1. Ahmad SF, Ansari MA, Nadeem A, Bakheet SA, Alqahtani F, Alhoshani AR, Alasmari F, Alsaleh NB, Attia SM. {{5-aminoisoquinolinone attenuates social behavior deficits and immune abnormalities in the BTBR T(+) Itpr3(tf)/J mouse model for autism}}. {Pharmacology, biochemistry, and behavior}. 2020; 189: 172859.
Autism spectrum disorder (ASD) is diagnosed by core symptoms including impaired social communication and the presence of repetitive and stereotypical behaviors. There is also evidence for immune dysfunction in individuals with ASD, but it is a disease that is still insufficiently controlled by current treatment strategies. The use of 5-aminoisoquinolinone (5-AIQ) ameliorates several immune-mediated symptoms including rheumatoid arthritis and colitis, and has neuroprotective properties; however, its role in ASD is not yet characterized. In this study, we investigated the effect of 5-AIQ on sociability tests, self-grooming, marble burying, and locomotor activities in BTBR T(+) Itpr3tf/J (BTBR) mice, which serve as an ASD animal model. We further investigated the possible molecular mechanism of 5-AIQ administration on CXCR4-, CXCR6-, IFN-gamma-, IL-22-, NOS2-, STAT1-, T-bet-, and RORgammaT-producing CD3(+) T cells isolated from the spleens of treated mice. We also explored its effects on mRNA expression in brain tissue. Our results showed that in BTBR mice, 5-AIQ treatment significantly prevented self-grooming and marble burying behaviors and enhanced social interactions without any adverse effects on locomotor activity/anxiety level. Additionally, 5-AIQ treatment substantially decreased CXCR4-, CXCR6-, IFN-gamma-, IL-22-, NOS2-, STAT1-, T-bet-, and RORgammaT-producing CD3(+) T cells in the spleen. Furthermore, 5-AIQ treatment decreased CXCR4, IFN-gamma, IL-22, STAT1, and RORgammaT mRNA expression levels in brain tissue. Our findings demonstrated that 5-AIQ improved behavioral and immune abnormalities associated with ASD, which supports the hypothesis that 5-AIQ has important therapeutic potential for the treatment of behavioral and neuroimmune dysfunctions in ASD.
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2. Bezawada N, Phang TH, Hold GL, Hansen R. {{Autism Spectrum Disorder and the Gut Microbiota in Children: A Systematic Review}}. {Annals of nutrition & metabolism}. 2020: 1-14.
INTRODUCTION: Differences in microbiota composition in children with autism spectrum disorder (ASD) compared to unaffected siblings and healthy controls have been reported in various studies. This study aims to systematically review the existing literature concerning the role of the gut microbiota in ASD. METHODS: An extensive literature search was conducted using MEDLINE and EMBASE databases to identify studies (January 1966 through July 2019). RESULTS: A total of 28 papers were included. The studies ranged from 12 to 104 participants who were aged between 2 and 18 years from various geographical areas. Majority of studies included faecal samples; however, 4 studies examined mucosal biopsies from different sites. The heterogeneity in ASD diagnostic methodology, gut site sampled and laboratory methods used made meta-analysis inappropriate. Species reported to be significantly higher in abundance in autistic children included Clostridium, Sutterella, Desulfovibrio and Lactobacillus. The findings are however inconsistent across studies. In addition, -potential confounding effects of antimicrobial use, gastrointestinal symptoms and diet on the gut microbiota are unclear due to generally poor assessment of these factors. CONCLUSION: It is clear that the gut microbiota is altered in ASD, although further exploration is needed on whether this is a cause or an effect of the condition.
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3. Esmaiel NN, Ashaat EA, Mosaad R, Fayez A, Ibrahim M, Abdallah ZY, Issa MY, Salem S, Ramadan A, El Wakeel MA, Ashaat NA, Zaki MS, Ismail S. {{The potential impact of COMT gene variants on dopamine regulation and phenotypic traits of ASD patients}}. {Behav Brain Res}. 2020; 378: 112272.
