1. Abu-Akel A, Wood SJ, Upthegrove R, Chisholm K, Lin A, Hansen PC, Gillespie SM, Apperly IA, Montag C. Psychosocial functioning in the balance between autism and psychosis: evidence from three populations. Molecular psychiatry. 2022.

Functional impairment is a core feature of both autism and schizophrenia spectrum disorders. While diagnostically independent, they can co-occur in the same individual at both the trait and diagnostic levels. The effect of such co-occurrence is hypothesized to worsen functional impairment. The diametric model, however, suggests that the disorders are etiologically and phenotypically diametrical, representing the extreme of a unidimensional continuum of cognition and behavior. A central prediction of this model is that functional impairment would be attenuated in individuals with mixed symptom expressions or genetic liability to both disorders. We tested this hypothesis in two clinical populations and one healthy population. In individuals with chronic schizophrenia and in individuals with first episode psychosis we evaluated the combined effect of autistic traits and positive psychotic symptoms on psychosocial functioning. In healthy carriers of alleles of copy number variants (CNVs) that confer risk for both autism and schizophrenia, we also evaluated whether variation in psychosocial functioning depended on the combined risk conferred by each CNV. Relative to individuals with biased symptom/CNV risk profiles, results show that functional impairments are attenuated in individuals with relatively equal levels of positive symptoms and autistic traits-and specifically stereotypic behaviors-, and in carriers of CNVs with relatively equal risks for either disorder. However, the pattern of effects along the « balance axis » varied across the groups, with this attenuation being generally less pronounced in individuals with high-high symptom/risk profile in the schizophrenia and CNV groups, and relatively similar for low-low and high-high individuals in the first episode psychosis group. Lower levels of functional impairments in individuals with « balanced » symptom profile or genetic risks would suggest compensation across mechanisms associated with autism and schizophrenia. CNVs that confer equal risks for both disorders may provide an entry point for investigations into such compensatory mechanisms. The co-assessment of autism and schizophrenia may contribute to personalized prognosis and stratification strategies.

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2. Artiles O, Saeed F. A Multi-Factorial Assessment of Functional Human Autistic Spectrum Brain Network Analysis. Proceedings IEEE International Conference on Bioinformatics and Biomedicine. 2021; 2021: 3526-31.

The variability of the results obtained by the statistical analysis of functional human brain networks depend on multiple factors such as: the source of the fMRI data, the brain parcellations, the graph theory measures, and the threshold values applied to the functional connectivity matrices to obtain adjacency matrices of sparse graphs. Therefore, the brain network used for down-stream analysis is heavily dependent on the methods that are applied to the fMRI data to obtain and analyze such networks. In this paper we present the preliminary results of a multi-factorial assessment of the statistical analysis of functional human brain networks. The assessment was performed in the functional human brain networks obtained from the resting state fMRI data of ten imaging sites provided by the Autism Brain Imaging Data Exchange (ABIDE) preprocessed functional magnetic resonance database, with six different functional brain parcellations, six different graph theory measures, and three different threshold values applied to the corresponding connectivity matrices to obtain sparse graphs. The statistical analysis to detect differences between the networks representing autism and control subjects were performed with four different statistical methods, using the p-values to determine the levels of significance of the analysis. Our main results show a strong dependence of functional human brain networks statistical analysis on the brain parcellations, and on the graph theory measures. Our results further show that the results of these analysis are less dependent on the statistical tests methods and on the threshold values of the sparse graphs for all practical purposes. An additional result is that the levels of significance of the statistical tests obtained for data provided by individual sites were much higher than the global levels of significance obtained by averaging the results of all the sites, implying that the best results on the analysis of functional human brain networks are obtained when the source of the fMRI data is the same for all the data. Since reproducibility and reliability of functional brain network statistical analysis is strongly dependent on the graphs obtained from fMRI data; our expectation is that the novel results presented in this paper would further help researchers in this field to develop methods that are reliable and reproducible.

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3. de la Torre-Aguilar MJ, Gomez-Fernandez A, Flores-Rojas K, Martin-Borreguero P, Mesa MD, Perez-Navero JL, Olivares M, Gil A, Gil-Campos M. Docosahexaenoic and Eicosapentaenoic Intervention Modifies Plasma and Erythrocyte Omega-3 Fatty Acid Profiles But Not the Clinical Course of Children With Autism Spectrum Disorder: A Randomized Control Trial. Frontiers in nutrition. 2022; 9: 790250.

