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Papers of the Week

  • 1) Hum Mol Genet. 2015 Jun 23. pii: ddv234. [Epub ahead of print]

    Epigenetic mechanisms in diurnal cycles of metabolism and neurodevelopment.

    Powell WT(1), LaSalle JM(1).
    Author information: 
    (1)Medical Microbiology and Immunology, Genome Center, MIND Institute, University
    of California, Davis, CA, 95616, USA.
    The circadian cycle is a genetically encoded clock that drives cellular rhythms
    of transcription, translation, and metabolism. The circadian clock interacts with
    the diurnal environment that also drives transcription and metabolism during
    light/dark, sleep/wake, hot/cold, and feast/fast daily and seasonal cycles.
    Epigenetic regulation provides a mechanism for cells to integrate genetic
    programs with environmental signals in order produce an adaptive and consistent
    output. Recent studies have revealed that DNA methylation is one epigenetic
    mechanism that entrains the circadian clock to a diurnal environment. We also
    review recent circadian findings in the epigenetic neurodevelopmental disorders
    Prader-Willi, Angelman, and Rett syndromes and hypothesize a link between optimal
    brain development and intact synchrony between circadian and diurnal rhythms.
    © The Author 2015. Published by Oxford University Press. All rights reserved. For
    Permissions, please email: journals.permissions@oup.com.
    PMID: 26105183  [PubMed - as supplied by publisher]
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  • 2) Dev Med Child Neurol. 2015 Jun 23. doi: 10.1111/dmcn.12838. [Epub ahead of print]

    A validation study of a modified Bouchard activity record that extends the concept of 'uptime' to Rett syndrome.

    Lor L(1), Hill K(1,)(2), Jacoby P(3), Leonard H(3), Downs J(1,)(3).
    Author information: 
    (1)School of Physiotherapy and Exercise Science, Curtin University, Perth, WA,
    Australia. (2)Lung Institute of Western Australia and Centre for Asthma, Allergy 
    and Respiratory Research, The University of Western Australia, Perth, WA,
    Australia. (3)Telethon Kids Institute, The University of Western Australia,
    Perth, WA, Australia.
    AIM: The aim of this study was to investigate the validity of using a Bouchard
    activity record (BAR) in individuals with Rett syndrome to measure physical
    activity, as compared with pragmatic criterion standard measures of walking
    status and step counts recorded using the StepWatch activity monitor (SAM).
    METHOD: During the waking hours of 1 day, 43 females (mean age 21y, SD 9y) wore a
    SAM whilst a proxy completed a modified BAR. Responses to the BAR were compared
    among participants, who were grouped according to walking status, using the
    Mann-Whitney two-sample rank-sum test. Relationships were sought between BAR
    responses and step counts using linear regression.
    RESULTS: According to the proxy-reported BAR responses, those who needed
    assistance with walking spent more time sitting (median [interquartile range] 9h 
    15min [8h 8min-10h 30min] vs 6h 15min [4h 15min-8h 30min]; p<0.001) and less time
    standing (1h [38min-1h 30min] vs 2h 15min [45min-3h 45min]; p=0.04) than those
    who could walk independently. In those who could walk independently, time
    classified as 'uptime' (standing and walking) using the BAR was associated with
    increased step count (r(2) =0.58; p<0.001).
    INTERPRETATION: These data support the validity of proxy-reported BAR responses. 
    In those who could walk independently, uptime, classified using the BAR, could be
    used to estimate daily step count. This tool offers an inexpensive method for
    clinicians to gain insights into physical activity levels in individuals with
    Rett syndrome.
    © 2015 Mac Keith Press.
    PMID: 26108439  [PubMed - as supplied by publisher]
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  • 3) J Autism Dev Disord. 2015 Jun 21. [Epub ahead of print]

    Strange Words: Autistic Traits and the Processing of Non-Literal Language.

