1. Ahmed AN, Raj SP. Self-compassion Intervention for Parents of Children with Developmental Disabilities: A Feasibility Study. Advances in neurodevelopmental disorders. 2022: 1-13.

OBJECTIVES: Parents of children with developmental disabilities (DDs) experience greater psychological distress (e.g., stress and depression) compared to parents of children without DDs. Self-compassion (i.e., responding with compassion to oneself during times of stress and difficulty) is associated with greater self-care as well as lower levels of stress, depression, and internalized stigma among parents of children with DDs. In this study, we tested the feasibility of a 4-week brief, asynchronous, online intervention targeting self-compassion among parents of children with DDs. METHODS: Participants were fifty parents (48 mothers; 2 fathers) of children with DDs. Participants’ ages ranged from 25 to 62 years (M = 42.1 years, SD = 7.9 years), and 88% of participants had one child with a DD, and the remaining parents had two or more children with DDs. Child diagnoses included Down syndrome, autism spectrum disorder, and intellectual disability. Feasibility was assessed in five domains (i.e., acceptability, demand, implementation, practicability, and limited efficacy) using a combination of self-report measures, qualitative feedback, and data on attrition. RESULTS: Most parents (84%) completed ≥ 3 modules, and 74% completed all four modules. Almost all parents (> 90%) reported that they would recommend the intervention to others. Paired-samples t-tests demonstrated significant pre-intervention to post-intervention increases in self-compassion and well-being, and significant reductions in parent depression and stress. CONCLUSIONS: Overall, data support feasibility of the 4-week intervention targeting parent self-compassion and provide preliminary efficacy data that need to be followed up in a larger randomized control trial.

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2. Alqaysi ME, Albahri AS, Hamid RA. Hybrid Diagnosis Models for Autism Patients Based on Medical and Sociodemographic Features Using Machine Learning and Multicriteria Decision-Making (MCDM) Techniques: An Evaluation and Benchmarking Framework. Computational and mathematical methods in medicine. 2022; 2022: 9410222.

METHOD: The three-phase framework integrated the MCDM and ML to develop the diagnosis models and evaluate and benchmark the best. Firstly, the new ASD-dataset-combined medical tests and sociodemographic characteristic features is identified and preprocessed. Secondly, developing the hybrid diagnosis models using the intersection process between three FS techniques and five ML algorithms introduces 15 models. The selected medical tests and sociodemographic features from each FS technique are weighted before feeding the five ML algorithms using the fuzzy-weighted zero-inconsistency (FWZIC) method based on four psychiatry experts. Thirdly, (i) formulate a dynamic decision matrix for all developed models based on seven evaluation metrics, including classification accuracy, precision, F1 score, recall, test time, train time, and AUC. (ii) The fuzzy decision by opinion score method (FDOSM) is used to evaluate and benchmark the 15 models concerning the seven evaluation metrics. RESULTS: Results reveal that (i) the three FS techniques have obtained a size different from the others in the number of the selected features; the sets were 39, 38, and 41 out of 48 features. Each set has its weights constructed by FWIZC. Considered sociodemographic features have been mostly selected more than medical tests within FS techniques. (ii) The first three best hybrid models were « ReF-decision tree, » « IG-decision tree, » and « Chi(2)-decision tree, » with score values 0.15714, 0.17539, and 0.29444. The best diagnosis model (ReF-decision tree) has obtained 0.4190, 0.0030, 0.9946, 0.9902, 0.9902, 0.9902, 0.9902, and 0.9951 for the C1=train time, C2=test time, C3=AUC, C4=CA, C5=F1 score, C6=precision, and C7=recall, respectively. The developed framework would be beneficial in advancing, accelerating, and selecting diagnosis tools in therapy with ASD. The selected model can identify severity as light, medium, or intense based on medical tests and sociodemographic weighted features.

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3. Brandenburg C, Griswold AJ, Van Booven DJ, Kilander MBC, Frei JA, Nestor MW, Dykxhoorn DM, Pericak-Vance MA, Blatt GJ. Transcriptomic analysis of isolated and pooled human postmortem cerebellar Purkinje cells in autism spectrum disorders. Frontiers in genetics. 2022; 13: 944837.

At present, the neuronal mechanisms underlying the diagnosis of autism spectrum disorder (ASD) have not been established. However, studies from human postmortem ASD brains have consistently revealed disruptions in cerebellar circuitry, specifically reductions in Purkinje cell (PC) number and size. Alterations in cerebellar circuitry would have important implications for information processing within the cerebellum and affect a wide range of human motor and non-motor behaviors. Laser capture microdissection was performed to obtain pure PC populations from a cohort of postmortem control and ASD cases and transcriptional profiles were compared. The 427 differentially expressed genes were enriched for gene ontology biological processes related to developmental organization/connectivity, extracellular matrix organization, calcium ion response, immune function and PC signaling alterations. Given the complexity of PCs and their far-ranging roles in response to sensory stimuli and motor function regulation, understanding transcriptional differences in this subset of cerebellar cells in ASD may inform on convergent pathways that impact neuronal function.

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4. Bury SM, Haschek A, Wenzel M, Spoor JR, Hedley D. Brief Report: Learning About Autism: Is the Source of Autism Knowledge Associated with Differences in Autism Knowledge, Autism Identity, and Experiences of Stigma. Journal of autism and developmental disorders. 2022.

People on the autism spectrum can learn about autism from various sources, likely differing in the information, portrayal, and discussion they offer. The present study investigates where autistic people learn about autism, and whether their information source is associated with their level of autism knowledge, perceptions of stigma, and development and expression of an autism identity. A survey of 198 Australian adults with an autism diagnosis showed that learning about autism from conventional sources (e.g., professionals, parents) was associated with more internalised stigma, lower endorsement of special abilities and autism identity, whereas online blogs and social media showed the opposite pattern as well as more accurate knowledge of autism. The findings raise questions about how authoritative sources of information discuss autism.

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5. Camasio A, Panzeri E, Mancuso L, Costa T, Manuello J, Ferraro M, Duca S, Cauda F, Liloia D. Linking neuroanatomical abnormalities in autism spectrum disorder with gene expression of candidate ASD genes: A meta-analytic and network-oriented approach. PloS one. 2022; 17(11): e0277466.

BACKGROUND: Autism spectrum disorder (ASD) is a set of developmental conditions with widespread neuroanatomical abnormalities and a strong genetic basis. Although neuroimaging studies have indicated anatomical changes in grey matter (GM) morphometry, their associations with gene expression remain elusive. METHODS: Here, we aim to understand how gene expression correlates with neuroanatomical atypicalities in ASD. To do so, we performed a coordinate-based meta-analysis to determine the common GM variation pattern in the autistic brain. From the Allen Human Brain Atlas, we selected eight genes from the SHANK, NRXN, NLGN family and MECP2, which have been implicated with ASD, particularly in regards to altered synaptic transmission and plasticity. The gene expression maps for each gene were built. We then assessed the correlation between the gene expression maps and the GM alteration maps. Lastly, we projected the obtained clusters of GM alteration-gene correlations on top of the canonical resting state networks, in order to provide a functional characterization of the structural evidence. RESULTS: We found that gene expression of most genes correlated with GM alteration (both increase and decrease) in regions located in the default mode network. Decreased GM was also correlated with gene expression of some ASD genes in areas associated with the dorsal attention and cerebellar network. Lastly, single genes were found to be significantly correlated with increased GM in areas located in the somatomotor, limbic and ganglia/thalamus networks. CONCLUSIONS: This approach allowed us to combine the well beaten path of genetic and brain imaging in a novel way, to specifically investigate the relation between gene expression and brain with structural damage, and individuate genes of potential interest for further investigation in the functional domain.

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6. Conner C, Henry AR, Solari EJ, Zajic MC. Conducting oral and written language adapted tele-assessments with early elementary-age children with autism spectrum disorder. Autism & developmental language impairments. 2022; 7: 23969415221133268.

