1. Alaerts K, Moerkerke M, Daniels N, Zhang Q, Grazia R, Steyaert J, Prinsen J, Boets B. Chronic oxytocin improves neural decoupling at rest in children with autism: an exploratory RCT. J Child Psychol Psychiatry;2024 (Feb 23)

BACKGROUND: Shifts in peak frequencies of oscillatory neural rhythms are put forward as a principal mechanism by which cross-frequency coupling/decoupling is implemented in the brain. During active neural processing, functional integration is facilitated through transitory formations of « harmonic » cross-frequency couplings, whereas « nonharmonic » decoupling among neural oscillatory rhythms is postulated to characterize the resting, default state of the brain, minimizing the occurrence of spurious, noisy, background couplings. METHODS: Within this exploratory, randomized, placebo-controlled trial, we assessed whether the transient occurrence of nonharmonic and harmonic relationships between peak-frequencies in the alpha (8-14 Hz) and theta (4-8 Hz) bands is impacted by intranasal administration of oxytocin, a neuromodulator implicated in improving homeostasis and reducing stress/anxiety. To do so, resting-state electroencephalography was acquired before and after 4 weeks of oxytocin administration (12 IU twice-daily) in children with autism spectrum disorder (8-12 years, n = 33 oxytocin; n = 34 placebo). At the baseline, neural assessments of children with autism were compared with those of a matched cohort of children without autism (n = 40). RESULTS: Compared to nonautistic peers, autistic children displayed a lower incidence of nonharmonic alpha-theta cross-frequency decoupling, indicating a higher incidence of spurious « noisy » coupling in their resting brain (p = .001). Dimensionally, increased neural coupling was associated with more social difficulties (p = .002) and lower activity of the parasympathetic « rest & digest » branch of the autonomic nervous system (p = .018), indexed with high-frequency heart-rate-variability. Notably, after oxytocin administration, the transient formation of nonharmonic cross-frequency configurations was increased in the cohort of autistic children (p < .001), indicating a beneficial effect of oxytocin on reducing spurious cross-frequency-interactions. Furthermore, parallel epigenetics changes of the oxytocin receptor gene indicated that the neural effects were likely mediated by changes in endogenous oxytocinergic signaling (p = .006). CONCLUSIONS: Chronic oxytocin induced important homeostatic changes in the resting-state intrinsic neural frequency architecture, reflective of reduced noisy oscillatory couplings and improved signal-to-noise properties.

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2. Albini M, Almacellas-Barbanoj A, Krawczun-Rygmaczewska A, Ciano L, Benfenati F, Michetti C, Cesca F. Alterations in KIDINS220/ARMS Expression Impact Sensory Processing and Social Behavior in Adult Mice. Int J Mol Sci;2024 (Feb 16);25(4)

Kinase D-interacting substrate of 220 kDa (Kidins220) is a transmembrane protein that participates in neural cell survival, maturation, and plasticity. Mutations in the human KIDINS220 gene are associated with a neurodevelopmental disorder (‘SINO’ syndrome) characterized by spastic paraplegia, intellectual disability, and in some cases, autism spectrum disorder. To better understand the pathophysiology of KIDINS220-linked pathologies, in this study, we assessed the sensory processing and social behavior of transgenic mouse lines with reduced Kidins220 expression: the CaMKII-driven conditional knockout (cKO) line, lacking Kidins220 in adult forebrain excitatory neurons, and the Kidins220floxed line, expressing constitutively lower protein levels. We show that alterations in Kidins220 expression levels and its splicing pattern cause impaired response to both auditory and olfactory stimuli. Both transgenic lines show impaired startle response to high intensity sounds, with preserved pre-pulsed inhibition, and strongly reduced social odor recognition. In the Kidins220floxed line, olfactory alterations are associated with deficits in social memory and increased aggressive behavior. Our results broaden our knowledge of the SINO syndrome; understanding sensory information processing and its deviations under neuropathological conditions is crucial for devising future therapeutic strategies to enhance the quality of life of affected individuals.

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3. Alsayouf HA, Alsarhan O, Khreisat W, Daoud A. Atomoxetine Treatment of Attention Deficit/Hyperactivity Disorder Symptoms in 3-6-Year-Old Children with Autism Spectrum Disorder: A Retrospective Cohort Study. Children (Basel);2024 (Jan 26);11(2)

Atomoxetine is indicated for the management of attention deficit/hyperactivity disorder (ADHD) in children and adolescents aged 6 to 18 years. Few studies have assessed the safety and tolerability of atomoxetine in younger patients. This retrospective cohort study included 133 children aged 3-6 years who were diagnosed with ADHD comorbid with autism spectrum disorder (ASD). The primary endpoint was the evaluation of the safety profile of atomoxetine. In total, 50 patients (37.6%) experienced adverse events (AEs), which led to treatment discontinuation in 23 patients (17.3%). The most common AEs were gastrointestinal (24.1%), aggression or hostility (12.8%), and increased hyperactivity (9.0%). In the 23 patients who discontinued treatment, all the AEs resolved after treatment ceased. Among the 110 patients who completed at least 6 months’ treatment, atomoxetine titrated to a dose of 1.2-1.8 mg/kg/day appeared to be well tolerated and effective. The Clinical Global Impression-Improvement score improved to 1 (« very much improved ») and 2 (« much improved ») in 62.4% and 20.3% of children, respectively, at their last visit. Overall, atomoxetine appeared to be well tolerated in younger children with comorbid ADHD and ASD. Nevertheless, close patient monitoring remains essential, and the study limitations necessitate caution in generalizing these findings to broader populations. Long-term prospective studies are required.

