1. Ameis SH, Haltigan JD, Lyon RE, Sawyer A, Mirenda P, Kerns CM, Smith IM, Vaillancourt T, Volden J, Waddell C, Zwaigenbaum L, Bennett T, Duku E, Elsabbagh M, Georgiades S, Ungar WJ, Zaidman-Zait A, Lai MC, Szatmari P. Middle-childhood executive functioning mediates associations between early-childhood autism symptoms and adolescent mental health, academic and functional outcomes in autistic children. Journal of child psychology and psychiatry, and allied disciplines. 2022; 63(5): 553-62.

BACKGROUND: Executive functioning (EF) varies in children with autism spectrum disorder (ASD) and is associated with clinical symptoms, academic, and adaptive functioning. Here, we examined whether middle-childhood EF mediates associations between early-childhood autism symptoms and adolescent outcomes in children with ASD. METHODS: The Pathways in ASD Cohort comprising children recruited at the time of ASD diagnosis (at 2-4 years-of-age) and followed prospectively across eight subsequent timepoints over ~10 years was used. A subset of Pathways participants (n = 250) with Behavior Rating Inventory of Executive Function (BRIEF)-Parent Form data from at least one timepoint when participants were school-aged was analyzed. A mediation framework was used to examine whether BRIEF-measured EF across age 7-10 years (middle-childhood) mediated associations between early-childhood autism symptoms (measured using the parent-report Social Responsiveness Scale across age 2-6 years) and clinical, academic, and functional outcomes, indexed at age >10-11.8 years (early-adolescence) using the Child Behavior Checklist (CBCL)-Internalizing and Externalizing Scales, Academic Performance from the Teacher’s Report Form, and Vineland Adaptive Behavior Scales. Models were rerun substituting clinician-rated and teacher-rated measures, where possible. RESULTS: Mediation models indicated a significant indirect effect of middle-childhood EF on associations between early-childhood autism symptoms and externalizing behavior, academic performance, or adaptive functioning in early adolescence; kappa squared (κ(2) ) effect sizes ranged from large to small. Model findings were stable across raters. Middle-childhood EF did not mediate associations between early-childhood autism symptoms and adolescent internalizing behavior. CONCLUSIONS: Among children with an ASD diagnosis, middle-childhood EF may be one pathway through which early-childhood autism symptoms influence a variety of outcomes in early-adolescence. An experimental study targeting middle-childhood EF to improve adolescent academic, emotional/behavioral, and adaptive functioning is needed to evaluate the clinical meaningfulness of these findings.

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2. Bam S, Buchanan E, Mahony C, O’Ryan C. DNA Methylation of PGC-1α Is Associated With Elevated mtDNA Copy Number and Altered Urinary Metabolites in Autism Spectrum Disorder. Frontiers in cell and developmental biology. 2021; 9: 696428.

Autism spectrum disorder (ASD) is a complex disorder that is underpinned by numerous dysregulated biological pathways, including pathways that affect mitochondrial function. Epigenetic mechanisms contribute to this dysregulation and DNA methylation is an important factor in the etiology of ASD. We measured DNA methylation of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α), as well as five genes involved in regulating mitochondrial homeostasis to examine mitochondrial dysfunction in an ASD cohort of South African children. Using targeted Next Generation bisulfite sequencing, we found differential methylation (p < 0.05) at six key genes converging on mitochondrial biogenesis, fission and fusion in ASD, namely PGC-1α, STOML2, MFN2, FIS1, OPA1, and GABPA. PGC-1α, the transcriptional regulator of biogenesis, was significantly hypermethylated at eight CpG sites in the gene promoter, one of which contained a putative binding site for CAMP response binding element 1 (CREB1) (p = 1 × 10(-6)). Mitochondrial DNA (mtDNA) copy number, a marker of mitochondrial function, was elevated (p = 0.002) in ASD compared to controls and correlated significantly with DNA methylation at the PGC-1α promoter and there was a positive correlation between methylation at PGC-1α CpG#1 and mtDNA copy number (Spearman's r = 0.2, n = 49, p = 0.04) in ASD. Furthermore, DNA methylation at PGC-1α CpG#1 and mtDNA copy number correlated significantly (p < 0.05) with levels of urinary organic acids associated with mitochondrial dysfunction, oxidative stress, and neuroendocrinology. Our data show differential methylation in ASD at six key genes converging on PGC-1α-dependent regulation of mitochondrial biogenesis and function. We demonstrate that methylation at the PGC-1α promoter is associated with elevated mtDNA copy number and metabolomic evidence of mitochondrial dysfunction in ASD. This highlights an unexplored role for DNA methylation in regulating specific pathways involved in mitochondrial biogenesis, fission and fusion contributing to mitochondrial dysfunction in ASD.