Catechol-O-methyltransferase (COMT) enzyme has a major role in the adjustment of catechol-dependent functions, for example, cognition, cardiac function, and pain processing. The pathogenesis of autism may be related to dysfunction in the midbrain dopaminergic system. Therefore, we aimed to clarify how COMT gene variants affect dopamine level, and its potential impact on phenotype traits of autistic patients. 52 autistic patients were subjected to comprehensive clinical investigation, sequencing of exon 4 of the COMT gene by direct Sanger Sequencing, and measuring of dopamine levels. The clinical presentations of autistic subjects were correlated with detected COMT variants and dopamine level. Our molecular results revealed that three COMT variants were found: rs8192488 [C>T], rs4680 (Val158Met) and rs4818 [C>G]. Within autistic subjects, Val158Met rs4680 carriers were significantly distributed (71.2% P=0.014) accompanied with abnormal dopamine, abnormal Electroencephalogram (EEG) and increasing the severity of autistic behaviour. As regards the haplotypes, CC/VM/CG block was significantly distributed among the autistic subjects (30.8%) presented with low mean dopamine level (15.8+/-4.7pg/ml, p=0.05), while CC/MM/CC were presented with high mean level (77.8+/-8.6pg/ml, p=0.05). Evidence is currently limited and preliminary, further studies are necessary in order to set up a coherent dopaminergic model of Autism Spectrum Disorder (ASD), which would further pave the way for an adequate treatment.
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4. Fang H, Wu Q, Li Y, Ren Y, Li C, Xiao X, Xiao T, Chu K, Ke X. {{Structural networks in children with autism spectrum disorder with regression: A graph theory study}}. {Behav Brain Res}. 2020; 378: 112262.
BACKGROUND: Regression is frequently described in Autism spectrum disorder (ASD). Limited comprehensive studies have been conducted in patients with ASD with regression. PURPOSE: To explore the network topological properties in ASD children with (ASD-R) and without (ASD-NR) regression. METHODS: In this study, 29 ASD-R, 68 ASD-NR, and 40 children with developmental delay (DD) were recruited. We utilized graph theory to characterize the white matter structure networks by using diffusion tensor imaging and T1-weighted imaging on a 3-T magnetic resonance system. Statistical analyses were performed using IBM SPSS (version 23). RESULTS: ANCOVA showed significant differences in global efficiency, characteristic path length and sigma among the ASD-R, ASD-NR and DD groups, but the difference was not significant between the ASD-R and ASD-NR groups. There were 10 common hubs based on regional degree and regional efficiency in all groups. The hubness of the left superior frontal gyrus-dorsolateral, left middle occipital gyrus and right precuneus were enhanced (by regional degree) and that of the right thalamus was reduced (by regional efficiency) in the ASD-R relative to the ASD-NR group. After controlling for the course of regression, the CARS scores were significantly correlated with the regional efficiency of the right precuneus in the ASD-R group. CONCLUSIONS: The ASD-R children were different from the ASD-NR children in the distribution of hub regions, although there were no global network property differences between them. In ASD-R children, the right precuneus (PCUN.R) might play an important role and relate to autism symptom severity.
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5. Kaufmann WE. {{Long QT interval in Rett syndrome: expanding the knowledge of a poorly understood phenomenon}}. {Dev Med Child Neurol}. 2020.
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6. LeClaire JP, Stille SO, Foster KD, Berg RG. {{Analyzing essays about treating adults with special health care needs and intellectual and developmental disabilities}}. {Journal of dental education}. 2020.
