1. Abreu AC, Navas MM, Fernández CP, Sánchez-Santed F, Fernández I. NMR-Based Metabolomics Approach to Explore Brain Metabolic Changes Induced by Prenatal Exposure to Autism-Inducing Chemicals. ACS chemical biology. 2021.

NMR offers the unique potential to holistically screen hundreds of metabolites and has already proved to be a powerful technique able to provide a global picture of a wide range of metabolic processes underlying complex and multifactorial diseases, such as neurodegenerative and neurodevelopmental diseases. The aim of this study was to apply an NMR-based metabolomics approach to explore brain metabolic changes in both male and female rats induced by prenatal exposure to two chemicals associated with autism disorders-the organophosphorus pesticide chlorpyrifos (CPF) and the antiepileptic drug valproic acid (VPA)-at different postnatal ages. Depending on the age and on the brain region (hippocampus and cerebellum), several metabolites were shown to be significantly affected by exposure to both compounds. The evaluation of the spectral profiles revealed that the nervous-system-specific metabolite N-acetylaspartate (NAA), amino acid neurotransmitters (e.g., glutamate, glutamine, GABA, glycine), pyroglutamic acid, unsaturated fatty acids, and choline-based compounds are discriminant biomarkers. Additionally, metabolic changes varied as a function of age, but importantly not of sex.

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2. Aishworiya R, Goh TJ, Sung M, Tay SKH. Correlates of adaptive skills in children with autism spectrum disorder. Autism. 2021 : 1362361321997287.

Despite improving services and care for individuals with autism spectrum disorder, functional outcomes such as daily living skills tend to be suboptimal for many. This study wanted to identify modifiable early intervention factors that are associated with better outcomes and possible high-risk groups of children who are at risk of poorer outcomes. Participants included 193 children aged between 5 and 12 years of age whose parents provided information on their family background and early intervention characteristics. These children also had their adaptive behaviour skills examined by formal testing. Results indicated that shorter wait time for early intervention was associated with better adaptive behaviour scores. Children from families with financial difficulties and lower paternal education were also at risk of poorer adaptive skills. Designing services for children with autism such that wait times to enter early intervention services are minimised following initial diagnosis can improve their eventual functional outcomes. Changes in healthcare policy to allow expedited entry or targeted intervention to children from low socio-economic status families can also enhance their eventual adaptive skill gains.

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3. Al Malki JS, Hussien NA, Al Malki F. Maternal toxoplasmosis and the risk of childhood autism : serological and molecular small-scale studies. BMC pediatrics. 2021 ; 21(1) : 133.

BACKGROUND : Toxoplasmosis resulting from infection with the Toxoplasma parasite has become an endemic disease worldwide. Recently, a few studies have reported a high prevalence of Toxoplasmosis infections among Saudi Arabian women. This disease could become life threatening for pregnant women and for immunodeficient people. There is evidence that infections during pregnancy, especially in the early stages, are associated with neurodevelopmental disorders. Autism disorder represents one of the most common neurodevelopmental disorders worldwide ; it is associated with delayed language development, weak communication interaction, and repetitive behavior. The relationship between prenatal toxoplasmosis and autism in childhood remains unclear. The present study aims to report a link between maternal toxoplasmosis and autistic offspring among Saudi Arabian women. METHOD : Blood samples (36 maternal, 36 from their non-autistic children, and 36 from their autistic children) were collected for serological and molecular evaluation. RESULTS : A toxoplasmosis infection was reported for 33.34% of participants using an ELISA assay (5.56% IgG+/IgM+, 11.11% IgG-/IgM+, and 16.67% IgG+/IgM-) ; however, a nested PCR assay targeting B1 toxoplasmosis specific genes recorded positive tests for 80.56% of the samples. In addition, the present study detected several points of mutation of mtDNA including NADH dehydrogenase (ND1, ND4) and Cyt B genes and the nDNA pyruvate kinase (PK) gene for autistic children infected with toxoplasmosis. CONCLUSION : Considering previous assumptions, we suggest that a maternal toxoplasmosis infection could have a role in the development of childhood autism linked to mtDNA and nDNA impairment.

