1. {{Generation and analysis of the Rett syndrome-associated MeCP2- null rat model}}. {Yi Chuan};2016 (Nov 20);38(11):1004-1011.
MeCP2 mutations are associated with the Rett syndrome (RTT). Currently, there is an urgent need for new animal models for RTT as the existing MeCP2 knockout mouse models fail to fully mimic the pathogenesis and symptoms of RTT patients. In order to investigate the role of MeCP2 in brain development and RTT pathogenesis, we aimed to set up the MeCP2-null rat model using the CRISPR/Cas9 technology. Firstly we constructed the MeCP2 targeting vector and then microinjected Cas9 mRNA and sgRNA mixtures into fertilized ova of SD rats. The sgRNA was designed to target the exon 2 of MeCP2. Next, knockout rats were confirmed using DNA sequencing and Western blotting. Lastly, phenotypes including growth and behaviors of MeCP2 knockout rats were analyzed. The results indicated that the MeCP2 knockout rats showed body weight loss, anxiety tendency and cognitive deficits. The MeCP2-null rat model established in this study recapitulates the major symptoms of RTT patients and provides an alternative tool for future studies of MeCP2 functions.
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2. Ben-Sasson A, Yom-Tov E. {{Online Concerns of Parents Suspecting Autism Spectrum Disorder in Their Child: Content Analysis of Signs and Automated Prediction of Risk}}. {J Med Internet Res};2016 (Nov 22);18(11):e300.
BACKGROUND: Online communities are used as platforms by parents to verify developmental and health concerns related to their child. The increasing public awareness of autism spectrum disorders (ASD) leads more parents to suspect ASD in their child. Early identification of ASD is important for early intervention. OBJECTIVE: To characterize the symptoms mentioned in online queries posed by parents who suspect that their child might have ASD and determine whether they are age-specific. To test the efficacy of machine learning tools in classifying the child’s risk of ASD based on the parent’s narrative. METHODS: To this end, we analyzed online queries posed by parents who were concerned that their child might have ASD and categorized the warning signs they mentioned according to ASD-specific and non-ASD-specific domains. We then used the data to test the efficacy with which a trained machine learning tool classified the degree of ASD risk. Yahoo Answers, a social site for posting queries and finding answers, was mined for queries of parents asking the community whether their child has ASD. A total of 195 queries were sampled for this study (mean child age=38.0 months; 84.7% [160/189] boys). Content text analysis of the queries aimed to categorize the types of symptoms described and obtain clinical judgment of the child’s ASD-risk level. RESULTS: Concerns related to repetitive and restricted behaviors and interests (RRBI) were the most prevalent (75.4%, 147/195), followed by concerns related to language (61.5%, 120/195) and emotional markers (50.3%, 98/195). Of the 195 queries, 18.5% (36/195) were rated by clinical experts as low-risk, 30.8% (60/195) as medium-risk, and 50.8% (99/195) as high-risk. Risk groups differed significantly (P<.001) in the rate of concerns in the language, social, communication, and RRBI domains. When testing whether an automatic classifier (decision tree) could predict if a query was medium- or high-risk based on the text of the query and the coded symptoms, performance reached an area under the receiver operating curve (ROC) curve of 0.67 (CI 95% 0.50-0.78), whereas predicting from the text and the coded signs resulted in an area under the curve of 0.82 (0.80-0.86). CONCLUSIONS: Findings call for health care providers to closely listen to parental ASD-related concerns, as recommended by screening guidelines. They also demonstrate the need for Internet-based screening systems that utilize parents' narratives using a decision tree questioning method. Lien vers le texte intégral (Open Access ou abonnement)
3. Burrows CA, Usher LV, Mundy PC, Henderson HA. {{The salience of the self: Self-referential processing and internalizing problems in children and adolescents with autism spectrum disorder}}. {Autism Res};2016 (Nov 20)
Children and adolescents with autism spectrum disorder (ASD) demonstrate atypical processing of, and memory for, self-referenced information, which may contribute to the heightened rates of co-occurring internalizing problems. We assessed affective and cognitive aspects of self-referential processing in verbally-fluent children with ASD (N = 79), and an age-matched comparison sample (COM, N = 73) of children without an autism diagnosis. We examined group differences in these two aspects of the self-system, and their joint contributions to individual differnces in internalizing problems. Using a self-referenced memory (SRM) task, participants indicated whether a series of positive and negative trait adjectives described themselves and a well-known fictional character. Participants were then surprised with a recognition memory test on the same adjectives. Overall, individuals with ASD showed a reduction in the extent to which they preferentially endorsed positive over negative trait adjectives about themselves, and a reduction in their preferential memory for self- over other-referenced information. Across the full sample, these two aspects of self-referential processing jointly predicted self-reported internalizing problems. Specifically, self-evaluations were strongly and inversely associated with internalizing problems but only for children with relatively high SRM. These findings suggest that the salience of the self influences the extent to which affective self-evaluations impact emotional functioning for youth both with and without ASD. Implications for basic (e.g., developmental) and translational (e.g., intervention) research are discussed. Autism Res 2016. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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4. Chen H, Uddin LQ, Zhang Y, Duan X. {{Atypical effective connectivity of thalamo-cortical circuits in autism spectrum disorder}}. {Autism Res};2016 (Nov);9(11):1183-1190.