OBJECTIVE: Analyze reflection essays written by one graduating class of students after an initial experience in a clinic for adults with special health care needs (SHCN) and intellectual and developmental disabilities, to draw insights from the patterns of observations expressed. METHODS: Essays were written by students from the University of Colorado School of Dental Medicine during the 2016-2017 academic year after completing a 1-day clinical experience treating this patient population. Readers identified 18 primary themes (PTs) previously identified in essays written during 2012-2013. RESULTS: The PT Complex communicating through third party was identified in 79.4% of essays. Least common were Frustrated patient could not understand (1.9%) and Frustrated patient could not talk (1.9%). Nine PTs were grouped to represent 3 component themes (CTs): CT1 Communication challenges, CT2 Behavioral challenge, and CT3 Altruistic responses. This grouping showed moderate internal reliability. A fourth, CT4 Emotional challenges, was rejected due to low internal reliability. CT1 was most frequently identified, followed by CT3 then CT2. Three PTs were chosen as indicative of desirable outcomes and were labeled outcome themes (OTs): OT1 Willing to see patients with SHCNs after graduation, OT2 Would like more Special Care Clinic (SCC) experiences in the future, and OT3 Looking forward to next SCC experience. Associations between CTs and OTs were not statistically significant, but provided useful insights. CONCLUSION: Reflection essays indicate discussion of strategies to manage behavioral challenges and encouragement of altruistic feelings are both vital in orientation sessions. These topics may be critical to positive student perceptions of the experience.
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7. Malow BA, Findling RL, Schroder CM, Maras A, Breddy J, Nir T, Zisapel N, Gringras P. {{Sleep, Growth, and Puberty After Two Years of Prolonged-Release Melatonin in Children With Autism Spectrum Disorder}}. {J Am Acad Child Adolesc Psychiatry}. 2020.
OBJECTIVE: A recent 3-month double-blind placebo-controlled study demonstrated efficacy and safety of child-appropriate prolonged-release melatonin (PedPRM) for insomnia in children with autism spectrum disorder (ASD). Here, we report on the long-term effects of PedPRM treatment on sleep, growth, body mass index, and pubertal development. METHOD: Eighty children and adolescents (96% ASD) ages 2-17.5 years who completed the double-blind placebo-controlled trial were given 2, 5 or 10 mg PedPRM nightly up to 104 weeks, followed by a 2 week placebo period to assess withdrawal effects. RESULTS: Improvements in child sleep disturbance, and caregivers’ satisfaction of their child’s sleep patterns, quality of sleep and quality of life were maintained throughout the 104- week treatment period (p < 0.001 vs. baseline for all). During the 2-week withdrawal placebo period, measures declined as compared to the treatment period but were still improved compared to baseline. PedPRM was generally safe; the most frequent treatment-related adverse events (AE) were fatigue (6.3%), somnolence (6.3%), and mood swings (4.2%). The changes in mean weight, height, body mass index (BMI) and pubertal status (Tanner staging done by a physician) were within normal ranges for age with no evidence of delay in BMI or pubertal development. CONCLUSION: Nightly PedPRM at optimal dose (2, 5, or 10 mg nightly) is safe and effective for long-term treatment in children and adolescents with ASD and insomnia. There were no observed detrimental effects on children's growth and pubertal development and no withdrawal or safety issues related to the use or discontinuation of the drug. Lien vers le texte intégral (Open Access ou abonnement)
8. Rakic M, Cabezas M, Kushibar K, Oliver A, Llado X. {{Improving the detection of autism spectrum disorder by combining structural and functional MRI information}}. {Neuroimage Clin}. 2020; 25: 102181.
Autism Spectrum Disorder (ASD) is a brain disorder that is typically characterized by deficits in social communication and interaction, as well as restrictive and repetitive behaviors and interests. During the last years, there has been an increase in the use of magnetic resonance imaging (MRI) to help in the detection of common patterns in autism subjects versus typical controls for classification purposes. In this work, we propose a method for the classification of ASD patients versus control subjects using both functional and structural MRI information. Functional connectivity patterns among brain regions, together with volumetric correspondences of gray matter volumes among cortical parcels are used as features for functional and structural processing pipelines, respectively. The classification network is a combination of stacked autoencoders trained in an unsupervised manner and multilayer perceptrons trained in a supervised manner. Quantitative analysis is performed on 817 cases from the multisite international Autism Brain Imaging Data Exchange I (ABIDE I) dataset, consisting of 368 ASD patients and 449 control subjects and obtaining a classification accuracy of 85.06 +/- 3.52% when using an ensemble of classifiers. Merging information from functional and structural sources significantly outperforms the implemented individual pipelines.