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3. Carsone B, Green K, Torrence W, Henry B. Systematic Review of Visual Motor Integration in Children with Developmental Disabilities. Occupational therapy international. 2021; 2021: 1801196.

Original research articles regarding visual motor integration skills in children with developmental disabilities and the impact of occupational therapy were identified, appraised, and synthesized. Twenty-four articles were chosen for this review. Themes were noted during the critique of articles. Three themes emerged: « age, » « gender, » and « diagnosis. » Regarding the impact on visual motor integration, there was strong evidence for age, moderate evidence for gender, and strong evidence for diagnosis. Future research investigating visual motor integration in children should control for age and diagnosis.

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4. Crump C, Sundquist J, Sundquist K. Preterm or Early Term Birth and Risk of Autism. Pediatrics. 2021; 148(3).

OBJECTIVES: Preterm birth has been linked with increased risk of autism spectrum disorder (ASD); however, potential causality, sex-specific differences, and association with early term birth are unclear. We examined whether preterm and early term birth are associated with ASD in a large population-based cohort. METHODS: A national cohort study was conducted of all 4 061 795 singleton infants born in Sweden during 1973-2013 who survived to age 1 year, who were followed-up for ASD identified from nationwide outpatient and inpatient diagnoses through 2015. Poisson regression was used to determine prevalence ratios for ASD associated with gestational age at birth, adjusting for confounders. Cosibling analyses were used to assess the influence of unmeasured shared familial (genetic and/or environmental) factors. RESULTS: ASD prevalences by gestational age at birth were 6.1% for extremely preterm (22-27 weeks), 2.6% for very to moderate preterm (28-33 weeks), 1.9% for late preterm (34-36 weeks), 2.1% for all preterm (<37 weeks), 1.6% for early term (37-38 weeks), and 1.4% for term (39-41 weeks). The adjusted prevalence ratios comparing extremely preterm, all preterm, or early term versus term, respectively, were 3.72 (95% confidence interval, 3.27-4.23), 1.35 (1.30-1.40), and 1.11 (1.08-1.13) among boys and 4.19 (3.45-5.09), 1.53 (1.45-1.62), and 1.16 (1.12-1.20) among girls (P < .001 for each). These associations were only slightly attenuated after controlling for shared familial factors. CONCLUSIONS: In this national cohort, preterm and early term birth were associated with increased risk of ASD in boys and girls. These associations were largely independent of covariates and shared familial factors, consistent with a potential causal relationship.

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5. Kalin NH. Understanding the Value and Limitations of MRI Neuroimaging in Psychiatry. The American journal of psychiatry. 2021; 178(8): 673-6.

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6. Longo S, Caporali C, Pisoni C, Borghesi A, Perotti G, Tritto G, Olivieri I, La Piana R, Tonduti D, Decio A, Ariaudo G, Spairani S, Naboni C, Gardella B, Spinillo A, Manzoni F, Tinelli C, Stronati M, Orcesi S. Neurodevelopmental outcome of preterm very low birth weight infants admitted to an Italian tertiary center over an 11-year period. Scientific reports. 2021; 11(1): 16316.

Preterm very low birth weight infants (VLBWi) are known to be at greater risk of adverse neurodevelopmental outcome. Identifying early factors associated with outcome is essential in order to refer patients for early intervention. Few studies have investigated neurodevelopmental outcome in Italian VLBWi. The aim of our longitudinal study is to describe neurodevelopmental outcome at 24 months of corrected age in an eleven-year cohort of 502 Italian preterm VLBWi and to identify associations with outcome. At 24 months, Griffiths’ Mental Developmental Scales were administered. Neurodevelopmental outcome was classified as: normal, minor sequelae (minor neurological signs, General Quotient between 76 and 87), major sequelae (cerebral palsy; General Quotient ≤ 75; severe sensory impairment). 75.3% showed a normal outcome, 13.9% minor sequelae and 10.8% major sequelae (3.8% cerebral palsy). Male gender, bronchopulmonary dysplasia, abnormal neonatal neurological assessment and severe brain ultrasound abnormalities were independently associated with poor outcome on multivariate ordered logistic regression. Rates of major sequelae are in line with international studies, as is the prevalence of developmental delay over cerebral palsy. Analysis of perinatal complications and the combination of close cUS monitoring and neurological assessment are still essential for early identification of infants with adverse outcome.

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7. Lord C, Bishop SL. Let’s Be Clear That « Autism Spectrum Disorder Symptoms » Are Not Always Related to Autism Spectrum Disorder. The American journal of psychiatry. 2021; 178(8): 680-2.

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8. Manic KS, Biju R, Patel W, Khan MA, Raja NSM, Uma S. Extraction and Evaluation of Corpus Callosum from 2D Brain MRI Slice: A Study with Cuckoo Search Algorithm. Computational and mathematical methods in medicine. 2021; 2021: 5524637.

