD and 27 neurotypical controls read vignettes whose protagonists commit harm either accidentally or intentionally, and then decided how much punishment the protagonist deserved. Emotional content was manipulated across scenarios through the use of graphic language (designed to trigger arousing negative responses) vs. plain (just-the-facts, emotionless) language. Off-line functional connectivity correlates of task performance were also analyzed. In ASD, emotional (graphic) descriptions amplified punishment ratings of accidental harms, associated with increased activity in fronto-temporo-limbic, precentral, and postcentral/supramarginal regions (critical for emotional and empathic processes), and reduced connectivity among the orbitofrontal cortex and the angular gyrus (involved in mentalizing). Language manipulation did not influence intentional harm processing in ASD. In conclusion, in arousing and ambiguous social situations that lack intentionality clues (i.e. graphic accidental harm scenarios), individuals with ASD would misuse their emotional responses as the main source of information to guide their moral decisions. Conversely, in face of explicit harmful intentions, they would be able to compensate their socioemotional alterations and assign punishment through non-emotional pathways. Despite limitations, such as the small sample size and low ecological validity of the task, results of the present study proved reliable and have relevant theoretical and translational implications.

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11. Krasny-Pacini A. Single-case experimental designs for child neurological rehabilitation and developmental disability research. Dev Med Child Neurol;2023 (Jan 31)

Single-case experimental designs (SCEDs) are a group of methodologies of growing interest, aiming to test the effectiveness of an intervention at the single-participant level, using a rigorous and prospective methodology. SCEDs may promote flexibility on how we design research protocols and inform clinical decision-making, especially for personalized outcome measures, inclusion of families with challenging needs, measurement of children’s progress in relation to parental implementation of interventions, and focus on personal goals. Design options for SCEDs are discussed in relation to an expected on/off effect of the intervention (e.g. school/environmental adaptation, assistive technology devices) or, alternatively, on an expected carry-on/maintenance of effects (interventions aiming to develop or restore a function). Randomization in multiple-baseline designs and ‘power’ calculations are explained. The most frequent reasons for not detecting an intervention effect in SCEDs are also presented, especially in relation to baseline length, trend, and instability. The use of SCEDs on the front and back ends of randomized controlled trials is discussed.

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12. Leslie AC, O’Sullivan M. The Triad of Childhood-Onset Schizophrenia, Autism Spectrum Disorder, and Catatonia: A Case Report. Schizophr Bull;2023 (Jan 31)

Childhood-onset schizophrenia (COS) is a rare and severe form of schizophrenia with an estimated prevalence of 1/10,000. Schizophrenia and Autism spectrum disorder (ASD) have shared phenotypic features and shared genetic etiology. There is growing research surrounding the co-occurrence of psychomotor syndromes like catatonia with neurodevelopmental disorders like ASD or psychiatric disorders like schizophrenia. In 2013, Shorter and Wachtel described a phenomenon of the ‘Iron Triangle’ where COS, ASD, and catatonia often co-occur. The Iron Triangle theory is based on observation of historical case literature, which showed that all three diagnoses in the Iron Triangle were routinely assigned to children and adolescents. The pattern of this « Iron Triangle » suggests there may be a single underlying pathology resulting in a unique mixed form of catatonia, autism, and psychosis. We describe the case of a boy with sequential development of COS, ASD, and catatonia who also has syndromic facial and musculoskeletal features. This case highlights overlapping diagnostic features of these three disorders and can help us better understand how « hidden » features of catatonia may occur in patients with COS or ASD but go unrecognized, because they are grouped as features under autism/schizophrenia rather than a distinct diagnosis of catatonia. Further study is warranted to elucidate if this phenotypic pattern constitutes a new single diagnosis that is not well understood, an endophenotype of schizophrenia, or if this is the result of phenomenological overlap between catatonia, ASD, and COS.

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13. Lewis S, Papadopoulos N, Mantilla A, Hiscock H, Whelan M, McGillivray J, Rinehart N. The impact of COVID-19 on sleep for autistic children: A systematic review. Res Autism Spectr Disord;2023 (Apr);102:102110.

