1. Butler LK, Tager-Flusberg H. Fine motor skill and expressive language in minimally verbal and verbal school-aged autistic children. Autism research : official journal of the International Society for Autism Research. 2022.

Fine motor skill is associated with expressive language outcomes in infants who have an autistic sibling and in young autistic children. Fewer studies have focused on school-aged children even though around 80% have motor impairments and 30% remain minimally verbal (MV) into their school years. Moreover, expressive language is not a unitary construct, but it is made up of components such as speech production, structural language, and social-pragmatic language use. We used natural language sampling to investigate the relationship between fine motor and speech intelligibility, mean length of utterance and conversational turns in MV and verbal autistic children between the ages of 4 and 7 while controlling for age and adaptive behavior. Fine motor skill predicted speech production, measured by percent intelligible utterances. Fine motor skill and adaptive behavior predicted structural language, measured by mean length of utterance in morphemes. Adaptive behavior, but not fine motor skill, predicted social-pragmatic language use measured by number of conversational turns. Simple linear regressions by group corrected for multiple comparisons showed that fine motor skill predicted intelligibility for MV but not verbal children. Fine motor skill and adaptive behavior predicted mean length of utterance for both MV and verbal children. These findings suggest that future studies should explore whether MV children may benefit from interventions targeting fine motor along with speech and language into their school years.

Lien vers le texte intégral (Open Access ou abonnement)

2. Cao C, Li Q, Chen Y, Zou M, Sun C, Li X, Wu L. Untargeted Metabolomic Analysis Reveals the Metabolic Disturbances and Exacerbation of Oxidative Stress in the Cerebral Cortex of a BTBR Mouse Model of Autism. Journal of molecular neuroscience : MN. 2022.

The etiology and pathology of autism spectrum disorders (ASDs) are still poorly understood, which largely limit the treatment and diagnosis of ASDs. Emerging evidence supports that abnormal metabolites in the cerebral cortex of a BTBR mouse model of autism are involved in the pathogenesis of autism. However, systematic study on global metabolites in the cerebral cortex of BTBR mice has not been conducted. The current study aims to characterize metabolic changes in the cerebral cortex of BTBR mice by using an untargeted metabolomic approach based on UPLC-Q-TOF/MS. C57BL/6 J mice were used as a control group. A total of 14 differential metabolites were identified. Compared with the control group, the intensities of PI(16:0/22:5(4Z,7Z,10Z,13Z,16Z)), PC(22:6(4Z,7Z,10Z,13Z,16Z,19Z)/18:1(9Z)), PA(16:0/18:1(11Z)), 17-beta-estradiol-3-glucuronide, and N6,N6,N6-trimethyl-L-lysine decreased significantly (p < 0.01) and the intensities of 2-oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline, LysoPC(20:4(5Z,8Z,11Z,14Z)/0:0), adenosine monophosphate, adenosine-5'-phosphosulfate, LacCer(d18:1/12:0),3-dehydro-L-gulonate, N-(1-deoxy-1-fructosyl)tryptophan, homovanillic acid, and LPA(0:0/18:1(9Z)) increased significantly (p < 0.01) in the BTBR group. These changes in metabolites were closely related to perturbations in lipid metabolism, energy metabolism, purine metabolism, sulfur metabolism, amino acid metabolism, and carnitine biosynthesis. Notably, exacerbation of the oxidative stress response caused by differential prooxidant metabolites led to alteration of antioxidative systems in the cerebral cortex and resulted in mitochondrial dysfunction, further leading to abnormal energy metabolism as an etiological mechanism of autism. A central role of abnormal metabolites in neurological functions associated with behavioral outcomes and disturbance of sulfur metabolism and carnitine biosynthesis were found in the cerebral cortex of BTBR mice, which helped increase our understanding for exploring the pathological mechanism of autism.