BACKGROUND: The pathogenesis of autism spectrum disorder (ASD) is under investigation and one of the main alterations relates to the metabolic and inflammatory system dysfunctions. Indeed, based on a possible deficit of omega-3 fatty acids (FAs) of patients with ASD and looking for an anti-inflammatory effect, dietary supplements with omega-3 fatty acids have been proposed. We aimed to evaluate differences in plasma and erythrocyte FA profiles and plasma cytokines in patients with infantile ASD after supplementation with docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids or placebo and both compared at baseline with a reference healthy group. METHODS: A double-blind, randomized placebo-controlled intervention with DHA/EPA for 6 months was carried out in 54 children between 2 and 6 years diagnosed with ASD. They were selected and randomly assigned into two groups: 19 children received 800 mg/day of DHA and 25 mg/day of EPA, or placebo. In addition, another reference group of 59 healthy children of the same age was included. Plasma lipids and cytokines, and FA profiles in plasma and erythrocytes were measured at baseline and after 6 months of treatment in ASD children, and at baseline in the reference group. RESULTS: There were no differences in demographic, anthropometric characteristics, and omega-3 intake between the healthy reference group and the ASD children at baseline. Children with ASD showed the higher plasma percentages of palmitic acid and total saturated FA and lower total omega-6 polyunsaturated FA (PUFA) compared with healthy children. An increased level of DHA and reduced EPA level in erythrocytes were detected in the ASD group vs. the reference group. After 6 months of treatment, the ASD group that received DHA enriched product significantly increased the plasma and erythrocyte percentages of DHA, but no differences were observed in the clinical test scores and other parameters as plasma cytokines between the two groups of ASD related to the intervention. CONCLUSION: Spanish children with ASD exhibit an appropriate omega-3 FA status in plasma and erythrocytes. Neither a clinical improvement of ASD children nor a better anti-inflammatory or fatty acid state has been found after an intervention with DHA/EPA for 6 months. So, the prescription of n-3 LC-PUFA and other dietary supplements in ASD should be only indicated after a confirmed alteration of FA metabolism or omega-3 LC-PUFA deficiency evaluated by specific erythrocyte FA. CLINICAL TRIAL REGISTRATION: [www.ClinicalTrials.gov], identifier [NCT03620097].

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4. Heijnen-Kohl SMJ, Hitzert B, Schmidt R, Geurts HM, van Alphen SPJ. Features and Needs of Autistic Older Adults: A Delphi Study of Clinical Experiences. Clinical gerontologist. 2022: 1-11.

OBJECTIVES: In geriatric psychiatry Autism Spectrum Disorders (ASD) are increasingly recognized. This study explores what clinicians know about diagnostic and/or therapeutic aspects of autistic older adults and how aging plays a role in the course of ASD. METHODS: A Delphi study outlines the point of view of 11 clinical experts in the Netherlands and Belgium (Flanders). RESULTS: Regarding diagnostics, age-specific aspects need to be considered. Age-related characteristics (cognitive differences, life events, co-occurring conditions) influence detecting autistic features in older adults. Regarding treatment, counseling methods need to be adapted. Psychoeducation, family therapy, couples therapy, behavioral counseling and psychopharmaca can be helpful in meeting the needs of autistic older adults. There was no consensus on the effects of aging on autistic older adults. CONCLUSIONS: Diagnosis and treatment of ASD need adaptation for autistic older adults. Further research is needed on the validation of measurement tools, recorded treatment, therapy, psychoeducation, and the effects of aging among people on the autism spectrum. CLINICAL IMPLICATIONS: Available knowledge helps clinicians to detect ASD in older adults and adapt to the specific features and needs of autistic older adults. The effects of aging on the course of ASD are unclear yet.

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5. Lee Y, Huh JR. Trust your gut, lest thou be anxious. Cell. 2022; 185(8): 1294-6.

Can gut-residing bacteria influence mood and anxiety? And can targeting bacteria-produced metabolites reduce anxiety? Based on two Nature and Nature Medicine papers, the answers to these questions are likely yes. Needham, Campbell, and colleagues identified bacteria that enhance anxiety-like behaviors in mice and ways to mitigate anxiety in autistic patients.

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6. Leoncini S, Signorini C, Boasiako L, Scandurra V, Hayek J, Ciccoli L, Rossi M, Canitano R, De Felice C. Breathing Abnormalities During Sleep and Wakefulness in Rett Syndrome: Clinical Relevance and Paradoxical Relationship With Circulating Pro-oxidant Markers. Frontiers in neurology. 2022; 13: 833239.