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4. Camerino C. The Pivotal Role of Oxytocin’s Mechanism of Thermoregulation in Prader-Willi Syndrome, Schaaf-Yang Syndrome, and Autism Spectrum Disorder. Int J Mol Sci;2024 (Feb 8);25(4)

Oxytocin (Oxt) regulates thermogenesis, and altered thermoregulation results in Prader-Willi syndrome (PWS), Schaaf-Yang syndrome (SYS), and Autism spectrum disorder (ASD). PWS is a genetic disorder caused by the deletion of the paternal allele of 15q11-q13, the maternal uniparental disomy of chromosome 15, or defects in the imprinting center of chromosome 15. PWS is characterized by hyperphagia, obesity, low skeletal muscle tone, and autism spectrum disorder (ASD). Oxt also increases muscle tonicity and decreases proteolysis while PWS infants are hypotonic and require assisted feeding in early infancy. This evidence inspired us to merge the results of almost 20 years of studies and formulate a new hypothesis according to which the disruption of Oxt’s mechanism of thermoregulation manifests in PWS, SYS, and ASD through thermosensory abnormalities and skeletal muscle tone. This review will integrate the current literature with new updates on PWS, SYS, and ASD and the recent discoveries on Oxt’s regulation of thermogenesis to advance the knowledge on these diseases.

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5. Ding N, Fu L, Qian L, Sun B, Li C, Gao H, Lei T, Ke X. The correlation between brain structure characteristics and emotion regulation ability in children at high risk of autism spectrum disorder. Eur Child Adolesc Psychiatry;2024 (Feb 24)

As indicated by longitudinal observation, autism has difficulty controlling emotions to a certain extent in early childhood, and most children’s emotional and behavioral problems are further aggravated with the growth of age. This study aimed at exploring the correlation between white matter and white matter fiber bundle connectivity characteristics and their emotional regulation ability in children with autism using machine learning methods, which can lay an empirical basis for early clinical intervention of autism. Fifty-five high risk of autism spectrum disorder (HR-ASD) children and 52 typical development (TD) children were selected to complete the skull 3D-T1 structure and diffusion tensor imaging (DTI). The emotional regulation ability of the two groups was compared using the still-face paradigm (SFP). The classification and regression models of white matter characteristics and white matter fiber bundle connections of emotion regulation ability in the HR-ASD group were built based on the machine learning method. The volume of the right amygdala (R(2) = 0.245) and the volume of the right hippocampus (R(2) = 0.197) affected constructive emotion regulation strategies. FA (R(2) = 0.32) and MD (R(2) = 0.34) had the predictive effect on self-stimulating behaviour. White matter fiber bundle connection predicted constructive regulation strategies (positive edging R(2) = 0.333, negative edging R(2) = 0.334) and mother-seeking behaviors (positive edging R(2) = 0.667, negative edging R(2) = 0.363). The emotional regulation ability of HR-ASD children is significantly correlated with the connections of multiple white matter fiber bundles, which is a potential neuro-biomarker of emotional regulation ability.

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6. Genovesi E, Yao YI, Mitchell E, Arad M, Diamant V, Panju A, Hanlon C, Tekola B, Hoekstra RA. Mapping awareness-raising and capacity-building materials on developmental disabilities for non-specialists: a review of the academic and grey literature. Int J Ment Health Syst;2024 (Feb 24);18(1):10.

Most children with developmental disabilities (DD), such as intellectual disabilities and autism, live in low- and middle-income countries (LMICs), where services are usually limited. Various governmental, non-governmental and research organisations in LMICs have developed awareness-raising campaigns and training and education resources on DD in childhood relevant to LMICs. This study aimed to comprehensively search and review freely available materials in the academic and grey literature, aimed at awareness raising, training and education on DD among non-specialist professionals and community members in LMICs. We consulted 183 experts, conducted key-word searches in five academic databases, four grey-literature databases and seventeen customised Google search engines. Following initial screening, we manually searched relevant systematic reviews and lists of resources and conducted forwards and backwards citation checks of included articles. We identified 7327 articles and resources after deduplication. We then used a rigorous multi-step screening process to select 78 training resources on DD relevant to LMICs, of which 43 aimed at informing and/or raising awareness DD, 16 highlighted specific strategies for staff in health settings and 19 in education settings. Our mapping analysis revealed that a wealth of materials is available for both global and local use, including comics, children’s books, flyers, posters, fact sheets, blogs, videos, websites pages, social media channels, handbooks and self-education guides, and training programmes or sessions. Twelve resources were developed for cross-continental or global use in LMICs, 19 were developed for and/or used in Africa, 23 in Asia, 24 in Latin America. Most resources were developed within the context where they were intended to be used. Identified gaps included a limited range of resources on intellectual disabilities, manuals for actively delivering training to staff in education settings and resources targeted at eastern European LMICs: future intervention development and adaptation efforts should address such gaps, to ensure capacity building materials exist for a sufficient variety of DD, settings and geographical areas. Beyond identifying these gaps, the value of the review lies in the compilation of summary tables of information on all freely available resources found, to support their selection and use in wider contexts. Information on the resource content, country of original development and copyright is provided to facilitate resource sharing and uptake.