BACKGROUND: Up to 80% of children with autism experience behavioural sleep problems, predominantly relating to bedtime resistance, sleep anxiety, sleep dysregulation, and shorter duration, which are associated with increased autistic symptom expression and emotional and behavioural difficulties. Researchers predicted the COVID-19 pandemic would worsen sleep and behavioural difficulties for autistic children, due to their need for routine and certainty. This systematic review is the first to focus on delineating the role of sleep disturbance in exacerbating autistic symptoms and internalising and externalising behaviours during the pandemic. METHOD: In this PROSPERO registered systematic review, we aggregated and synthesised findings from empirical studies from 2020 onwards that included children with autism and examined sleep outcomes, using narrative and framework synthesis due to the variety of methods and designs employed. We identified additional relevant themes through inductive thematic analysis. RESULTS: Seventy-one studies met the search criteria, and we selected seventeen for review following screening and quality assessment. These studies reported mixed findings; with strongest support for worsening of sleep problems typically experienced by autistic children, including difficulties with sleep regulation and shorter sleep duration. Further, sleep problems were associated with increased expression of autistic characteristics. CONCLUSIONS: Preliminary findings of worsening sleep and increased autistic characteristics for autistic children throughout the COVID-19 pandemic highlight the need for ongoing, accessible and flexible service provision during exposure to environmental stressors. We propose that behavioural sleep interventions are well suited to telehealth adaptation and play an important role in supporting families when in-person treatment for sleep problems is not possible.

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14. Lin J, de Rezende VL, de Aguiar da Costa M, de Oliveira J, Gonçalves CL. Cholesterol metabolism pathway in autism spectrum disorder: From animal models to clinical observations. Pharmacol Biochem Behav;2023 (Jan 28);223:173522.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by a persistent impairment of social skills, including aspects of perception, interpretation, and response, combined with restricted and repetitive behavior. ASD is a complex and multifactorial condition, and its etiology could be attributed to genetic and environmental factors. Despite numerous clinical and experimental studies, no etiological factor, biomarker, and specific model of transmission have been consistently associated with ASD. However, an imbalance in cholesterol levels has been observed in many patients, more specifically, a condition of hypocholesterolemia, which seems to be shared between ASD and ASD-related genetic syndromes such as fragile X syndrome (FXS), Rett syndrome (RS), and Smith- Lemli-Opitz (SLO). Furthermore, it is known that alterations in cholesterol levels lead to neuroinflammation, oxidative stress, impaired myelination and synaptogenesis. Thus, the aim of this review is to discuss the cholesterol metabolic pathways in the ASD context, as well as in genetic syndromes related to ASD, through clinical observations and animal models. In fact, SLO, FXS, and RS patients display early behavioral markers of ASD followed by cholesterol disturbances. Several studies have demonstrated the role of cholesterol in psychiatric conditions and how its levels modulate brain neurodevelopment. This review suggests an important relationship between ASD pathology and cholesterol metabolism impairment; thus, some strategies could be raised – at clinical and pre-clinical levels – to explore whether cholesterol metabolism disturbance has a generally adverse effect in exacerbating the symptoms of ASD patients.

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15. Liu D, Bu D, Li H, Wang Q, Ding X, Fang X. Intestinal metabolites and the risk of autistic spectrum disorder: A two-sample Mendelian randomization study. Front Psychiatry;2022;13:1034214.

BACKGROUND: Observational studies have reported a strong association between autistic spectrum disorder (ASD) and intestinal metabolites. However, it is unclear whether this correlation is causally or violated by confounding or backward causality. Therefore, this study explored the potential causal relationship between intestinal metabolites and dependent metabolites on ASD. METHODS: We used a two-sample Mendelian random analysis and selected variants closely related to intestinal flora-dependent metabolites as instrumental variables. MR-Egger, inverse variance weighted (IVW), MR-PRESSO, maximum likelihood, and weighted median were performed to reveal their causal relationships. Ten metabolites were studied, which included trimethylamine-N-oxide, betaine, carnitine, choline, glutamate, kynurenine, phenylalanine, serotonin, tryptophan, and tyrosine. Sensitivity tests were also performed to evaluate the robustness of the MR study. RESULTS: The IVW method revealed that serotonin may increase the ASD risk (OR 1.060, 95% CI: 1.006-1.118), while choline could decrease the ASD risk (OR 0.925, 95% CI: 0.868-0.988). However, no definite causality was observed between other intestinal metabolites (e.g., trimethylamine-N-oxide, betaine, and carnitine) with ASD. Additionally, neither the funnel plot nor the MR-Egger test showed horizontal pleiotropy, and the MR-PRESSO test found no outliers. Cochran’s Q test showed no significant heterogeneity among the studies, suggesting the robustness of the study. CONCLUSION: Our study found potential causality from intestinal metabolites on ASD. Clinicians are encouraged to offer preventive measures to such populations.

