Pubmed du 21/08/19

mercredi 21 août 2019

1. Correction for Shpigler et al., Deep evolutionary conservation of autism-related genes. Proceedings of the National Academy of Sciences of the United States of America. 2019.

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2. Asgarihafshejani A, Nashmi R, Delaney KR. Cell-Genotype Specific Effects of Mecp2 Mutation on Spontaneous and Nicotinic Acetylcholine Receptor-Evoked Currents in Medial Prefrontal Cortical Pyramidal Neurons in Female Rett Model Mice. Neuroscience. 2019 ; 414 : 141-53.

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutation in the X-linked MECP2 gene. Random X-inactivation produces a mosaic of mutant (MT) and wild-type (WT) neurons in female Mecp2+/- (het) mice. Many RTT symptoms are alleviated by increasing activity in medial prefrontal cortex (mPFC) in RTT model mice (Howell et al., 2017). Using a GFP-MeCP2 fusion protein to distinguish WT from MT pyramidal neurons in mPFC we found cell autonomous (cell genotype specific) and non-autonomous effects of MeCP2 deficiency on spontaneous excitatory/inhibitory balance, nicotinic acetylcholine receptor (nAChR) currents and evoked activity. MT Layer 5 and 6 (L5, L6) neurons of male nulls, and MT L6 of het mice had reduced spontaneous excitatory synaptic input compared to WT in wild-type male (WTm), female (WTf) and het mice. Inhibitory synaptic charge in MT L6 equaled WT in 2-4-month hets. At 6-7months inhibitory charge in WT in het slices was increased compared to both MT in het and WT in WTf ; however, in hets the excitatory/inhibitory charge ratio was still greater in WT compared to MT. nAChR currents were reduced in L6 of nulls and MT L6 in het slices compared to WT neurons of het, WTm and WTf. At 2-4months, ACh perfusion increased frequency of inhibitory currents to L6 neurons equally in all genotypes but increased excitatory inputs to MT and WT in hets less than WT in WTfs. Unexpectedly ACh perfusion evoked greater sustained IPSC and EPSC input to L5 neurons of nulls compared to WTm.

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3. Bal VH, Fok M, Lord C, Smith IM, Mirenda P, Szatmari P, Vaillancourt T, Volden J, Waddell C, Zwaigenbaum L, Bennett T, Duku E, Elsabbagh M, Georgiades S, Ungar WJ, Zaidman-Zait A. Predictors of longer-term development of expressive language in two independent longitudinal cohorts of language-delayed preschoolers with Autism Spectrum Disorder. J Child Psychol Psychiatry. 2019.

BACKGROUND : Studies estimate that 30% of individuals with autism are minimally verbal. Understanding what factors predict longer-term expressive development in children with language delays is critical to inform identification and treatment of those at-risk for persistent language impairments. The present study examined predictors of expressive language development in language-delayed preschoolers followed through later school-age and young adulthood. METHODS : Children using single words or less on the Autism Diagnostic Observation Schedule (ADOS) at approximately 3 years old were drawn from the Early Diagnosis (EDX) and Pathways in ASD longitudinal cohorts. Age-3 predictors of Age-19 ADOS language level were identified using Classification and Regression Trees (CART) in the EDX sample. Linear mixed models examined the effects of CART-identified predictors on Vineland expressive communication (VExp) trajectories from Age-3 to Age-19. The same linear mixed models were examined in the Pathways sample, identifying predictors of VExp from ages 3 to 10.5 years. RESULTS : Significantly delayed fine motor skills (T-score < 20) was the strongest CART predictor of Age-19 language. In the linear mixed models, time, Age-3 fine motor skills and initiation of joint attention (IJA) predicted VExp trajectories in the EDX sample, even when controlling for Age-3 visual receptive abilities. In the Pathways sample, time and Age-3 fine motor skills were significant predictors of VExp trajectories ; IJA and cognitive skills were not significant predictors. CONCLUSIONS : Marked deficits in fine motor skills may be a salient proxy marker for identifying language-delayed children with ASD who are at risk for persistent language impairments. This finding adds to the literature demonstrating a relation between motor and language development in ASD. Investigating individual skill areas (e.g., fine motor and nonverbal problem-solving skills), rather than broader indices of developmental level (e.g., nonverbal IQ) may provide important cues to understanding longer-term language outcomes that can be targeted in early intervention.

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4. Bridgemohan C, Cochran DM, Howe YJ, Pawlowski K, Zimmerman AW, Anderson GM, Choueiri R, Sices L, Miller KJ, Ultmann M, Helt J, Forbes PW, Farfel L, Brewster SJ, Frazier JA, Neumeyer AM. Investigating Potential Biomarkers in Autism Spectrum Disorder. Frontiers in integrative neuroscience. 2019 ; 13 : 31.