    McKenna PE(1), Glass A, Rajendran G, Corley M.
    Author information: 
    (1)Psychology, SLS, Heriot-Watt University, Edinburgh, Scotland, UK.
    Previous investigations into metonymy comprehension in ASD have confounded
    metonymy with anaphora, and outcome with process. Here we show how these
    confounds may be avoided, using data from non-diagnosed participants classified
    using Autism Quotient. Participants read sentences containing target words with
    novel or established metonymic senses (e.g., Finland, Vietnam) in literal- or
    figurative-supporting contexts. Participants took longer to read target words in 
    figurative contexts, especially where the metonymic sense was novel. Importantly,
    participants with higher AQs took longer still to read novel metonyms. This
    suggests a focus for further exploration, in terms of potential differences
    between individuals diagnosed with ASD and their neurotypical counterparts, and
    more generally in terms of the processes by which comprehension is achieved.
    PMID: 26093391  [PubMed - as supplied by publisher]
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  • 4) Epilepsy Behav. 2015 Jun 20;50:40-45. doi: 10.1016/j.yebeh.2015.05.040. [Epub ahead of print]

    Cytokine-dependent bidirectional connection between impaired social behavior and susceptibility to seizures associated with maternal immune activation in mice.

    Washington J 3rd(1), Kumar U(1), Medel-Matus JS(1), Shin D(1), Sankar R(2),
    Mazarati A(3).
    Author information: 
    (1)Department of Pediatrics, David Geffen School of Medicine at UCLA, USA.
    (2)Department of Pediatrics, David Geffen School of Medicine at UCLA, USA;
    Department of Neurology, David Geffen School of Medicine at UCLA, USA; UCLA
    Children's Discovery and Innovation Institute, USA. (3)Department of Pediatrics, 
    David Geffen School of Medicine at UCLA, USA; UCLA Children's Discovery and
    Innovation Institute, USA. Electronic address: mazarati@ucla.edu.
    Maternal immune activation (MIA) results in the development of autism in the
    offspring via hyperactivation of IL-6 signaling. Furthermore, experimental
    studies showed that the MIA-associated activation of interleukin-1β (IL-1β)
    concurrently with IL-6 increases the rate and the severity of hippocampal
    kindling in mice, thus, offering an explanation for autism-epilepsy comorbidity. 
    We examined whether epileptic phenotype triggered by prenatal exposure to IL-6
    and IL-1β combination is restricted to kindling or whether it is reproducible in 
    another model of epilepsy, whereby spontaneous seizures develop following kainic 
    acid (KA)-induced status epilepticus. We also examined whether in mice prenatally
    exposed to IL-6 and IL-6+IL-1β, the presence of spontaneous seizures would
    exacerbate autism-like features. Between days 12 and 16 of pregnancy, C57BL/6J
    mice received daily injections of IL-6, IL-1β, or IL-6+IL-1β combination. At
    postnatal day 40, male offspring were examined for the presence of social
    behavioral deficit, and status epilepticus was induced by intrahippocampal KA
    injection. After 6weeks of monitoring for spontaneous seizures, sociability was
    tested again. Both IL-6 and IL-6+IL-1β offspring presented with social behavioral
    deficit. Prenatal exposure to IL-6 alleviated, while such exposure to IL-6+IL-1β 
    exacerbated, the severity of KA-induced epilepsy. Increased severity of epilepsy 
    in the IL-6+IL-1β mice correlated with the improvement of autism-like behavior.
    We conclude that complex and not necessarily agonistic relationships exist
    between epileptic and autism-like phenotypes in an animal model of MIA coupled
    with KA-induced epilepsy and that the nature of these relationships depends on
    components of MIA involved.
    Copyright © 2015 Elsevier Inc. All rights reserved.
    PMID: 26103532  [PubMed - as supplied by publisher]
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  • 5) Neuroreport. 2015 Aug 5;26(11):638-641.

    Increased serum levels of brain-derived neurotrophic factor in autism spectrum disorder.