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9. Silleresi S, Prevost P, Zebib R, Bonnet-Brilhault F, Conte D, Tuller L. {{Identifying Language and Cognitive Profiles in Children With ASD via a Cluster Analysis Exploration: Implications for the New ICD-11}}. {Autism Res}. 2020.
The new version of the International Classification of Diseases (ICD-11) mentions the existence of four different profiles in the verbal part of the Autism Spectrum Disorder (ASD), describing them as combinations of either spared or impaired functional language and intellectual abilities. The aim of the present study was to put ASD heterogeneity to the forefront by exploring whether clear profiles related to language and intellectual abilities emerge when investigation is extended to the entire spectrum, focusing on verbal children. Our study proposed a systematic investigation of both language (specifically, structural language abilities) and intellectual abilities (specifically, nonverbal cognitive abilities) in 51 6- to 12-year-old verbal children with ASD based on explicitly motivated measures. For structural language abilities, sentence repetition and nonword repetition tasks were selected; for nonverbal cognitive abilities, we chose Raven’s Progressive Matrices, as well as Matrix Reasoning and Block Design from the Wechsler Scales. An integrative approach based on cluster analyses revealed five distinct profiles. Among these five profiles, all four logically possible combinations of structural language and nonverbal abilities mentioned in the ICD-11 were detected. Three profiles emerged among children with normal language abilities and two emerged among language-impaired children. Crucially, the existence of discrepant profiles of abilities suggests that children with ASD can display impaired language in presence of spared nonverbal intelligence or spared language in the presence of impaired nonverbal intelligence, reinforcing the hypothesis of the existence of a separate language module in the brain. LAY SUMMARY: The present work put Autism Spectrum Disorder heterogeneity to the forefront by exploring whether clear profiles related to language and cognitive abilities emerge when investigation is extended to the entire spectrum (focusing on verbal children). The use of explicitly motivated measures of both language and cognitive abilities and of an unsupervised machine learning approach, the cluster analysis, (a) confirmed the existence of all four logically possible profiles evoked in the new ICD-11, (b) evoked the existence of (at least) a fifth profile of language/cognitive abilities, and (c) reinforced the hypothesis of a language module in the brain. (c) 2020 International Society for Autism Research, Wiley Periodicals, Inc.
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10. Southwell DG, Seifikar H, Malik R, Lavi K, Vogt D, Rubenstein JL, Sohal VS. {{Interneuron transplantation rescues social behavior deficits without restoring wild-type physiology in a mouse model of autism with excessive synaptic inhibition}}. {J Neurosci}. 2020.
Manipulations that enhance GABAergic inhibition have been associated with improved behavioral phenotypes in autism models, suggesting that autism may be treated by correcting underlying deficits of inhibition. Interneuron transplantation is a method for increasing recipient synaptic inhibition, and it has been considered a prospective therapy for conditions marked by deficient inhibition, including neuropsychiatric disorders. It is unknown, however, whether interneuron transplantation may be therapeutically effective only for conditions marked by reduced inhibition, and it is also unclear whether transplantation improves behavioral phenotypes solely by normalizing underlying circuit defects. To address these questions, we studied the effects of interneuron transplantation in male and female mice lacking the autism-associated gene, Pten, in GABAergic interneurons. Pten mutant mice exhibit social behavior deficits, elevated synaptic inhibition in prefrontal cortex, abnormal baseline and social interaction-evoked electrocencephalogram (EEG) signals, and an altered composition of cortical interneuron subtypes. Transplantation of wild type embryonic interneurons from the medial ganglionic eminence into the prefrontal cortex of neonatal Pten mutants rescued social behavior despite exacerbating excessive levels of synaptic inhibition. Furthermore, transplantation did not normalize recipient EEG signals measured during baseline states. Interneuron transplantation can thus correct behavioral deficits even when those deficits are associated with elevated synaptic inhibition. Moreover, transplantation does not exert therapeutic effects solely by restoring wild type circuit states. Our findings indicate that interneuron transplantation could offer a novel cell-based approach to autism treatment, while challenging assumptions that effective therapies must reverse underlying circuit defects.Significance StatementImbalances between neural excitation and inhibition are hypothesized to contribute to the pathophysiology of autism. Interneuron transplantation is a method for altering recipient inhibition, and it has been considered a prospective therapy for neuropsychiatric disorders, including autism. Here the authors have examined the behavioral and physiological effects of interneuron transplantation in a mouse genetic model of autism. They demonstrate that transplantation rescues recipient social interaction deficits without correcting a common measure of recipient inhibition, or circuit-level physiological measures. These findings demonstrate interneuron transplantation can exert therapeutic behavioral effects without necessarily restoring wild type circuit states, while highlighting the potential of interneuron transplantation as an autism therapy.
