1. {{Correction for Patel et al., Neurotensin stimulates sortilin and mTOR in human microglia inhibitable by methoxyluteolin, a potential therapeutic target for autism}}. {Proc Natl Acad Sci U S A};2016 (Nov 1)
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2. Banerjee A, Rikhye RV, Breton-Provencher V, Tang X, Li C, Li K, Runyan CA, Fu Z, Jaenisch R, Sur M. {{Jointly reduced inhibition and excitation underlies circuit-wide changes in cortical processing in Rett syndrome}}. {Proc Natl Acad Sci U S A};2016 (Nov 1)
Rett syndrome (RTT) arises from loss-of-function mutations in methyl-CpG binding protein 2 gene (Mecp2), but fundamental aspects of its physiological mechanisms are unresolved. Here, by whole-cell recording of synaptic responses in MeCP2 mutant mice in vivo, we show that visually driven excitatory and inhibitory conductances are both reduced in cortical pyramidal neurons. The excitation-to-inhibition (E/I) ratio is increased in amplitude and prolonged in time course. These changes predict circuit-wide reductions in response reliability and selectivity of pyramidal neurons to visual stimuli, as confirmed by two-photon imaging. Targeted recordings reveal that parvalbumin-expressing (PV+) interneurons in mutant mice have reduced responses. PV-specific MeCP2 deletion alone recapitulates effects of global MeCP2 deletion on cortical circuits, including reduced pyramidal neuron responses and reduced response reliability and selectivity. Furthermore, MeCP2 mutant mice show reduced expression of the cation-chloride cotransporter KCC2 (K+/Cl- exporter) and a reduced KCC2/NKCC1 (Na+/K+/Cl- importer) ratio. Perforated patch recordings demonstrate that the reversal potential for GABA is more depolarized in mutant mice, but is restored by application of the NKCC1 inhibitor bumetanide. Treatment with recombinant human insulin-like growth factor-1 restores responses of PV+ and pyramidal neurons and increases KCC2 expression to normalize the KCC2/NKCC1 ratio. Thus, loss of MeCP2 in the brain alters both excitation and inhibition in brain circuits via multiple mechanisms. Loss of MeCP2 from a specific interneuron subtype contributes crucially to the cell-specific and circuit-wide deficits of RTT. The joint restoration of inhibition and excitation in cortical circuits is pivotal for functionally correcting the disorder.
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3. Beggiato A, Peyre H, Maruani A, Scheid I, Rastam M, Amsellem F, Gillberg CI, Leboyer M, Bourgeron T, Gillberg C, Delorme R. {{Gender differences in autism spectrum disorders: Divergence among specific core symptoms}}. {Autism Res};2016 (Nov 3)
Community-based studies have consistently shown a sex ratio heavily skewed towards males in autism spectrum disorders (ASD). The factors underlying this predominance of males are largely unknown, but the way girls score on standardized categorical diagnostic tools might account for the underrecognition of ASD in girls. Despite the existence of different norms for boys and girls with ASD on several major screening tests, the algorithm of the Autism Diagnosis Interview-Revised (ADI-R) has not been reformulated. The aim of our study was to investigate which ADI-R items discriminate between males and females, and to evaluate their weighting in the final diagnosis of autism. We then conducted discriminant analysis (DA) on a sample of 594 probands including 129 females with ASD, recruited by the Paris Autism Research International Sibpair (PARIS) Study. A replication analysis was run on an independent sample of 1716 probands including 338 females with ASD, recruited through the Autism Genetics Resource Exchange (AGRE) program. Entering the raw scores for all ADI-R items as independent variables, the DA correctly classified 78.9% of males and 72.9% of females (P < 0.001) in the PARIS cohort, and 72.2% of males and 68.3% of females (P < 0.0001) in the AGRE cohort. Among the items extracted by the stepwise DA, four belonged to the ADI-R algorithm used for the final diagnosis of ASD. In conclusion, several items of the ADI-R that are taken into account in the diagnosis of autism significantly differentiates between males and females. The potential gender bias thus induced may participate in the underestimation of the prevalence of ASD in females. Autism Res 2016,. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc. Lien vers le texte intégral (Open Access ou abonnement)
4. Chakraborti B, Verma D, Karmakar A, Jaiswal P, Sanyal A, Paul D, Sinha S, Singh AS, Guhathakurta S, Roychowdhury A, Panda CK, Ghosh S, Mohanakumar KP, Mukhophadhyay K, Rajamma U. {{Genetic variants of MAOB affect serotonin level and specific behavioral attributes to increase autism spectrum disorder (ASD) susceptibility in males}}. {Prog Neuropsychopharmacol Biol Psychiatry};2016 (Nov 3);71:123-136.