    Wang M(1), Chen H, Yu T, Cui G, Jiao A, Liang H.
    Author information: 
    (1)aDepartment of Neurology, Yantaishan Hospital Departments of bNeurosurgery
    cOncology, Yuhuangding Hospital, Yantai, People's Republic of China.
    The aim of this study was to investigate the potential role of brain-derived
    neurotrophic factor (BDNF) in children with autism spectrum disorders (ASD) by
    measuring serum circulating levels of BDNF as well as calcium and comparing them 
    with age-matched and sex-matched normal controls. The study included 75
    drug-naive ASD children and 75 age-sex-matched healthy children. The
    concentration of serum BDNF was determined using the enzyme-linked immunosorbent 
    assay method at baseline. Clinical information was collected. The severity of ASD
    was assessed at admission using the Childhood Autism Rating Scale total score.
    The results indicated that the mean serum BDNF levels were significantly
    (P<0.0001) higher in children with ASD compared with the control cases
    (17.59±5.55 vs. 11.21±2.79 ng/ml; t=8.902). On the basis of the receiver
    operating characteristic curve, the optimal cutoff value of serum BDNF levels as 
    an indicator for auxiliary diagnosis of autism was projected to be 12.65 ng/ml,
    which yielded a sensitivity of 80.8% and a specificity of 70.2%; the area under
    the curve was 0.840 [95% confidence interval (CI), 0.777-0.904]. In univariate
    logistic regression analysis, with an unadjusted odds ratio of 9.42 (95% CI,
    4.33-25.95; P<0.0001), BDNF of 12.65 ng/ml or more had an association with a
    diagnosis of ASD. After adjusting for possible covariates, BDNF of 12.65 ng/ml or
    more is still an independent indicator of ASD, with an adjusted odds ratio of
    7.33 (95% CI, 2.98-16.55; P<0.0001). Serum BDNF levels may be associated
    independently with the severity of ASD, and higher BDNF levels could be
    considered an independent diagnostic marker of ASD.
    PMID: 26103118  [PubMed - as supplied by publisher]
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  • 6) Autism. 2015 Jun 22. pii: 1362361315589477. [Epub ahead of print]

    Deficits in metacognitive monitoring in mathematics assessments in learners with autism spectrum disorder.

    Brosnan M(1), Johnson H(2), Grawemeyer B(3), Chapman E(2), Antoniadou K(4),
    Hollinworth M(2).
    Author information: 
    (1)University of Bath, UK pssmjb@bath.ac.uk. (2)University of Bath, UK.
    (3)University of London, UK. (4)Maastricht University, The Netherlands.
    Children and adults with autism spectrum disorder have been found to have
    deficits in metacognition that could impact upon their learning. This study
    explored metacognitive monitoring in 28 (23 males and 5 females) participants
    with autism spectrum disorder and 56 (16 males and 40 females) typically
    developing controls who were being educated at the same level. Participants were 
    asked a series of mathematics questions. Based upon previous research, after each
    question they were asked two metacognitive questions: (1) whether they thought
    they had got the answer correct or not (or 'don't know') and (2) whether they
    meant to get the answer correct or not (or 'don't know'). Participants with
    autism spectrum disorder were significantly more likely than the typically
    developing group to erroneously think that they had got an incorrect answer
    correct. Having made an error, those with autism spectrum disorder were also
    significantly more likely to report that they had meant to make the error.
    Different patterns in the types of errors made were also identified between the
    two groups. Deficits in metacognition were identified for the autism spectrum
    disorder group in the learning of mathematics. This is consistent with
    metacognitive research from different contexts and the implications for
    supporting learning in autism spectrum disorder are discussed.
    © The Author(s) 2015.
    PMID: 26101449  [PubMed - as supplied by publisher]
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  • 7) J Autism Dev Disord. 2015 Jun 23. [Epub ahead of print]

    Mothers' Parenting Behaviors in Families of School-Aged Children with Autism Spectrum Disorder: An Observational and Questionnaire Study.