Background : Early identification and treatment of individuals with autism spectrum disorder (ASD) improves outcomes, but specific evidence needed to individualize treatment recommendations is lacking. Biomarkers that could be routinely measured within the clinical setting could potentially transform clinical care for patients with ASD. This demonstration project employed collection of biomarker data during regular autism specialty clinical visits and explored the relationship of biomarkers with clinical ASD symptoms. Methods : Eighty-three children with ASD, aged 5-10 years, completed a multi-site feasibility study integrating the collection of biochemical (blood serotonin, urine melatonin sulfate excretion) and clinical (head circumference, dysmorphology exam, digit ratio, cognitive and behavioral function) biomarkers during routine ASD clinic visits. Parents completed a demographic survey and the Aberrant Behavior Checklist-Community. Cognitive function was determined by record review. Data analysis utilized Wilcoxon two-sample tests and Spearman correlations. Results : Participants were 82% male, 63% White, 19% Hispanic, with a broad range of functioning. Group means indicated hyperserotonemia. In a single regression analysis adjusting for race and median household income, higher income was associated with higher levels of blood serotonin and urine melatonin sulfate excretion levels (p = 0.004 and p = 0.04, respectively). Melatonin correlated negatively with age (p = 0.048) and reported neurologic problems (p = 0.02). Dysmorphic status correlated with higher reported stereotyped behavior (p = 0.02) and inappropriate speech (p = 0.04). Conclusion : This demonstration project employed collection of multiple biomarkers, allowed for examination of associations between biochemical and clinical measures, and identified several findings that suggest direction for future studies. This clinical research model has promise for integrative biomarker research in individuals with complex, heterogeneous neurodevelopmental disorders such as ASD.

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5. Dai YX, Tai YH, Chang YT, Chen TJ, Chen MH. Increased Risk of Atopic Diseases in the Siblings of Patients with Autism Spectrum Disorder : A Nationwide Population-Based Cohort Study. J Autism Dev Disord. 2019.

Several studies have shown a strong association between atopic diseases and autism spectrum disorder (ASD). However, the risk of atopic diseases in individuals having ASD-affected siblings has never been investigated. This nationwide population-based cohort study included 2762 individuals with ASD-affected siblings and 11,048 controls. Diagnoses of atopic diseases, including asthma, atopic dermatitis, allergic rhinitis, and allergic conjunctivitis, were ascertained from 1996 or the birth data to the end of 2011. Individuals with ASD-affected siblings had a higher risk for asthma, atopic dermatitis, allergic rhinitis, allergic conjunctivitis, and multiple atopic diseases compared with controls. In conclusion, individuals with ASD-affected siblings were more likely than were the controls to develop atopic diseases, suggesting shared familial mechanisms underlying the two conditions.

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6. Harris JC. The Necessity to Identify Subtypes of Autism Spectrum Disorder. JAMA Psychiatry. 2019.

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7. Hossain MD, Kabir MA. Detecting Child Autism Using Classification Techniques. Studies in health technology and informatics. 2019 ; 264 : 1447-8.

Autism spectrum disorder (ASD) is a brain development disorder that restricts a person’s communication abilities and social interaction capabilities from natural growth. In this paper, we have applied various supervised classification techniques to detect the presence of child autism. Our findings show that the Sequential Minimal Optimization (SMO) classifier performs best to detect ASD cases with the highest accuracy and minimum execution time and error rate. We also identify the most dominant features in dectecting child autism.

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8. Kaczmarek LK. Loss of NaV1.2-Dependent Backpropagating Action Potentials in Dendrites Contributes to Autism and Intellectual Disability. Neuron. 2019 ; 103(4) : 551-3.

Mutations in voltage-dependent sodium channels cause severe autism/intellectual disability. In this issue of Neuron, Spratt et al. (2019) show that lowering expression of Nav1.2 channels attenuates backpropagation of action potentials into dendrites of cortical neurons, preventing spike-timing-dependent synaptic plasticity.

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9. Kumari D, Gazy I. Towards Mechanism-Based Treatments for Fragile X Syndrome. Brain Sci. 2019 ; 9(8).

Fragile X syndrome (FXS) is the most common heritable form of intellectual disability, as well as the most common known monogenic cause of autism spectrum disorder (ASD), affecting 1 in 4000-8000 people worldwide [...].

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10. Lim YH, Lee HC, Falkmer T, Allison GT, Tan T, Lee WL, Morris SL. Effect of Visual Information on Postural Control in Children with Autism Spectrum Disorder. J Autism Dev Disord. 2019.