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11. Steinman G, Mankuta D. {{The role of oligopeptides in preventing autism}}. {Med Hypotheses}. 2020; 138: 109604.
Previous reports in this series point to insufficient insulin-like growth factor-1 (IGF1) in the newborn as the key to brain dysconnectivity characteristic of autism. Such a deficiency should be detectable in the baby’s blood at or soon after birth. Breast-feeding exclusively for the first year of postpartum life or supplementation with oral agents to raise the serum IGF1 level, such a cyclo-glycylproline, could be helpful for this purpose.
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12. Turner VR, Ledford JR, Lord AK, Harbin ER. {{Response shaping to improve food acceptance for children with autism: Effects of small and large food sets}}. {Res Dev Disabil}. 2020; 98: 103574.
BACKGROUND: Food selectivity, characterized by food refusal, limited food repertoire, or preference for certain types of foods, is common among children with ASD. METHOD: In this study, researchers examined the effects of a response shaping procedure using a large rotating food set and a small constant food set on food acceptance for two boys with ASD. The small set consisted of three foods that were presented during every session; the large set consisted of 15 foods, of which three were presented during each session, in randomly ordered sets. Researchers measured the percentage of correct behaviors and the cumulative number of foods with which participants interacted. Two concurrently operating multiple baseline across behaviors designs were used to assess whether the shaping procedure resulted in increased correct responding compared to baseline conditions, and whether the intervention was differentially effective with large versus small food sets. RESULTS: The procedures were similar in efficiency for one participant, although he ate many more foods in the large set condition. For the other participant, shaping was successful at increasing some acceptance behaviors (e.g., putting food in his mouth) but only the small set resulted in eating a new food. CONCLUSIONS: Practitioners should consider use of less restrictive or intrusive interventions to promote food acceptance and the use of larger sets of foods, modified to include fewer foods in the case of poor response to intervention.
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13. Vettori S, Dzhelyova M, Van der Donck S, Jacques C, Van Wesemael T, Steyaert J, Rossion B, Boets B. {{Combined frequency-tagging EEG and eye tracking reveal reduced social bias in boys with autism spectrum disorder}}. {Cortex}. 2019; 125: 135-48.
Developmental accounts of autism spectrum disorder (ASD) state that infants and children with ASD are spontaneously less attracted by and less proficient in processing social stimuli such as faces. This is hypothesized to partly underlie social communication difficulties in ASD. While in some studies a reduced preference for social stimuli has been shown in individuals with ASD, effect sizes are moderate and vary across studies, stimuli, and designs. Eye tracking, often the methodology of choice to study social preference, conveys information about overt orienting processes but conceals covert attention, possibly resulting in an underestimation of the effects. In this study, we recorded eye tracking and electroencephalography (EEG) during fast periodic visual stimulation to address this issue. We tested 21 boys with ASD (8-12 years old) and 21 typically developing (TD) control boys, matched for age and IQ. Streams of variable images of faces were presented at 6 Hz alongside images of houses presented at 7.5 Hz or vice versa, while children were engaged in an orthogonal task. While frequency-tagged neural responses were larger in response to faces than simultaneously presented houses in both groups, this effect was much larger in TD boys than in boys with ASD. This group difference in saliency of social versus non-social processing is significant after 5 sec of stimulus presentation and holds throughout the entire trial. Although there was no interaction between group and stimulus category for simultaneously recorded eye-tracking data, eye tracking and EEG measures were strongly correlated. We conclude that frequency-tagging EEG, allowing monitoring of both overt and covert processes, provides a fast, objective and reliable measure of decreased preference for social information in ASD.