BACKGROUND AND AIMS: Due to the COVID-19 pandemic, tele-health has gained popularity for both providing services and delivering assessments to children with disabilities. In this manuscript, we discuss the process of collecting standardized oral language, reading, and writing tele-assessment data with early elementary children with autism spectrum disorder (ASD) and offer preliminary findings related to child and parent engagement and technology issues. METHODS: The data presented are from pretest assessments during an efficacy study examining the electronic delivery of a listening comprehension intervention for children with ASD. Pretest sessions included a battery of standardized language, reading, and writing assessments, conducted over Zoom. The authors operationalized and developed a behavioral codebook of three overarching behavioral categories (parent involvement, child disengagement, and technology issues). Researchers coded videos offline to record frequencies of indicated behaviors across participants and assessment subtests. RESULTS: Involvement from parents accounted for the highest number of codes. Children showed some disengagement during assessment sessions. Technology issues were minimal. Behavioral categories appeared overall limited but varied across participants and assessments. CONCLUSIONS: Parent involvement behaviors made up approximately two-thirds of the coded behaviors. Child disengagement behaviors made up approximately one-fourth of the coded behaviors, and these behaviors occurred more frequently across many different participants (with lower frequencies but greater coverage across children). Technology problems specific to responding to assessment items were relatively uncommon. IMPLICATIONS: Clear guidelines including assessment preparation, modification of directions, and guidelines for parents who remain present are among the implications discussed. We also provide practical implications for continued successful adapted tele-assessments for children with ASD.

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7. Deng X, Zhang J, Liu R, Liu K. Classifying ASD based on time-series fMRI using spatial-temporal transformer. Computers in biology and medicine. 2022; 151(Pt B): 106320.

As the prevalence of autism spectrum disorder (ASD) increases globally, more and more patients need to receive timely diagnosis and treatment to alleviate their suffering. However, the current diagnosis method of ASD still adopts the subjective symptom-based criteria through clinical observation, which is time-consuming and costly. In recent years, functional magnetic resonance imaging (fMRI) neuroimaging techniques have emerged to facilitate the identification of potential biomarkers for diagnosing ASD. In this study, we developed a deep learning framework named spatial-temporal Transformer (ST-Transformer) to distinguish ASD subjects from typical controls based on fMRI data. Specifically, a linear spatial-temporal multi-headed attention unit is proposed to obtain the spatial and temporal representation of fMRI data. Moreover, a Gaussian GAN-based data balancing method is introduced to solve the data unbalance problem in real-world ASD datasets for subtype ASD diagnosis. Our proposed ST-Transformer is evaluated on a large cohort of subjects from two independent datasets (ABIDE I and ABIDE II) and achieves robust accuracies of 71.0% and 70.6%, respectively. Compared with state-of-the-art methods, our results demonstrate competitive performance in ASD diagnosis.

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8. DeVeney SL, Kyvelidou A, Mather P. A home-based longitudinal study of vocalization behaviors across infants at low and elevated risk of autism. Autism & developmental language impairments. 2021; 6: 23969415211057658.

BACKGROUND AND AIMS: The purpose of this exploratory study was to expand existing literature on prelinguistic vocalizations by reporting results of the first home-based longitudinal study examining a wide variety of behaviors and characteristics, including early vocalizations, across infants at low and elevated risk of autism spectrum disorder (ASD). The study of vocalizations and vocalization changes across early developmental periods shows promise in reflecting early clinically significant differences across infants at low and elevated risk of ASD. Observations of early vocalizations and their differences during infancy could provide a reliable and essential component of an early developmental profile that would lower the average diagnostic age for ASD. However, studies employing observation of vocalization behaviors have been limited and often conducted in laboratory settings, reducing the external generalization of the findings. METHODS: The present study was conducted to determine the consistency of previous findings with longitudinal data collected in home environments. Infants in the present study represented elevated risk from two etiological backgrounds, (a) infants born prematurely and with low birth weight and (b) infants who had an older sibling diagnosed with ASD. All data were collected in the infants’ homes and compared with data collected from infants with low likelihood of ASD. The study included 44 participants (31 in the low-risk sample, 13 in the high-risk sample) with vocalization behaviors observed at 6- and 12-months through 20-min semi-structured play interactions with caregivers. Observations were video-recorded and later coded for speech and non-speech vocalizations. RESULTS: Differences in the 6-month vocalization behaviors were not statistically significant across risk levels of ASD. By 12 months; however, risk group differences were evident in the total number of vocalizations overall with specific differences across groups representing moderate to large, clinically relevant effects. Infants at low risk of ASD demonstrated significantly greater developmental change between 6- and 12-months than did the infants at high risk. Data were also reviewed for differences across high-risk group etiologies. CONCLUSIONS: The present study was unique and innovative in a number of ways as the first home-based longitudinal study examining infant vocal behaviors across low and high risk of ASD. Many of the present study findings were consistent with previous cross-sectional investigations of infants at elevated risk for ASD, indicating support for further home-based longitudinal study in this area. Findings also indicated some preliminary subgroup differences between high-risk etiologies of ASD. Vocalization differences across high risk groups had not been previously addressed in the literature. IMPLICATIONS: Vocalization differences are notable by 12-months of age between infants at low and elevated risk of ASD and infants at high risk demonstrated reduced developmental changes between 6- and 12-months compared to the infants at low risk. Observation of early infant vocalization behaviors may reasonably occur in the home, providing early childhood professionals and researchers with empirical support for data collection of child-caregiver interactions in this setting. Potential differences across high-risk etiologies warrant further investigation.

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9. Duan L, Liu J, Yin H, Wang W, Liu L, Shen J, Wang Z. Dynamic changes in spatiotemporal transcriptome reveal maternal immune dysregulation of autism spectrum disorder. Computers in biology and medicine. 2022; 151(Pt B): 106334.

Maternal immune activation (MIA) during pregnancy is known to be an environmental risk factor for neurodevelopment and autism spectrum disorder (ASD). However, it is unclear at which fetal brain developmental windows and regions MIA induces ASD-related neurodevelopmental transcriptional abnormalities. The non-chasm differentially expressed genes (DEGs) involved in MIA inducing ASD during fetal brain developmental windows were identified by performing the differential expression analysis and comparing the common DEGs among MIA at four different gestational development windows, ASD with multiple brain regions from human patients and mouse models, and human and mouse embryonic brain developmental trajectory. The gene set and functional enrichment analyses were performing to identify MIA dysregulated ASD-related the fetal neurodevelopmental windows and brain regions and function annotations. Additionally, the networks were constructed using Cytoscape for visualization. MIA at E12.5 and E14.5 increased the risk of distinct brain regions for ASD. MIA-driven transcriptional alterations of non-chasm DEGs, during the coincidence brain developmental windows between human and mice, involving ASD-relevant synaptic components, as well as immune- and metabolism-related functions and pathways. Furthermore, a great number of non-chasm brain development-, immune-, and metabolism-related DEGs were overlapped in at least two existing ASD-associated databases, suggesting that the others could be considered as the candidate targets to construct the model mice for explaining the pathological changes of ASD when environmental factors (MIA) and gene mutation effects co-occur. Overall, our search supported that transcriptome-based MIA dysregulated the brain development-, immune-, and metabolism-related non-chasm DEGs at specific embryonic brain developmental window and region, leading to abnormal embryonic neurodevelopment, to induce the increasing risk of ASD.

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10. Eapen V, Winata T, Gilbert M, Nair R, Khan F, Lucien A, Islam R, Masi A, Lam-Cassettari C, Mendoza Diaz A, Dissanayake C, Karlov L, Descallar J, Eastwood J, Hasan I, Jalaludin B, Kohlhoff J, Liaw ST, Lingam R, Ong N, Tam CWM, Woolfenden S, Barbaro J. Parental experience of an early developmental surveillance programme for autism within Australian general practice: a qualitative study. BMJ open. 2022; 12(11): e064375.