Visual information is crucial for postural control. Visual processing in children with autism spectrum disorder (ASD) was hypothesized to be less efficient and thus they would display a less stable standing posture than typically developing children. The present study compared the static standing responses and attentional demands of 15 children with ASD and 18 control participants in conditions of eyes open and eyes closed. The results showed that postural responses and attention invested in standing were similar between the participant groups in the two visual conditions. Both groups displayed a more stable posture when their eyes were open in comparison to eyes closed. The finding suggests that normal postural control development could occur in children with ASD.

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11. Nevison C, Zahorodny W. Race/Ethnicity-Resolved Time Trends in United States ASD Prevalence Estimates from IDEA and ADDM. J Autism Dev Disord. 2019.

Race-specific time trends in Autism Spectrum Disorder prevalence are tracked among 3-5 year-olds and 8 year-olds identified by the U.S. Individuals with Disabilities Education Act (IDEA) and the Autism and Developmental Disabilities Monitoring (ADDM) Network, respectively. White ASD prevalence historically has been higher than other racial groups but plateaued for IDEA birth cohorts from 2004 to 2007 before resuming its increase. Black and Hispanic IDEA prevalence increased continuously and caught up to whites by birth year 2008 and 2013, respectively, with black prevalence subsequently exceeding white prevalence in the majority of states. Plateaus in white prevalence occurred in some ADDM states for birth years 2002-2006, but IDEA trends suggest prevalence will increase across all racial groups in ADDM’s birth year 2008 report.

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12. O’Neill J, Bansal R, Goh S, Rodie M, Sawardekar S, Peterson BS. Parsing the Heterogeneity of Brain Metabolic Disturbances in Autism Spectrum Disorder. Biol Psychiatry. 2019.

BACKGROUND : Despite rising prevalence of autism spectrum disorder (ASD), its brain bases remain uncertain. Abnormal levels of N-acetyl compounds, glutamate+glutamine, creatine+phosphocreatine, or choline compounds measured by proton magnetic resonance spectroscopy suggest that neuron or glial density, mitochondrial energetic metabolism, and/or inflammation contribute to ASD neuropathology. The neuroanatomic distribution of these metabolites could help evaluate leading theories of ASD. However, most prior magnetic resonance spectroscopy studies had small samples (all <60, most <20), interrogated only a small fraction of the brain, and avoided assessing effects of age, sex, and IQ. METHODS : We acquired near-whole-brain magnetic resonance spectroscopy of N-acetyl compounds, glutamate+glutamine, creatine+phosphocreatine, and choline compounds in 78 children and adults with ASD and 96 typically developing children and adults, rigorously evaluating effects of diagnosis and severity on metabolites, as moderated by age, sex, and IQ. RESULTS : Effects of ASD and its severity included reduced levels of multiple metabolites in white matter and the perisylvian cortex and elevated levels in the posterior cingulate, consistent with white matter and social-brain theories of ASD. Regionally, both slower and faster decreases of metabolites with age were observed in ASD versus TD. Male-female metabolite differences were widely smaller in ASD than typically developing children and adults. ASD-specific decreases in metabolites with decreasing IQ occurred in several brain areas. CONCLUSIONS : Results support multifocal abnormal neuron or glial density, mitochondrial energetics, or neuroinflammation in ASD, alongside widespread starkly atypical moderating effects of age, sex, and IQ. These findings help parse the neurometabolic signature for ASD by phenotypic heterogeneity.

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13. Ostrolenk A, Bao VA, Mottron L, Collignon O, Bertone A. Reduced multisensory facilitation in adolescents and adults on the Autism Spectrum. Sci Rep. 2019 ; 9(1) : 11965.

Individuals with autism are reported to integrate information from visual and auditory channels in an idiosyncratic way. Multisensory integration (MSI) of simple, non-social stimuli (i.e., flashes and beeps) was evaluated in adolescents and adults with (n = 20) and without autism (n = 19) using a reaction time (RT) paradigm using audio, visual, and audiovisual stimuli. For each participant, the race model analysis compares the RTs on the audiovisual condition to a bound value computed from the unimodal RTs that reflects the effect of redundancy. If the actual audiovisual RTs are significantly faster than this bound, the race model is violated, indicating evidence of MSI. Our results show that the race model violation occurred only for the typically-developing (TD) group. While the TD group shows evidence of MSI, the autism group does not. These results suggest that multisensory integration of simple information, void of social content or complexity, is altered in autism. Individuals with autism may not benefit from the advantage conferred by multisensory stimulation to the same extent as TD individuals. Altered MSI for simple, non-social information may have cascading effects on more complex perceptual processes related to language and behaviour in autism.

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14. Platos M, Pisula E. Service use, unmet needs, and barriers to services among adolescents and young adults with autism spectrum disorder in Poland. BMC health services research. 2019 ; 19(1) : 587.