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7. Hayden-Evans M, Evans K, Milbourn B, D’Arcy E, Chamberlain A, Afsharnejad B, Whitehouse A, Bölte S, Girdler S. Validating the International Classification of Functioning, Disability and Health Core Sets for Autism in a Sample of Australian School-Aged Children on the Spectrum. J Autism Dev Disord;2024 (Feb 24)

Assessing functioning of children on the autism spectrum is necessary to determine the level of support they require to participate in everyday activities across contexts. The International Classification of Functioning, Disability and Health (ICF) is a comprehensive biopsychosocial framework recommended for classifying health-related functioning in a holistic manner, across the components of body functions, activities and participation, and environmental factors. The ICF Core Sets (ICF-CSs) are sub-sets of relevant codes from the broader framework that provide a basis for developing condition-specific measures. This study combined the ICF-CSs for autism, attention deficit hyperactivity disorder (ADHD) and cerebral palsy (CP) to validate the ICF-CSs for autism in an Australian sample of school-aged children. This cross-sectional study involved caregivers of school-aged children on the spectrum (n = 70) completing an online survey and being visited in their homes by an occupational therapist to complete the proxy-report measure based on the ICF-CSs for autism, ADHD and CP. Absolute and relative frequencies of ratings for each of the codes included in the measure were calculated and reported, along with the number of participants who required clarification to understand the terminology used. Findings indicate that the body functions and activities and participation represented in the ICF-CSs for autism were the most applicable for the sample. However, findings relating to environmental factors were less conclusive. Some codes not currently included in the ICF-CSs for autism may warrant further investigation, and the language used in measures based on the ICF-CSs should be revised to ensure clarity.

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8. Iyer SH, Yeh MY, Netzel L, Lindsey MG, Wallace M, Simeone KA, Simeone TA. Dietary and Metabolic Approaches for Treating Autism Spectrum Disorders, Affective Disorders and Cognitive Impairment Comorbid with Epilepsy: A Review of Clinical and Preclinical Evidence. Nutrients;2024 (Feb 17);16(4)

Epilepsy often occurs with other neurological disorders, such as autism, affective disorders, and cognitive impairment. Research indicates that many neurological disorders share a common pathophysiology of dysfunctional energy metabolism, neuroinflammation, oxidative stress, and gut dysbiosis. The past decade has witnessed a growing interest in the use of metabolic therapies for these disorders with or without the context of epilepsy. Over one hundred years ago, the high-fat, low-carbohydrate ketogenic diet (KD) was formulated as a treatment for epilepsy. For those who cannot tolerate the KD, other diets have been developed to provide similar seizure control, presumably through similar mechanisms. These include, but are not limited to, the medium-chain triglyceride diet, low glycemic index diet, and calorie restriction. In addition, dietary supplementation with ketone bodies, polyunsaturated fatty acids, or triheptanoin may also be beneficial. The proposed mechanisms through which these diets and supplements work to reduce neuronal hyperexcitability involve normalization of aberrant energy metabolism, dampening of inflammation, promotion of endogenous antioxidants, and reduction of gut dysbiosis. This raises the possibility that these dietary and metabolic therapies may not only exert anti-seizure effects, but also reduce comorbid disorders in people with epilepsy. Here, we explore this possibility and review the clinical and preclinical evidence where available.

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9. Lamanna J, Meldolesi J. Autism Spectrum Disorder: Brain Areas Involved, Neurobiological Mechanisms, Diagnoses and Therapies. Int J Mol Sci;2024 (Feb 19);25(4)