OBJECTIVES: Implementing support and services early in the life course has been shown to promote positive developmental outcomes for children at high likelihood of developmental conditions including autism. This study examined parents’/caregivers’ experiences and perceptions about a digital developmental surveillance pathway for autism, the autism surveillance pathway (ASP), and usual care, the surveillance as usual (SaU) pathway, in the primary healthcare general practice setting. DESIGN: This qualitative study involves using a convenience selection process of the full sample of parents/caregivers that participated in the main programme, ‘General Practice Surveillance for Autism’, a cluster-randomised controlled trial study. All interviews were audio-recorded, transcribed and coded using NVivo V.12 software. An inductive thematic interpretive approach was adopted and data were analysed thematically. PARTICIPANTS: Twelve parents/caregivers of children with or without a developmental condition/autism (who participated in the main programme) in South Western Sydney and Melbourne were interviewed. SETTINGS: All interviews were completed over the phone. RESULTS: There were seven major themes and 20 subthemes that included positive experiences, such as pre-existing patient-doctor relationships and their perceptions on the importance of knowing and accessing early support/services. Barriers or challenges experienced while using the SaU pathway included long waiting periods, poor communication and lack of action plans, complexity associated with navigating the healthcare system and lack of understanding by general practitioners (GPs). Common suggestions for improvement included greater awareness/education for parents/carers and the availability of accessible resources on child development for parents/caregivers. CONCLUSION: The findings support the use of digital screening tools for developmental surveillance, including for autism, using opportunistic contacts in the general practice setting. TRIAL REGISTRATION NUMBER: ANZCTR (ACTRN12619001200178).

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11. Feldman JI, Garla V, Dunham K, Markfeld JE, Bowman SM, Golden AJ, Daly C, Kaiser S, Mailapur N, Raj S, Santapuram P, Suzman E, Augustine AE, Muhumuza A, Cascio CJ, Williams KL, Kirby AV, Keceli-Kaysili B, Woynaroski TG. Longitudinal Relations Between Early Sensory Responsiveness and Later Communication in Infants with Autistic and Non-autistic Siblings. Journal of autism and developmental disorders. 2022: 1-13.

Early differences in sensory responsiveness may contribute to difficulties with communication among autistic children; however, this theory has not been longitudinally assessed in infants at increased familial versus general population-level likelihood for autism (Sibs-autism vs. Sibs-NA) using a comprehensive battery of sensory responsiveness and communication. In a sample of 40 infants (20 Sibs-autism, of whom six were later diagnosed with autism; 20 Sibs-NA), we tested (a) associations between sensory responsiveness at 12-18 months and communication 9 months later and (b) evaluated whether such associations were moderated by sibling group, autism diagnosis, or age. We found negative zero-order correlations between sensory responsiveness (i.e., caregiver reported hyperresponsiveness and hyporesponsiveness; an observational measure of hyperresponsiveness) and later communication. Additionally, caregiver reported sensory seeking was negatively associated with later expressive communication only in Sibs-NA. Limitations include our relatively small sample size of infants diagnosed with autism. Implications for future research are discussed.

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12. Francis G, Deniz E, Torgerson C, Toseeb U. Play-based interventions for mental health: A systematic review and meta-analysis focused on children and adolescents with autism spectrum disorder and developmental language disorder. Autism & developmental language impairments. 2022; 7: 23969415211073118.

BACKGROUND AND AIMS: Play-based interventions are used ubiquitously with children with social, communication, and language needs but the impact of these interventions on the mental health of this group of children is unknown. Despite their pre-existing challenges, the mental health of children with developmental language disorder (DLD) and autism spectrum disorder (ASD) should be given equal consideration to the other more salient features of their condition. To this aim, a systematic literature review with meta-analysis was undertaken to assess the impact of play-based interventions on mental health outcomes from studies of children with DLD and ASD, as well as to identify the characteristics of research in this field. METHODS: The study used full systematic review design reported to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines (PRISMA prisma-statement.org) with pre-specified inclusion criteria and explicit, transparent and replicable methods at each stage of the review. The study selection process involved a rigorous systematic search of seven academic databases, double screening of abstracts, and full-text screening to identify studies using randomised controlled trial (RCT) and quasi-experimental (QE) designs to assess mental health outcomes from interventions supporting children with DLD and ASD. For reliability, data extraction of included studies, as well as risk of bias assessments were conducted by two study authors. Qualitative data were synthesised narratively and quantified data were used in the metaanalytic calculation. MAIN CONTRIBUTION: A total of 2,882 papers were identified from the literature search which were double screened at the abstract (n  =  1,785) and full-text (n  =  366) levels resulting in 10 papers meeting the criteria for inclusion in the review. There were 8 RCTs and 2 QEs using 7 named play-based interventions with ASD participants only. Meta-analysis of 5 studies addressing positive mental health outcomes (e.g. positive affect and emotional functioning) found a significant overall intervention effect (Cohen’s d = 1.60 (95% CI [0.37, 2.82], p = 0.01); meta-analysis of 6 studies addressing negative mental health outcomes (e.g., negative affect, internalising and externalising problems) found a non-significant overall intervention effect (Cohen’s d = 0.04 -0.17 (95% CI [-0.04, 0.51], p = 0.88). CONCLUSIONS: A key observation is the diversity of study characteristics relating to study sample size, duration of interventions, study settings, background of interventionists, and variability of specific mental health outcomes. Play-based interventions appear to have a beneficial effect on positive, but not negative, mental health in children with ASD. There are no high quality studies investigating the efficacy of such interventions in children with DLD. IMPLICATIONS: This review provides good evidence of the need for further research into how commonly used play-based interventions designed to support the social, communication, and language needs of young people may impact the mental health of children with ASD or DLD.

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13. Guan Q, Men S, Lunsky Y, Juurlink DN, Bronskill SE, Wunsch H, Gomes T. New opioid use and risk of opioid-related adverse events among adults with intellectual and developmental disabilities in Ontario, Canada. BJPsych open. 2022; 8(6): e208.

BACKGROUND: Individuals with intellectual and developmental disability (IDD) can have a high prevalence of pain, which can be managed with prescription opioids. However, the prevalence of substance use disorder is also high in this population, raising concern about opioid-related adverse events. AIMS: To assess the risk of opioid-related adverse events following opioid initiation among adults with versus without IDD. METHOD: We conducted a population-based, propensity score matched cohort study on all adults starting prescription opioid therapy in Ontario, Canada, between January 2013 and December 2018. The outcomes of interest were opioid toxicity, new opioid use disorder (OUD) diagnosis and dose escalation (≥90 mg morphine or equivalent) in the year after opioid initiation. We used Cox proportional hazards models to assess the association between IDD diagnosis and each outcome. RESULTS: The hazards of opioid toxicity and OUD were significantly higher in those with IDD compared with those without IDD in unmatched analyses (opioid toxicity hazard ratio 3.19, 95% CI 2.81-5.18; OUD hazard ratio 2.36, 95% CI 2.10-2.65), whereas the hazard of dose escalation was significantly lower (hazard ratio 0.76, 95% CI 0.66-0.88). Findings were no longer significant in propensity score matched models for opioid toxicity and dose escalation, whereas the hazard of OUD diagnosis was attenuated substantially in those with IDD (hazard ratio 0.79, 95% CI 0.68-0.91). CONCLUSIONS: IDD diagnosis is not a driver of opioid-related harm. The increased risk we observed is likely driven by various risk factors often present in this population.

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14. Kaufmann WE, Raspa M, Bann CM, Gable JM, Harris HK, Budimirovic DB, Lozano R. Latent Class Analysis Identifies Distinctive Behavioral Subtypes in Children with Fragile X Syndrome. Journal of autism and developmental disorders. 2022.

Fragile X syndrome (FXS) is characterized by variable neurobehavioral abnormalities, which leads to difficulties in developing and evaluating treatments and in determining accurate prognosis. We employed a pediatric cross-sectional sample (1,072 males, 338 females) from FORWARD, a clinic-based natural history study, to identify behavioral subtypes by latent class analysis. Input included co-occurring behavioral conditions, sleep and sensory problems, autistic behavior scales (SCQ, SRS-2), and the Aberrant Behavior Checklist revised for FXS (ABC(FX)). A 5-class solution yielded the most clinically meaningful, pharmacotherapy independent behavioral groups with distinctive SCQ, SRS-2, and ABC(FX) profiles, and adequate non-overlap (≥ 71%): « Mild » (31%), « Moderate without Social Impairment » (32%), « Moderate with Social Impairment » (7%), « Moderate with Disruptive Behavior » (20%), and « Severe » (9%). Our findings support FXS subtyping, for improving clinical management and therapeutic development.

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15. Krishnamurthy K, Chan MMY, Han YMY. Neural substrates underlying effortful control deficit in autism spectrum disorder: a meta-analysis of fMRI studies. Scientific reports. 2022; 12(1): 20603.