Serotonergic system participates in various developmental processes and modulation of behaviour. Autism Spectrum Disorder (ASD) is characterized by a range of behavioral symptoms scaling from mild to severe. Abnormal 5-HT synthesis and signalling, platelet hyperserotonemia and amelioration of repetitive behaviours by SSRI are some of the key findings, which reinforced the hypothesis that serotonergic genes might act as ASD susceptible genes. Therefore, genes encoding monoamine oxidases A/B (MAOA/MAOB) received special attention as these genes are located on the X-chromosome and the gene products are responsible for 5-HT degradation. In the present study, we conducted population-based association analysis of eight markers of MAOB with ASD in a study cohort of 203 cases and 236 controls form India and examined its effect on platelet 5-HT content and behaviour. Gender-specific changes were observed for the contrasting LD between pair of markers among cases and controls. Case-control analysis demonstrated over-distribution of major C allele of rs2283728 and rs2283727 in male and female ASD cases respectively. Haplotypic distribution and interaction among markers showed more robust effect in male cases. Interestingly, male ASD cases displayed higher platelet 5-HT content in comparison to the respective controls. Quantitative trait analysis revealed significant correlation of genetic variants and haplotypes of MAOB markers, rs1799836 and rs6324 with increased platelet 5-HT level and CARS scores for specific behavioral symptoms respectively in males. This study suggests that MAOB increases ASD risk in males, possibly through its sex-specific regulatory effect on 5-HT metabolism and behavior.
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5. Engberg-Pedersen E, Christensen RV. {{Mental states and activities in Danish narratives: children with autism and children with language impairment}}. {J Child Lang};2016 (Nov 2):1-26.
This study focuses on the relationship between content elements and mental-state language in narratives from twenty-seven children with autism (ASD), twelve children with language impairment (LI), and thirty typically developing children (TD). The groups did not differ on chronological age (10;6-14;0) and non-verbal cognitive skills, and the groups with ASD and TD did not differ on language measures. The children with ASD and LI had fewer content elements of the storyline than the TD children. Compared with the TD children, the children with ASD used fewer subordinate clauses about the characters’ thoughts, and preferred talking about mental states as reported speech, especially in the form of direct speech. The children with LI did not differ from the TD children on these measures. The results are discussed in the context of difficulties with socio-cognition in children with ASD and of language difficulties in children with LI.