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16. Mendez-Vazquez H, Roach RL, Nip K, Sathler MF, Garver T, Danzman RA, Moseley MC, Roberts JP, Koch ON, Steger AA, Lee R, Arikkath J, Kim S. The autism-associated loss of δ-catenin functions disrupts social behaviors. bioRxiv;2023 (Jan 12)

δ-catenin is expressed in excitatory synapses and functions as an anchor for the glutamatergic AMPA receptor (AMPAR) GluA2 subunit in the postsynaptic density. The glycine 34 to serine (G34S) mutation in the δ-catenin gene is found in autism spectrum disorder (ASD) patients and induces loss of δ-catenin functions at excitatory synapses, which is presumed to underlie ASD pathogenesis in humans. However, how the G34S mutation causes loss of δ-catenin functions to induce ASD remains unclear. Here, using neuroblastoma cells, we discover that the G34S mutation generates an additional phosphorylation site for glycogen synthase kinase 3β (GSK3β). This promotes δ-catenin degradation and causes the reduction of δ-catenin levels, which likely contributes to the loss of δ-catenin functions. Synaptic δ-catenin and GluA2 levels in the cortex are significantly decreased in mice harboring the δ-catenin G34S mutation. The G34S mutation increases glutamatergic activity in cortical excitatory neurons while it is decreased in inhibitory interneurons, indicating changes in cellular excitation and inhibition. δ-catenin G34S mutant mice also exhibit social dysfunction, a common feature of ASD. Most importantly, inhibition of GSK3β activity reverses the G34S-induced loss of δ-catenin function effects in cells and mice. Finally, using δ-catenin knockout mice, we confirm that δ-catenin is required for GSK3β inhibition-induced restoration of normal social behaviors in δ-catenin G34S mutant animals. Taken together, we reveal that the loss of δ-catenin functions arising from the ASD-associated G34S mutation induces social dysfunction via alterations in glutamatergic activity and that GSK3β inhibition can reverse δ-catenin G34S-induced synaptic and behavioral deficits. SIGNIFICANCE STATEMENT: δ-catenin is important for the localization and function of glutamatergic AMPA receptors at synapses in many brain regions. The glycine 34 to serine (G34S) mutation in the δ-catenin gene is found in autism patients and results in the loss of δ-catenin functions. δ-catenin expression is also closely linked to other autism-risk genes involved in synaptic structure and function, further implying that it is important for the autism pathophysiology. Importantly, social dysfunction is a key characteristic of autism. Nonetheless, the links between δ-catenin functions and social behaviors are largely unknown. The significance of the current research is thus predicated on filling this gap by discovering the molecular, cellular, and synaptic underpinnings of the role of δ-catenin in social behaviors.

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17. Ni W, Lu H, Wang Q, Song C, Yi L. Vigilance or avoidance: How do autistic traits and social anxiety modulate attention to the eyes?. Front Neurosci;2022;16:1081769.