Effortful control comprises attentional control, inhibitory control, and cognitive flexibility subprocesses. Effortful control is impaired in individuals with autism spectrum disorder, yet its neural underpinnings remain elusive. By conducting a coordinate-based meta-analysis, this study compared the brain activation patterns between autism and typically developing individuals and examined the effect of age on brain activation in each effortful control subprocesses. Meta-analytic results from 22 studies revealed that, individuals with autism showed hypoactivation in the default mode network for tasks tapping inhibitory control functioning (threshold-free cluster enhancement p < 0.001). When these individuals perform tasks tapping attentional control and cognitive flexibility, they exhibited aberrant activation in various brain networks including default mode network, dorsal attention, frontoparietal, visual and somatomotor networks (uncorrected ps < 0.005). Meta-regression analyses revealed that brain regions within the default mode network showed a significant decreasing trend in activation with increasing age (uncorrected p < 0.05). In summary, individuals with autism showed aberrant activation patterns across multiple brain functional networks during all cognitive tasks supporting effortful control, with some regions showing a decrease in activation with increasing age.

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16. Li Z, Hutchings-Hay C, Byford S, Tchanturia K. How to support adults with anorexia nervosa and autism: Qualitative study of clinical pathway case series. Frontiers in psychiatry. 2022; 13: 1016287.

INTRODUCTION: Previous research has explored the overlapping presentation between autism and eating disorders (ED). This study aims to summarize the clinical challenges associated with co-occurring autism and anorexia nervosa (AN) based on clinicians’ case notes and minutes from case discussions, to understand how to better support people with the comorbidity. METHOD: Thematic analysis was conducted on de-identified notes on 20 cases with AN and autistic characteristics and minutes from case discussions. Themes relevant to clinical challenges in supporting those with the comorbidity were identified, and a thematic map was produced to visually represent the results. RESULTS: The key challenges faced by clinicians when treating patients with AN and autism included: communication difficulties, maintaining boundaries, autism screening, presence of other comorbidities, sensory difficulties, atypical presentation of eating difficulties, cognitive rigidity, and emotional difficulties. Adaptations to resolve some of these difficulties included exposure-based food experiments, keeping a record of patients’ self-reported communication preferences, individual-level modification of communication style, and providing tools for patients to identify emotions. CONCLUSIONS AND IMPLICATIONS: Further exploration to establish the effectiveness of the adaptations is warranted. Furthermore, tools for differentiating between ED, autism and other comorbidities are needed to help clinicians clarify the cause of a presenting symptom, and help them to best support and maintain boundaries with patients.

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17. Liu A, Cai C, Wang Z, Wang B, He J, Xie Y, Deng H, Liu S, Zeng S, Yin Z, Wang M. Inductively coupled plasma mass spectrometry based urine metallome to construct clinical decision models for autism spectrum disorder. Metallomics : integrated biometal science. 2022.

BACKGROUND: The global prevalence of autism spectrum disorder (ASD) is on the rise, and high levels of exposure to toxic heavy metals may be associated with this increase. Urine analysis is a noninvasive method for investigating the accumulation and excretion of heavy metals. The aim of this study was to identify ASD-associated urinary metal markers. METHODS: Overall, 70 children with ASD and 71 children with typical development (TD) were enrolled in this retrospective case-control study. In this metallomics investigation, inductively coupled plasma mass spectrometry was performed to obtain the urine profile of 27 metals. RESULTS: Children with ASD could be distinguished from children with TD based on the urine metal profile, with ASD children showing an increased urine metal Shannon diversity. A metallome-wide association analysis was used to identify seven ASD-related metals in urine, with cobalt, aluminum, selenium, and lithium significantly higher, and manganese, mercury, and titanium significantly lower in the urine of children with ASD than in children with TD. The least absolute shrinkage and selection operator (LASSO) machine learning method was used to rank the seven urine metals in terms of their effect on ASD. On the basis of these seven urine metals, we constructed a LASSO regression model for ASD classification and found an area under the receiver operating characteristic curve of 0.913. We also constructed a clinical prediction model for ASD based on the seven metals that were different in the urine of children with ASD and found that the model would be useful for the clinical prediction of ASD risk. CONCLUSIONS: The study findings suggest that altered urine metal concentrations may be an important risk factor for ASD, and we recommend further exploration of the mechanisms and clinical treatment measures for such alterations.

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18. Mathée-Scott J, Ellis Weismer S. Naturalistic parent-child reading frequency and language development in toddlers with and without autism. Autism & developmental language impairments. 2022; 7: 23969415221136740.

BACKGROUND AND AIMS: The efficacy of parent-child reading for supporting language development has been well-established in the neurotypical (NT) literature. For children with autism spectrum disorder, (ASD) who may be at risk for delays in language development, prior research has shown promise for shared book-reading interventions. Yet there has been limited research on naturalistic parent-child reading with autistic children to date. The present study aimed to fill this missing link in the current literature. METHODS: Fifty-seven autistic toddlers participated at two developmental time points: Time 1 (Mage = 30.4 months) and Time 2 (Mage = 43.8 months). An NT control group (N = 31) was matched on age to a subset of the ASD group (N = 33). We assessed group differences in parent-child reading frequency between age-matched NT and autistic groups. Using a one-year follow-up design, we evaluated the relationship between parent-child reading and autistic children’s language development. RESULTS: Cross-group comparisons revealed that parents of age-matched NT children reported significantly more frequent weekly parent-child reading than parents of autistic toddlers. After a one-year follow-up with the autistic group, within-group analyses revealed that greater frequency of parent-child reading (controlling for maternal education, books in the home, and autism symptom severity) was associated with larger growth in autistic toddlers’ receptive and expressive language skills. CONCLUSIONS AND IMPLICATIONS: These findings have important clinical implications as they emphasize the potential of parent-child reading for supporting autistic children’s language development. Findings demonstrate that frequency of parent-child reading is associated with language development over one year. Findings also demonstrate that parents of autistic children engage in less frequent parent-child reading than parents of age-matched NT peers, suggesting these parents may face more barriers to implementing parent-child reading than parents of NT children.

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19. Mattie LJ, Hamrick LR. Early communication development in infants and toddlers with Fragile X syndrome. Autism & developmental language impairments. 2022; 7: 23969415221099403.

BACKGROUND AND AIMS: Individuals with fragile X syndrome (FXS) characteristically struggle with language and communication throughout the life course, but there is limited research on the development of communication before 24 months. The purpose of this study is to describe the early communication of infants and toddlers with FXS using the Communication and Symbolic Behavior Scales-Caregiver Questionnaire (CSBS-CQ), a standardized communication screening measure, as compared to the reported normative data of the CSBS-CQ and identify the percentage of infants and toddlers who scored within the range of concern. Documenting how children with FXS perform on screening measures can provide a quick snapshot of skills to help clinicians determine the need for services. METHODS: Participants were 22 infants and toddlers with FXS between 6 and 29 months. Performance on the CSBS-CQ was compared to the measure’s normative data. The CSBS-CQ was completed by mothers, and children were administered the Mullen Scales of Early Learning. Because co-occurring autism is common in FXS, the presence of autism was determined using a clinical best estimate procedure. RESULTS: Overall and within the domains and subdomains of the CSBS-CQ, infants and toddlers with FXS had significantly lower scores than the normative data. Further, 68.2% of our sample was in the range of concern for their overall communication score. The presence of autism led to consistently lower scores, and more infants and toddlers with FXS + autism scored within the range of concern. CONCLUSIONS: Our findings suggest that delays in early communication are evident in comparison to typically developing norms before 24 months. These findings also emphasize that infants and toddlers with FXS would likely benefit from early language intervention given that 68.2% of our sample was in the range of concern for their overall communication score. IMPLICATIONS: Early identification and developmental monitoring of children with FXS will help to determine concerns in communication and other domains of development. While early communication broadly may not be an early indicator of autism in FXS, some specific skills, such as eye gaze, may serve as such an indicator. Screening measures, like the CSBS-CQ, may help monitor both early communication impairments and autism symptoms. Infants and toddlers with FXS, regardless of autism status, will benefit from early language interventions.

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20. Oudet S, Howard K, Durrleman S. Early years autism and bilingualism: An interpretative phenomenological analysis of parent perceptions during lockdown. Autism & developmental language impairments. 2022; 7: 23969415221138704.