Lien vers le texte intégral (Open Access ou abonnement)

3. Costanzo V, Narzisi A, Cerullo S, Crifaci G, Boncoddo M, Turi M, Apicella F, Tancredi R, Muratori F, Calderoni S, Billeci L. High-Risk Siblings without Autism: Insights from a Clinical and Eye-Tracking Study. Journal of personalized medicine. 2022; 12(11).

Joint attention (JA)-the human ability to coordinate our attention with that of other people-is impaired in the early stage of Autism Spectrum Disorder (ASD). However, little is known about the JA skills in the younger siblings of children with ASD who do not develop ASD at 36 months of age [high-risk (HR)-noASD]. In order to advance our understanding of this topic, a prospective multicenter observational study was conducted with three groups of toddlers (age range: 18-33 months): 17 with ASD, 19 with HR-noASD and 16 with typical development (TD). All subjects underwent a comprehensive clinical assessment and an eye-tracking experiment with pre-recorded stimuli in which the visual patterns during two tasks eliciting initiating joint attention (IJA) were measured. Specifically, fixations, transitions and alternating gaze were analyzed. Clinical evaluation revealed that HR-noASD subjects had lower non-verbal cognitive skills than TD children, while similar levels of restricted and repetitive behaviors and better social communication skills were detected in comparison with ASD children. Eye-tracking paradigms indicated that HR-noASD toddlers had visual patterns resembling TD in terms of target-object-to-face gaze alternations, while their looking behaviors were similar to ASD toddlers regarding not-target-object-to-face gaze alternations. This study indicated that high-risk, unaffected siblings displayed a shared profile of IJA-eye-tracking measures with both ASD patients and TD controls, providing new insights into the characterization of social attention in this group of toddlers.

Lien vers le texte intégral (Open Access ou abonnement)

4. Das S, Zomorrodi R, Mirjalili M, Kirkovski M, Blumberger DM, Rajji TK, Desarkar P. Machine learning approaches for electroencephalography and magnetoencephalography analyses in autism spectrum disorder: A systematic review. Progress in neuro-psychopharmacology & biological psychiatry. 2022; 123: 110705.

There are growing application of machine learning models to study the intricacies of non-linear and non-stationary characteristics of electroencephalography (EEG) and magnetoencephalography (MEG) data in neurobiologically complex and heterogeneous conditions such as autism spectrum disorder (ASD). Such tools have potential diagnostic applications, and given the highly heterogeneous presentation of ASD, might prove fruitful in early detection and therefore could facilitate very early intervention. We conducted a systematic review (PROSPERO ID#CRD42021257438) by searching PubMed, EMBASE, and PsychINFO for machine learning approaches for EEG and MEG analyses in ASD. Thirty-nine studies were identified, of which the majority (18) used support vector machines for classification; other successful methods included deep learning. Thirty-seven studies were found to employ EEG and two were found to employ MEG. This systematic review indicate that machine learning methods can be used to classify ASD, predict ASD diagnosis in high-risk infants as early as 3 months of age, predict ASD symptom severity, and classify states of cognition in ASD with high accuracy. Replication studies testing validity, reproducibility and generalizability in tandem with randomized controlled trials in ASD populations will likely benefit the field.

Lien vers le texte intégral (Open Access ou abonnement)

5. Erdogan MA, Bozkurt MF, Erbas O. Effects of prenatal testosterone exposure on the development of autism-like behaviours in offspring of Wistar rats. International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience. 2022.