BACKGROUND : Despite a growing number of adolescents and adults diagnosed with autism spectrum disorder (ASD), little is known about service needs and barriers to services in this population. Existing research shows that youth with ASD are more underserved as they approach final years of their high school education and that adequate services for individuals with ASD after transition to adulthood are even scarcer. However, few studies have directly compared differences in service availability between adolescents and adults with ASD, and even fewer studies are published on service use outside Anglo-Saxon countries. The purpose of the present study was to examine service access, perceived barriers, and unmet needs, as reported by parents of adolescents and young adults with ASD in Poland. METHODS : The study used a subsample of parents of young people with ASD (aged 12-38 years ; N = 311) from the Polish Autism Survey - a survey covering different areas of functioning of people with ASD in Poland, based on a convenience sample. Responding parents were recruited via different service providers, social media, and press, and completed a survey using a web platform or a paper-and-pencil questionnaire. RESULTS : As expected, adults used services less often than adolescents, with 80.1% of adolescents and 61.1% of adults with ASD using services in the previous 12 months. Mental health services were among the most used and the most needed services, followed by educational services, while needs for sensory/motor services remained largely unmet. Young people with a coexisting intellectual disability used more services than those without it. Non-governmental organizations, private clinics, and schools were the most common service providers. Parents indicated that most of young people with ASD had unmet service needs for services (93.5%) and faced barriers to access them (82.7%). Low-income families and those living outside large cities were at the highest risk of facing barriers to service access. CONCLUSIONS : The results confirm still a thin body of evidence from different countries suggesting that adolescents and adults with ASD were both largely underserved populations. Policy-makers should address economic, regional, and age-related inequities in access to services for individuals with ASD.

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15. Rademacher S, Eickholt BJ. PTEN in Autism and Neurodevelopmental Disorders. Cold Spring Harbor perspectives in medicine. 2019.

Phosphatase and tensin homolog (PTEN) is a classical tumor suppressor that antagonizes phosphatidylinositol 3-phosphate kinase (PI3K)/AKT signaling. Although there is a strong association of PTEN germline mutations with cancer syndromes, they have also been described in a subset of patients with autism spectrum disorders with macrocephaly characterized by impairments in social interactions and communication, repetitive behavior and, occasionally, epilepsy. To investigate PTEN’s role during neurodevelopment and its implication for autism, several conditional Pten knockout mouse models have been generated. These models are valuable tools to understand PTEN’s spatiotemporal roles during neurodevelopment. In this review, we will highlight the anatomical and phenotypic results from animal studies and link them to cellular and molecular findings.

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16. Roberts TPL, Matsuzaki J, Blaskey L, Bloy L, Edgar JC, Kim M, Ku M, Kuschner ES, Embick D. Delayed M50/M100 evoked response component latency in minimally verbal/nonverbal children who have autism spectrum disorder. Mol Autism. 2019 ; 10 : 34.

Abnormal auditory neuromagnetic M50 and M100 responses, reflecting primary/secondary auditory cortex processing, have been reported in children who have autism spectrum disorder (ASD). Some studies have reported an association between delays in these responses and language impairment. However, as most prior research has focused on verbal individuals with ASD without cognitive impairment, rather little is known about neural activity during auditory processing in minimally verbal or nonverbal children who have ASD (ASD-MVNV)-children with little or no speech and often significant cognitive impairment. To understand the neurophysiological mechanisms underlying auditory processing in ASD-MVNV children, magnetoencephalography (MEG) measured M50 and M100 responses arising from left and right superior temporal gyri during tone stimuli in three cohorts : (1) MVNV children who have ASD (ASD-MVNV), (2) verbal children who have ASD and no intellectual disability (ASD-V), and (3) typically developing (TD) children. One hundred and five participants (8-12 years) were included in the final analyses (ASD-MVNV : n = 16, 9.85 +/- 1.32 years ; ASD-V : n = 55, 10.64 +/- 1.31 years ; TD : n = 34, 10.18 +/- 1.36 years). ASD-MVNV children showed significantly delayed M50 and M100 latencies compared to TD. These delays tended to be greater than the corresponding delays in verbal children with ASD. Across cohorts, delayed latencies were associated with language and communication skills, assessed by the Vineland Adaptive Behavior Scale Communication Domain. Findings suggest that auditory cortex neural activity measures could be dimensional objective indices of language impairment in ASD for either diagnostic (e.g., via threshold or cutoff) or prognostic (considering the continuous variable) use.

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17. Rodgaard EM, Jensen K, Vergnes JN, Soulieres I, Mottron L. Temporal Changes in Effect Sizes of Studies Comparing Individuals With and Without Autism : A Meta-analysis. JAMA Psychiatry. 2019.