Autism spectrum disorder (ASD) is a neurodevelopment disorder characterized by atypical connectivity within and across multiple brain systems. We aimed to explore information transmission from the sensory periphery to information processing centers of the brain across thalamo-cortical circuits in ASD. A large multicenter dataset from the autism brain imaging data exchange was utilized. A thalamus template derived from the Automatic Anatomic Labeling atlas was subdivided into six subregions corresponding to six cortical regions using a « winner-takes-all » strategy. Granger causality analysis (GCA) was then applied to calculate effective connectivity from subregions of the thalamus to the corresponding cortical regions. Results demonstrate reduced effective connectivity from the thalamus to left prefrontal cortex (P = 0.023), right posterior parietal cortex (P = 0.03), and bilateral temporal cortex (left: P = 0.014; right: P = 0.015) in ASD compared with healthy control (HC) participants. The GCA values of the thalamus-bilateral temporal cortex connections were significantly negatively correlated with communication scores as assessed by the autism diagnostic observation schedule in the ASD group (left: P = 0.037; right: P = 0.007). Age-related analyses showed that the strengths of the thalamus-bilateral temporal cortex connections were significantly positively correlated with age in the HC group (left: P = 0.013; right: P = 0.016), but not in the ASD group (left: P = 0.506; right: P = 0.219). These results demonstrate impaired thalamo-cortical information transmission in ASD and suggest that atypical development of thalamus-temporal cortex connections may relate to communication deficits in the disorder. Autism Res 2016, 9: 1183-1190. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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5. D NL, Bertolin M, E LS, Keith C, Braddock B, Kaufman DA. {{Parents Perceive Improvements in Socio-emotional Functioning in Adolescents with ASD Following Social Skills Treatment}}. {J Autism Dev Disord};2016 (Nov 21)
The current study examined the effectiveness of a social skills treatment (PEERS) for improving socio-emotional competencies in a sample of high-functioning adolescents with ASD. Neuropsychological and self- and parent-report measures assessing social, emotional, and behavioral functioning were administered before and after treatment. Following social skills treatment, adolescents with ASD exhibited decreased aggression, anxiety, and withdrawal, as well as improvements in emotional responsiveness, adaptability, leadership, and participation in activities of daily living, though no change was found in affect recognition abilities. These findings suggest that PEERS social skills treatment improves particular aspects of emotional, behavioral, and social functioning that may be necessary for developing and maintaining quality peer relationships and remediating social isolation in adolescents with ASD.
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6. Dan B. {{DMCN 2016 highlights: cerebral palsy epidemiology, communication in autism, and more}}. {Dev Med Child Neurol};2016 (Dec);58(12):1205.
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7. Dell’Osso L, Luche RD, Gesi C, Moroni I, Carmassi C, Maj M. {{From Asperger’s Autistischen Psychopathen to DSM-5 Autism Spectrum Disorder and Beyond: A Subthreshold Autism Spectrum Model}}. {Clin Pract Epidemiol Ment Health};2016;12:120-131.
Growing interest has recently been devoted to partial forms of autism, lying at the diagnostic boundaries of those conditions previously diagnosed as Asperger’s Disorder. This latter includes an important retrieval of the European classical psychopathological concepts of adult autism to which Hans Asperger referred in his work. Based on the review of Asperger’s Autistische Psychopathie, from first descriptions through the DSM-IV Asperger’s Disorder and up to the recent DSM-5 Autism Spectrum Disorder, the paper aims to propose a Subthreshold Autism Spectrum Model that encompasses not only threshold-level manifestations but also mild/atypical symptoms, gender-specific features, behavioral manifestations and personality traits associated with Autism Spectrum Disorder. This model includes, but is not limited to, the so-called broad autism phenotype spanning across the general population that does not fully meet Autism Spectrum Disorder criteria. From this perspective, we propose a subthreshold autism as a unique psychological/behavioral model for research that could help to understand the neurodevelopmental trajectories leading from autistic traits to a broad range of mental disorders.
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8. D’Mello AM, Moore DM, Crocetti D, Mostofsky SH, Stoodley CJ. {{Cerebellar gray matter differentiates children with early language delay in autism}}. {Autism Res};2016 (Nov);9(11):1191-1204.