BACKGROUND: A neurodevelopmental disease, autism spectrum disorder (ASD) occurs in males three times more commonly than girls. Higher prenatal testosterone exposure may result in autistic-like behaviour in boys, according to earlier research. It is unclear how fetal testosterone affects the development of autism. In this study, we tested the hypothesis that prenatal testosterone exposure in an animal model may result in autistic behaviors by modifying seratonin, dopamine, IGF-1, and oxytocin levels. MATERIALS AND METHODS: Group 1 (control, n = 6) and Group 2 (testosterone undecanoate, n = 6) of female rats were randomly assigned. For two to three days during the oestrus cycle, female rats were housed with a reproductive male (three females/one male). On the tenth day of gestation, rats in Group 1 received 1 ml/kg% 0.9 NaCl saline whereas rats in Group 2 received 250 mg/kg testosterone undecanoate. Until weaning on postnatal day 21 (P21), the mothers were permitted to care for their pups. On P21, 40 littermates-10 male and female for control, 10 male and female from mothers that exposed to testosterone-were arbitrarily split up and housed. On P50, these mature rats were tested for their behavior. The rats were then sacrificed. The brain tissue was subjected to histological examinations as well as biochemical tests for homovanillic acid (HVA), 5-Hydroxyindoleacetic acid (5-HIAA), oxytocin and Insulin-like growth factor-1 (IGF-1). RESULTS: The groups differed significantly in the behavioral examinations (three-chamber social test, passive avoidance learning analysis, open field test), with the testosterone-exposed groups exhibiting autistic symptoms to a higher extent. When compared to the control groups, testosterone exposure caused significant histological changes in the hippocampus CA1 and CA3 areas, including gliosis and cell death of neurons. In the testosterone-exposed groups, HVA, 5-HIAA and IGF-1 tissue expressions in the brain elevated whereas oxytocin levels reduced. These findings point to a potential connection between neurodevelopmental disorders like ASD and exposure to testosterone during gestation. CONCLUSION: Overall, we revealed that prenatal testosterone exposure led to autistic traits by elevating seratonin, dopamine, and IGF-1 levels while lowering oxytocin levels.

Lien vers le texte intégral (Open Access ou abonnement)

6. Gates JA, Gerber AH, Miller CE, Lerner MD. Quantifying social skill deficits and strengths profiles in autistic youth. Child development. 2022.

While social difficulties in autism are well-established, questions remain regarding whether these represent challenges in acquiring or performing such skills, reduced social strengths, or a unique distribution across these domains (i.e., social profile). This study empirically derived social profiles of 211 autistic and non-autistic youth (M(age) = 13.50; Autistic N = 150; Male N = 151; 85.3% White). Assessments occurred between 2016 and 2020. Results showed that autistic youth exhibit significantly more social acquisition and performance deficits and fewer strengths than nonautistic youth (ds = -.44 to .65). Performance deficits were most-and acquisition deficits least-prominent within autistic profiles, potentially implicating longstanding theoretical models of social difficulties in autism, and supporting new, idiographic approaches for conceptualizing, assessing, and treating social challenges.

Lien vers le texte intégral (Open Access ou abonnement)

7. Haddad Derafshi B, Danko T, Chanda S, Batista PJ, Litzenburger U, Lee QY, Ng YH, Sebin A, Chang HY, Südhof TC, Wernig M. The autism risk factor CHD8 is a chromatin activator in human neurons and functionally dependent on the ERK-MAPK pathway effector ELK1. Scientific reports. 2022; 12(1): 22425.

The chromodomain helicase DNA-binding protein CHD8 is the most frequently mutated gene in autism spectrum disorder. Despite its prominent disease involvement, little is known about its molecular function in the human brain. CHD8 is a chromatin regulator which binds to the promoters of actively transcribed genes through genomic targeting mechanisms which have yet to be fully defined. By generating a conditional loss-of-function and an endogenously tagged allele in human pluripotent stem cells, we investigated the molecular function and the interaction of CHD8 with chromatin in human neurons. Chromatin accessibility analysis and transcriptional profiling revealed that CHD8 functions as a transcriptional activator at its target genes in human neurons. Furthermore, we found that CHD8 chromatin targeting is cell context-dependent. In human neurons, CHD8 preferentially binds at ETS motif-enriched promoters. This enrichment is particularly prominent on the promoters of genes whose expression significantly changes upon the loss of CHD8. Indeed, among the ETS transcription factors, we identified ELK1 as being most highly correlated with CHD8 expression in primary human fetal and adult cortical neurons and most highly expressed in our stem cell-derived neurons. Remarkably, ELK1 was necessary to recruit CHD8 specifically to ETS motif-containing sites. These findings imply that ELK1 and CHD8 functionally cooperate to regulate gene expression and chromatin states at MAPK/ERK target genes in human neurons. Our results suggest that the MAPK/ERK/ELK1 axis potentially contributes to the pathogenesis caused by CHD8 mutations in human neurodevelopmental disorders.