BACKGROUND: Breathing abnormalities are common in Rett syndrome (RTT), a pervasive neurodevelopmental disorder almost exclusively affecting females. RTT is linked to mutations in the methyl-CpG-binding protein 2 (MeCP2) gene. Our aim was to assess the clinical relevance of apneas during sleep-wakefulness cycle in a population with RTT and the possible impact of apneas on circulating oxidative stress markers. METHODS: Female patients with a clinical diagnosis of typical RTT (n = 66), MECP2 gene mutation, and apneas were enrolled (mean age: 12.5 years). Baseline clinical severity, arterial blood gas analysis, and red blood cell count were assessed. Breathing was monitored during the wakefulness and sleep states (average recording time: 13 ± 0.5 h) with a portable polygraphic screening device. According to prevalence of breath holdings, the population was categorized into the wakefulness apnea (WA) and sleep apnea (SA) groups, and apnea-hypopnea index (AHI) was calculated. The impact of respiratory events on oxidative stress was assessed by plasma and intra-erythrocyte non-protein-bound iron (P-NPBI and IE-NPBI, respectively), and plasma F(2)-isoprostane (F(2)-IsoP) assays. RESULTS: Significant prevalence of obstructive apneas with values of AHI > 15 was present in 69.7% of the population with RTT. The group with SA showed significantly increased AHI values > 15 (p = 0.0032), total breath holding episodes (p = 0.007), and average SpO(2) (p = 0.0001) as well as lower nadir SpO(2) (p = 0.0004) compared with the patients with WAs. The subgroups of patients with WA and SA showed no significant differences in arterial blood gas analysis variables (p > 0.089). Decreased mean cell hemoglobin (MCH) (p = 0.038) was observed in the group with WAs. P-NPBI levels were significantly higher in the group with WA than in that with SAs (p = 0.0001). Stepwise multiple linear regression models showed WA being related to nadir SpO(2), average SpO(2), and P-NPBI (adjusted R (2) = 0.613, multiple correlation coefficient = 0.795 p < 0.0001), and P-NPBI being related to average SpO(2), blood PaCO(2), red blood cell mean corpuscular volume (MCV), age, and topiramate treatment (adjusted R (2) = 0.551, multiple correlation coefficient = 0.765, p < 0.0001). CONCLUSION: Our findings indicate that the impact of apneas in RTT is uneven according to the sleep-wakefulness cycle, and that plasma redox active iron represents a potential novel therapeutic target.

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7. Li X, Yang C, An Z, Wang X, Su R, Kang J. Localization and diagnosis of abnormal channels in children with ASD based on WMSSE and ASI. Journal of neuroscience methods. 2022; 375: 109595.

BACKGROUND: The purpose of this study is to explore the differences of resting EEG in children with autism spectrum disorders and then analyze the sensitive channels with significant differences, to provide support for the accurate differential diagnosis of autism spectrum disorder (ASD). NEW METHOD: Based on the weighted multi-scale sample entropy (WMSSE) algorithm and amplitude synchronization index (ASI) algorithm of EEG, this paper comprehensively evaluates the brain state of ASD children from the two aspects of brain function complexity and brain function synchronization connectivity. Further, by combining the support vector machine (SVM) classification model to explore the location of abnormal channels of ASD children and realize the diagnosis of ASD children. RESULTS: The WMSSE of the ASD group was lower than that of the healthy group. Furthermore, there was a significant difference in the F3/F4 channels and F7/F8 channels (P < 0.05), and the synchronization of the brain in the ASD group was also lower than that of the healthy group in Delta, Theta, Alpha, Beta band. Finally, combined with the WMSSE and ASI features of the F3/F4 channels (posterior frontal lobe) and F7/F8 channels (anterior temporal lobe), the classification accuracy and AUC value of ASD patients calculated by the SVM classification model were 82.7 ± 3.2%/ 0.795 (F3 / F4 channels), 89.8 ± 1.7%/ 0.812 (F7 / F8 channels). COMPARISON WITH EXISTING METHODS: It avoids the one-sided problem of single analysis complexity and synchronous connectivity, and provides a research basis for the comprehensive evaluation of ASD brain function. CONCLUSION: WMSSE and ASI can be used as effective potential biomarkers for ASD diagnosis, and F7 and F8 channels can be preliminarily located as abnormal sensitive channels for ASD brain regulation. It also proves that the feature analysis of comprehensive complexity and synchronous connectivity is more conducive to the abnormal diagnosis of ASD patients.

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8. Mitchelson H, Adams D, Simpson K. Factors and experiences that influence school mobility for autistic students: A systematic review. The British journal of educational psychology. 2022.