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4. Amar M, Pramod AB, Yu NK, Herrera VM, Qiu LR, Moran-Losada P, Zhang P, Trujillo CA, Ellegood J, Urresti J, Chau K, Diedrich J, Chen J, Gutierrez J, Sebat J, Ramanathan D, Lerch JP, Yates JR, 3rd, Muotri AR, Iakoucheva LM. Autism-linked Cullin3 germline haploinsufficiency impacts cytoskeletal dynamics and cortical neurogenesis through RhoA signaling. Mol Psychiatry. 2021.

E3-ubiquitin ligase Cullin3 (Cul3) is a high confidence risk gene for autism spectrum disorder (ASD) and developmental delay (DD). To investigate how Cul3 mutations impact brain development, we generated a haploinsufficient Cul3 mouse model using CRISPR/Cas9 genome engineering. Cul3 mutant mice exhibited social and cognitive deficits and hyperactive behavior. Brain MRI found decreased volume of cortical regions and changes in many other brain regions of Cul3 mutant mice starting from early postnatal development. Spatiotemporal transcriptomic and proteomic profiling of embryonic, early postnatal and adult brain implicated neurogenesis and cytoskeletal defects as key drivers of Cul3 functional impact. Specifically, dendritic growth, filamentous actin puncta, and spontaneous network activity were reduced in Cul3 mutant mice. Inhibition of small GTPase RhoA, a molecular substrate of Cul3 ligase, rescued dendrite length and network activity phenotypes. Our study identified defects in neuronal cytoskeleton and Rho signaling as the primary targets of Cul3 mutation during brain development.

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5. Arutiunian V, Lopukhina A, Minnigulova A, Shlyakhova A, Davydova E, Pereverzeva D, Sorokin A, Tyushkevich S, Mamokhina U, Danilina K, Dragoy O. Language Abilities of Russian Primary-School-Aged Children with Autism Spectrum Disorder : Evidence from Comprehensive Assessment. J Autism Dev Disord. 2021.

The purpose of the present research was to comprehensively assess the language abilities of Russian primary-school-aged children with Autism Spectrum Disorder (ASD), varying in non-verbal IQ, at all linguistic levels (phonology, lexicon, morphosyntax, and discourse) in production and comprehension. Yet, the influence of such non-language factors as children’s age, the severity of autistic traits, and non-verbal IQ on language functioning was studied. Our results indicate a high variability of language skills in children with ASD (from normal to impaired) which is in line with the previous studies. Interestingly, the number of children with normal language abilities was related to the linguistic levels : according to more complex morphosyntax and discourse tests, fewer children with ASD were within the normal range unlike the results in simpler phonological and lexical tests. Importantly, we found that language abilities were best predicted by non-verbal IQ but were independent from age and the severity of autistic traits. The findings support the claim that formal language assessment of children with ASD needs to include all linguistic levels, from phonology to discourse, for helping speech-language therapists to choose an appropriate therapy target.

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6. Celik H, Acikel SB, Ozdemir MAF, Aksoy E, Oztoprak U, Ceylan N, Yuksel D. Evaluation of the clinical characteristics of children with autism spectrum disorder and epilepsy and the perception of their parents on quality of life. Epilepsy research. 2021 ; 172 : 106599.

BACKGROUND AND AIM : Autism spectrum disorder (ASD) is among the serious clinical pictures of early childhood, and its main symptoms are qualitative dysfunction in social interactions with impairment of verbal and nonverbal communication and limitations in interests and activities. METHODS : This study aimed to examine the clinical conditions that mediate this comorbidity, compare parental quality of life in isolated ASD and ASD with epilepsy, demonstrate the relationships between clinical and EEG findings obtained in diagnostic evaluation, and examine the results in light of the literature. RESULTS : The study sample consisted of 154 ASD patients ; 26 were girls (16.9 %) and 128 (83.1 %) were boys. Of the patients with epilepsy, seizures were focal in 14 patients (9.1 %), generalized in 9 patients (5.8 %), and unspecified in 1 patient (0.6 %). Intellectual ability was found to be a significant predictor of epilepsy diagnosis. Mean (SD) total scores in the Quality of Life in Autism Questionnaire were 131.84 (10.68) among mothers of children with ASD-epilepsy and 148.33 (14.03) among mothers of children with ASD alone (P < .001). CONCLUSION : Many psychiatric and medical conditions can co-occur with ASD. Determining the prognostic criteria for ASD is of great importance in coordinating lifelong autism rehabilitation. Improving autism-specific symptoms will benefit children with ASD as well as help mitigate parental anxiety.