AIM: This study explores how bilingual parents of autistic children made language decisions for their families, how the event of the SARS-CoV-2 pandemic and subsequent lockdown impacted the communication environment of their households, and whether these experiences affected their language habits. METHOD: Semi-structured interviews were conducted with five bilingual parents of autistic children who lived through lockdown in France. Data were analysed using interpretative phenomenological analysis. Demographic and background information was collected using an adapted version of the Questionnaire for Parents of Bilingual Children. RESULTS: Participants reported conflicting advice given by a range of practitioners. Parents expressed differing beliefs about the impact of language choices on their children. Parents described active engagement with their children’s home-learning as generally positive. Parents identified an increase in children’s exposure to their first language during the lockdown. Parents reported an increase in children’s overall communication abilities. CONCLUSION: Parents believed that their children’s positive communication development during lockdown was related to increased exposure to their first language(s), and direct involvement in their children’s learning programs.

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21. Perinelli MG, Cloherty M. Identification of autism in cognitively able adults with epilepsy: A narrative review and discussion of available screening and diagnostic tools. Seizure. 2022; 104: 6-11.

The recent NICE epilepsy Guideline (NG217; 2022) recommends that epilepsy professionals need to be alert to autism when considering mental health presentations, behavioural difficulties and as a marker for referral for whole genome sequencing for those patients with epilepsy of unknown cause. However, this relies upon the existence of valid autism screens for people with epilepsy (PWE). We found few studies of autism in cognitively able PWE. This represents an important gap in the literature. We describe different autism screening and diagnostic tools; two screening tools have been used specifically for adult PWE who are cognitively able (AQ, SRS-AS). The AQ is more psychometrically robust, but there may be an overlap between these screening questions and questions relevant to some psychiatric disorders. Formal gold-standard diagnostic tools (module 4 of ADOS-2, ADI-R or 3Di or 3Di-Adult) would benefit from studies of their application to cognitively able PWE. More research is needed to understand the characteristics of autism in cognitively able PWE and to ascertain the appropriate screening and diagnostic tools for this cohort.

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22. Price KM, Wigg KG, Eising E, Feng Y, Blokland K, Wilkinson M, Kerr EN, Guger SL, Fisher SE, Lovett MW, Strug LJ, Barr CL. Hypothesis-driven genome-wide association studies provide novel insights into genetics of reading disabilities. Translational psychiatry. 2022; 12(1): 495.

Reading Disability (RD) is often characterized by difficulties in the phonology of the language. While the molecular mechanisms underlying it are largely undetermined, loci are being revealed by genome-wide association studies (GWAS). In a previous GWAS for word reading (Price, 2020), we observed that top single-nucleotide polymorphisms (SNPs) were located near to or in genes involved in neuronal migration/axon guidance (NM/AG) or loci implicated in autism spectrum disorder (ASD). A prominent theory of RD etiology posits that it involves disturbed neuronal migration, while potential links between RD-ASD have not been extensively investigated. To improve power to identify associated loci, we up-weighted variants involved in NM/AG or ASD, separately, and performed a new Hypothesis-Driven (HD)-GWAS. The approach was applied to a Toronto RD sample and a meta-analysis of the GenLang Consortium. For the Toronto sample (n = 624), no SNPs reached significance; however, by gene-set analysis, the joint contribution of ASD-related genes passed the threshold (p~1.45 × 10(-2), threshold = 2.5 × 10(-2)). For the GenLang Cohort (n = 26,558), SNPs in DOCK7 and CDH4 showed significant association for the NM/AG hypothesis (sFDR q = 1.02 × 10(-2)). To make the GenLang dataset more similar to Toronto, we repeated the analysis restricting to samples selected for reading/language deficits (n = 4152). In this GenLang selected subset, we found significant association for a locus intergenic between BTG3-C21orf91 for both hypotheses (sFDR q < 9.00 × 10(-4)). This study contributes candidate loci to the genetics of word reading. Data also suggest that, although different variants may be involved, alleles implicated in ASD risk may be found in the same genes as those implicated in word reading. This finding is limited to the Toronto sample suggesting that ascertainment influences genetic associations.

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23. Saure E, Castrén M, Mikkola K, Salmi J. Intellectual disabilities moderate sex/gender differences in autism spectrum disorder: a systematic review and meta-analysis. Journal of intellectual disability research : JIDR. 2022.

BACKGROUND: Girls/women with autism spectrum disorder (ASD) are suggested to exhibit different symptom profiles than boys/men with ASD. Accumulating evidence suggests that intellectual disability (ID) may affect sex/gender differences in ASD. However, a systematic review and meta-analysis on this topic is missing. METHODS: Two databases (MEDLINE and PsycINFO) were used to search for studies reporting sex/gender differences (girls/women versus boys/men) in social communication and interaction, restrictive and repetitive behaviour and interests (RRBIs), sensory processing, and linguistic and motor abilities in ASD. The final sample consisted of 79 studies. The meta-analysis was performed with Review Manager using a random-effects model. Participants with ASD without and with ID were analysed as separate subgroups, and the effects in these two subgroups were also compared with each other. RESULTS: Girls/women with ASD without ID displayed fewer RRBIs, more sensory symptoms and less problems in linguistic abilities than their boys/men counterparts. In contrast, girls/women with ASD with ID displayed more social difficulties and RRBIs, poorer linguistic abilities and more motor problems than boys/men with ASD with ID. Comparisons of groups of participants with ASD without ID versus participants with ASD with ID confirmed differences in sex/gender effects on social difficulties, sensory processing, linguistic abilities and motor abilities. CONCLUSIONS: Our results clearly suggest that the female phenotype of ASD is moderated by ID. Among individuals with ASD with ID, girls/women seem to be more severely affected than boys/men, whereas among individuals with ASD without ID, girls/women with ASD may have less symptoms than boys/men. Such phenotypic differences could be a potential cause of underrecognition of girls/women with ASD, and it is also possible that observed phenotypic differences may reflect underdiagnosing of girls/women with ASD.

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24. Skjegstad CL, Trevor C, Swanborough H, Roswandowitz C, Mokros A, Habermeyer E, Frühholz S. Psychopathic and autistic traits differentially influence the neural mechanisms of social cognition from communication signals. Translational psychiatry. 2022; 12(1): 494.

Psychopathy is associated with severe deviations in social behavior and cognition. While previous research described such cognitive and neural alterations in the processing of rather specific social information from human expressions, some open questions remain concerning central and differential neurocognitive deficits underlying psychopathic behavior. Here we investigated three rather unexplored factors to explain these deficits, first, by assessing psychopathy subtypes in social cognition, second, by investigating the discrimination of social communication sounds (speech, non-speech) from other non-social sounds, and third, by determining the neural overlap in social cognition impairments with autistic traits, given potential common deficits in the processing of communicative voice signals. The study was exploratory with a focus on how psychopathic and autistic traits differentially influence the function of social cognitive and affective brain networks in response to social voice stimuli. We used a parametric data analysis approach from a sample of 113 participants (47 male, 66 female) with ages ranging between 18 and 40 years (mean 25.59, SD 4.79). Our data revealed four important findings. First, we found a phenotypical overlap between secondary but not primary psychopathy with autistic traits. Second, primary psychopathy showed various neural deficits in neural voice processing nodes (speech, non-speech voices) and in brain systems for social cognition (mirroring, mentalizing, empathy, emotional contagion). Primary psychopathy also showed deficits in the basal ganglia (BG) system that seems specific to the social decoding of communicative voice signals. Third, neural deviations in secondary psychopathy were restricted to social mirroring and mentalizing impairments, but with additional and so far undescribed deficits at the level of auditory sensory processing, potentially concerning deficits in ventral auditory stream mechanisms (auditory object identification). Fourth, high autistic traits also revealed neural deviations in sensory cortices, but rather in the dorsal auditory processing streams (communicative context encoding). Taken together, social cognition of voice signals shows considerable deviations in psychopathy, with differential and newly described deficits in the BG system in primary psychopathy and at the neural level of sensory processing in secondary psychopathy. These deficits seem especially triggered during the social cognition from vocal communication signals.

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25. Slušná D, Rodríguez A, Salvadó B, Vicente A, Hinzen W. Relations between language, non-verbal cognition, and conceptualization in non- or minimally verbal individuals with ASD across the lifespan. Autism & developmental language impairments. 2021; 6: 23969415211053264.