Early language delay (ELD) is one of the earliest indicators of autism spectrum disorder (ASD), and predicts later cognitive and behavioral outcomes. We aimed to determine the neural correlates of ELD in autism, and examine the relationships between gray matter (GM), age of first word/phrase, and core ASD symptoms. We used voxel-based morphometry to examine whole-brain differences in GM in 8-13 year old children with autism (n = 13 ELD; n = 22 non-ELD) and 35 age-matched typically developing (TD) children. Multiple regression analyses examined the relationships between GM, age of first word/phrase, and autism diagnostic observation schedule (ADOS) scores. Composite age of first word/phrase negatively correlated with GM throughout the cerebellum. Both ASD groups (ELD and non-ELD) had reduced GM in right cerebellar Crus I/II when compared to TD children. Left cerebellar Crus I/II was the only region in the brain that differentiated ELD and non-ELD children, with ELD children showing reduced GM relative to both non-ELD and TD groups. Groupxscore interactions converged in left Crus I/II, such that the non-ELD group showed poorer ADOS scores with increasing GM, whereas the ELD group showed poorer ADOS scores as GM decreased. Reduced GM in right cerebellar Crus I/I was related ASD diagnosis, while children with ELD showed additional reduced GM in left Crus I/II. These findings highlight the importance of specific cerebellar networks in both ASD and early language development, and suggest that bilateral disruption in cerebellar regions that interconnect with fronto-parietal networks could impact language acquisition in ASD. Autism Res 2016, 9: 1191-1204. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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9. Gao Y, Sheng C, Xie RH, Sun W, Asztalos E, Moddemann D, Zwaigenbaum L, Walker M, Wen SW. {{New Perspective on Impact of Folic Acid Supplementation during Pregnancy on Neurodevelopment/Autism in the Offspring Children – A Systematic Review}}. {PLoS One};2016;11(11):e0165626.
It has been conclusively established that folic acid supplementation prior to and during early pregnancy (up to 12 weeks of gestation) can prevent neural tube defects (NTDs). We hypothesized that folate effects may extend from neuro-structural defects to alterations in neuro-behavioural and emotional skills including autism spectrum disorders (ASDs) and other developmental disorders. The objective of this review was to comprehensively evaluate evidence on the impact of folic acid on neurodevelopment other than NTDs. We conducted an online search of relevant literature compiled by the National Library of Medicine from Medline and EMBASE (searched on Dec 31, 2014: http://www.ncbi.nlm.nih.gov/entrez/query/fcgi and http://www.elsevier.com/online-tools/embase). We first created 3 files (search restricted to English literature) using the following key words: 1) folate or folic acid (171322 papers identified by this search); 2) maternal or pregnancy or pregnant or gestation or gestational or prenatal or antenatal or periconception or periconceptional (1349219 papers identified by this search); and 3) autism or autism spectrum disorders or developmental delay or development or neurodevelopment or mental or cognitive or language or personal-social or gross motor or fine motor or behaviour or intellectual or intelligence or Bayley Scale (8268145 papers identified by this search). We then merged the 3 files and reviewed the papers that addressed these three issues simultaneously. A total of 22 original papers that examined the association between folic acid supplementation in human pregnancy and neurodevelopment/autism were identified after the screening, with 15 studies showing a beneficial effect of folic acid supplementation on neurodevelopment/autism, 6 studies showed no statistically significant difference, while one study showed a harmful effect in > 5 mg folic acid supplementation/day during pregnancy. Folic acid supplementation in pregnancy may have beneficial effects on the neurodevelopment of children beyond its proven effect on NTDs.
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10. Gozes I. {{Sexual divergence in activity-dependent neuroprotective protein impacting autism, schizophrenia, and Alzheimer’s disease}}. {J Neurosci Res};2017 (Jan 2);95(1-2):652-660.
Discovered in our laboratory, activity-dependent neuroprotective protein (ADNP) interacts with key regulatory proteins, including the chromatin remodeling complex SWI/SNF, proteins associated with RNA splicing, RNA translation, microtubule dynamics, and autophagy. ADNP regulates > 400 genes during mouse embryonic development and is essential for neural tube closure. ADNP key functions extend from mice to men, with mutations causing ADNP-related ID/autism syndrome, also known as the Helsmoortel-Van der Aa syndrome. ADNP mRNA increases in lymphocytes derived from schizophrenia patients and in patients suffering from mild cognitive impairment (MCI) and further increases in Alzheimer’s disease patients compared with controls. Serum ADNP levels correlate with IQ. NAP (davunetide), an ADNP snippet drug candidate, protects cognition in patients suffering from amnestic MCI preceding Alzheimer’s disease and significantly enhances functional daily activities in schizophrenia patients toward future development. It is important to note that ADNP is sexually regulated in the brains of birds, mice, and men and in lymphocytes of patients suffering from schizophrenia. ADNP haploinsufficiency in mice results in significantly decreased axonal transport (with male-female differences) changes in gene expression in a sex-dependent manner, including key regulatory mechanisms during brain and heart development and function and behavioral outcomes. These findings pave the path for better understanding of brain function through the prism of sex differences. (c) 2016 Wiley Periodicals, Inc.
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11. Gulati S, Hossain S, Squires J. {{Editorial: Autism – Hype and Hope}}. {Indian J Pediatr};2016 (Nov 22)
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12. Hamilton AF, Lind F. {{Audience effects: what can they tell us about social neuroscience, theory of mind and autism?}}. {Cult Brain};2016;4(2):159-177.
An audience effect arises when a person’s behaviour changes because they believe someone else is watching them. Though these effects have been known about for over 110 years, the cognitive mechanisms of the audience effect and how it might vary across different populations and cultures remains unclear. In this review, we examine the hypothesis that the audience effect draws on implicit mentalising abilities. Behavioural and neuroimaging data from a number of tasks are consistent with this hypothesis. We further review data suggest that how people respond to audiences may vary over development, personality factors, cultural background and clinical diagnosis including autism and anxiety disorder. Overall, understanding and exploring the audience effect may contribute to our models of social interaction, including reputation management and mentalising.