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7. Eldeeb S, Susam BT, Akcakaya M, Conner CM, White SW, Mazefsky CA. Trial by trial EEG based BCI for distress versus non distress classification in individuals with ASD. Sci Rep. 2021 ; 11(1) : 6000.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is often accompanied by impaired emotion regulation (ER). There has been increasing emphasis on developing evidence-based approaches to improve ER in ASD. Electroencephalography (EEG) has shown success in reducing ASD symptoms when used in neurofeedback-based interventions. Also, certain EEG components are associated with ER. Our overarching goal is to develop a technology that will use EEG to monitor real-time changes in ER and perform intervention based on these changes. As a first step, an EEG-based brain computer interface that is based on an Affective Posner task was developed to identify patterns associated with ER on a single trial basis, and EEG data collected from 21 individuals with ASD. Accordingly, our aim in this study is to investigate EEG features that could differentiate between distress and non-distress conditions. Specifically, we investigate if the EEG time-locked to the visual feedback presentation could be used to classify between WIN (non-distress) and LOSE (distress) conditions in a game with deception. Results showed that the extracted EEG features could differentiate between WIN and LOSE conditions (average accuracy of 81%), LOSE and rest-EEG conditions (average accuracy 94.8%), and WIN and rest-EEG conditions (average accuracy 94.9%).

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8. Feng K, Zhao Y, Yu Q, Deng J, Wu J, Liu L. Can probiotic supplements improve the symptoms of autism spectrum disorder in children ? : A protocol for systematic review and meta analysis. Medicine. 2021 ; 100(10) : e18621.

INTRODUCTION : Autism spectrum disorder (ASD) is a neurodevelopmental disorder with increasing incidence. The externalizing and internalizing problems among children with ASD often persistent and highly impair functioning of both the child and the family. Children with ASD often develop gut-related comorbidities and dysbiosis can have negative effects on not only the gastrointestinal (GI) tract, but also psychological symptoms. Dietary exclusions and probiotic supplements also have been investigated in the management of ASD symptoms. Especially, there is some anecdotal evidence that probiotics supplements are able to alleviate GI symptoms as well as improve behaviors in children with ASD. METHOD AND ANALYSIS : This review will report on overall studies that include randomized control trials, randomized cross-over studies and cluster-randomized trials designs that consider curative effect in children with ASD by probiotic supplements. We will search 6 databases : MEDLINE, Embase, Scopus, PubMed, The Cochrane Library, and Web of Science and we will perform a manual search the journal Autism and information of ongoing or unpublished studies. The Mixed Methods Appraisal Tool (MMAT) will be used to assess quality of articles and the Jadad scale will be used to assess for bias. Assessment of publication bias will be performed using funnel plots generated by Comprehensive Meta-Analysis (CMA) 3.0 software. Clarifying the evidence in this area will be important for future research directions when reformulating and promoting the therapeutic regime in the field. ETHICS AND DISSEMINATION : There are no human participants, data, or tissue being directly studied for the purposes of the review ; therefore, ethics approval and consent to participate are not applicable. The results of this study will be presented at conferences and published in peer-reviewed journals. REGISTRATION AND STATUS : PROSPERO 2019 CRD42019132754.

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9. Höfer J, Hoffmann F, Dörks M, Kamp-Becker I, Küpper C, Poustka L, Roepke S, Roessner V, Stroth S, Wolff N, Bachmann CJ. Health Services Use and Costs in Individuals with Autism Spectrum Disorder in Germany : Results from a Survey in ASD Outpatient Clinics. J Autism Dev Disord. 2021.