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6. Gev T, Rosenan R, Golan O. {{Unique effects of The transporters animated series and of parental support on emotion recognition skills of children with ASD: Results of a randomized controlled trial}}. {Autism Res};2016 (Nov 3)
Emotion recognition (ER) and understanding deficits are characteristic of autism spectrum disorder (ASD). The Transporters (TT) animated series has shown promising results in teaching children with ASD to recognize emotions, with mixed findings about generalization and maintenance of effects. This study aimed to evaluate the unique role of TT and of parental support in the acquisition, generalization, and maintenance of acquired ER skills in children with ASD. 77 Israeli children with high functioning ASD, aged 4-7 were randomly assigned into four groups according to a 2 x 2 design of the factors Series (TT, control series) and Parental Support (with/without). Thirty typically developing children, matched to the ASD groups on mental age, were tested with no intervention. Participants’ ER (on three generalization levels) and emotional vocabulary (EV) were tested pre and post 8 weeks of intervention, and at 3 months’ follow-up. Compared to the control series, watching TT significantly improved children’s ER skills at all generalization levels, with good skill maintenance. All groups improved equally on EV. The amount of parental support given, in the groups that had received it, contributed to the generalization and maintenance of ER skills. Autism severity negatively correlated with ER improvement. The current study provides evidence to the unique role of TT in ER skill acquisition, generalization, and maintenance in children with high functioning ASD. In addition, this study provides evidence for a successful cultural adaptation of TT to a non-English speaking culture. Autism Res 2016,. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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7. Kawabe K, Kondo S, Matsumoto M, Seo K, Ochi M, Oka Y, Horiuchi F, Ueno SI. {{Developmental quotient to estimate intelligence in autism spectrum disorder}}. {Pediatr Int};2016 (Oct);58(10):963-966.
BACKGROUND: Autism spectrum disorders (ASD) are characterized by persistent deficits in social communication and social interaction across contexts, and are associated with restricted patterns of behavior. The developmental quotient (DQ) is based on the developmental age and chronological age of children. This study investigated the utility of the DQ to estimate cognitive ability in young children with ASD. METHODS: The DQ and intelligence quotient (IQ) were assessed using the Kyoto Scale of Psychological Development 2001 (KSPD) and Wechsler Intelligence Scale for Children-III (WISC-III), respectively. The correlation between the DQ and IQ was then analyzed among children with ASD. RESULTS: We enrolled 18 children with ASD (16 boys, two girls; age, 63.6 +/- 9.4 months; age range, 45-83 months). Overall, Cognitive-Adaptive and Language-Social DQ scores were significantly correlated with IQ score in the full scale, verbal, and performance domains. Full-scale IQ and overall DQ had a linear correlation (y = -22.747 + 1.177x, R2 = 0.677, R = 0.823). CONCLUSIONS: The DQ scores obtained using the KSPD were a reasonable estimate of cognitive ability in children with ASD. The KSPD may be a useful alternative to the WISC-III for young children with ASD and could facilitate earlier assessment.
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8. Lieb-Lundell CC. {{Three Faces of Fragile X}}. {Phys Ther};2016 (Nov);96(11):1782-1790.
Fragile X syndrome (FXS) is the first of 3 syndromes identified as a health condition related to fragile X mental retardation (FMR1) gene dysfunction. The other 2 syndromes are fragile X-associated primary ovarian insufficiency syndrome (FXPOI) and fragile X-associated tremor/ataxia syndrome (FXTAS), which together are referred to as fragile X-associated disorders (FXDs). Collectively, this group comprises the 3 faces of fragile X. Even though the 3 conditions share a common genetic defect, each one is a separate health condition that results in a variety of body function impairments such as motor delay, musculoskeletal issues related to low muscle tone, coordination limitations, ataxia, tremor, undefined muscle aches and pains, and, for FXTAS, a late-onset neurodegeneration. Although each FXD condition may benefit from physical therapy intervention, available evidence as to the efficacy of intervention appropriate to FXDs is lacking. This perspective article will discuss the genetic basis of FMR1 gene dysfunction and describe health conditions related to this mutation, which have a range of expressions within a family. Physical therapy concerns and possible assessment and intervention strategies will be introduced. Understanding the intergenerational effect of the FMR1 mutation with potential life-span expression is a key component to identifying and treating the health conditions related to this specific genetic condition.
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9. McKnight LM, O’Malley-Keighran MP, Carroll C. {{‘Just wait then and see what he does’: a speech act analysis of healthcare professionals’ interaction coaching with parents of children with autism spectrum disorders}}. {Int J Lang Commun Disord};2016 (Nov);51(6):757-768.