Importance : The definition and nature of autism have been highly debated, as exemplified by several revisions of the DSM (DSM-III, DSM-IIIR, DSM-IV, and DSM-5) criteria. There has recently been a move from a categorical view toward a spectrum-based view. These changes have been accompanied by a steady increase in the prevalence of the condition. Changes in the definition of autism that may increase heterogeneity could affect the results of autism research ; specifically, a broadening of the population with autism could result in decreasing effect sizes of group comparison studies. Objective : To examine the correlation between publication year and effect size of autism-control group comparisons across several domains of published autism neurocognitive research. Data Sources : This meta-analysis investigated 11 meta-analyses obtained through a systematic search of PubMed for meta-analyses published from January 1, 1966, through January 27, 2019, using the search string autism AND (meta-analysis OR meta-analytic). The last search was conducted on January 27, 2019. Study Selection : Meta-analyses were included if they tested the significance of group differences between individuals with autism and control individuals on a neurocognitive construct. Meta-analyses were only included if the tested group difference was significant and included data with a span of at least 15 years. Data Extraction and Synthesis : Data were extracted and analyzed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline using fixed-effects models. Main Outcomes and Measures : Estimated slope of the correlation between publication year and effect size, controlling for differences in methods, sample size, and study quality. Results : The 11 meta-analyses included data from a total of 27723 individuals. Demographic data such as sex and age were not available for the entire data set. Seven different psychological and neurologic constructs were analyzed based on data from these meta-analyses. Downward temporal trends for effect size were found for all constructs (slopes : -0.067 to -0.003), with the trend being significant in 5 of 7 cases : emotion recognition (slope : -0.028 [95% CI, -0.048 to -0.007]), theory of mind (-0.045 [95% CI, -0.066 to -0.024]), planning (-0.067 [95% CI, -0.125 to -0.009]), P3b amplitude (-0.048 [95% CI, -0.093 to -0.004]), and brain size (-0.047 [95% CI, -0.077 to -0.016]). In contrast, 3 analogous constructs in schizophrenia, a condition that is also heterogeneous but with no reported increase in prevalence, did not show a similar trend. Conclusions and Relevance : The findings suggest that differences between individuals with autism and those without the diagnosis have decreased over time and that possible changes in the definition of autism from a narrowly defined and homogenous population toward an inclusive and heterogeneous population may reduce our capacity to build mechanistic models of the condition.

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18. Ruta L, Chiarotti F, Arduino GM, Apicella F, Leonardi E, Maggio R, Carrozza C, Chericoni N, Costanzo V, Turco N, Tartarisco G, Gagliano A, Allison C, Baron Cohen S, Pioggia G, Muratori F. Validation of the Quantitative Checklist for Autism in Toddlers in an Italian Clinical Sample of Young Children With Autism and Other Developmental Disorders. Frontiers in psychiatry. 2019 ; 10 : 488.

Background : The Quantitative Checklist for Autism in Toddlers (Q-CHAT) is parent-report screening questionnaire for detecting threshold and sub-threshold autistic features in toddlers. The Q-CHAT is a dimensional measure normally distributed in the general population sample and is able to differentiate between a group of children with a diagnosis of autism and unselected toddlers. Objectives : We aim to investigate the psychometric properties, score distribution, and external validity of the Q-CHAT in an Italian clinical sample of young children with autism versus children with developmental delay and typically developing children. Method : N = 126 typically developing children (TD), n = 139 children with autism, and n = 50 children presenting developmental delay (DD) were administered the Q-CHAT. Standardized measures of cognitive functions, language, and behaviors were also obtained. Results : The Q-CHAT scores were normally distributed and demonstrated adequate internal consistency and good item to total score correlations. The mean Q-CHAT score in the autism group was significantly higher than those found in the DD sample and TD children. No difference on the mean Q-CHAT score between DD and TD children was found. The accuracy of the Q-CHAT to discriminate between autism and TD was very good. Two different cut-points (27 and 31, respectively) maximized sensitivity and specificity for autism versus TD and DD, respectively. Finally, higher Q-CHAT scores were correlated with lower language and social communication skills. Conclusions : In clinical settings, the Q-CHAT demonstrated good psychometric properties and external validity to discriminate autism children not just from children with typical development but also from children with developmental delay.

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19. Sadeghi S, Pouretemad H, Khosrowabadi R, Fathabadi J, Nikbakht S. Behavioral and electrophysiological evidence for parent training in young children with autism symptoms and excessive screen-time. Asian J Psychiatr. 2019 ; 45 : 7-12.