    Boonen H(1), van Esch L, Lambrechts G, Maljaars J, Zink I, Van Leeuwen K, Noens
    Author information: 
    (1)Parenting and Special Education Research Unit, KU Leuven, Leopold
    Vanderkelenstraat 32, Box 3765, 3000, Leuven, Belgium,
    Although parents of children with ASD face specific challenges in parenting, only
    a few studies have empirically investigated parenting behaviors among these
    parents. The current study examined differences in parenting behaviors between
    mothers of school-aged children with ASD (n = 30) and mothers of typically
    developing children (n = 39), using both an observational measure and a
    self-report questionnaire. Results indicated that mothers of children with ASD
    obtained significantly lower scores on Sensitivity and Provision of structure as 
    measured during the observation. They reported significantly higher scores on
    Material rewarding and Adapting the environment on the questionnaire. When
    controlling for parenting stress, the group differences on Sensitivity and
    Material rewarding did not remain significant.
    PMID: 26100852  [PubMed - as supplied by publisher]
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  • 8) J Autism Dev Disord. 2015 Jun 23. [Epub ahead of print]

    Female Autism Phenotypes Investigated at Different Levels of Language and Developmental Abilities.

    Howe YJ(1), O'Rourke JA, Yatchmink Y, Viscidi EW, Jones RN, Morrow EM.
    Author information: 
    (1)Division of Developmental Behavioral Pediatrics, Department of Pediatrics,
    Hasbro Children's/Rhode Island Hospital, Brown University, Providence, RI, USA.
    This study investigated the differences in clinical symptoms between females and 
    males with autism spectrum disorder (ASD) across three verbal ability groups
    (nonverbal, phrase and fluent speech), based on which Autism Diagnostic
    Observation Schedule module was administered to 5723 individuals in four research
    datasets. In the Simons Simplex Collection and Autism Treatment Network, females 
    with ASD and phrase or fluent speech had lower cognitive, adaptive, and social
    abilities than males. In the Autism Genetics Resource Exchange and the Autism
    Consortium, females with phrase or fluent speech had similar or better adaptive
    and social abilities than males. Females who were nonverbal had similar
    cognitive, adaptive, and social abilities as males. Population-based longitudinal
    studies of verbally fluent females with ASD are needed.
    PMID: 26100851  [PubMed - as supplied by publisher]
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  • 9) Psychiatry Res. 2015 Jun 11. pii: S0165-1781(15)00335-2. doi: 10.1016/j.psychres.2015.05.048. [Epub ahead of print]

    Changes in autistic trait indicators in parents and their children with ASD: A preliminary longitudinal study.

    Hasegawa C(1), Kikuchi M(2), Yoshimura Y(1), Hiraishi H(1), Munesue T(3),
    Takesaki N(4), Higashida H(1), Oi M(1), Minabe Y(3), Asada M(5).
    Author information: 
    (1)Research Center for Child Mental Development, Kanazawa University, Kanazawa,
    Japan. (2)Research Center for Child Mental Development, Kanazawa University,
    Kanazawa, Japan; Department of Psychiatry and Neurobiology, Graduate School of
    Medical Science, Kanazawa University, Kanazawa, Japan. Electronic address:
    mitsuru@zc4.so-net.ne.jp. (3)Research Center for Child Mental Development,
    Kanazawa University, Kanazawa, Japan; Department of Psychiatry and Neurobiology, 
    Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
    (4)Department of Psychiatry and Neurobiology, Graduate School of Medical Science,
    Kanazawa University, Kanazawa, Japan. (5)Department of Adaptive Machine Systems, 
    Graduate School of Engineering, Osaka University, Suita, Japan.
    This study investigated whether the longitudinal changes in symptom severity in
    children with autism spectrum disorder (ASD) are associated with changes in the
    parents׳ autistic traits. The results demonstrated two significant correlations
    between the changes in children׳s Social Responsiveness Scale (SRS) scores and
    the Social Responsiveness Scale (SRS) score changes in either the father or both 
    parents. Autistic symptom mitigation in ASD children was associated with
    increased empathy levels in their parents.
    Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    PMID: 26099658  [PubMed - as supplied by publisher]
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  • 10) Mol Autism. 2015 Jun 12;6:35. doi: 10.1186/s13229-015-0031-2. eCollection 2015.