BACKGROUND & AIMS: Individuals with non- or minimally verbal autism (nvASD) are primarily characterized by a severe speech production deficit, with speech limited to no or only a few words by school age. Significant unclarity remains over variability in language profiles across the lifespan, the nature of the language impairment seen, and (dis-) associations between linguistic and nonverbal cognitive measures. METHODS: To address these questions, we recruited both a school-age and an adult group with nvASD (total N = 49) and investigated relations between expressive and receptive language, and between these and nonverbal intelligence quotient (NVIQ) and sense-making capacities (the ComFor test). RESULTS: Results revealed limited variation across this sample in receptive language, which in turn predicted expressive language levels. Importantly, an upward trend in verbal mental age (VMA) across increasing chronological age was seen in the youngsters (only). A radical dissociation between NVIQ and both expressive and receptive language transpired as well, and a subset of individuals with normal NVIQ were comparable in terms of any other cognitive aspect. Sense-making reached symbolic levels in 62.2% of the sample and loaded on both verbal and nonverbal factors. CONCLUSIONS: These patterns inform theories of nvASD by revealing an impairment that is not conceptualizable as one of expressive language only, sharply limits learning opportunities across the lifespan, and cannot be compensated for by nonverbal cognition. IMPLICATIONS: These findings stress the need to seize developmental opportunities that may disappear when youngsters turn into adults, via therapies that specifically target language as a central cognitive system comprising both production and comprehension.

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26. Stein Duker LI, Goodman E, Pomponio Davidson A, Mosqueda L. Caregiver perspectives on barriers and facilitators to primary care for autistic adults: A qualitative study. Frontiers in medicine. 2022; 9: 1022026.

BACKGROUND: Primary care is associated with greater access to healthcare services and improved health outcomes. However, autistic adults report challenges accessing and utilizing primary care, in addition to unmet healthcare needs. The need to minimize existing barriers and identify strategies to facilitate successful healthcare encounters is increasingly important as autistic adults represent a growing segment of society. Minimal research has examined primary healthcare encounters for this population. METHODS: As part of a larger convergent parallel design mixed-methods study that recruited autistic adults, caregivers of autistic adults, and primary care providers treating autistic adults, interviews were conducted with 31 caregivers of autistic adults. Caregivers were predominantly female (94%), and the autistic adult they cared for were primarily male (87%), with a mean age of 24 years. Thematic analysis was employed to elucidate the barriers to care, suggestions to mitigate challenges, and/or successful strategies implemented during care encounters for autistic adults, as reported by their caregivers. RESULTS: Reported here are the results only from the caregiver interviews, in which seven themes emerged: (1) finding a primary care provider; (2) patient-provider communication; (3) anxiety due to unpredictability, an overstimulating sensory environment, and waiting time; (4) participation of consumers in the healthcare process; (5) stigma and assumptions about autism; (6) caregiver experiences; and (7) the impact of culture and ethnicity on care. CONCLUSION: Findings from this study have the potential to inform the development of, or improve existing, client-centered interventions to improve primary healthcare services for autistic adults.

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27. Sun CK, Cheng YS, Chen IW, Chiu HJ, Chung W, Tzang RF, Fan HY, Lee CW, Hung KC. Impact of parental rheumatoid arthritis on risk of autism spectrum disorders in offspring: A systematic review and meta-analysis. Frontiers in medicine. 2022; 9: 1052806.

BACKGROUND: To investigate the association of risk of offspring autism spectrum disorder (ASD) with both maternal and paternal rheumatoid arthritis (RA). METHODS: The Embase, Medline, Cochrane Library databases were searched for studies that investigated the association of parental RA with risk of offspring ASD. The primary outcome was the associations of maternal/paternal RA with the risk of offspring ASD. Subgroup analyses were conducted based on the timing of maternal RA diagnosis (i.e., before/after childbirth) and geographical location (i.e., Western vs. Asian countries) of studies. RESULTS: Ten studies published between 2005 and 2022 involving 6,177,650 participants were analyzed. Pooled results revealed a significant association between maternal RA and the risk of ASD (OR = 1.246, p < 0.001, 10 studies), while there was no association of paternal RA with the risk of offspring ASD (OR = 1.104, p = 0.253, four studies). Subgroup analysis demonstrated no correlation between diagnosis of maternal RA before childbirth and the risk of offspring ASD (OR = 1.449, p = 0.192, four studies), while there was a significant association of maternal RA regardless of the timing of diagnosis with the risk of offspring ASD (OR = 1.227, p = 0.001, six studies). Subgroup analysis on geographical location showed a significant association of maternal RA with the risk of offspring ASD regardless of the study location (all p < 0.05). CONCLUSION: Our findings supported an association between maternal RA and an elevated risk of ASD in offspring. However, given the limited numbers of studies investigating the risk of offspring ASD in mothers diagnosed with RA before childbirth, further studies are warranted to elucidate this issue. SYSTEMATIC REVIEW REGISTRATION: [www.crd.york.ac.uk/prospero/], identifier [CRD42022358470].

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28. Sung YS, Lin CY, Chu SY, Lin LY. Emotion Dysregulation Mediates the Relationship Between Sensory Processing and Behavior Problems in Young Children with Autism Spectrum Disorder: A Preliminary Study. Journal of autism and developmental disorders. 2022.

Emotion dysregulation is one of the challenges that children with autism spectrum disorder (ASD) and their families face. It is unclear whether emotion dysregulation plays a mediating role in the relationship between sensory processing patterns and problem behaviors among these children. This study examined the relations between emotion dysregulation, behavioral problems, and sensory processing patterns among fifty-seven young children with ASD. Behavioral problems and sensory processing patterns were moderately to strongly correlated with emotion dysregulation. The relationship between sensory processing patterns and behavioral problems was significant with emotion dysregulation as a mediator. These findings help identify the relationship between emotion dysregulation, sensory processing patterns, and behavioral problems to facilitate the planning of intervention strategies for young children with ASD.

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29. Uddin MN, Manley K, Lawrence DA. Altered meningeal immunity contributing to the autism-like behavior of BTBR T (+) Itpr3 (tf) /J mice. Brain, behavior, & immunity – health. 2022; 26: 100563.

Autism spectrum disorder (ASD) is a complicated neurodevelopmental disorder, which is categorized by deficiency of social contact and communication, and stereotyped forms of performance. Meningeal immunity conditions the immune reflection and immune defense in the meningeal area involving meningeal lymphatic organization, glymphatic structure, immune cells, and cytokines. The development of meningeal immunity dysfunction might be the leading cause for many neural diseases including ASD. The inbred mouse strain BTBRT + Itpr3tf/J (BTBR) shows multiple ASD-like behavioral phenotypes, thus making this strain a widely used animal model for ASD. In our previous study, we reported an altered peripheral immune profile in BTBR mice. Herein, we are investigating immunological and neural interactions associated with the aberrant behavior of BTBR mice. BTBR mice have an increased level of immune cell deposition in the meninges along with a higher level of CD4(+) T cells expressing CD25 and of B and myeloid cells expressing more MHCII than C57BL/6 (B6) mice, which have normal behaviors. BTBR mice also have higher levels of autoantibodies to dsDNA, Aquaporin-4, NMDAR1, Pentraxin/SAP and Caspr2 than B6 mice, which may affect neural functions. Interestingly, the T regulatory (Treg) cell population and their function was significantly reduced in the meninges and brain draining lymph nodes, which may explain the increased level of activated B and T cells in the meninges of BTBR mice. A low level of Treg cells, less IL-10 production by Treg, and activated T and B cells in meninges together with higher autoantibody levels might contribute to the development of autism-like behavior through neuroinflammation, which is known to be increased in BTBR mice.

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30. Urbinati C, Lanzillotta C, Cosentino L, Valenti D, Quattrini MC, Di Crescenzo L, Prestia F, Pietraforte D, Perluigi M, Di Domenico F, Vacca RA, De Filippis B. Chronic treatment with the anti-diabetic drug metformin rescues impaired brain mitochondrial activity and selectively ameliorates defective cognitive flexibility in a female mouse model of Rett syndrome. Neuropharmacology. 2022: 109350.