Autism spectrum disorders (ASD) are associated with high services use, but European data on costs are scarce. Utilisation and annual costs of 385 individuals with ASD (aged 4-67 years ; 18.2% females ; 37.4% IQ < 85) from German outpatient clinics were assessed. Average annual costs per person were 3287 EUR, with psychiatric inpatient care (19.8%), pharmacotherapy (11.1%), and occupational therapy (11.1%) being the largest cost components. Females incurred higher costs than males (4864 EUR vs. 2936 EUR). In a regression model, female sex (Cost Ratio : 1.65), lower IQ (1.90), and Asperger syndrome (1.54) were associated with higher costs. In conclusion, ASD-related health costs are comparable to those of schizophrenia, thus underlining its public health relevance. Higher costs in females demand further research.

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10. Horinouchi T, Maeyama K, Nagai M, Mizobuchi M, Takagi Y, Okada Y, Kato T, Nishimura M, Kawasaki Y, Yoshioka M, Takada S, Matsumoto H, Nakamachi Y, Saegusa J, Fukushima S, Fujioka K, Tomioka K, Nagase H, Nozu K, Iijima K, Nishimura N. Genetic Analysis of UGT1A1 Polymorphisms Using Preserved Dried Umbilical Cord for Assessing the Potential of Neonatal Jaundice as a Risk Factor for Autism Spectrum Disorder in Children. J Autism Dev Disord. 2021.

Neonatal jaundice has been suggested as a perinatal risk factor for autism spectrum disorder (ASD). We examined UGT1A1 polymorphisms to assess the potential of neonatal jaundice as a risk factor for ASD in children by using DNA extracted from preserved umbilical cord. In total, 79 children with ASD were genotyped for UGT1A1*28 (c.-41-40dup), UGT1A1*6 (c.211 G > A), and UGT1A1*27 (c.686 C > A). The allele frequency of UGT1A1*6 (OR = 1.34, p = 0.26) and UGT1A1*28 (OR = 0.80, p = 0.54) and the prevalence of UGT1A1*28/*6 diplotypes did not differ significantly from those in the control population. No UGT1A1*27 allele was detected in the subjects. ASD symptom assessment scores were not associated with UGT1A1*28/*6/*27 genotypes or UGT1A1*28/*6 diplotypes. These results suggest that neonatal jaundice is not significantly associated with ASD.

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11. Jang J, White SP, Esler AN, Kim SH, Klaiman C, Megerian JT, Morse A, Nadler C, Kanne SM. Diagnostic Evaluations of Autism Spectrum Disorder during the COVID-19 Pandemic. J Autism Dev Disord. 2021 : 1-12.

A global pandemic has significantly impacted the ability to conduct diagnostic evaluations for autism spectrum disorder (ASD). In the wake of the coronavirus, autism centers and providers quickly needed to implement innovative diagnostic processes to adapt in order to continue serve patient needs while minimizing the spread of the virus. The International Collaborative for Diagnostic Evaluation of Autism (IDEA) is a grassroots organization that came together to discuss standards of care during the pandemic and to provide a forum wherein providers communicated decisions. This white paper is intended to provide examples of how different centers adjusted their standard approaches to conduct diagnostic evaluations for ASD during the pandemic and to provide insight to other centers as they go through similar challenges.

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12. Kitagawa K, Matsumura K, Baba M, Kondo M, Takemoto T, Nagayasu K, Ago Y, Seiriki K, Hayata-Takano A, Kasai A, Takuma K, Hashimoto R, Hashimoto H, Nakazawa T. Intranasal oxytocin administration ameliorates social behavioral deficits in a POGZ(WT/Q1038R) mouse model of autism spectrum disorder. Molecular brain. 2021 ; 14(1) : 56.

Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder characterized by core symptoms of impaired social behavior and communication. Recent studies have suggested that the oxytocin system, which regulates social behavior in mammals, is potentially involved in ASD. Mouse models of ASD provide a useful system for understanding the associations between an impaired oxytocin system and social behavior deficits. However, limited studies have shown the involvement of the oxytocin system in the behavioral phenotypes in mouse models of ASD. We have previously demonstrated that a mouse model that carries the ASD patient-derived de novo mutation in the pogo transposable element derived with zinc finger domain (POGZ(WT/Q1038R) mice), showed ASD-like social behavioral deficits. Here, we have explored whether oxytocin (OXT) administration improves impaired social behavior in POGZ(WT/Q1038R) mice and found that intranasal oxytocin administration effectively restored the impaired social behavior in POGZ(WT/Q1038R) mice. We also found that the expression level of the oxytocin receptor gene (OXTR) was low in POGZ(WT/Q1038R) mice. However, we did not detect significant changes in the number of OXT-expressing neurons between the paraventricular nucleus of POGZ(WT/Q1038R) mice and that of WT mice. A chromatin immunoprecipitation assay revealed that POGZ binds to the promoter region of OXTR and is involved in the transcriptional regulation of OXTR. In summary, our study demonstrate that the pathogenic mutation in the POGZ, a high-confidence ASD gene, impairs the oxytocin system and social behavior in mice, providing insights into the development of oxytocin-based therapeutics for ASD.

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13. Lim A, Young RL, Brewer N. Autistic Adults May Be Erroneously Perceived as Deceptive and Lacking Credibility. J Autism Dev Disord. 2021.

We hypothesized that autistic adults may be erroneously judged as deceptive or lacking credibility due to demonstrating unexpected and atypical behaviors. Thirty autistic and 29 neurotypical individuals participated in video-recorded interviews, and we measured their demonstration of gaze aversion, repetitive body movements, literal interpretation of figurative language, poor reciprocity, and flat affect. Participants (N = 1410) viewed one of these videos and rated their perception of the individual’s truthfulness or credibility. The hypothesis was partially supported, with autistic individuals perceived as more deceptive and less credible than neurotypical individuals when telling the truth. However, this relationship was not influenced by the presence of any of the target behaviors, but instead, by the individual’s overall presentation.

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14. Puig-Lagunes Á A, Rocha L, Morgado-Valle C, BeltrÁn-Parrazal L, LÓpez-Meraz ML. Brain and plasma amino acid concentration in infant rats prenatally exposed to valproic acid. Anais da Academia Brasileira de Ciencias. 2021 ; 93(2) : e20190861.

Autism spectrum disorder is associated with alterations in GABAergic and glutamatergic neurotransmission. Here, we aimed to determine the concentration of GABA, glutamate, glutamine, aspartate, taurine, and glycine in brain tissue and plasma of rats prenatally exposed to valproic acid (VPA), a well-characterized experimental model of autism. Pregnant rats were injected with VPA (600mg/Kg) during the twelfth-embryonic-day. Control rats were injected with saline. On the fourteen-postnatal-day, rats from both groups (males and females) were anesthetized, euthanized by decapitation and their brain dissected out. The frontal cortex, hippocampus, amygdala, brain stem and cerebellum were dissected and homogenized. Homogenates were centrifuged and supernatants were used to quantify amino acid concentrations by HPLC coupled with fluorometric detection. Blood samples were obtained by a cardiac puncture ; plasma was separated and deproteinized to quantify amino acid concentration by HPLC. We found that, in VPA rats, glutamate and glutamine concentrations were increased in hippocampus and glycine concentration was increased in cortex. We did not find changes in other regions or in plasma amino acid concentration in the VPA group with respect to control group. Our results suggest that VPA exposure in utero may impair inhibitory and excitatory amino acid transmission in the infant brain.

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15. Tung YH, Lin HY, Chen CL, Shang CY, Yang LY, Hsu YC, Tseng WI, Gau SS. Whole Brain White Matter Tract Deviation and Idiosyncrasy From Normative Development in Autism and ADHD and Unaffected Siblings Link With Dimensions of Psychopathology and Cognition. Am J Psychiatry. 2021 : appiajp202020070999.