Recent studies have shown the relationship between excessive screen time and autism symptoms. Unfortunately, there are no studies that evaluated the interventions for children with autism symptoms and excessive screen-time. This paper is a preliminary attempt to examine the effects of parent training on the duration of screen-time, repetitive behaviors and brain electrophysiological characteristics in young children with subthreshold autism symptoms and excessive screen time. Results showed that after the 2 months’ parent-child interaction, children’s screen-time and repetitive behaviors decreased and EEG ratio power in some channels changed. Our findings suggest that parent training have positive effects on young children with excessive screen-time and autism symptoms.

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20. Spratt PWE, Ben-Shalom R, Keeshen CM, Burke KJ, Jr., Clarkson RL, Sanders SJ, Bender KJ. The Autism-Associated Gene Scn2a Contributes to Dendritic Excitability and Synaptic Function in the Prefrontal Cortex. Neuron. 2019 ; 103(4) : 673-85.e5.

Autism spectrum disorder (ASD) is strongly associated with de novo gene mutations. One of the most commonly affected genes is SCN2A. ASD-associated SCN2A mutations impair the encoded protein NaV1.2, a sodium channel important for action potential initiation and propagation in developing excitatory cortical neurons. The link between an axonal sodium channel and ASD, a disorder typically attributed to synaptic or transcriptional dysfunction, is unclear. Here we show that NaV1.2 is unexpectedly critical for dendritic excitability and synaptic function in mature pyramidal neurons in addition to regulating early developmental axonal excitability. NaV1.2 loss reduced action potential backpropagation into dendrites, impairing synaptic plasticity and synaptic strength, even when NaV1.2 expression was disrupted in a cell-autonomous fashion late in development. These results reveal a novel dendritic function for NaV1.2, providing insight into cellular mechanisms probably underlying circuit and behavioral dysfunction in ASD.

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21. Ueoka I, Pham HTN, Matsumoto K, Yamaguchi M. Autism Spectrum Disorder-Related Syndromes : Modeling with Drosophila and Rodents. International journal of molecular sciences. 2019 ; 20(17).

Whole exome analyses have identified a number of genes associated with autism spectrum disorder (ASD) and ASD-related syndromes. These genes encode key regulators of synaptogenesis, synaptic plasticity, cytoskeleton dynamics, protein synthesis and degradation, chromatin remodeling, transcription, and lipid homeostasis. Furthermore, in silico studies suggest complex regulatory networks among these genes. Drosophila is a useful genetic model system for studies of ASD and ASD-related syndromes to clarify the in vivo roles of ASD-associated genes and the complex gene regulatory networks operating in the pathogenesis of ASD and ASD-related syndromes. In this review, we discuss what we have learned from studies with vertebrate models, mostly mouse models. We then highlight studies with Drosophila models. We also discuss future developments in the related field.

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22. VanDam M, Yoshinaga-Itano C. Use of the LENA Autism Screen with Children who are Deaf or Hard of Hearing. Medicina (Kaunas, Lithuania). 2019 ; 55(8).

Background and Objectives : This systematic review reports the evidence from the literature concerning the potential for using an automated vocal analysis, the Language ENvironment Analysis (LENA, LENA Research Foundation, Boulder, CO, USA) in the screening process for children at risk for autism spectrum disorder (ASD) and deaf or hard of hearing (D/HH). ASD and D/HH have increased comorbidity, but current behavioral diagnostic and screening tools have limitations. The LENA Language Autism Screen (LLAS) may offer an additional tool to disambiguate ASD from D/HH in young children. Materials and Methods : We examine empirical reports that use automatic vocal analysis methods to differentiate disordered from typically developing children. Results : Consensus across the sampled scientific literature shows support for use of automatic methods for screening and disambiguation of children with ASD and D/HH. There is some evidence of vocal differentiation between ASD, D/HH, and typically-developing children warranting use of the LLAS, but additional empirical evidence is needed to better understand the strengths and weaknesses of the tool. Conclusions : The findings reported here warrant further, more substantive, methodologically-sound research that is fully powered to show a reliable difference. Findings may be useful for both clinicians and researchers in better identification and understanding of communication disorders.

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23. Verma AK, Khan E, Mishra SK, Jain N, Kumar A. Piperine Modulates Protein Mediated Toxicity in Fragile X-Associated Tremor/Ataxia Syndrome through Interacting Expanded CGG Repeat (r(CGG)(exp)) RNA. ACS chemical neuroscience. 2019 ; 10(8) : 3778-88.