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13. Hicks SD, Middleton FA. {{A Comparative Review of microRNA Expression Patterns in Autism Spectrum Disorder}}. {Front Psychiatry};2016;7:176.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by a wide spectrum of deficits in social interaction, communication, and behavior. There is a significant genetic component to ASD, yet no single gene variant accounts for >1% of incidence. Posttranscriptional mechanisms such as microRNAs (miRNAs) regulate gene expression without altering the genetic code. They are abundant in the developing brain and are dysregulated in children with ASD. Patterns of miRNA expression are altered in the brain, blood, saliva, and olfactory precursor cells of ASD subjects. The ability of miRNAs to regulate broad molecular pathways in response to environmental stimuli makes them an intriguing player in ASD, a disorder characterized by genetic predisposition with ill-defined environmental triggers. In addition, the availability and extracellular stability of miRNAs make them an ideal candidate for biomarker discovery. Here, we discuss 27 miRNAs with overlap across ASD studies, including 3 miRNAs identified in 3 or more studies (miR-23a, miR-146a, and miR-106b). Together, these 27 miRNAs have 1245 high-confidence mRNA targets, a significant number of which are expressed in the brain. Furthermore, these mRNA targets demonstrate over-representation of autism-related genes with enrichment of neurotrophic signaling molecules. Brain-derived neurotrophic factor, a molecule involved in hippocampal neurogenesis and altered in ASD, is targeted by 6 of the 27 miRNAs of interest. This neurotrophic pathway represents one intriguing mechanism by which perturbations in miRNA signaling might influence central nervous system development in children with ASD.
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14. Kiep M, Spek AA. {{Executive functioning in men and women with an autism spectrum disorder}}. {Autism Res};2016 (Nov 22)
Executive functioning (EF) is thought to be linked to autism spectrum disorders (ASD) specific symptoms. The majority of research has focused on children and adolescents with ASD and, therefore, little is known about EF in adults. Furthermore, little is known about gender differences. Ninety-nine men and forty women with ASD were compared with and 35 neurotypical men 25 neurotypical women. Participants were matched on age, total intelligence, and verbal ability. The following instruments were used to measure executive functioning: digit span and letter and number sequencing of the WAIS-III, Tower of Hanoi, WCST, and Verbal fluency. Multiple analysis of variance was conducted to determine group differences. Women with ASD performed worse on the working memory tasks of the WAIS-III than neurotypical women. Furthermore, women with ASD had more perseverations on the WCST than neurotypical women. The gender comparison in the ASD group showed differences in performance on mental flexibility (WCST), working memory (WAIS-III), generativity and self-monitoring (Verbal fluency). However, these differences were unequivocal and no gender specific cognitive profile could be pinpointed. Individual strengths and frailties should be highlighted in clinical practice, as impairments in EF can be under influence of the overall cognitive abilities of the individual. Furthermore, gender differences were found. This could explain differences in representation of ASD symptoms in both groups. These differences show how important thorough diagnostics are. Autism Res 2016. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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15. Lai CL, Lau Z, Lui SS, Lok E, Tam V, Chan Q, Cheng KM, Lam SM, Cheung EF. {{Meta-analysis of neuropsychological measures of executive functioning in children and adolescents with high-functioning autism spectrum disorder}}. {Autism Res};2016 (Nov 22)
Existing literature on the profile of executive dysfunction in autism spectrum disorder showed inconsistent results. Age, comorbid attention-deficit/hyperactivity disorder (ADHD) and cognitive abilities appeared to play a role in confounding the picture. Previous meta-analyses have focused on a few components of executive functions. This meta-analysis attempted to delineate the profile of deficit in several components of executive functioning in children and adolescents with high-functioning autism spectrum disorder (HFASD). Ninety-eight English published case-control studies comparing children and adolescents with HFASD with typically developing controls using well-known neuropsychological measures to assess executive functions were included. Results showed that children and adolescents with HFASD were moderately impaired in verbal working memory (g = 0.67), spatial working memory (g = 0.58), flexibility (g = 0.59), planning (g = 0.62), and generativity (g = 0.60) except for inhibition (g = 0.41). Subgroup analysis showed that impairments were still significant for flexibility (g = 0.57-0.61), generativity (g = 0.52-0.68), and working memory (g = 0.49-0.56) in a sample of autism spectrum disorder (ASD) subjects without comorbid ADHD or when the cognitive abilities of the ASD group and the control group were comparable. This meta-analysis confirmed the presence of executive dysfunction in children and adolescents with HFASD. These deficits are not solely accounted for by the effect of comorbid ADHD and the general cognitive abilities. Our results support the executive dysfunction hypothesis and contribute to the clinical understanding and possible development of interventions to alleviate these deficits in children and adolescents with HFASD. Autism Res 2016. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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16. Lai MC, Lerch JP, Floris DL, Ruigrok AN, Pohl A, Lombardo MV, Baron-Cohen S. {{Imaging sex/gender and autism in the brain: Etiological implications}}. {J Neurosci Res};2017 (Jan 2);95(1-2):380-397.