INTRODUCTION: Social anxiety disorder (SAD) and autism spectrum disorder (ASD) are highly overlapping in symptoms and have a high rate of comorbidity, posing challenges in diagnosis and intervention for both disorders. Both disorders are linked to abnormal attention to the eyes, yet how they interactively modulate the attentional process to the eyes remains unclear. METHODS: In this study, we explored how autistic traits and social anxiety in college students separately and together affected different temporal stages of attention to the eyes. Participants were instructed to view virtual faces for 10 s and make an emotional judgment, while their eye movements were recorded. RESULTS: We found that social anxiety and autistic traits affected different temporal stages of eye-looking. Social anxiety only affected the first fixation duration on the eyes, while autistic traits were associated with eye avoidance at several time points in the later stage. More importantly, we found an interactive effect of autistic traits and social anxiety on the initial attention to the eyes: Among people scoring high on autistic traits, social anxiety was related to an early avoidance of the eyes as well as attention maintenance once fixated on the eyes. DISCUSSION: Our study suggests the separate and interactive roles of social anxiety and autistic traits in attention to the eyes. It contributes to a deeper understanding of the mechanisms of social attention in both SAD and ASD and highlights the application of psychiatric diagnoses using eye-tracking techniques.

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18. Oosting DR, Howard MS, Carter AS. Reciprocal Associations Between Language Ability and Social Functioning Development in Pre-verbal Autistic Children. J Autism Dev Disord;2023 (Jan 31)

Longitudinal research on language abilities and social functioning in young children suggests that gains in one domain affect gains in the other. However, few studies have examined inter-relations of language and social functioning jointly among young children diagnosed with autism spectrum disorder (ASD). Pre-verbal toddlers with ASD are a group of particular clinical relevance, given that greater language abilities at school entry have been associated with positive long-term adjustment in many areas, including adaptive and social functioning. Reduced attention to and engagement in social interactions among autistic toddlers who are not yet speaking may interfere with language development concurrently and over time. The present study examined reciprocal associations between language ability and social functioning over a 2-year period across three time points in a sample of 90 pre-verbal autistic toddlers using cross-lagged panel analyses conducted in MPlus. Cross-lagged panel analyses revealed significant within-timepoint synchronous correlations, within-domain autoregressive paths over time, and as hypothesized, reciprocal significance in all cross-lagged paths. For very young pre-verbal children with ASD, language ability and social functioning appear to exert concurrent and cascading developmental influences on one another. Targeting both language and social functioning simultaneously may enhance intervention efficacy for very young pre-verbal children with ASD.

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19. Rafiei M, Nakhostin-Ansari A, Meshkat S, Khosravi A, Memari AH. Public awareness and stigma of autism spectrum disorder in Iran; An online survey. Res Dev Disabil;2023 (Jan 31);134:104441.

BACKGROUND: There is no systematic examination of the Iranian general population’s knowledge of autism spectrum disorders (ASD). AIM: In this study, we aimed to assess stigma and knowledge about ASD among Iranian people and determine the sociodemographic factors associated with them. METHODS AND PROCEDURES: This study was conducted as a cross-sectional online survey from April to May 2020, using a convenience sampling method. We designed an online questionnaire using Google forms. We sent a message explaining the study goals and the link to the online questionnaire to groups on popular social platforms in Iran. We used Autism Stigma and Knowledge Questionnaire (ASK-Q) to assess ASD knowledge and stigma. OUTCOMES AND RESULTS: In total, 600 individuals participated in the study, of whom 301 (50.2 %) were women and 299 (49.8 %) were men. Out of 600 participants, 216 (36 %) had adequate knowledge of the diagnosis/symptoms subscale, 206 (34.3 %) for the etiology subscale, 200 (33.3 %) for the treatment subscale, and 260 (43.4 %) had no stigma toward ASD. CONCLUSIONS AND IMPLICATIONS: The level of knowledge about ASD is insufficient among Iranian people of this study. People with lower knowledge of ASD, including older adults and individuals with lower educational levels, may benefit the most from ASD awareness interventions.

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20. Rahmatullah N, Schmitt LM, De Stefano L, Post S, Robledo J, Chaudhari GR, Pedapati E, Erickson CA, Portera-Cailliau C, Goel A. Hypersensitivity to distractors in Fragile X syndrome from loss of modulation of cortical VIP interneurons. bioRxiv;2023 (Jan 3)

Attention deficit is one of the most prominent and disabling symptoms in Fragile X Syndrome (FXS). Hypersensitivity to sensory stimuli contributes to attention difficulties by overwhelming and/or distracting affected individuals, which disrupts activities of daily living at home and learning at school. We find that auditory or visual distractors selectively impair visual discrimination performance in both humans and mice with FXS, but not their typically developing controls. Vasoactive intestinal polypeptide (VIP) neurons were significantly modulated by incorrect responses in the post-stimulus period during early distractor trials in WT mice, consistent with their known role as ‘error’ signals. Strikingly, however, VIP cells from Fmr1 (-/-) mice showed little modulation in error trials, and this correlated with their poor performance on the distractor task. Thus, VIP interneurons and their reduced modulatory influence on pyramidal cells, could be a potential therapeutic target for attentional difficulties in FXS.