Autism spectrum disorder (ASD), affecting over 2% of the pre-school children population, includes an important fraction of the conditions accounting for the heterogeneity of autism. The disease was discovered 75 years ago, and the present review, based on critical evaluations of the recognized ASD studies from the beginning of 1990, has been further developed by the comparative analyses of the research and clinical reports, which have grown progressively in recent years up to late 2023. The tools necessary for the identification of the ASD disease and its related clinical pathologies are genetic and epigenetic mutations affected by the specific interaction with transcription factors and chromatin remodeling processes occurring within specific complexes of brain neurons. Most often, the ensuing effects induce the inhibition/excitation of synaptic structures sustained primarily, at dendritic fibers, by alterations of flat and spine response sites. These effects are relevant because synapses, established by specific interactions of neurons with glial cells, operate as early and key targets of ASD. The pathology of children is often suspected by parents and communities and then confirmed by ensuing experiences. The final diagnoses of children and mature patients are then completed by the combination of neuropsychological (cognitive) tests and electro-/magneto-encephalography studies developed in specialized centers. ASD comorbidities, induced by processes such as anxieties, depressions, hyperactivities, and sleep defects, interact with and reinforce other brain diseases, especially schizophrenia. Advanced therapies, prescribed to children and adult patients for the control of ASD symptoms and disease, are based on the combination of well-known brain drugs with classical tools of neurologic and psychiatric practice. Overall, this review reports and discusses the advanced knowledge about the biological and medical properties of ASD.

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10. Loffi RG, Cruz TKF, Paiva GM, Souto DO, Barreto SR, Santana PAN, Nascimento A, Costa FRM, Cota EB, Haase VG. Theoretical-Methodological Foundations for the Global Integration Method (Método de Integração Global-MIG) in the Treatment of Autism Spectrum Disorder. Children (Basel);2024 (Feb 2);11(2)

Currently, there is no intervention model for autism spectrum disorder (ASD) that addresses all levels and factors of the International Classification of Functioning, Disability and Health (ICF, WHO). The most researched programs focus on naturalistic, developmental and behavioral approaches to socio-communication. Less attention has been paid to motor and environmental reactivity aspects (behavior/interest restriction and sensory reactivity). The evidence rationale for the Global Integration Method (MIG, « Método de Integração Global »), a model addressing sensorimotor reactivity in addition to socio-communication, is presented. MIG is an integrative, interdisciplinary, family-oriented intervention and naturalistic program that addresses all levels and moderating factors of ASD’s impact. MIG’s theoretical rationale is based on the predictive coding impairment and embodied cognition hypotheses. MIG incorporates both bottom-up (flexible therapeutic suit, social-motor synchronization) and top-down (schematic social information processing, narratives, imagery) strategies to promote the building and use of accurate, flexible and context-sensitive internal predictive models. MIG is based on the premises that predictive coding improves both socio-communication and environmental reactivity, and that the postural stabilization provided by the flexible therapeutic suit frees information processing resources for socio-cognitive learning. MIG builds on interdisciplinary, professionally and parentally mediated work based on behavioral principles of intensive training in a situated environment.

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11. Noshadian M, Ragerdi Kashani I, Asadi-Golshan R, Zarini D, Ghafari N, Zahedi E, Pasbakhsh P. Benefits of bone marrow mesenchymal stem cells compared to their conditioned medium in valproic acid-induced autism in rats. Mol Biol Rep;2024 (Feb 24);51(1):353.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by repetitive behaviors, a limited range of activities, and deficiencies in social communications. Bone marrow mesenchymal stem cells (BM-MSCs), which secrete factors that stimulate surrounding microenvironment, and BM-MSCs conditioned medium (BM-MSCs-CM), which contains cell-secreted products, have been speculated to hold potential as a therapy for ASD. This study aimed to compare the therapeutic effects of BM-MSCs and BM-MSCs-CM on behavioral and microglial changes in an animal model of autism induced by valproic acid (VPA). METHODS AND RESULTS: Pregnant Wistar rats were administered by VPA at a dose of 600 mg/kg at 12.5 days post-conception. After birth, male pups were included in the study. At 6 weeks of age, one group of rats received intranasal administration of BM-MSCs, while another group received BM-MSCs-CM. The rats were allowed to recover for 2 weeks. Behavioral tests, quantitative real-time polymerase chain reaction (qRT-PCR), and immunohistochemistry were performed. Both BM-MSCs and BM-MSCs-CM administration significantly improved some behavioral deficits. Furthermore, these treatments notably reduced Iba-1 marker associated with microgliosis. Additionally, there was a significant reduction in the expression of pro-inflammatory cytokines IL-1β and IL-6, and an increase in the levels of the anti-inflammatory cytokine IL-10 in rats administered by BM-MSCs and BM-MSCs-CM. CONCLUSIONS: Post-developmental administration of BM-MSCs and BM-MSCs-CM can ameliorate prenatal neurodevelopmental deficits, restore cognitive and social behaviors, and modulate microglial and inflammatory markers. Results indicated that the improvement rate was higher in the BM-MSCs group than BM-MSCs-CM group.

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12. Ohki CMY, Benazzato C, van der Linden V, França JV, Toledo CM, Machado RRG, Araujo DB, Oliveira DBL, Neris RS, Assunção-Miranda I, de Oliveira Souza IN, Nogueira CO, Leite PEC, van der Linden H, Figueiredo CP, Durigon EL, Clarke JR, Russo FB, Beltrão-Braga PCB. Zika virus infection impairs synaptogenesis, induces neuroinflammation, and could be an environmental risk factor for autism spectrum disorder outcome. Biochim Biophys Acta Mol Basis Dis;2024 (Feb 24):167097.