The work proposes a computer-based diagnosis method (CBDM) to delineate and assess the corpus callosum (CC) segment from the 2-dimensional (2D) brain magnetic resonance images (MRI). The proposed CBDM consists of two parts: (1) preprocessing and (2) postprocessing sections. The preprocessing tools have a multithreshold technique with the chaotic cuckoo search (CCS) algorithm and a preferred threshold procedure. The postprocessing employs a delineation process for extracting the CC section. The proposed CBDM finally extracts the vital CC parameters, such as total brain area (TBA) and CC area (CCA) to classify the considered 2D MRI slices into the control and autism spectrum disorder (ASD) groups. This attempt considers the benchmark brain MRI database which includes ABIDE and MIDAS for the experimental investigation. The results obtained with ABIDE dataset are further confirmed against the fuzzy C-means driven level set (FCM + LS) and multiphase level set (MLS) technique and the proposed CBDM with Shannon entropy along with active contour (SE + AC) presented improved result in comparison to the existing methodologies. Further, the performance of CBDM is confirmed on MIDAS and clinical dataset. The experimental outcomes approve that the proposed CBDM extracts the CC section from the 2D MR brain images that have higher accuracy compared to alternative techniques.

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9. McGowan EC, Sheinkopf SJ. Autism and Preterm Birth: Clarifying Risk and Exploring Mechanisms. Pediatrics. 2021; 148(3).

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10. Shi B, Wu W, Dai M, Zeng J, Luo J, Cai L, Wan B, Jing J. Cognitive, Language, and Behavioral Outcomes in Children With Autism Spectrum Disorders Exposed to Early Comprehensive Treatment Models: A Meta-Analysis and Meta-Regression. Frontiers in psychiatry. 2021; 12: 691148.

Background: Early comprehensive treatment models (CTMs) have been developed as effective treatments for children with autism spectrum disorder (ASD). Numerous studies have suggested that CTMs can improve short-term outcomes, but little is known about precise outcome information in childhood. The current meta-analysis reviewed studies reporting broader outcomes in children with ASD who had ever participated in a CTM and examined the predictors of developmental gains. Methods: We searched eight databases up to June 13, 2019, for relevant trials and natural experiments. Longitudinal studies were selected if they investigated the outcomes of CTMs. Two meta-analyses were undertaken to provide a summary estimate of change in treatment outcomes and to evaluate the effect of CTMs; one used the standardized mean change between the pretest and posttest, and the other was a classical meta-analysis. Stratified and random-effects meta-regression analyses were performed to search for outcome differences among studies. Results: Eighteen intervention studies (involving 495 children with ASD) met all the inclusion criteria: 12 used early intensive behavioral intervention (EIBI), and two used the Early Start Denver Model (ESDM). Outcomes were categorized into three parts: cognitive, language and behavioral (e.g., adaptive functioning and symptomatology). Overall, most children with ASD who had ever participated in an early CTM made gains in many areas of functioning, especially in terms of symptom- and language-related outcomes. Stratified analyses indicated that the ESDM displayed the largest effect on IQ improvement (ES = 1.37, 95% CI: 0.95 to 1.80), while EIBI was more effective for symptom reduction (ES = -1.27, 95% CI: -1.96 to -0.58). Further, meta-regression suggested that interventions with parent involvement, higher intensity, and longer treatment hours yielded greater improvements in IQ and social adaptive functioning, respectively. Conclusion: The results demonstrate a positive association between CTMs and better prognosis in childhood, especially regarding symptoms, and language. However, most extant research involves small, non-randomized studies, preventing definitive conclusions from being drawn. Clearly, the outcomes of children with ASD are still far from normal, especially with respect to adaptive functioning, and the four mediating variables pertaining to treatment elements can affect their gains, including approach, implementer, intensity, and total treatment hours. Systematic Review Registration: [www.crd.york.ac.uk/PROSPERO], identifier [CRD42019146859].

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11. Wadhera T, Kakkar D. Analysis of simultaneous visual and complex neural dynamics during cognitive learning to diagnose ASD. Physical and engineering sciences in medicine. 2021; 44(4): 1081-94.