BACKGROUND: Autistic students are reported to move schools at a high rate, but little is understood about why this is happening. What is known is that the effects of school mobility can negatively impact both short- and long-term outcomes, particularly the child’s learning, behaviours, mental health and school retention. AIMS: The aim of this systematic review was to synthesize the research on factors and experiences which influence the family’s decision to move their autistic child to another school. METHODS: A protocol was registered with PROPERO (ID: CRD4202120794). Searches were conducted with ERIC, Scopus and Web of Science and seven studies were identified. RESULTS: The studies focused on three main types of mobility: mainstream-to-mainstream school moves, moving between mainstream and segregated schools, and moving between mainstream and homeschool. Parents’ concerns for their child’s learning, social experiences and mental health, as well as their own interactions with their child’s school, influenced the decision to leave. Whilst there were similarities across the studies for reasons to move, there were also differences based upon the settings between which students moved. CONCLUSION: The findings highlight the need for further research across all school mobility types to better understand the reasons underpinning high rates of school mobility for autistic students.

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9. Obst B, Roesler M, Fato P, Goff C. Supporting Children on the Autism Spectrum as They Experience the Challenges of COVID-19. NASN school nurse (Print). 2022: 1942602×221089047.

The response to the COVID-19 pandemic has amplified stress and social isolation for many children, but those children living with a diagnosis of autism spectrum disorder (ASD) have been disproportionately affected. Prior to the pandemic, children with ASD often faced social isolation due to struggles with their social communication and social development. Planning for children with ASD to return to community experiences, including school, appointments, and even recreational activities, will require an understanding of the impact of COVID-19 on the child and their family. As the child and family are working to adjust to changes like new routines, sleep patterns, and sensory issues as a result of the pandemic, the pediatric nursing community should be knowledgeable and prepared to develop creative opportunities to meet the needs of this vulnerable population.

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10. Scala M, Grasso EA, Di Cara G, Riva A, Striano P, Verrotti A. The Pathophysiological Link Between Reelin and Autism: Overview and New Insights. Frontiers in genetics. 2022; 13: 869002.

Reelin is a secreted extracellular matrix protein playing pivotal roles in neuronal migration and cortical stratification during embryonal brain development. In the adult brain, its activity is crucial for synaptic plasticity, memory processing, and cognition. Genetic alterations in RELN have been variably reported as possible contributors to the pathogenesis of autism spectrum disorders (ASD). In particular, GCCs repeats in the 5’UTR, and single nucleotide polymorphysms (SNPs) in RELN have been suggested to affect brain development and predispose to autism. We reviewed pertinent literature on RELN expression and haplotypes transmission in children with ASD, critically analyzing available evidence in support of the pathophysiological association between Reelin deficiency and ASD.

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11. Skoglund C, Leknes S, Heilig M. The partial µ-opioid agonist buprenorphine in autism spectrum disorder: a case report. Journal of medical case reports. 2022; 16(1): 152.

BACKGROUND: There are currently no approved medications for impaired social cognition and function, core symptoms of autism spectrum disorder. We describe marked improvement of these symptoms with long-term low-dose administration of the partial µ-opioid agonist buprenorphine. We discuss these observations in the context of a role for endogenous opioid systems in social attachment, and theories integrating those findings mechanistically with autism spectrum disorder. CASE PRESENTATION: M, a 43-year-old Caucasian male, is medically healthy. Despite social difficulties since childhood, he completed high school with better-than-average grades, but failed university education. A psychiatric evaluation in his twenties diagnosed attention deficit hyperactivity disorder but also noted symptoms of coexisting autism spectrum disorder. M accidentally came across buprenorphine in his late twenties and experienced progressively improved social functioning on a low daily dosage (0.5-1.0 mg/day), an effect maintained for 15 years. He lived independently and maintained a part-time occupation. After abrupt discontinuation of treatment, his autistic symptoms returned, and function deteriorated. Following evaluation by our team, buprenorphine was resumed, with gradual return to prior level of functioning. An attempt to formally evaluate M both on and off medication was agreed with him and approved by the Swedish Ethics Authority, but medication had to be resumed when the patient worsened following discontinuation. CONCLUSIONS: According to the µ-opioid receptor balance model, both excessive and deficient μ-receptor activity may negatively influence social behavior, and accordingly both opioid agonist and opioid antagonist treatment may be able to improve social functioning, depending on an individual’s opioid tone before treatment. Our case report is consistent with these hypotheses, and given the extensive unmet medical needs in individuals with autism spectrum disorders, randomized controlled trial appears warranted.