BACKGROUND: There is evidence indicating that parent training programmes including interaction coaching of parents of children with autism spectrum disorders (ASD) can increase parental responsiveness, promote language development and social interaction skills in children with ASD. However, there is a lack of research exploring precisely how healthcare professionals use language in interaction coaching. AIMS: To identify the speech acts of healthcare professionals during individual video-recorded interaction coaching sessions of a Hanen-influenced parent training programme with parents of children with ASD. METHODS & PROCEDURES: This retrospective study used speech act analysis. Healthcare professional participants included two speech-language therapists and one occupational therapist. Sixteen videos were transcribed and a speech act analysis was conducted to identify the form and functions of the language used by the healthcare professionals. Descriptive statistics provided frequencies and percentages for the different speech acts used across the 16 videos. OUTCOMES & RESULTS: Six types of speech acts used by the healthcare professionals during coaching sessions were identified. These speech acts were, in order of frequency: Instructing, Modelling, Suggesting, Commanding, Commending and Affirming. The healthcare professionals were found to tailor their interaction coaching to the learning needs of the parents. A pattern was observed in which more direct speech acts were used in instances where indirect speech acts did not achieve the intended response. CONCLUSIONS & IMPLICATIONS: The study provides an insight into the nature of interaction coaching provided by healthcare professionals during a parent training programme. It identifies the types of language used during interaction coaching. It also highlights additional important aspects of interaction coaching such as the ability of healthcare professionals to adjust the directness of the coaching in order to achieve the intended parental response to the child’s interaction. The findings may be used to increase the awareness of healthcare professionals about the types of speech acts used during interaction coaching as well as the manner in which coaching sessions are conducted.
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10. Miller KM, Xing G, Walker CK. {{Meconium exposure and autism risk}}. {J Perinatol};2016 (Nov 03)
OBJECTIVE: This study aims to determine whether fetal meconium passage is associated with autism. STUDY DESIGN: This retrospective birth cohort analysis of 9 945 896 children born in California 1991 to 2008 linked discharge diagnosis and procedure codes for prenatal stressors, meconium-stained amniotic fluid (MSAF) and meconium aspiration syndrome (MAS) with autism diagnoses for 47 277 children through 2012. We assessed the relative risk of autism by meconium status using logistic regression, adjusting for demographic and clinical features. RESULTS: Children exposed to meconium (MSAF and MAS) were more likely to be diagnosed with autism in comparison with unexposed children (0.60% and 0.52%, vs 0.47%, respectively). In adjusted analyses, there was a small increase in autism risk associated with MSAF exposure (adjusted relative risk (aRR) 1.18, 95% confidence interval (CI) 1.12 to 1.25), and a marginal association that failed to achieve significance between MAS and autism (aRR 1.08, 95% CI 0.98 to 1.20). CONCLUSION: Resuscitation of neonates with respiratory compromise from in utero meconium exposure may mitigate long-term neurodevelopmental damage.Journal of Perinatology advance online publication, 3 November 2016; doi:10.1038/jp.2016.200.
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11. O’Dwyer L, Tanner C, van Dongen EV, Greven CU, Bralten J, Zwiers MP, Franke B, Heslenfeld D, Oosterlaan J, Hoekstra PJ, Hartman CA, Groen W, Rommelse N, Buitelaar JK. {{Decreased Left Caudate Volume Is Associated with Increased Severity of Autistic-Like Symptoms in a Cohort of ADHD Patients and Their Unaffected Siblings}}. {PLoS One};2016;11(11):e0165620.