Zika virus (ZIKV) infection was first associated with Central Nervous System (CNS) infections in Brazil in 2015, correlated with an increased number of newborns with microcephaly, which ended up characterizing the Congenital Zika Syndrome (CZS). Here, we investigated the impact of ZIKV infection on the functionality of iPSC-derived astrocytes. Besides, we extrapolated our findings to a Brazilian cohort of 136 CZS children and validated our results using a mouse model. Interestingly, ZIKV infection in neuroprogenitor cells compromises cell migration and causes apoptosis but does not interfere in astrocyte generation. Moreover, infected astrocytes lost their ability to uptake glutamate while expressing more glutamate transporters and secreted higher levels of IL-6. Besides, infected astrocytes secreted factors that impaired neuronal synaptogenesis. Since these biological endophenotypes were already related to Autism Spectrum Disorder (ASD), we extrapolated these results to a cohort of children, now 6-7 years old, and found seven children with ASD diagnosis (5.14 %). Additionally, mice infected by ZIKV revealed autistic-like behaviors, with a significant increase of IL-6 mRNA levels in the brain. Considering these evidence, we inferred that ZIKV infection during pregnancy might lead to synaptogenesis impairment and neuroinflammation, which could increase the risk for ASD.

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13. Perosanz A, Martínez O, Espinosa-Blanco P, García I, Al-Rashaida M, López-Paz JF. Comparative analysis of emotional facial expression recognition and empathy in children with prader-willi syndrome and autism spectrum disorder. BMC Psychol;2024 (Feb 23);12(1):94.

BACKGROUND: Prader-Willi Syndrome (PWS) is a rare neurodevelopmental disorder that is often comorbid with Autism Spectrum Disorder (ASD). Due to the close association between these two conditions, and recognizing that Theory of Mind (ToM) is related to social behaviors in ASD, there is a growing interest in studying the reciprocity of social communication between these two groups. METHOD: The primary objective of this study was to compare how children (n = 45) with PWS (n = 15), ASD (n = 15), and a control group (n = 15) respond to emotion recognition of facial expressions and empathy, which are both concepts related to ToM. The study utilized two tools named FEEL and Deusto-e-Motion 1.0. We also evaluated the Working Memory index of the WISC-IV scale, the Social Perception domain of the NEPSY-II battery, and the SCQ in both clinical groups. RESULTS: Our findings suggest that individuals with PWS exhibit lower accuracy in recognizing facial expressions and empathy compared to the control group. Both clinical groups exhibited a delayed reaction time compared to the control group. Children with PWS display difficulties in recognizing emotions of disgust and surprise. In terms of cognitive empathy, children with PWS showed a greater inclination to respond to disgust as compared to children with ASD. CONCLUSIONS: This study represents the initial stage in comprehending the emotional and empathetic abilities of children with PWS and ASD. The findings can provide valuable insights for developing future interventions.

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14. Siemann J, Kroeger A, Bender S, Muthuraman M, Siniatchkin M. Segregated Dynamical Networks for Biological Motion Perception in the Mu and Beta Range Underlie Social Deficits in Autism. Diagnostics (Basel);2024 (Feb 13);14(4)

OBJECTIVE: Biological motion perception (BMP) correlating with a mirror neuron system (MNS) is attenuated in underage individuals with autism spectrum disorder (ASD). While BMP in typically-developing controls (TDCs) encompasses interconnected MNS structures, ASD data hint at segregated form and motion processing. This coincides with less fewer long-range connections in ASD than TDC. Using BMP and electroencephalography (EEG) in ASD, we characterized directionality and coherence (mu and beta frequencies). Deficient BMP may stem from desynchronization thereof in MNS and may predict social-communicative deficits in ASD. Clinical considerations thus profit from brain-behavior associations. METHODS: Point-like walkers elicited BMP using 15 white dots (walker vs. scramble in 21 ASD (mean: 11.3 ± 2.3 years) vs. 23 TDC (mean: 11.9 ± 2.5 years). Dynamic Imaging of Coherent Sources (DICS) characterized the underlying EEG time-frequency causality through time-resolved Partial Directed Coherence (tPDC). Support Vector Machine (SVM) classification validated the group effects (ASD vs. TDC). RESULTS: TDC showed MNS sources and long-distance paths (both feedback and bidirectional); ASD demonstrated distinct from and motion sources, predominantly local feedforward connectivity, and weaker coherence. Brain-behavior correlations point towards dysfunctional networks. SVM successfully classified ASD regarding EEG and performance. CONCLUSION: ASD participants showed segregated local networks for BMP potentially underlying thwarted complex social interactions. Alternative explanations include selective attention and global-local processing deficits. SIGNIFICANCE: This is the first study applying source-based connectivity to reveal segregated BMP networks in ASD regarding structure, cognition, frequencies, and temporal dynamics that may explain socio-communicative aberrancies.