Metformin is the most common anti-diabetic drug and a promising therapy for disorders beyond diabetes, including Rett syndrome (RTT), a rare neurologic disease characterized by severe intellectual disability. A 10-day-long treatment rescued aberrant mitochondrial activity and restrained oxidative stress in a female RTT mouse model. However, this treatment regimen did not improve the phenotype of RTT mice. In the present study, we demonstrate that a 4-month-long treatment with metformin (150 mg/Kg/day, delivered in drinking bottles) provides a selective normalization of cognitive flexibility defects in RTT female mice at an advanced stage of disease, but it does not affect their impaired general health status and abnormal motor skills. The 4-month-long treatment also rescues the reduced activity of mitochondrial respiratory chain complex activities, the defective brain ATP production and levels as well as the increased production of reactive oxidizing species in the whole blood of RTT mice. A significant boost of PGC-1α-dependent pathways related to mitochondrial biogenesis and antioxidant defense occurs in the brain of RTT mice that received the metformin treatment. Further studies will have to verify whether these effects may underlie its long-lasting beneficial effects on brain energy metabolism.

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31. Urchs SGW, Tam A, Orban P, Moreau C, Benhajali Y, Nguyen HD, Evans AC, Bellec P. Functional connectivity subtypes associate robustly with ASD diagnosis. eLife. 2022; 11.

Our understanding of the changes in functional brain organization in autism is hampered by the extensive heterogeneity that characterizes this neurodevelopmental disorder. Data driven clustering offers a straightforward way to decompose autism heterogeneity into subtypes of connectivity and promises an unbiased framework to investigate behavioral symptoms and causative genetic factors. Yet, the robustness and generalizability of functional connectivity subtypes is unknown. Here, we show that a simple hierarchical cluster analysis can robustly relate a given individual and brain network to a connectivity subtype, but that continuous assignments are more robust than discrete ones. We also found that functional connectivity subtypes are moderately associated with the clinical diagnosis of autism, and these associations generalize to independent replication data. We explored systematically 18 different brain networks as we expected them to associate with different behavioral profiles as well as different key regions. Contrary to this prediction, autism functional connectivity subtypes converged on a common topography across different networks, consistent with a compression of the primary gradient of functional brain organization, as previously reported in the literature. Our results support the use of data driven clustering as a reliable data dimensionality reduction technique, where any given dimension only associates moderately with clinical manifestations.

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32. Valderrama A, Martinez A, Charlebois K, Guerrero L, Forgeot d’Arc B. For autistic persons by autistic persons: Acceptability of a structured peer support service according to key stakeholders. Health expectations : an international journal of public participation in health care and health policy. 2022.

INTRODUCTION: Social support is a protective factor in the mental health of autistic people. Furthermore, prejudice regarding autistic people is a constraint for the development of social support programmes by autistic peers. METHODS: The objective of this study is to describe the anticipated acceptability of structured peer support programmes for and by autistic persons. Fifteen key stakeholders (six autistic adults, four caregivers and five service providers) participated in in-depth semistructured interviews. A qualitative thematic analysis of the content of the verbatim was carried out. FINDINGS: We found that while a structured peer social support programme is acceptable to autistic people and caregivers, there was no consensus among service providers. The latter expressed doubts about the ability of autistic people to offer support. The framing of discussions between peers, the training of peer helpers, the support for autistic leadership and an organization that considers the communicational and sensory characteristics of autistic persons, could influence adherence to such a programme. Moreover, a space without service providers is an important condition for the acceptability of a peer support programme. CONCLUSION: A structured peer support service for and by autistic persons could be an innovative way to answer the unmet support needs of autistic people. It seems essential to anticipate potential barriers and facilitators and to communicate among health professionals to promote this approach and reduce possible prejudice about the ability of autistic people to offer support to their peers. More studies are necessary. PATIENT OR PUBLIC CONTRIBUTION: Fifteen key stakeholders who are involved in autistic people’s trajectory of service and support participated in this research. We are a research team composed of healthcare professionals and researchers, in addition to one member of our team being an autistic advocate and a mental health peer-support mentor. Two members of our team are also parents of autistic children. The comprehensibility of the questions for the interview was consulted and discussed with one autistic advocate-collaborator.

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33. Walsh MJM, Ofori E, Pagni BA, Chen K, Sullivan G, Braden BB. Preliminary findings of accelerated visual memory decline and baseline brain correlates in middle-age and older adults with autism: The case for hippocampal free-water. Frontiers in aging neuroscience. 2022; 14: 1029166.

Research aimed at understanding cognitive and brain aging in adults with autism spectrum disorder (ASD) is growing, but critical longitudinal work is scant. Adults with ASD struggle with tasks involving visual memory compared with neurotypical adults (NT). This may be related to differences in size or integrity of the hippocampus and its’ primary structural connectivity pathway, the fornix. The aim of this study was to describe preliminary findings of longitudinal aging trajectories in short- and long-term visual memory abilities in middle-age and older adults with ASD, compared with matched NT adults. We then evaluated baseline multi-modal imaging metrics of the hippocampal system, including the relatively novel metric of free-water, as potential correlates of longitudinal memory change in the ASD group. Middle-age and older adults with ASD (n = 25) and matched NT adults (n = 25) between the ages of 40 and 70 years were followed longitudinally at ~2-year intervals (range 2-5 years). Participants completed the Wechsler Memory Scale III Visual Reproduction task. Longitudinal mixed models were utilized to detect group differences in memory change with baseline age and sex as covariates. Hippocampal volume was measured via T1-weighted MRI images with FreeSurfer. Fornix fractional anisotropy and hippocampal and fornix free-water were measured from diffusion tensor imaging scans. Exploratory correlations were run between individual hippocampal system metrics and longitudinal slopes of visual memory change. There was a significant group by time interaction for long-term visual memory, such that middle-age and older adults with ASD declined faster than matched NT adults. There was no group by time interaction for short-term visual memory. Baseline hippocampal free-water was the only hippocampal system metric that correlated with long-term visual memory change in the ASD group. As one of the first longitudinal cognitive and brain aging studies in middle-age and older adults with ASD, our findings suggest vulnerabilities for accelerated long-term visual memory decline, compared to matched NT adults. Further, baseline hippocampal free-water may be a predictor of visual memory change in middle-age and older adults with ASD. These preliminary findings lay the groundwork for future prognostic applications of MRI for cognitive aging in middle-age and older adults with ASD.

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34. Wang X, Ling Z, Luo T, Zhou Q, Zhao G, Li B, Xia K, Li J. Severity of Autism Spectrum Disorder Symptoms Associated with de novo Variants and Pregnancy-Induced Hypertension. Journal of autism and developmental disorders. 2022.

Genetic factors, particularly, de novo variants (DNV), and an environment factor, exposure to pregnancy-induced hypertension (PIH), were reported to be associated with risk of autism spectrum disorder (ASD); however, how they jointly affect the severity of ASD symptom is unclear. We assessed the severity of core ASD symptoms affected by functional de novo variants or PIH. We selected phenotype data from Simon’s Simplex Collection database, used genotypes from previous studies, and created linear regression models. We found that ASD patients carrying DNV with PIH exposure had increased adaptive and cognitive ability, decreased social problems, and enhanced repetitive behaviors; however, there was no difference in patients without DNV between those with or without PIH exposure. In addition, the DNV genes carried by patients exposed to PIH were enriched in ubiquitin-dependent proteolytic processes, highlighting how candidate genes in pathways and environments interact. The results indicate the joint contribution of DNV and PIH to ASD.

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35. Wang YC, Chen CH, Yang CY, Ling P, Hsu KS. High-Fat Diet Exacerbates Autistic-Like Restricted Repetitive Behaviors and Social Abnormalities in CC2D1A Conditional Knockout Mice. Molecular neurobiology. 2022.