The male preponderance in autism prevalence has brought together the disparate topics of sex/gender and autism research. Two directions of neuroimaging studies on the relationships between sex/gender and autism may inform male-specific risk mechanisms and female-specific protective mechanisms of autism. First, we review how sex/gender moderates autism-related brain changes and how this informs general models of autism etiology. Better-powered human neuroimaging studies suggest that the brain characteristics of autism are qualitatively, rather than simply quantitatively, different between males and females. However, age and comorbidities might substantially moderate the pattern of differences. Second, we review how the relationship between autism-related brain changes (separately in males and females) and normative brain sex/gender differences informs specific etiological-developmental mechanisms. Both human and animal studies converge to indicate that the brain characteristics of autism are partly associated with normative brain sex/gender differences, suggesting convergence or overlap between the mechanisms leading to and modifying the development of autism and the mechanisms underlying sex differentiation and/or gender socialization. Future animal work needs to investigate sex differences in rodent mutants modeling autism-relevant genes and environmental exposures. Future human work needs to address the substantial phenotypic and etiological heterogeneity of autism and to focus on longitudinal neuroimaging studies (from early development) on the developmental trajectories of sex/gender-differential neural characteristics of autism. Combining animal and human work links up the causal chain from etiological factors, brain and physical development, to phenotypes. These together help delineate the different roles of sex and gender in relation to risk vs. protective mechanisms. (c) 2016 Wiley Periodicals, Inc.
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17. Li J, Qiu L, Xu L, Pedapati EV, Erickson CA, Sunar U. {{Characterization of autism spectrum disorder with spontaneous hemodynamic activity}}. {Biomed Opt Express};2016 (Oct 1);7(10):3871-3881.
Functional near-infrared spectroscopy (fNIRS) was used to investigate spontaneous hemodynamic activity in the temporal cortex for typically developing (TD) children and children with autism spectrum disorder (ASD). Forty-seven children participated in the experiments including twenty-five with ASD. Compared with TD children, children with ASD showed weaker bilateral resting-state functional connectivity (RSFC), but much stronger fluctuation magnitude in terms of oxy-hemoglobin (HbO2) and deoxy-hemoglobin (Hb). Differentiating between ASD and TD based on a support vector machine (SVM) model including bilateral RSFC and the fluctuation power of HbO2 and Hb as variables could achieve high accurate classification with sensitivity of 81.6% and specificity of 94.6%. This study demonstrates optical brain imaging has the potential for screening children with risk of ASD.
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18. Maule J, Stanworth K, Pellicano E, Franklin A. {{Ensemble perception of color in autistic adults}}. {Autism Res};2016 (Nov 22)
Dominant accounts of visual processing in autism posit that autistic individuals have an enhanced access to details of scenes [e.g., weak central coherence] which is reflected in a general bias toward local processing. Furthermore, the attenuated priors account of autism predicts that the updating and use of summary representations is reduced in autism. Ensemble perception describes the extraction of global summary statistics of a visual feature from a heterogeneous set (e.g., of faces, sizes, colors), often in the absence of local item representation. The present study investigated ensemble perception in autistic adults using a rapidly presented (500 msec) ensemble of four, eight, or sixteen elements representing four different colors. We predicted that autistic individuals would be less accurate when averaging the ensembles, but more accurate in recognizing individual ensemble colors. The results were consistent with the predictions. Averaging was impaired in autism, but only when ensembles contained four elements. Ensembles of eight or sixteen elements were averaged equally accurately across groups. The autistic group also showed a corresponding advantage in rejecting colors that were not originally seen in the ensemble. The results demonstrate the local processing bias in autism, but also suggest that the global perceptual averaging mechanism may be compromised under some conditions. The theoretical implications of the findings and future avenues for research on summary statistics in autism are discussed. Autism Res 2016,. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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19. Millar-Buchner P, Philp AR, Gutierrez N, Villanueva S, Kerr B, Flores CA. {{Severe changes in colon epithelium in the Mecp2-null mouse model of Rett syndrome}}. {Mol Cell Pediatr};2016 (Dec);3(1):37.
BACKGROUND: Rett syndrome is best known due to its severe and devastating symptoms in the central nervous system. It is produced by mutations affecting the Mecp2 gene that codes for a transcription factor. Nevertheless, evidence for MECP2 activity has been reported for tissues other than those of the central nervous system. Patients affected by Rett presented with intestinal affections whose origin is still not known. We have observed that the Mecp2-null mice presented with episodes of diarrhea, and decided to study the intestinal phenotype in these mice. METHODS: Mecp2-null mice or bearing the conditional intestinal deletion of MECP2 were used. Morphometirc and histologic analysis of intestine, and RT-PCR, western blot and immunodetection were perfomed on intestinal samples of the animals. Electrical parameters of the intestine were determined by Ussing chamber experiments in freshly isolated colon samples. RESULTS: First we determined that MECP2 protein is mainly expressed in cells of the lower part of the colonic crypts and not in the small intestine. The colon of the Mecp2-null mice was shorter than that of the wild-type. Histological analysis showed that epithelial cells of the surface have abnormal localization of key membrane proteins like ClC-2 and NHE-3 that participate in the electroneutral NaCl absorption; nevertheless, electrogenic secretion and absorption remain unaltered. We also detected an increase in a proliferation marker in the crypts of the colon samples of the Mecp2-null mice, but the specific silencing of Mecp2 from intestinal epithelium was not able to recapitulate the intestinal phenotype of the Mecp2-null mice. CONCLUSIONS: In summary, we showed that the colon is severely affected by Mecp2 silencing in mice. Changes in colon length and epithelial histology are similar to those observed in colitis. Changes in the localization of proteins that participate in fluid absorption can explain watery stools, but the exclusive deletion of Mecp2 from the intestine did not reproduce colon changes observed in the Mecp2-null mice, indicating the participation of other cells in this phenotype and the complex interaction between different cell types in this disease.