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15. Singh JKA, Ling WH, Sivanesom RS, Huay CCS, Lan ACS. Age at autism spectrum disorder diagnosis and its association with child and family characteristics in a tertiary care hospital in Malaysia. Autism Res;2024 (Feb 23)

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder. Despite the absence of a cure, early diagnosis and intensive early intervention can improve the outcomes. However, little is known about the median age at ASD diagnosis in Malaysia or the child/family characteristics associated with early diagnosis. Therefore, this study aimed to determine the median age at ASD diagnosis among Malaysian children presenting to the country’s largest public tertiary neurodevelopmental center and to investigate the possible demographic, child, and family characteristics associated with an early age at diagnosis. Data were collected between February 2017 and February 2019 from a database maintained by the child development unit of the country’s largest publicly funded tertiary hospital, containing data from an ethnically diverse population. Among Malaysian children attending the clinic, the median age at ASD diagnosis was 48 months. Early autism diagnosis (<36 months of age) was associated with increased severity of social communication and interaction impairments, coexisting intellectual impairment, children from high socioeconomic status families, and children who receive joint care from their families and a maid or babysitter. The study findings highlight the socioeconomic inequalities in the country, a lack of parental awareness of early ASD signs, and the presence of cultural influences on the age at diagnosis of ASD.

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16. Suprunowicz M, Tomaszek N, Urbaniak A, Zackiewicz K, Modzelewski S, Waszkiewicz N. Between Dysbiosis, Maternal Immune Activation and Autism: Is There a Common Pathway?. Nutrients;2024 (Feb 16);16(4)

Autism spectrum disorder (ASD) is a neuropsychiatric condition characterized by impaired social interactions and repetitive stereotyped behaviors. Growing evidence highlights an important role of the gut-brain-microbiome axis in the pathogenesis of ASD. Research indicates an abnormal composition of the gut microbiome and the potential involvement of bacterial molecules in neuroinflammation and brain development disruptions. Concurrently, attention is directed towards the role of short-chain fatty acids (SCFAs) and impaired intestinal tightness. This comprehensive review emphasizes the potential impact of maternal gut microbiota changes on the development of autism in children, especially considering maternal immune activation (MIA). The following paper evaluates the impact of the birth route on the colonization of the child with bacteria in the first weeks of life. Furthermore, it explores the role of pro-inflammatory cytokines, such as IL-6 and IL-17a and mother’s obesity as potentially environmental factors of ASD. The purpose of this review is to advance our understanding of ASD pathogenesis, while also searching for the positive implications of the latest therapies, such as probiotics, prebiotics or fecal microbiota transplantation, targeting the gut microbiota and reducing inflammation. This review aims to provide valuable insights that could instruct future studies and treatments for individuals affected by ASD.

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17. Toutain M, Dollion N, Henry L, Grandgeorge M. How Do Children and Adolescents with ASD Look at Animals? A Scoping Review. Children (Basel);2024 (Feb 6);11(2)

Autism spectrum disorder (ASD) is characterized by interaction and communication differences, entailing visual attention skill specificities. Interactions with animals, such as in animal-assisted interventions or with service dogs, have been shown to be beneficial for individuals with ASD. While interacting with humans poses challenges for them, engaging with animals appears to be different. One hypothesis suggests that differences between individuals with ASD’s visual attention to humans and to animals may contribute to these interaction differences. We propose a scoping review of the research on the visual attention to animals of youths with ASD. The objective is to review the methodologies and tools used to explore such questions, to summarize the main results, to explore which factors may contribute to the differences reported in the studies, and to deduce how youth with ASD observe animals. Utilizing strict inclusion criteria, we examined databases between 1942 and 2023, identifying 21 studies in international peer-reviewed journals. Three main themes were identified: attentional engagement and detection, visual exploration, and behavior. Collectively, our findings suggest that the visual attention of youths with ASD towards animals appears comparable to that of neurotypical peers, at least in 2D pictures (i.e., eye gaze patterns). Future studies should explore whether these results extend to real-life interactions.

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18. Turner AJ, Chander H, Kodithuwakku Arachchige SNK, Griffith A, Chen PL, Chen CJ, Knight AC, Bates-Brantley K, Stratton-Gadke K, Smith JC. The Effects of an Inclusive Badminton Program on Static Postural Control for Individuals with Intellectual and Developmental Disabilities. Int J Environ Res Public Health;2024 (Feb 10);21(2)