Autism spectrum disorder (ASD) represents a heterogeneous group of neurodevelopmental disorders characterized by deficits in social communication, social interaction, and the presence of restricted repetitive behaviors. The cause of ASD involves complex interactions between genetic and environmental factors. Haploinsufficiency of the Coiled-coil and C2 domain containing 1A (Cc2d1a) gene is causally linked to ASD, and obesity has been associated with worse outcomes for ASD. High-fat diet (HFD) feeding leads to the development of obesity and metabolic dysfunction; however, the effect of HFD on pre-existing autistic-like phenotypes remains to be clarified. Here, we report that male Cc2d1a conditional knockout (cKO) mice fed with HFD, from weaning onwards and throughout the experimental period, show a marked aggravation in autistic-like phenotypes, manifested in increased restricted repetitive behaviors and impaired performance in the preference for social novelty, but not in sociability and cognitive impairments assessed using the object location memory, novel object recognition, and Morris water maze tests. HFD feeding also results in increased numbers of reactive microglia and astrocytes, and exacerbates reductions in dendritic complexity and spine density of hippocampal CA1 pyramidal neurons. Furthermore, we demonstrate that chronic treatment with minocycline, a semisynthetic tetracycline-derived antibiotic, rescues the observed behavioral and morphological deficits in Cc2d1a cKO mice fed with HFD. Collectively, these findings highlight an aggravating role of HFD in pre-existing autistic-like phenotypes and suggest that minocycline treatment can alleviate abnormal neuronal morphology and behavioral symptoms associated with ASD resulted from the interplay between genetic and environmental risk factors.

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36. Wei H, Li Y, Zhang Y, Luo J, Wang S, Dong Q, Tao Y, Gong L, Feng Y, Shi M, Cao Z, Liu Y, Chen L, Liu X, Dai Y, Qu L, Song Z, Chen J, Li T, Cheng Q. Awareness and knowledge of autism spectrum disorder in Western China: Promoting early identification and intervention. Frontiers in psychiatry. 2022; 13: 970611.

PURPOSE: Given the increasing prevalence of autism spectrum disorder (ASD) and the public health problems it creates; early identification and interventions are needed to improve the prognosis of ASD. Hence, this study surveyed different groups of people who are likely to have early contact with autistic children to provide an informed basis for early detection and effective diagnosis and interventions. METHODS: Three groups of people were recruited for the study from Changshou District and Wushan County of Chongqing, in Western China: 269 medical workers, 181 educators, and 188 community residents. Their understanding and knowledge of autism was measured using a self-made questionnaire. RESULTS: The positive finding was that the three groups had a certain level of understanding of autism, but they had some misunderstandings of the core problems, and there were significant differences in the understanding of autism among the three groups. Younger medical workers knew more about autism than older ones did. The ability of educators and community residents to identify autistic symptoms was positively related to their level of education and their experience with autistic children. Television and the internet were the main sources of information about autism for participants. CONCLUSIONS: The medical workers, educators, and community residents in the investigated areas in western China may be able to identify early signs of autism but have an inadequate understanding of autism. In areas far from cities, it is necessary to strengthen the training of medical workers in primary health care to promote autism screening and referral in educational institutions and communities. Using internet technology to provide public education and professional training about autism in remote areas could be a very promising method in Western China.

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37. Welsh JP, Munson J, St John T, Meehan CN, Tran Abraham EN, Reitz F, Begay KK, Dager SR, Estes AM. Relationship of Impairments in Associative Learning With Intellectual Disability and Cerebellar Hypoplasia in Children With Autism. Neurology. 2022.

BACKGROUND AND OBJECTIVES: The severity of autism spectrum disorder (ASD) varies widely and is associated with intellectual disability (ID) and brain dysmorphology. We tested the hypothesis that the heterogeneity of ASD can be accounted for, in part, by altered associative learning measured by eye-blink conditioning (EBC) paradigms, used to test for forebrain and cerebellar dysfunction across the full range of ASD severity and intellectual ability. METHODS: Children in this cohort study were diagnosed with ASD or typical development (TD); most children were recruited from a 10-year longitudinal study. Outcome measures were the percentage and timing of conditioned eye-blink responses (CRs) acquired to a tone, recorded photometrically and related to measures of ASD severity, IQ, and age-2 brain morphometry by MRI. A sequence of trace and delay EBC was used. Analysis of variance, t-test, and logistic regression (LR) were employed. RESULTS: Sixty-two children were studied at school-age. Nine ASD children with ID since age 2 (ASD+ID; IQ=49±6; 11.9±0.2 years-old [±SD]) learned more slowly than thirty TD children (IQ=120±16; 10.5±1.5 years-old [±SD]) during trace EBC and showed atypically early-onset CRs (1.4 SD pre-TD) related to hypoplasia of the cerebellum at age 2 but not of the amygdala, hippocampus, or cerebral cortex. Conversely, sixteen ASD children with robust intellectual development since age 2 (IQ=100±3; 12.0±0.4 years-old [±SD]) learned typically but showed early-onset CRs only during long-delay EBC (0.8 SD pre-TD) unrelated to hypoplasia of any measured brain area. Using sixteen EBC measures, binary LR classified ASD and TD with 80% accuracy (95%CI=72-88%), 81% sensitivity (95%CI=69-92%), and 79% specificity (95%CI=68-91%); multinomial LR more accurately classified children based on ID (94% accuracy, 95%CI=89-100%) than ASD severity (85% accuracy, 95%CI=77-93%). Separate analyses of thirty-nine children with MRI (2.1±0.3 years-old [±SD]) indicated that cerebellar hypoplasia did not predict ASD+ID over ages 2-4 (Cohen’s d=0.3), as compared to early-onset CRs during age-11 trace EBC (Cohen’s d=-1.3). CONCLUSIONS: Trace EBC reveals the relationship between cerebellar hypoplasia and ASD+ID likely by engaging cerebro-cerebellar circuits involved in intellectual ability and implicit timing. Follow-up prospective studies using associative learning can determine whether ID can be predicted in children with early ASD diagnoses.

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38. Wilkinson M, Keehn RJJ, Linke AC, You Y, Gao Y, Alemu K, Correas A, Rosen BQ, Kohli JS, Wagner L, Sridhar A, Marinkovic K, Müller RA. fMRI BOLD and MEG theta power reflect complementary aspects of activity during lexicosemantic decision in adolescents with ASD. Neuroimage Reports. 2022; 2(4).

Neuroimaging studies of autism spectrum disorder (ASD) have been predominantly unimodal. While many fMRI studies have reported atypical activity patterns for diverse tasks, the MEG literature in ASD remains comparatively small. Our group recently reported atypically increased event-related theta power in individuals with ASD during lexicosemantic processing. The current multimodal study examined the relationship between fMRI BOLD signal and anatomically-constrained MEG (aMEG) theta power. Thirty-three adolescents with ASD and 23 typically developing (TD) peers took part in both fMRI and MEG scans, during which they distinguished between standard words (SW), animal words (AW), and pseudowords (PW). Regions-of-interest (ROIs) were derived based on task effects detected in BOLD signal and aMEG theta power. BOLD signal and theta power were extracted for each ROI and word condition. Compared to TD participants, increased theta power in the ASD group was found across several time windows and regions including left fusiform and inferior frontal, as well as right angular and anterior cingulate gyri, whereas BOLD signal was significantly increased in the ASD group only in right anterior cingulate gyrus. No significant correlations were observed between BOLD signal and theta power. Findings suggest that the common interpretation of increases in BOLD signal and theta power as ‘activation’ require careful differentiation, as these reflect largely distinct aspects of regional brain activity. Some group differences in dynamic neural processing detected with aMEG that are likely relevant for lexical processing may be obscured by the hemodynamic signal source and low temporal resolution of fMRI.

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39. Wilson AC. Development and validation of the conversation questionnaire: A psychometric measure of communication challenges generated from the self-reports of autistic people. Autism & developmental language impairments. 2022; 7: 23969415221123286.

Existing measures of communication challenges in autism are based on diagnostic criteria and research/clinical observations of autistic people, rather than what autistic people themselves identify as difficulties. In this study, the Conversation Questionnaire (CQ) was developed based on community engagement with autistic people to identify what they find challenging about conversation. This new tool was then administered online to autistic, dyslexic and neurotypical people (N = 312) in a validation phase of the study. Item-response theory modelling indicated that a two-dimensional structure accounted for response patterns. These dimensions reflected difficulties knowing what to say (15 items) and engaging in behaviours possibly disruptive to neurotypical conversation (21 items). The dimensions showed good internal consistency and convergent and discriminant validity, and could distinguish between autistic and neurotypical people (d = 1.59 and d = 2.07 respectively). The CQ might help contribute to diagnostic assessment for autism in adults as part of a holistic assessment. The questionnaire might also be useful with other neurodiverse groups, and provide a tool for clinicians and researchers to identify individuals’ strengths and difficulties in conversation (e.g., as part of interventions in speech and language therapy).

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