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21. Strang JF, McClellan LS, Li S, Jack AE, Wallace GL, McQuaid GA, Kenworthy L, Anthony LG, Lai MC, Pelphrey KA, Thalberg AE, Nelson EE, Phan JM, Sadikova E, Fischbach AL, Thomas J, Vaidya CJ. The autism spectrum among transgender youth: default mode functional connectivity. Cereb Cortex;2023 (Jan 31)

The common intersection of autism and transgender identities has been described in clinical and community contexts. This study investigates autism-related neurophenotypes among transgender youth. Forty-five transgender youth, evenly balanced across non-autistic, slightly subclinically autistic, and full-criteria autistic subgroupings, completed resting-state functional magnetic resonance imaging to examine functional connectivity. Results confirmed hypothesized default mode network (DMN) hub hyperconnectivity with visual and motor networks in autism, partially replicating previous studies comparing cisgender autistic and non-autistic adolescents. The slightly subclinically autistic group differed from both non-autistic and full-criteria autistic groups in DMN hub connectivity to ventral attention and sensorimotor networks, falling between non-autistic and full-criteria autistic groups. Autism traits showed a similar pattern to autism-related group analytics, and also related to hyperconnectivity between DMN hub and dorsal attention network. Internalizing, gender dysphoria, and gender minority-related stigma did not show connectivity differences. Connectivity differences within DMN followed previously reported patterns by designated sex at birth (i.e. female birth designation showing greater within-DMN connectivity). Overall, findings suggest behavioral diagnostics and autism traits in transgender youth correspond to observable differences in DMN hub connectivity. Further, this study reveals novel neurophenotypic characteristics associated with slightly subthreshold autism, highlighting the importance of research attention to this group.

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22. Wang JY, Sonico GJ, Salcedo-Arellano MJ, Hagerman RJ, Martínez-Cerdeño V. A postmortem MRI study of cerebrovascular disease and iron content at end-stage of fragile X-associated tremor/ataxia syndrome. Res Sq;2023 (Jan 11)

Brain changes at end-stage of fragile X-associated tremor/ataxia syndrome (FXTAS) are largely unknown due to mobility impairment. We conducted a postmortem MRI study of FXTAS to quantify cerebrovascular disease, brain atrophy, and iron content and examined their relationships using principal component analysis (PCA). Intracranial hemorrhage (ICH) was observed in 4/17 FXTAS cases among which one was confirmed by histologic staining. Compared with seven control brains, FXTAS cases showed higher ratings of T2-hyperintensities (indicating cerebral small vessel disease) in the cerebellum, globus pallidus, and frontoparietal white matter and significant atrophy in cerebellar white matter, red nucleus, and dentate nucleus. PCA of FXTAS cases revealed negative associations of T2-hyperintensity ratings with anatomic volumes and iron content in the white matter, hippocampus, and amygdala, that were independent from highly correlated number of regions with ICH and iron content in subcortical nuclei. Post hoc analysis confirmed PCA findings and further revealed increased iron content in the white matter, hippocampus, and amygdala in FXTAS cases than controls after adjusting for T2-hyperintensity ratings. These findings indicate that both ischemic and hemorrhagic brain damage may occur in FXTAS, with the former marked by demyelination/iron depletion and atrophy and the latter, ICH and iron accumulation in basal ganglia.

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23. Wang R, Chaudhari P, Davatzikos C. Bias in machine learning models can be significantly mitigated by careful training: Evidence from neuroimaging studies. Proc Natl Acad Sci U S A;2023 (Feb 7);120(6):e2211613120.