Autism spectrum disorder (ASD) symptoms frequently occur in individuals with attention-deficit/hyperactivity disorder (ADHD). While there is evidence that both ADHD and ASD have differential structural brain correlates, knowledge of the structural brain profile of individuals with ADHD with raised ASD symptoms is limited. The presence of ASD-like symptoms was measured by the Children’s Social Behavior Questionnaire (CSBQ) in a sample of typically developing controls (n = 154), participants with ADHD (n = 239), and their unaffected siblings (n = 144) between the ages of 8 and 29. Structural magnetic resonance imaging (MRI) correlates of ASD ratings were analysed by studying the relationship between ASD ratings and grey matter volumes using mixed effects models which controlled for ADHD symptom count and total brain volume. ASD ratings were significantly elevated in participants with ADHD relative to controls and unaffected siblings. For the entire group (participants with ADHD, unaffected siblings and TD controls), mixed effect models revealed that the left caudate nucleus volume was negatively correlated with ASD ratings (t = 2.83; P = 0.005). The current findings are consistent with the role of the caudate nucleus in executive function, including the selection of goals based on the evaluation of action outcomes and the use of social reward to update reward representations. There is a specific volumetric profile associated with subclinical ASD-like symptoms in participants with ADHD, unaffected siblings and controls with the caudate nucleus and globus pallidus being of critical importance in predicting the level of ASD-like symptoms in all three groups.
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12. Park HR, Kim IH, Kang H, Lee DS, Kim BN, Kim DG, Paek SH. {{Nucleus accumbens deep brain stimulation for a patient with self-injurious behavior and autism spectrum disorder: functional and structural changes of the brain: report of a case and review of literature}}. {Acta Neurochir (Wien)};2016 (Nov 3)
The aim of this report was to investigate the clinical outcome of deep brain stimulation (DBS) for autism spectrum disorder (ASD) and the functional and structural changes in the brain after DBS. We present a 14-year-old boy with ASD and self-injurious behavior (SIB) refractory with medical and behavioral therapy. He was treated by bilateral nucleus accumbens (NAc) DBS. Remarkable clinical improvement was observed following NAc DBS. Brain fluorodeoxyglucose-positron emission tomography (FDG-PET) and magnetic resonance imaging (MRI) volumetric studies revealed that the metabolism in the prefrontal and the frontal cortex as well as the occipital cortex was markedly decreased in association with the decreased cortical volumes in those areas 2 years after NAc DBS. The therapeutic potential of NAc DBS is suggested for the clinical improvement of patients with ASD and SIB with structural and functional changes after DBS.
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13. Patel AB, Tsilioni I, Leeman SE, Theoharides TC. {{Neurotensin stimulates sortilin and mTOR in human microglia inhibitable by methoxyluteolin, a potential therapeutic target for autism}}. {Proc Natl Acad Sci U S A};2016 (Sep 23)
We had reported elevated serum levels of the peptide neurotensin (NT) in children with autism spectrum disorders (ASD). Here, we show that NT stimulates primary human microglia, the resident immune cells of the brain, and the immortalized cell line of human microglia-SV40. NT (10 nM) increases the gene expression and release (P < 0.001) of the proinflammatory cytokine IL-1beta and chemokine (C-X-C motif) ligand 8 (CXCL8), chemokine (C-C motif) ligand 2 (CCL2), and CCL5 from human microglia. NT also stimulates proliferation (P < 0.05) of microglia-SV40. Microglia express only the receptor 3 (NTR3)/sortilin and not the NTR1 or NTR2. The use of siRNA to target sortilin reduces (P < 0.001) the NT-stimulated cytokine and chemokine gene expression and release from human microglia. Stimulation with NT (10 nM) increases the gene expression of sortilin (P < 0.0001) and causes the receptor to be translocated from the cytoplasm to the cell surface, and to be secreted extracellularly. Our findings also show increased levels of sortilin (P < 0.0001) in the serum from children with ASD (n = 36), compared with healthy controls (n = 20). NT stimulation of microglia-SV40 causes activation of the mammalian target of rapamycin (mTOR) signaling kinase, as shown by phosphorylation of its substrates and inhibition of these responses by drugs that prevent mTOR activation. NT-stimulated responses are inhibited by the flavonoid methoxyluteolin (0.1-1 muM). The data provide a link between sortilin and the pathological findings of microglia and inflammation of the brain in ASD. Thus, inhibition of this pathway using methoxyluteolin could provide an effective treatment of ASD. Lien vers le texte intégral (Open Access ou abonnement)
14. Puscian A, Leski S, Kasprowicz G, Winiarski M, Borowska J, Nikolaev T, Boguszewski PM, Lipp HP, Knapska E. {{Eco-HAB as a fully automated and ecologically relevant assessment of social impairments in mouse models of autism}}. {Elife};2016 (Oct 12);5
Eco-HAB is an open source, RFID-based system for automated measurement and analysis of social preference and in-cohort sociability in mice. The system closely follows murine ethology. It requires no contact between a human experimenter and tested animals, overcoming the confounding factors that lead to irreproducible assessment of murine social behavior between laboratories. In Eco-HAB, group-housed animals live in a spacious, four-compartment apparatus with shadowed areas and narrow tunnels, resembling natural burrows. Eco-HAB allows for assessment of the tendency of mice to voluntarily spend time together in ethologically relevant mouse group sizes. Custom-made software for automated tracking, data extraction, and analysis enables quick evaluation of social impairments. The developed protocols and standardized behavioral measures demonstrate high replicability. Unlike classic three-chambered sociability tests, Eco-HAB provides measurements of spontaneous, ecologically relevant social behaviors in group-housed animals. Results are obtained faster, with less manpower, and without confounding factors.