OBJECTIVE : The heterogeneity of autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) preclude definitive identification of neurobiomarkers and biological risks. High clinical overlap suggests multifaceted circuit-level alterations across diagnoses, which remains elusive. This study investigated whether individuals with ADHD or ASD and their unaffected siblings constitute a spectrum of neurodevelopmental conditions in terms of white matter etiology. METHODS : Sex-specific white matter tract normative development was modeled from diffusion MRI of 626 typically developing control subjects (ages 5-40 years ; 376 of them male). Individualized metrics estimating white matter tract deviation from the age norm were derived for 279 probands with ADHD, 175 probands with ASD, and their unaffected siblings (ADHD, N=121 ; ASD, N=72). RESULTS : ASD and ADHD shared diffuse white matter tract deviations in the commissure and association tracts (rho=0.54 ; p<0.001), while prefrontal corpus callosum deviated more remarkably in ASD (effect size=-0.36 ; p<0.001). Highly correlated deviance patterns between probands and unaffected siblings were found in both ASD (rho=0.69 ; p<0.001) and ADHD (rho=0.51 ; p<0.001), but only unaffected sisters of ASD probands showed a potential endophenotype in long-range association fibers and projection fibers connecting prefrontal regions. ADHD and ASD shared significant white matter tract idiosyncrasy (rho=0.55 ; p<0.001), particularly in tracts connecting prefrontal regions, not identified in either sibling group. Canonical correlation analysis identified multiple dimensions of psychopathology/cognition across categorical entities ; autistic, visual memory, intelligence/planning/inhibition, nonverbal-intelligence/attention, working memory/attention, and set-shifting/response-variability were associated with distinct sets of white matter tract deviations. CONCLUSIONS : When conceptualizing neurodevelopmental disorders as white matter tract deviations from normative patterns, ASD and ADHD are more alike than different. The modest white matter tract alterations in siblings suggest potential endophenotypes in these at-risk populations. This study further delineates brain-driven dimensions of psychopathology/cognition, which may help clarify within-diagnosis heterogeneity and high between-diagnosis co-occurrence.

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16. Zhang Y, Zeng J, Wu D, Li X, Chen Y, Dai S, Wang B, Qi Y, Lu J. Effect and safety of acupuncture for autism spectrum disorders : A protocol for systematic review and meta-analysis. Medicine. 2021 ; 100(11) : e22269.

BACKGROUND : Autism spectrum disorder (ASD) is a complex neurodevelopmental condition, which is characterized by impairment in social interaction or communication and lack of flexibility of imagination and behavior. Acupuncture is one of the most common modality of Traditional Chinese medicine (TCM) and has been used to treat various disease in clinical practice for more than 2000 years in China by correcting disharmony and dysregulation of body. It has sometimes been used as a treatment aimed at improving ASD symptoms and outcomes, but its clinical effectiveness and safety has not been rigorously reviewed. We will plan to conduct a systematic review and meta-analysis to summarize the current evidence on the effects and safety of acupuncture for ASD. METHODS : The following databases will be searched : PubMed, the Cochrane Library, Embase, Wanfang Data, China National Knowledge Infrastructure, SinoMed, and VIP. Randomised controlled trials will be included to evaluate the effect and safety of acupuncture on patients with ASD. The primary outcome will be the core features of ASD. The risk of bias will be assessed by the Cochrane risk of bias tool. We will conduct a meta-analysis and sensitivity analysis, as well as a subgroup analysis if high heterogeneity is present, using Revman 5.3. We will use funnel plots to identify potential reporting biases. The Grading of Recommendations Assessment, Development and Evaluation will be used to evaluate the quality of evidence. RESULTS : This study will be to assess the effect and safety of acupuncture for ASD. CONCLUSIONS : This study will assess the effect of acupuncture for ASD and provide reliable evidence for the choice of treatments. ETHICS AND DISSEMINATION : The protocol will not need ethical approval because no issues of participant privacy exist. The results of this systematic review will provide evidence about the effect and safety of acupuncture for ASD. The results will be disseminated through peer review.

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