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12. Vershkov D, Yilmaz A, Yanuka O, Nielsen AL, Benvenisty N. Genome-wide screening for genes involved in the epigenetic basis of fragile X syndrome. Stem cell reports. 2022.

Fragile X syndrome (FXS), the most prevalent heritable form of intellectual disability, is caused by the transcriptional silencing of the FMR1 gene. The epigenetic factors responsible for FMR1 inactivation are largely unknown. Here, we initially demonstrated the feasibility of FMR1 reactivation by targeting a single epigenetic factor, DNMT1. Next, we established a model system for FMR1 silencing using a construct containing the FXS-related mutation upstream to a reporter gene. This construct was methylated in vitro and introduced into a genome-wide loss-of-function (LOF) library established in haploid human pluripotent stem cells (PSCs), allowing the identification of genes whose functional loss reversed the methylation-induced silencing of the FMR1 reporter. Selected candidate genes were further analyzed in haploid- and FXS-patient-derived PSCs, highlighting the epigenetic and metabolic pathways involved in FMR1 regulation. Our work sheds light on the mechanisms responsible for CGG-expansion-mediated FMR1 inactivation and offers novel targets for therapeutic FMR1 reactivation.

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13. Wang B, Qin Y, Wu Q, Li X, Xie D, Zhao Z, Duan S. mTOR Signaling Pathway Regulates the Release of Proinflammatory Molecule CCL5 Implicated in the Pathogenesis of Autism Spectrum Disorder. Frontiers in immunology. 2022; 13: 818518.

Autism spectrum disorder (ASD) is a complex pervasive neurodevelopmental disorder and neuroinflammation may contribute to the pathogenesis of ASD. However, the exact mechanisms of abnormal release of proinflammatory mediators in ASD remain poorly understood. This study reports elevated plasma levels of the proinflammatory chemokine (C-C motif) ligand 5 (CCL5) in children with ASD, suggesting an aberrant inflammatory response appearing in the development of ASD. Mining of the expression data of brain or blood tissue from individuals with ASD reveals that mTOR signaling is aberrantly activated in ASD patients. Our in vitro study shows that suppression of mTOR reduces the gene expression and release of CCL5 from human microglia, supporting that CCL5 expression is regulated by mTOR activity. Furthermore, bacterial lipopolysaccharide (LPS)-induced CCL5 expression can be counteracted by siRNA against NF-κB, suggests a determining role of NF-κB in upregulating CCL5 expression. However, a direct regulatory relationship between the NF-κB element and the mTOR signaling pathway was not observed in rapamycin-treated cells. Our results show that the phosphorylated CREB can be induced to suppress CCL5 expression by outcompeting NF-κB in binding to CREB-binding protein (CREBBP) once the mTOR signaling pathway is inhibited. We propose that the activation of mTOR signaling in ASD may induce the suppression of phosphorylation of CREB, which in turn results in the increased binding of CREBBP to NF-κB, a competitor of phosphorylated CREB to drive expression of CCL5. Our study sheds new light on the inflammatory mechanisms of ASD and paves the way for the development of therapeutic strategy for ASD.

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14. Wang L, Feng J, Zhang Y, Wang T. Effect of the Early Start Denver Model on Children With Autism Spectrum Disorder Syndrome of Different Traditional Chinese Medicine Types in Northeast China. Frontiers in pediatrics. 2022; 10: 851109.

BACKGROUND: The clinical presentation of children with autism spectrum disorder (ASD) is heterogeneous, and there are little data available on the treatment of children with different types of ASD. We sought to explore which traditional Chinese medicine (TCM) syndrome type was more effective for children with ASD after 3 months of Early Denver Model intervention and to analyze the reasons for its efficacy from the perspective of TCM. METHODS: This was a retrospective study. The subjects were children with ASD who were first diagnosed at the Developmental Behavioral Pediatrics, the First Hospital of Jilin University, between December 2018 and September 2019. Eighty-nine children were divided into a kidney jing deficiency group, a liver qi stagnation group, and a group with deficiency of both the heart and spleen. RESULTS: After treatment, the total Autism Behavior Checklist (ABC), Autism Treatment Evaluation Checklist, and Childhood Autism Rating Scale scores were significantly reduced in the three groups (p < 0.05) compared to before treatment. Significant improvements were seen in all five domains of the Griffiths Development Scales-Chinese version in the LQ group (p < 0.05). After intervention, the LQ group showed greater improvements compared to the other two groups in the language, eye-hand coordination, body and object use, social and self-help, and total ABC scores. CONCLUSION: Our study showed that Early Denver Model intervention is effective in the treatment of three syndrome types of children with ASD, with the LQ group experiencing the most significant effects.

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