The purpose of the study was to examine static postural control/balance in young adults with intellectual and developmental disabilities (IDD) and typically developing (TD) young adults before, during, and after an inclusive badminton intervention. Eight participants (four IDD-BADM and four TD-BADM) participated in a 12-week inclusive badminton intervention, with the other eight participants as matched controls (four IDD-CONTR and four TD-CONTR) (74.19 kg ± 9.8 kg, 171.96 cm ± 5.4 cm; 21.7 ± 1.8 years of age; nine females and seven males; eight with IDD and eight TD). The study followed a repeated measures design (pre, mid, post) before the intervention, at 6 weeks, and after 12 weeks. Static postural sway conditions included: bilateral stance eyes open (20 s), eyes closed (10 s), foam eyes open (20 s), foam eyes closed (10 s), and unilateral stance eyes open (10 s) and foam eyes open (10 s). Sway measurements included: average anterior/posterior (A/P) displacement (in), average medial/lateral (M/L) displacement (in), average 95% ellipsoid area (in(2)), and average velocity (ft/s). Significant time × group interactions were reported for average velocity (EO) (p = 0.030), average length (EO) (p = 0.030), 95% ellipsoid area (EO) (p = 0.049), and average A/P displacement (1LEO) (p = 0.036) for IDD-BADM. Significant time main effects were reported for average A/P displacement (FEO) (p = 0.040) for IDD groups. Significant time main effects were reported for average M/L displacement (EO) (p = 0.001), (EC) (p = 0.004), (FEO) (p = 0.005), (FEC) (p = 0.004), and average A/P displacement (EO) (p = 0.006) and (FEO) (p = 0.005) for TD groups. An inclusive badminton program indicated evidence of improved static postural control for those with IDD. However, no significant differences were reported for TD peers.

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19. Tyszkiewicz-Gromisz B, Burdzicka-Wołowik J, Tymosiewicz P, Gromisz W. Parental Competences and Stress Levels in Mothers of Children with Autism Spectrum Disorders and Children Developing Neurotypically. J Clin Med;2024 (Feb 16);13(4)

(1) Background: the aim of this study was to explore parental competences and stress levels in the mothers of children with autism in relation to the mothers of neurotypical children. (2) Methods: the study used the Parental Competence Test and the PSS-10 scale to assess the intensity of stress related to one’s own life situation over the past month. Forty mothers of children with ASD (n = 20) and neurotypical children (n = 20) participated in the study. (3) Results: the mothers of children with ASD showed higher levels of stress (p = 0.0002). The mothers of neurotypical children achieved higher scores in parental competences (r = -0.49). The competence of mothers of children with ASD was correlated with rigour (r = 0.50), permissiveness (r = -0.60), overprotectiveness (r = 0.71), and helplessness (r = -0.77). (4) Conclusions: mothers of children with autism demonstrate lower parental competences than mothers of neurotypical children. Mothers of children with autism are less rigorous but more permissive, overprotective, and helpless. They tend to become heavily involved with their child. An overprotective attitude and greater tolerance for antisocial behaviours among parents of children with ASDs protect them from excessive stress.

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20. Xue Y, Dong HY, Feng JY, Bai MS, Li D, Yang H, Jia FY. Parent-child interaction related to brain functional alterations and development outcomes in autism spectrum disorder: A study based on resting state-fMRI. Res Dev Disabil;2024 (Feb 24);147:104701.

BACKGROUND: Limited study has investigated the influence of parent-child interaction on brain functional alterations and development outcomes of autism spectrum disorder (ASD) children. This pilot study aimed to explore the relationship between parent-child interaction, brain functional activities and development outcomes of ASD children. METHODS: and Procedures: 653 ASD with an average age of 41.06 ± 10.88 months and 102 typically developmental (TD) children with an average age of 44.35 ± 18.39 months were enrolled in this study, of whom 155 ASD completed brain rs-fMRI scans. The amplitude of low-frequency fluctuations (ALFF) and regional homogeneity (ReHo) measured using resting-state functional magnetic resonance imaging (rs-fMRI) data reflect local brain function. The parent-child interaction was assessed by the Chinese Parent-child Interaction Scale (CPCIS). Childhood Autism Rating Scale (CARS) and developmental quotient (DQ) indicated development outcomes. OUTCOMES AND RESULTS: Total CPCIS score was negatively correlated with CARS total score, and positively correlated with DQ. The frequency of parent-child interaction was negatively correlated with ALFF values in the left median cingulate and paracingulate gyri (DCG.L) and ReHo values in the right superior frontal gyrus, medial (SFGmed.R)(P < 0.05, FDR correction). ALFF values in the DCG.L and ReHo values in the SFGmed.R play complete mediating roles in the relationship between parent-child interaction and performance DQ. CONCLUSION AND IMPLICATIONS: This study suggest that parent-child interaction has an impact on autistic characteristics and DQ of ASD children. Local brain regions with functional abnormalities in the DCG.L and SFGmed.R may be a crucial factors affecting the performance development of ASD children with reduced parent-child interaction.