The interactions between gaze processing and neural activities mediate cognition. The present paper aims to identify the involvement of visual and neural dynamics in shaping the cognitive behavior in Autism Spectrum Disorder (ASD). Electroencephalogram (EEG) and Eye-tracker signals of ASD and Typically Developing (TD) are recorded while performing two difficulty levels of a maze-based experimental task. During task, the performance metrics, complex neural measures extracted from EEG data using Visibility Graph (VG) algorithm and visual measures extracted from eye-tracker data are analyzed and compared. For both task levels, the cognition processing is examined via performance metrics (reaction-time and poor accuracy), gaze measures (saccade, fixation duration and blinkrate) and VG-based metrics (average weighted degree, clustering coefficient, path length, global efficiency, mutual information). An engagement in cognitive processing in ASD is revealed statistically by high reaction time, poor accuracy, increased fixation duration, raised saccadic amplitude, higher blink rate, reduced average weighted degree, global efficiency, mutual information as well as higher eigenvector centrality and path length. Over the course of repetitive trials, the cognitive improvement is although poor in ASD compared to TDs, the reconfigurations of visual and neural network dynamics revealed activation of Cognitive Learning (CL) in ASD. Furthermore, the correlation of gaze-EEG measures reveal that independent brain region functioning is not impaired but declined mutual interaction of brain regions causes cognitive deficit in ASD. And correlation of EEG-gaze measures with clinical severity measured by Autism Diagnostic Observation Schedule(ADOS) suggest that visual-neural activities reveals social behavior/cognition in ASD. Thus, visual and neural dynamics together support the revelation of the cognitive behavior in ASD.

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12. Wickstrom J, Farmer C, Green Snyder L, Mitz AR, Sanders SJ, Bishop S, Thurm A. Patterns of delay in early gross motor and expressive language milestone attainment in probands with genetic conditions versus idiopathic ASD from SFARI registries. Journal of child psychology and psychiatry, and allied disciplines. 2021; 62(11): 1297-307.

BACKGROUND: Recent large-scale initiatives have led to systematically collected phenotypic data for several rare genetic conditions implicated in autism spectrum disorder (ASD). The onset of developmentally expected skills (e.g. walking, talking) serve as readily quantifiable aspects of the behavioral phenotype. This study’s aims were: (a) describe the distribution of ages of attainment of gross motor and expressive language milestones in several rare genetic conditions, and (b) characterize the likelihood of delays in these conditions compared with idiopathic ASD. METHODS: Participants aged 3 years and older were drawn from two Simons Foundation Autism Research Initiative registries that employed consistent phenotyping protocols. Inclusion criteria were a confirmed genetic diagnosis of one of 16 genetic conditions (Simons Searchlight) or absence of known pathogenic genetic findings in individuals with ASD (SPARK). Parent-reported age of acquisition of three gross motor and two expressive language milestones was described and categorized as on-time or delayed, relative to normative expectations. RESULTS: Developmental milestone profiles of probands with genetic conditions were marked by extensive delays (including nonattainment), with highest severity in single gene conditions and more delays than idiopathic ASD in motor skills. Compared with idiopathic ASD, the median odds of delay among the genetic groups were higher by 8.3 times (IQR 5.8-16.3) for sitting, 12.4 times (IQR 5.3-19.5) for crawling, 26.8 times (IQR 7.7-41.1) for walking, 2.7 times (IQR 1.7-5.5) for single words, and 5.7 times (IQR 2.7-18.3) for combined words. CONCLUSIONS: Delays in developmental milestones, particularly in gross motor skills, are frequent and may be among the earliest indicators of differentially affected developmental processes in specific genetically defined conditions associated with ASD, as compared with those with clinical diagnoses of idiopathic ASD. The possibility of different developmental pathways leading to ASD-associated phenotypes should be considered when deciding how to employ specific genetic conditions as models for ASD.

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13. Zerbi V, Pagani M, Markicevic M, Matteoli M, Pozzi D, Fagiolini M, Bozzi Y, Galbusera A, Scattoni ML, Provenzano G, Banerjee A, Helmchen F, Basson MA, Ellegood J, Lerch JP, Rudin M, Gozzi A, Wenderoth N. Brain mapping across 16 autism mouse models reveals a spectrum of functional connectivity subtypes. Molecular psychiatry. 2021; 26(12): 7610-20.

Autism Spectrum Disorder (ASD) is characterized by substantial, yet highly heterogeneous abnormalities in functional brain connectivity. However, the origin and significance of this phenomenon remain unclear. To unravel ASD connectopathy and relate it to underlying etiological heterogeneity, we carried out a bi-center cross-etiological investigation of fMRI-based connectivity in the mouse, in which specific ASD-relevant mutations can be isolated and modeled minimizing environmental contributions. By performing brain-wide connectivity mapping across 16 mouse mutants, we show that different ASD-associated etiologies cause a broad spectrum of connectional abnormalities in which diverse, often diverging, connectivity signatures are recognizable. Despite this heterogeneity, the identified connectivity alterations could be classified into four subtypes characterized by discrete signatures of network dysfunction. Our findings show that etiological variability is a key determinant of connectivity heterogeneity in ASD, hence reconciling conflicting findings in clinical populations. The identification of etiologically-relevant connectivity subtypes could improve diagnostic label accuracy in the non-syndromic ASD population and paves the way for personalized treatment approaches.

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