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20. Monterrey JC, Philips J, Cleveland S, Tanaka S, Barnes P, Hallmayer JF, Reiss AL, Lazzeroni LC, Hardan AY. {{Incidental brain MRI findings in an autism twin study}}. {Autism Res};2016 (Nov 22)
Brain magnetic resonance imaging (MRI) studies suggest the prevalence of asymptomatic « incidental » findings (IF) in autism spectrum disorder (ASD) is similar to that of neurotypically developing (NT) controls. However, given the causes of IF may include both genetic and environmental factors, a twin study would facilitate comparing brain IF between ASD and NT subjects. MRI scans were examined to assess the prevalence of brain IF in twin « case pairs » (at least one twin with diagnosis of ASD) and twin « control pairs » (NT). Fifty case pairs and thirty-two control pairs were analyzed. IF were found in 68% of subjects with ASD, 71% of unaffected ASD siblings, and in 58% of control subjects (P = 0.4). IF requiring clinical follow-up occurred more frequently in subjects with ASD compared to NT controls (17% vs. 5%, respectively; P = 0.02). The concordance rate of IF in twins was 83%. A mixed effects model found younger age, male sex, and « family environment » to be significantly associated with IF. There was no difference in the prevalence rate of IF between ASD subjects and NT controls. More IF required clinical follow-up in ASD subjects compared to NT controls. The prevalence rate of IF observed in this twin study was higher than rates previously reported in singleton studies. Our results suggest the shared environment of twins – perhaps in utero – increases the risk of brain IF. Brain MRI in the initial work-up of ASD may be indicated in twins, especially in males. Autism Res 2016. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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21. Naaijen J, Zwiers MP, Amiri H, Williams SC, Durston S, Oranje B, Brandeis D, Boecker-Schlier R, Ruf M, Wolf I, Banaschewski T, Glennon JC, Franke B, Buitelaar JK, Lythgoe DJ. {{Fronto-Striatal Glutamate in Autism Spectrum Disorder and Obsessive Compulsive Disorder}}. {Neuropsychopharmacology};2016 (Nov 21)
Autism spectrum disorders (ASD) and obsessive compulsive disorder (OCD) are often comorbid with the overlap based on compulsive behaviors. Although previous studies suggest glutamatergic deficits in fronto-striatal brain areas in both disorders, this is the first study to directly compare the glutamate concentrations across the two disorders with those in healthy control participants using both categorical and dimensional approaches. In the current multi-center study (four centers), we used proton magnetic resonance spectroscopy (1H MRS) in 51 children with ASD, 29 with OCD, and 53 healthy controls (aged 8 to 13 years) to investigate glutamate (Glu) concentrations in two regions of the fronto-striatal circuit: midline anterior cingulate cortex (ACC) and left dorsal striatum. Spectra were processed with Linear Combination Model (LCModel). Group comparisons were performed with one-way analyses of variance including sex, medication use, and scanner site as covariates. Additionally, a dimensional analysis was performed, linking glutamate with a continuous measure of compulsivity across disorders. There was a main group effect for ACC glutamate (p=0.019). Contrast analyses showed increased glutamate both in children with ASD and OCD compared to controls (p=0.007), but no differences between the two disorders (p=0.770). Dimensional analyses revealed a positive correlation between compulsive behavior (measured with the Repetitive Behavior Scale) and ACC glutamate (rho=0.24, p=0.03). These findings were robust across sites. No differences were found in the striatum. The current findings confirm overlap between ASD and OCD in terms of glutamate involvement. Glutamate concentration in ACC seems to be associated with the severity of compulsive behavior.Neuropsychopharmacology accepted article preview online, 21 November 2016. doi:10.1038/npp.2016.260.
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22. Procyshyn TL, Hurd PL, Crespi BJ. {{Association testing of vasopressin receptor 1a microsatellite polymorphisms in non-clinical autism spectrum phenotypes}}. {Autism Res};2016 (Nov 22)
Variation in the arginine vasopressin receptor 1a (AVPR1a) gene is associated with autism risk in clinical populations and with variation in social behavior in non-clinical populations. However, whether a relationship exists between AVPR1a polymorphisms and non-clinical manifestations of autism spectrum phenotypes has not been established. In this study, 873 Caucasian university students were administered the Autism-spectrum Quotient (AQ) questionnaire and genotyped for the RS1 and RS3 microsatellites. A significant association was found between RS3 microsatellite variation and AQ score, with the long/long RS3 genotype associated with higher AQ score. Analysis by sex revealed that the association was only significant for females. Significantly higher AQ scores were also observed for individuals with a specific RS3 allele (« target allele »), which previous researchers have associated with increased autism risk, impaired bonding, and reduced altruistic behavior. Analyses excluding carriers of target alleles indicated that the findings were driven by their presence or absence. Examination of AQ questionnaire subscales indicated that associations with RS3 were mediated predominantly by variation in attention switching, a cognitive function commonly impaired in autism. Effects on attention may thus mediate these relationships and represent one direction for future research. The findings also indicate, for AVPR1a, the importance of testing for sex differences and effects of target alleles. No associations were observed between RS1 microsatellite variation and AQ score. Overall, this work supports the idea that autism risk genes contribute to behavioral variation in the general population, with AVPR1a polymorphisms relating to a healthy individual’s location on the autism phenotype continuum. Autism Res 2016. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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23. Romero-Martinez A, Moya-Albiol L, Vinkhuyzen AA, Polderman TJ. {{Genetic and environmental contributions to the inverse association between specific autistic traits and experience seeking in adults}}. {Am J Med Genet B Neuropsychiatr Genet};2016 (Dec);171(8):1198.