An expansion of CGG tandem repeats in the 5’ untranslated region (5’-UTR) of fragile X mental retardation 1 (FMR1) gene causes fragile X-associated tremor/ataxia syndrome (FXTAS). The transcripts of these expanded repeats r(CGG)(exp) either form RNA foci or undergo the repeat-associated non-ATG (RAN) translation that produces toxic homopolymeric proteins in neuronal cells. The discovery of small molecule modulators that possess a strong binding affinity and high selectivity to these toxic expanded repeats RNA could be a promising therapeutic approach to cure the expanded repeat-associated neurological diseases. Therefore, here we sought to test the therapeutic potential of a natural alkaloid, piperine, by assessing its ability to bind and neutralize the toxicity of r(CGG)(exp) RNA motif. To accomplish this first, we have determined the affinity of piperine to r(CGG)(exp) RNA using fluorescence-based binding assay and isothermal titration calorimetry assay. These assays showed that piperine forms a thermodynamically favorable interaction with r(CGG)(exp) RNA with high selectivity to the G-rich RNA motif. Interaction of piperine with r(CGG)(exp) motif was further validated using several biophysical techniques such as CD, CD melting, NMR spectroscopy, and gel retardation assay. Moreover, piperine was also found to be effective for improving the r(CGG)(exp) associated splicing defects and RAN translation in a FXTAS cell model system. Our results effectively provided the evidence that piperine strongly interacts with r(CGG)(exp) RNA and could be used as a suitable candidate for therapeutic development against FXTAS.

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24. Vulchanova M, Chahboun S, Galindo-Prieto B, Vulchanov V. Gaze and Motor Traces of Language Processing : Evidence from Autism Spectrum Disorders in Comparison to Typical Controls. Cognitive neuropsychology. 2019 : 1-27.

We investigated what strategies underlie figurative language processing in two groups of participants distinguished by the presence of a developmental deficit, highly-verbal participants with autism, and control participants without autism in two age ranges each. Individuals with autism spectrum disorder are characterised by impaired social interaction and communication. Even at the high end of the spectrum, where structural language is adequate, difficulties in comprehending non-literal aspects of language are widely attested. The exact causes of these problems are, however, still open to debate. In an interactive sentence-picture matching task participants selected the most suitable image representation of a non-literal figurative expression that matched the target meaning, while their eye-movements and hand movements were being tracked. Our results suggest that individuals with ASD have different processing patterns than typically developing peers when interpreting figurative language, even when they provide the correct answers. Both children with and without autism, and participants with autism display greater uncertainty and competition between alternatives when providing the answer, often reflected in also considering the literal interpretation of the expression against its target figurative meaning. We provide evidence that expression transparency and decomposability play a central role in figurative language processing across all groups.

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25. Wiebe S, Nagpal A, Truong VT, Park J, Skalecka A, He AJ, Gamache K, Khoutorsky A, Gantois I, Sonenberg N. Inhibitory interneurons mediate autism-associated behaviors via 4E-BP2. Proceedings of the National Academy of Sciences of the United States of America. 2019.

Translational control plays a key role in regulation of neuronal activity and behavior. Deletion of the translational repressor 4E-BP2 in mice alters excitatory and inhibitory synaptic functions, engendering autistic-like behaviors. The contribution of 4E-BP2-dependent translational control in excitatory and inhibitory neurons and astrocytic cells to these behaviors remains unknown. To investigate this, we generated cell-type-specific conditional 4E-BP2 knockout mice and tested them for the salient features of autism, including repetitive stereotyped behaviors (self-grooming and marble burying), sociability (3-chamber social and direct social interaction tests), and communication (ultrasonic vocalizations in pups). We found that deletion of 4E-BP2 in GABAergic inhibitory neurons, defined by Gad2, resulted in impairments in social interaction and vocal communication. In contrast, deletion of 4E-BP2 in forebrain glutamatergic excitatory neurons, defined by Camk2a, or in astrocytes, defined by Gfap, failed to cause autistic-like behavioral abnormalities. Taken together, we provide evidence for an inhibitory-cell-specific role of 4E-BP2 in engendering autism-related behaviors.

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26. Xiol C, Vidal S, Pascual-Alonso A, Blasco L, Brandi N, Pacheco P, Gerotina E, O’Callaghan M, Pineda M, Armstrong J. X chromosome inactivation does not necessarily determine the severity of the phenotype in Rett syndrome patients. Sci Rep. 2019 ; 9(1) : 11983.

Rett syndrome (RTT) is a severe neurological disorder usually caused by mutations in the MECP2 gene. Since the MECP2 gene is located on the X chromosome, X chromosome inactivation (XCI) could play a role in the wide range of phenotypic variation of RTT patients ; however, classical methylation-based protocols to evaluate XCI could not determine whether the preferentially inactivated X chromosome carried the mutant or the wild-type allele. Therefore, we developed an allele-specific methylation-based assay to evaluate methylation at the loci of several recurrent MECP2 mutations. We analyzed the XCI patterns in the blood of 174 RTT patients, but we did not find a clear correlation between XCI and the clinical presentation. We also compared XCI in blood and brain cortex samples of two patients and found differences between XCI patterns in these tissues. However, RTT mainly being a neurological disease complicates the establishment of a correlation between the XCI in blood and the clinical presentation of the patients. Furthermore, we analyzed MECP2 transcript levels and found differences from the expected levels according to XCI. Many factors other than XCI could affect the RTT phenotype, which in combination could influence the clinical presentation of RTT patients to a greater extent than slight variations in the XCI pattern.