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15. Root JR, Stevenson BS, Davis LL, Geddes-Hall J, Test DW. {{Establishing Computer-Assisted Instruction to Teach Academics to Students with Autism as an Evidence-Based Practice}}. {J Autism Dev Disord};2016 (Nov 3)
Computer-assisted instruction (CAI) is growing in popularity and has demonstrated positive effects for students with disabilities, including those with autism spectrum disorder (ASD). In this review, criteria for group experimental and single case studies were used to determine quality (Horner et al., Exceptional Children 71:165-179, 2005; Gersten et al., Exceptional Children 71:149-164, 2005; National Technical Assistance Center on Transition Center 2015). Included studies of high and adequate quality were further analyzed in terms of content, context, and specific instructional practices. Based on the NTACT criteria, this systematic review has established CAI as an evidence-based practice for teaching academics to students with ASD with support from 10 single-case and two group design studies of high or adequate quality. Suggestions for future research and implications for practice are discussed.
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16. Van Eylen L, Boets B, Cosemans N, Peeters H, Steyaert J, Wagemans J, Noens I. {{Executive functioning and local-global visual processing: candidate endophenotypes for autism spectrum disorder?}}. {J Child Psychol Psychiatry};2016 (Nov 2)
BACKGROUND: Heterogeneity within autism spectrum disorder (ASD) hampers insight in the etiology and stimulates the search for endophenotypes. Endophenotypes should meet several criteria, the most important being the association with ASD and the higher occurrence rate in unaffected ASD relatives than in the general population. We evaluated these criteria for executive functioning (EF) and local-global (L-G) visual processing. METHODS: By administering an extensive cognitive battery which increases the validity of the measures, we examined which of the cognitive anomalies shown by ASD probands also occur in their unaffected relatives (n = 113) compared to typically developing (TD) controls (n = 100). Microarrays were performed, so we could exclude relatives from probands with a de novo mutation in a known ASD susceptibility copy number variant, thus increasing the probability that genetic risk variants are shared by the ASD relatives. An overview of studies investigating EF and L-G processing in ASD relatives was also provided. RESULTS: For EF, ASD relatives – like ASD probands – showed impairments in response inhibition, cognitive flexibility and generativity (specifically, ideational fluency), and EF impairments in daily life. For L-G visual processing, the ASD relatives showed no anomalies on the tasks, but they reported more attention to detail in daily life. Group differences were similar for siblings and for parents of ASD probands, and yielded larger effect sizes in a multiplex subsample. The group effect sizes for the comparison between ASD probands and TD individuals were generally larger than those of the ASD relatives compared to TD individuals. CONCLUSIONS: Impaired cognitive flexibility, ideational fluency and response inhibition are strong candidate endophenotypes for ASD. They could help to delineate etiologically more homogeneous subgroups, which is clinically important to allow assigning ASD probands to different, more targeted, interventions.