Despite the great promise that machine learning has offered in many fields of medicine, it has also raised concerns about potential biases and poor generalization across genders, age distributions, races and ethnicities, hospitals, and data acquisition equipment and protocols. In the current study, and in the context of three brain diseases, we provide evidence which suggests that when properly trained, machine learning models can generalize well across diverse conditions and do not necessarily suffer from bias. Specifically, by using multistudy magnetic resonance imaging consortia for diagnosing Alzheimer’s disease, schizophrenia, and autism spectrum disorder, we find that well-trained models have a high area-under-the-curve (AUC) on subjects across different subgroups pertaining to attributes such as gender, age, racial groups and different clinical studies and are unbiased under multiple fairness metrics such as demographic parity difference, equalized odds difference, equal opportunity difference, etc. We find that models that incorporate multisource data from demographic, clinical, genetic factors, and cognitive scores are also unbiased. These models have a better predictive AUC across subgroups than those trained only with imaging features, but there are also situations when these additional features do not help.

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24. Weir EM. Autism, Physical Health Conditions, and a Need for Reform. JAMA Pediatr;2023 (Jan 30)

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25. Williams ZJ, Schaaf R, Ausderau KK, Baranek GT, Barrett DJ, Cascio CJ, Dumont RL, Eyoh EE, Failla MD, Feldman JI, Foss-Feig JH, Green HL, Green SA, He JL, Kaplan-Kahn EA, Keçeli-Kaysılı B, MacLennan K, Mailloux Z, Marco EJ, Mash LE, McKernan EP, Molholm S, Mostofsky SH, Puts NAJ, Robertson CE, Russo N, Shea N, Sideris J, Sutcliffe JS, Tavassoli T, Wallace MT, Wodka EL, Woynaroski TG. Examining the Latent Structure and Correlates of Sensory Reactivity in Autism: A Multi-site Integrative Data Analysis by the Autism Sensory Research Consortium. Res Sq;2023 (Jan 10)

Background Differences in responding to sensory stimuli, including sensory hyperreactivity (HYPER), hyporeactivity (HYPO), and sensory seeking (SEEK) have been observed in autistic individuals across sensory modalities, but few studies have examined the structure of these « supra-modal » traits in the autistic population. Methods Leveraging a combined sample of 3,868 autistic youth drawn from 12 distinct data sources (ages 3-18 years and representing the full range of cognitive ability), the current study used modern psychometric and meta-analytic techniques to interrogate the latent structure and correlates of caregiver-reported HYPER, HYPO, and SEEK within and across sensory modalities. Bifactor statistical indices were used to both evaluate the strength of a « general response pattern » factor for each supra-modal construct and determine the added value of « modality-specific response pattern » scores (e.g., Visual HYPER). Bayesian random-effects integrative data analysis models were used to examine the clinical and demographic correlates of all interpretable HYPER, HYPO and SEEK (sub)constructs. Results All modality-specific HYPER subconstructs could be reliably and validly measured, whereas certain modality-specific HYPO and SEEK subconstructs were psychometrically inadequate when measured using existing items. Bifactor analyses unambiguously supported the validity of a supra-modal HYPER construct (ω (H)  = .800), whereas a coherent supra-modal HYPO construct was not supported (ω (H)  = .611), and supra-modal SEEK models suggested a more limited version of the construct that excluded some sensory modalities (ω (H)  = .799; 4/7 modalities). Within each sensory construct, modality-specific subscales demonstrated substantial added value beyond the supra-modal score. Meta-analytic correlations varied by construct, although sensory features tended to correlate most strongly with other domains of core autism features and co-occurring psychiatric symptoms. Certain subconstructs within the HYPO and SEEK domains were also associated with lower adaptive behavior scores. Limitations: Conclusions may not be generalizable beyond the specific pool of items used in the current study, which was limited to parent-report of observable behaviors and excluded multisensory items that reflect many « real-world » sensory experiences. Conclusion Psychometric issues may limit the degree to which some measures of supra-modal HYPO/SEEK can be interpreted. Depending on the research question at hand, modality-specific response pattern scores may represent a valid alternative method of characterizing sensory reactivity in autism.

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