Lien vers le texte intégral (Open Access ou abonnement)

8. Khundrakpam B, Bhutani N, Vainik U, Gong J, Al-Sharif N, Dagher A, White T, Evans AC. A critical role of brain network architecture in a continuum model of autism spectrum disorders spanning from healthy individuals with genetic liability to individuals with ASD. Molecular psychiatry. 2022.

Studies have shown cortical alterations in individuals with autism spectrum disorders (ASD) as well as in individuals with high polygenic risk for ASD. An important addition to the study of altered cortical anatomy is the investigation of the underlying brain network architecture that may reveal brain-wide mechanisms in ASD and in polygenic risk for ASD. Such an approach has been proven useful in other psychiatric disorders by revealing that brain network architecture shapes (to an extent) the disorder-related cortical alterations. This study uses data from a clinical dataset-560 male subjects (266 individuals with ASD and 294 healthy individuals, CTL, mean age at 17.2 years) from the Autism Brain Imaging Data Exchange database, and data of 391 healthy individuals (207 males, mean age at 12.1 years) from the Pediatric Imaging, Neurocognition and Genetics database. ASD-related cortical alterations (group difference, ASD-CTL, in cortical thickness) and cortical correlates of polygenic risk for ASD were assessed, and then statistically compared with structural connectome-based network measures (such as hubs) using spin permutation tests. Next, we investigated whether polygenic risk for ASD could be predicted by network architecture by building machine-learning based prediction models, and whether the top predictors of the model were identified as disease epicenters of ASD. We observed that ASD-related cortical alterations as well as cortical correlates of polygenic risk for ASD implicated cortical hubs more strongly than non-hub regions. We also observed that age progression of ASD-related cortical alterations and cortical correlates of polygenic risk for ASD implicated cortical hubs more strongly than non-hub regions. Further investigation revealed that structural connectomes predicted polygenic risk for ASD (r = 0.30, p < 0.0001), and two brain regions (the left inferior parietal and left suparmarginal) with top predictive connections were identified as disease epicenters of ASD. Our study highlights a critical role of network architecture in a continuum model of ASD spanning from healthy individuals with genetic risk to individuals with ASD. Our study also highlights the strength of investigating polygenic risk scores in addition to multi-modal neuroimaging measures to better understand the interplay between genetic risk and brain alterations associated with ASD.

Lien vers le texte intégral (Open Access ou abonnement)

9. Looden T, Floris DL, Llera A, Chauvin RJ, Charman T, Banaschewski T, Murphy D, Marquand AF, Buitelaar JK, Beckmann CF. Patterns of connectome variability in autism across five functional activation tasks: findings from the LEAP project. Molecular autism. 2022; 13(1): 53.

BACKGROUND: Autism spectrum disorder (autism) is a complex neurodevelopmental condition with pronounced behavioral, cognitive, and neural heterogeneities across individuals. Here, our goal was to characterize heterogeneity in autism by identifying patterns of neural diversity as reflected in BOLD fMRI in the way individuals with autism engage with a varied array of cognitive tasks. METHODS: All analyses were based on the EU-AIMS/AIMS-2-TRIALS multisite Longitudinal European Autism Project (LEAP) with participants with autism (n = 282) and typically developing (TD) controls (n = 221) between 6 and 30 years of age. We employed a novel task potency approach which combines the unique aspects of both resting state fMRI and task-fMRI to quantify task-induced variations in the functional connectome. Normative modelling was used to map atypicality of features on an individual basis with respect to their distribution in neurotypical control participants. We applied robust out-of-sample canonical correlation analysis (CCA) to relate connectome data to behavioral data. RESULTS: Deviation from the normative ranges of global functional connectivity was greater for individuals with autism compared to TD in each fMRI task paradigm (all tasks p < 0.001). The similarity across individuals of the deviation pattern was significantly increased in autistic relative to TD individuals (p < 0.002). The CCA identified significant and robust brain-behavior covariation between functional connectivity atypicality and autism-related behavioral features. CONCLUSIONS: Individuals with autism engage with tasks in a globally atypical way, but the particular spatial pattern of this atypicality is nevertheless similar across tasks. Atypicalities in the tasks originate mostly from prefrontal cortex and default mode network regions, but also speech and auditory networks. We show how sophisticated modeling methods such as task potency and normative modeling can be used toward unravelling complex heterogeneous conditions like autism.