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24. Saad K, Abdel-Rahman AA, Elserogy YM, Al-Atram AA, El-Houfey AA, Othman HA, Bjorklund G, Jia F, Urbina MA, Abo-Elela MG, Ahmad FA, Abd El-Baseer KA, Ahmed AE, Abdel-Salam AM. {{Randomized controlled trial of vitamin D supplementation in children with autism spectrum disorder}}. {J Child Psychol Psychiatry};2016 (Nov 21)
BACKGROUND: Autism spectrum disorder (ASD) is a frequent developmental disorder characterized by pervasive deficits in social interaction, impairment in verbal and nonverbal communication, and stereotyped patterns of interests and activities. It has been previously reported that there is vitamin D deficiency in autistic children; however, there is a lack of randomized controlled trials of vitamin D supplementation in ASD children. METHODS: This study is a double-blinded, randomized clinical trial (RCT) that was conducted on 109 children with ASD (85 boys and 24 girls; aged 3-10 years). The aim of this study was to assess the effects of vitamin D supplementation on the core symptoms of autism in children. ASD patients were randomized to receive vitamin D3 or placebo for 4 months. The serum levels of 25-hydroxycholecalciferol (25 (OH)D) were measured at the beginning and at the end of the study. The autism severity and social maturity of the children were assessed by the Childhood Autism Rating Scale (CARS), Aberrant Behavior Checklist (ABC), Social Responsiveness Scale (SRS), and the Autism Treatment Evaluation Checklist (ATEC). TRIAL REGISTRATION NUMBER: UMIN-CTR Study Design: trial number: UMIN000020281. RESULTS: Supplementation of vitamin D was well tolerated by the ASD children. The daily doses used in the therapy group was 300 IU vitamin D3/kg/day, not to exceed 5,000 IU/day. The autism symptoms of the children improved significantly, following 4-month vitamin D3 supplementation, but not in the placebo group. This study demonstrates the efficacy and tolerability of high doses of vitamin D3 in children with ASD. CONCLUSIONS: This study is the first double-blinded RCT proving the efficacy of vitamin D3 in ASD patients. Depending on the parameters measured in the study, oral vitamin D supplementation may safely improve signs and symptoms of ASD and could be recommended for children with ASD. At this stage, this study is a single RCT with a small number of patients, and a great deal of additional wide-scale studies are needed to critically validate the efficacy of vitamin D in ASD.
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25. Spann MN, Sourander A, Surcel HM, Hinkka-Yli-Salomaki S, Brown AS. {{Prenatal toxoplasmosis antibody and childhood autism}}. {Autism Res};2016 (Nov 22)
There is evidence that some maternal infections during the prenatal period are associated with neurodevelopmental disorders, such as childhood autism. However, the association between autism and Toxoplasma gondii (T. gondii), an intracellular parasite, remains unclear. The authors examined whether serologically confirmed maternal antibodies to T. gondii are associated with odds of childhood autism in offspring. The study is based on a nested case-control design of a large national birth cohort (N = 1.2 million) and the national psychiatric registries in Finland. There were 874 cases of childhood autism and controls matched 1:1 on date of birth, sex, birthplace and residence in Finland. Maternal sera were prospectively assayed from a national biobank for T. gondii IgM and IgG antibodies; IgG avidity analyses were also performed. High maternal T. gondii IgM antibody was associated with a significantly decreased odds of childhood autism. Low maternal T. gondii IgG antibody was associated with increased offspring odds of autism. In women with high T. gondii IgM antibodies, the IgG avidity was high for both cases and controls, with the exception of three controls. The findings suggest that the relationship between maternal T. gondii antibodies and odds of childhood autism may be related to the immune response to this pathogen or the overall activation of the immune system. Autism Res 2016. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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26. Torres EB, Denisova K. {{Motor noise is rich signal in autism research and pharmacological treatments}}. {Sci Rep};2016 (Nov 21);6:37422.