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21. Yilmaz Sukranli Z, Korkmaz Bayram K, Mehmetbeyoglu E, Doganyigit Z, Beyaz F, Sener EF, Taheri S, Ozkul Y, Rassoulzadegan M. Trans Species RNA Activity: Sperm RNA of the Father of an Autistic Child Programs Glial Cells and Behavioral Disorders in Mice. Biomolecules;2024 (Feb 7);14(2)

Recently, we described the alteration of six miRNAs in the serum of autistic children, their fathers, mothers, siblings, and in the sperm of autistic mouse models. Studies in model organisms suggest that noncoding RNAs participate in transcriptional modulation pathways. Using mice, approaches to alter the amount of RNA in fertilized eggs enable in vivo intervention at an early stage of development. Noncoding RNAs are very numerous in spermatozoa. Our study addresses a fundamental question: can the transfer of RNA content from sperm to eggs result in changes in phenotypic traits, such as autism? To explore this, we used sperm RNA from a normal father but with autistic children to create mouse models for autism. Here, we induced, in a single step by microinjecting sperm RNA into fertilized mouse eggs, a transcriptional alteration with the transformation in adults of glial cells into cells affected by astrogliosis and microgliosis developing deficiency disorders of the ‘autism-like’ type in mice born following these manipulations. Human sperm RNA alters gene expression in mice, and validates the possibility of non-Mendelian inheritance in autism.

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22. Yoon CD, Xia Y, Terol AK, Meadan H, Lee JD. Correlation Between Gaze Behaviors and Social Communication Skills of Young Autistic Children: A Meta-Analysis of Eye-Tracking Studies. J Autism Dev Disord;2024 (Feb 24)

This meta-analysis examined correlations between eye-tracking measures of gaze behaviors manifested during dynamic salient social stimuli and behavioral assessment measures of social communication skills of young autistic children. We employed a multilevel model with random effects to perform three separate meta-analyses for correlation between social communication skills and (a) all gaze behaviors, (b) gaze duration, and (c) gaze transition. Subsequently, we performed meta-regression to assess the role of four moderators, including age, continuum of naturalness of stimuli, gaze metric, and area of interest, on correlation effect sizes that were heterogeneous at the population level. A total of 111 correlation coefficients from 17 studies for 1132 young autistic children or children with high-likelihood for autism (M(age range) = 6-95 months) were included in this meta-analysis. The correlation effect sizes for all three meta-analyses were significant, supporting the relation between improved gaze behaviors and better social communication skills. In addition, age, gaze metric, and area of interest were significant moderators. This suggests the importance of identifying meaningful gaze behaviors related to social communication skills and the increasingly influential role of gaze behaviors in shaping social communication skills as young autistic children progress through the early childhood stage. The continuum of naturalness of stimuli, however, was revealed to trend towards having a significant moderating effect. Lastly, it is important to note the evidence of potential publication bias. Our findings are discussed in the context of early identification and intervention and unraveling the complex nature of autism.

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23. Zhou L, Jiang P, Zhao L, Fei X, Tang Y, Luo Y, Gong H, Wang X, Li X, Li S, Zhang C, Yang H, Fan X. Ligustilide inhibits Purkinje cell ferritinophagy via the ULK1/NCOA4 pathway to attenuate valproic acid-induced autistic features. Phytomedicine;2024 (Feb 15);126:155443.

BACKGROUND: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder in which social impairment is the core symptom. Presently, there are no definitive medications to cure core symptoms of ASD, and most therapeutic strategies ameliorate ASD symptoms. Treatments with proven efficacy in autism are imminent. Ligustilide (LIG), an herbal monomer extracted from Angelica Sinensis and Chuanxiong, is mainly distributed in the cerebellum and widely used in treating neurological disorders. However, there are no studies on its effect on autistic-like phenotypes and its mechanism of action. PURPOSE: Investigate the efficacy and mechanism of LIG in treating ASD using two Valproic acid(VPA)-exposed and BTBR T + Itpr3tf/J (BTBR) mouse models of autism. METHODS: VPA-exposed mice and BTBR mice were given LIG for treatment, and its effect on autistic-like phenotype was detected by behavioral experiments, which included a three-chamber social test. Subsequently, RNA-Sequence(RNA-Seq) of the cerebellum was performed to observe the biological changes to search target pathways. The autophagy and ferroptosis pathways screened were verified by WB(Western Blot) assay, and the cerebellum was stained by immunofluorescence and examined by electron microscopy. To further explore the therapeutic mechanism, ULK1 agonist BL-918 was used to block the therapeutic effect of LIG to verify its target effect. RESULTS: Our work demonstrates that LIG administration from P12-P14 improved autism-related behaviors and motor dysfunction in VPA-exposed mice. Similarly, BTBR mice showed the same improvement. RNA-Seq data identified ULK1 as the target of LIG in regulating ferritinophagy in the cerebellum of VPA-exposed mice, as evidenced by activated autophagy, increased ferritin degradation, iron overload, and lipid peroxidation. We found that VPA exposure-induced ferritinophagy occurred in the Purkinje cells, with enhanced NCOA4 and Lc3B expressions. Notably, the therapeutic effect of LIG disappeared when ULK1 was activated. CONCLUSION: LIG treatment inhibits ferritinophagy in Purkinje cells via the ULK1/NCOA4-dependent pathway. Our study reveals for the first time that LIG treatment ameliorates autism symptoms in VPA-exposed mice by reducing aberrant Purkinje ferritinophagy. At the same time, our study complements the pathogenic mechanisms of autism and introduces new possibilities for its therapeutic options.

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