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27. Xu S, Li M, Yang C, Fang X, Ye M, Wei L, Liu J, Li B, Gan Y, Yang B, Huang W, Li P, Meng X, Wu Y, Jiang G. Altered Functional Connectivity in Children With Low-Function Autism Spectrum Disorders. Front Neurosci. 2019 ; 13 : 806.

Neuroimaging studies have shown that autism spectrum disorders (ASDs) may be associated with abnormalities in brain structures and functions at rest as well as during cognitive tasks. However, it remains unclear if functional connectivity (FC) of all brain neural networks is also changed in these subjects. In this study, we acquired functional magnetic resonance imaging scans from 93 children with ASD and 79 matched healthy subjects. Group independent component analysis was executed for all of the participants to estimate FC. One-sample t-tests were then performed to obtain the networks for each group. Group differences in the different brain networks were tested using two-sample t-tests. Finally, relationships between abnormal FC and clinical variables were investigated with Pearson’s correlation analysis. The results from one-sample t-tests revealed nine networks with similar spatial patterns in these two groups. When compared with the controls, children with ASD showed increased connectivity in the right dorsolateral superior frontal gyrus and left middle frontal gyrus (MFG) within the occipital pole network. Children with ASD also showed decreased connectivity in the left gyrus rectus, left middle occipital gyrus, right angular gyrus, right MFG and right inferior frontal gyrus (IFG), orbital part within the lateral visual network (LVN), the left IFG, right precuneus, and right angular gyrus within the left frontoparietal (cognition) network. Furthermore, the mean FC values within the LVN showed significant positive correlations with total score of the Childhood Autism Rating Scale. Our findings indicate that abnormal FC extensively exists within some networks in children with ASD. This abnormal FC may constitute a biomarker of ASD. Our results are an important contribution to the study of neuropathophysiological mechanisms in children with ASD.

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28. Yavuz-Kodat E, Reynaud E, Geoffray MM, Limousin N, Franco P, Bourgin P, Schroder CM. Validity of Actigraphy Compared to Polysomnography for Sleep Assessment in Children With Autism Spectrum Disorder. Frontiers in psychiatry. 2019 ; 10 : 551.

Actigraphy (ACT) is a non-invasive objective assessment tool for the study of sleep-wake rhythms. It is of particular interest in children with autism spectrum disorder (ASD), as sleep disorders are highly prevalent and have a significant impact on both cognitive and behavioral functions. As polysomnography (PSG), the gold standard for the assessment of sleep, is difficult to perform in children with ASD, ACT has become a tool of choice but has not yet been validated against PSG using state-of-the-art methodology. The main objective of this study was to assess, for the first time, the validity of ACT compared to PSG for the measurement of sleep in children with ASD. During the same night of hospitalization, PSG and ACT were conducted in 26 children (6 girls and 20 boys ; mean age 5.4 years +/- 1.6) diagnosed with ASD according to DSM-5 criteria and standardized diagnostic scales. Sleep parameters were total sleep time (TST), sleep latency (SL), wake after sleep onset (WASO), and sleep efficiency (SE). To compare PSG and ACT, we conducted sleep parameter agreement analyses including : intraclass correlation coefficient (ICC), Bland-Altman plots, and equivalence tests. The comparison also included an epoch-by-epoch (EBE) agreement analysis to determine sensitivity (ability to detect sleep) and specificity (ability to detect wake). According to equivalence tests, the difference between ACT and PSG measures was clinically acceptable for TST (<30 min, p < 0.01), SL (<15 min, p < 0.001), and SE (10%, p < 0.01), but not for WASO (<15 min, p = 0.13). There was a good agreement between methods for SL (ICC = 0.79) and TST (ICC = 0.85) and a moderate agreement for WASO (ICC = 0.73) and SE (ICC = 0.68). The EBE agreement analysis revealed a high sensitivity (0.94 +/- 0.06) and moderate specificity (0.5 +/- 0.2). Since sleep disorders are one of the most common comorbidities within the ASD population and are highly prevalent, it is essential to validate objective tools of assessment. To our knowledge, our study is the first to validate ACT compared to PSG, using a state-of-the-art methodology, in children with ASD. The results suggest ACT to be a valid method to evaluate sleep within this population, with a good reliability for most sleep parameters.

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