The human body is in constant motion, from every breath that we take, to every visibly purposeful action that we perform. Remaining completely still on command is a major achievement as involuntary fluctuations in our motions are difficult to keep under control. Here we examine the noise-to-signal ratio of micro-movements present in time-series of head motions extracted from resting-state functional magnetic resonance imaging scans in 1048 participants. These included individuals with autism spectrum disorders (ASD) and healthy-controls in shared data from the Autism Brain Imaging Data Exchange (ABIDE) and the Attention-Deficit Hyperactivity Disorder (ADHD-200) databases. We find excess noise and randomness in the ASD cases, suggesting an uncertain motor-feedback signal. A power-law emerged describing an orderly relation between the dispersion and shape of the probability distribution functions best describing the stochastic properties under consideration with respect to intelligence quotient (IQ-scores). In ASD, deleterious patterns of noise are consistently exacerbated with the presence of secondary (comorbid) neuropsychiatric diagnoses, lower verbal and performance intelligence, and autism severity. Importantly, such patterns in ASD are present whether or not the participant takes psychotropic medication. These data unambiguously establish specific noise-to-signal levels of head micro-movements as a biologically informed core feature of ASD.
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27. Warner G, Howlin P, Salomone E, Moss J, Charman T. {{Profiles of children with Down syndrome who meet screening criteria for autism spectrum disorder (ASD): a comparison with children diagnosed with ASD attending specialist schools}}. {J Intellect Disabil Res};2016 (Nov 21)
BACKGROUND: Recent research suggests that around 16% to 18% of children with Down syndrome (DS) also meet diagnostic criteria for autism spectrum disorder (ASD). However, there are indications that profiles of autism symptoms in this group may vary from those typically described in children with ASD. METHOD: Rates of autism symptoms and emotional and behavioural problems among children with DS who screened positive for ASD on the Social Communication Questionnaire (SCQ) (n = 183) were compared with a group of children with clinical diagnoses of ASD (n = 189) attending specialist schools in the UK. Groups were matched for age and approximate language level (use of phrase speech). RESULTS: Profiles of autistic symptoms in the two groups were generally similar, but children with DS meeting ASD cut-off on the SCQ tended to show fewer problems in reciprocal social interaction than those in the ASD group. They also showed slightly lower rates of emotional and peer-related problems. The results mostly confirm findings from a previous study in which the original validation sample for the SCQ was used as a comparison group. CONCLUSION: Findings suggest that children with DS who meet screening criteria for ASD show similar profiles of communication and repetitive behaviours to those typically described in autism. However, they tend to have relatively milder social difficulties. It is important that clinicians are aware of this difference if children with DS and ASD are to be correctly diagnosed and eligible for specialist intervention and education services.
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28. Xiao X, Fang H, Wu J, Xiao C, Xiao T, Qian L, Liang F, Xiao Z, Chu KK, Ke X. {{Diagnostic model generated by MRI-derived brain features in toddlers with autism spectrum disorder}}. {Autism Res};2016 (Nov 22)
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with core symptoms of atypical social interaction, communication, and restricted, repetitive patterns of behavior, interests, and activities. Although the pathophysiologic mechanism of ASD is unclarified yet, the neuroanatomical features are considered as valuable predictors for discriminating ASD from others. But there has been relatively little scientific study about predictive power of different neuroanatomical features of early age ASD. A total of 85 participants, 46 (mean age 27 +/- 4 months) with ASD and 39 (mean age 28 +/- 4 months) with development delay (DD), were included in the present study. The predictive models generated by support vector machines, naive bayes, and random forest was compared based on the regional average cortical surface area. Features like regional cortical thickness, cortical volume, and cortical surface area were evaluated between the models generated by Random Forest, and the classification performance of the predictive models, generated by the top 10, top 20, or top 30 factors in RF classifiers, was compared. The predictive model generated by regional average cortical thickness of regions with top 20 highest importance of random forest classifier showed best accuracy (ACC) (80.9 +/- 1.5), specificity (81 +/- 4), sensitivity (81.3 +/- 1.2), and area under the receiver operating characteristic curve (0.88 +/- 0.01). Overall, thickness-based classification, outperforming the volume-based classification and surface area-based classification in ASD and random forest, is the optimal approach for of neuroimaging data mining in this small size set. Autism Res 2016,. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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29. Yadav S, Tiwari V, Singh M, Yadav RK, Roy S, Devi U, Gautam S, Rawat JK, Ansari MN, Saeedan AS, Prakash A, Saraf SA, Kaithwas G. {{Comparative efficacy of alpha-linolenic acid and gamma-linolenic acid to attenuate valproic acid-induced autism-like features}}. {J Physiol Biochem};2016 (Nov 22)
The present study was undertaken to elucidate the effect of alpha-linolenic acid (ALA, 18:3, omega-3) and gamma-linolenic acid (GLA, 18:3, omega-6) on experimental autism features induced by early prenatal exposure to valproic acid (VPA) in albino wistar pups. The pups were scrutinized on the accounts of behavioral, biochemical, and inflammatory markers, and the results suggested that the GLA can impart significant protection in comparison to ALA against VPA-induced autism features. When scrutinized histopathologically, the cerebellum of the GLA-treated animals was evident for more marked protection toward neuronal degeneration and neuronal loss in comparison to ALA. Concomitant administration of ALA and GLA with VPA demonstrated a marked cutdown in the Pgp 9.5 expression with GLA having more pronounced effect. Henceforth, it can be concluded that ALA and GLA can impart favorable protection against the VPA-induced autism-like features with GLA having pronounced effect.