Lien vers le texte intégral (Open Access ou abonnement)

10. Nogueira HA, de Castro CT, da Silva DCG, Pereira M. Melatonin for sleep disorders in people with autism: Systematic review and meta-analysis. Progress in neuro-psychopharmacology & biological psychiatry. 2022; 123: 110695.

Melatonin is a potential therapeutic intervention for improving sleep quality in people with autistic spectrum disorder (ASD). We investigate the effect of using melatonin as a sleep disorder treatment in people with ASD. Interventionist studies were searched in seven databases. A total of 595 references were identified, 15 of which were eligible for the systemic review and meta-analysis. Melatonin use presented a positive effect on total sleep time (standardized mean difference- SMD = 0.78; 95%CI = 0.35; 1.21; I(2) = 91%), on sleep latency (SMD = 1.23; 95%CI = 0.35; 2.11; I(2) = 94%), and on sleep efficiency (SMD = -0.70; 95%CI = -1.23; -0.16; I(2) = 91%) when comparing the intervention group with the placebo/control group via the global analysis. According to the global analysis, the wake after sleep onset and night awakening parameters were not statistically significant. Melatonin has possible efficacy over total time, latency, and efficiency sleep parameters.

Lien vers le texte intégral (Open Access ou abonnement)

11. Sacrey LR, Zwaigenbaum L, Brian JA, Smith IM, Armstrong V, Vaillancourt T, Schmidt LA. Behavioral and physiological differences during an emotion-evoking task in children at increased likelihood for autism spectrum disorder. Development and psychopathology. 2022: 1-11.

Literature examining emotional regulation in infants with autism spectrum disorder (ASD) has focused on parent report. We examined behavioral and physiological responses during an emotion-evoking task designed to elicit emotional states in infants. Infants at an increased likelihood for ASD (IL; have an older sibling with ASD; 96 not classified; 29 classified with ASD at age two) and low likelihood (LL; no family history of ASD; n = 61) completed the task at 6, 12, and 18 months. The main findings were (1) the IL-ASD group displayed higher levels of negative affect during toy removal and negative tasks compared to the IL non-ASD and LL groups, respectively, (2) the IL-ASD group spent more time looking at the baseline task compared to the other two groups, and (3) the IL-ASD group showed a greater increase in heart rate from baseline during the toy removal and negative tasks compared to the LL group. These results suggest that IL children who are classified as ASD at 24 months show differences in affect, gaze, and heart rate during an emotion-evoking task, with potential implications for understanding mechanisms related to emerging ASD.

Lien vers le texte intégral (Open Access ou abonnement)

12. Townsend AN, Guzick AG, Hertz AG, Kerns CM, Goodman WK, Berry LN, Kendall PC, Wood JJ, Storch EA. Anger Outbursts in Youth with ASD and Anxiety: Phenomenology and Relationship with Family Accommodation. Child psychiatry and human development. 2022.

Anger outbursts (AO) are associated with severe symptoms, impairment and poorer treatment outcomes for anxious children, though limited research has examined AO in youth with co-occurring autism and anxiety disorders. This study examined AO in children with autism and anxiety by evaluating clinical characteristics, family accommodation, and changes in AO following anxiety-focused treatment. The sample comprised 167 youth with autism and anxiety enrolled in a multi-site randomized clinical trial comparing standard care CBT for anxiety, CBT adapted for youth with autism, and usual care. Most participants (60%) had AO, which contributed to impairment above and beyond anxiety and autism. AO impacted functional impairment indirectly through a pathway of parental accommodation. AO reduced with anxiety-focused treatment. Findings highlight that AO are common in this population and uniquely contribute to functional impairment, indicating a need for direct targeting in treatment.

Lien vers le texte intégral (Open Access ou abonnement)

13. Wang L, Xie Z, Zhao D. Spring is not yet here: raising a child with ASD in rural southwest China. Disability and rehabilitation. 2022: 1-12.

PURPOSE: This study aims to reveal the parenting experiences of parents of children with autism spectrum disorder (ASD) in rural southwest China under the framework of ecological systems theory. MATERIALS AND METHODS: Semi-structured interviews were conducted with 21 parents of children with ASD from rural southwest China and the interview data were analyzed using the three coding steps of the grounded theory method, namely open, axial, and selective coding. RESULTS: The results showed four themes: challenges from within the family; relationships between parents, the school, and the community; scarcity and low accessibility of available resources and services; the culture of discriminating against people with disabilities and the loss of eligibility for welfare. The mismatch between the needs of families of children with ASD and the resources available in social-environmental systems is the major issue faced by parents. CONCLUSIONS: Raising a child with ASD in rural southwest China is affected by the interactions between the families and the internal structures in different environmental systems. The culture of discriminating against people with disabilities formed in the macrosystem could be the essential factor that affects the smoothness of the parenting process of children with ASD. The diagnosis of a child with autism spectrum disorder (ASD) is a difficult and stressful experience for the parents of the child and the whole family.This study highlights the mismatch between parent/family needs, and the resources in different environmental systems of rural southwest China, which may have a limiting effect on the rehabilitation of children with ASD.Emphasis on effective collaboration between social systems to help families with ASD children develop more supportive social conditions should be included in the discussion of rehabilitation projects.The educational and psychological interventions for parents of ASD children should be included in the rehabilitation, which enhance their scientific understanding of self-identity, family and social environment and parenting style. eng.

Lien vers le texte intégral (Open Access ou abonnement)

14. Xu YJ, Liu PP, Yan ZZ, Mi TW, Wang YY, Li Q, Teng ZQ, Liu CM. KW-2449 and VPA exert therapeutic effects on human neurons and cerebral organoids derived from MECP2-null hESCs. Stem cell research & therapy. 2022; 13(1): 534.

BACKGROUND: Rett syndrome (RTT), mainly caused by mutations in methyl-CpG binding protein 2 (MECP2), is one of the most prevalent neurodevelopmental disorders in girls. However, the underlying mechanism of MECP2 remains largely unknown and currently there is no effective treatment available for RTT. METHODS: We generated MECP2-KO human embryonic stem cells (hESCs), and differentiated them into neurons and cerebral organoids to investigate phenotypes of MECP2 loss-of-function, potential therapeutic agents, and the underlying mechanism by transcriptome sequencing. RESULTS: We found that MECP2 deletion caused reduced number of hESCs-derived neurons and simplified dendritic morphology. Moreover, MECP2-KO cortical organoids exhibited fewer neural progenitor cells and neurons at day 60. Electrophysiological recordings showed that MECP2 deletion altered synaptic activity in organoids. Transcriptome analysis of organoids identified many genes in the PI3K-AKT pathway downregulated following MECP2 deletion. Treatment with either KW-2449 or VPA, small molecules for the activation of PI3K-AKT signaling pathway, alleviated neuronal deficits and transcriptome changes in MECP2-KO human neuronal models. CONCLUSIONS: These findings suggest that KW-2449 and VPA might be promising drugs for RTT treatment.

Lien vers le texte intégral (Open Access ou abonnement)