    Measuring the value of social engagement in adults with and without autism.

    Dubey I(1), Ropar D(1), Hamilton AF(2).
    Author information: 
    (1)School of Psychology, University of Nottingham, University Park, Nottingham,
    NG7 2RD UK. (2)Institute of Cognitive Neuroscience, University College London,
    Alexandra House, 17 Queen Square, London, WC1N 3AR UK.
    BACKGROUND: Differences in social communication are commonly reported in autism
    spectrum condition (ASC). A recent theory attributes this to a reduced motivation
    to engage with others, that is, deficits in social motivation. However, there are
    currently few simple, direct, behavioural ways to test this claim. This study
    uses a new behavioural measure of social motivation to test if preferences for
    direct gaze and face stimuli are linked to autistic traits or an ASC diagnosis.
    Our novel choose-a-movie (CAM) paradigm measures the effort participants invest
    to see particular stimuli. This aspect of social motivation is also known as
    social seeking.
    METHODS: In experiment 1, 80 typical adults completed the CAM task and a measure 
    of autistic traits. In experiment 2, 30 adults with ASC and 24 age/IQ-matched
    typical adults completed the CAM paradigm.
    RESULTS: The results from study one showed that typical adults prefer social
    stimuli over non-social, but this preference is weaker in those with higher
    levels of autistic traits. In study two, adults with ASC showed a significant
    reduction in their preference for direct gaze but little difference in their
    preference for faces without direct gaze.
    CONCLUSIONS: These data show that social motivation can be measured in a simple, 
    direct, behavioural paradigm. Furthermore, adults with ASC prefer direct gaze
    less than typical adults but may not avoid faces without direct gaze. This data
    advance our understanding of how social motivation may differ between those with 
    and without autism.
    PMID: 26097674  [PubMed]
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  • 11) J Neurodev Disord. 2015;7(1):19. doi: 10.1186/s11689-015-9111-z. Epub 2015 Jun 14.

    Memory in language-impaired children with and without autism.

    Hill AP(1), van Santen J(1), Gorman K(1), Langhorst BH(2), Fombonne E(3).
    Author information: 
    (1)Center for Spoken Language Understanding, Oregon Health & Science University, 
    Portland, OR USA ; Institute on Development and Disability, Oregon Health &
    Science University, Portland, OR USA ; Department of Pediatrics, Oregon Health & 
    Science University, 3181 SW Sam Jackson Park Road, GH40, Portland, OR 97239 USA. 
    (2)Department of Behavioral Neuroscience, Oregon Health & Science University,
    Portland, OR USA. (3)Institute on Development and Disability, Oregon Health &
    Science University, Portland, OR USA ; Department of Psychiatry, Oregon Health & 
    Science University, Portland, OR USA.
    BACKGROUND: A subgroup of young children with autism spectrum disorders (ASD)
    have significant language impairments (phonology, grammar, vocabulary), although 
    such impairments are not considered to be core symptoms of and are not unique to 
    ASD. Children with specific language impairment (SLI) display similar impairments
    in language. Given evidence for phenotypic and possibly etiologic overlap between
    SLI and ASD, it has been suggested that language-impaired children with ASD
    (ASD + language impairment, ALI) may be characterized as having both ASD and SLI.
    However, the extent to which the language phenotypes in SLI and ALI can be viewed
    as similar or different depends in part upon the age of the individuals studied. 
    The purpose of the current study is to examine differences in memory abilities,
    specifically those that are key "markers" of heritable SLI, among young
    school-age children with SLI, ALI, and ALN (ASD + language normal).
    METHODS: In this cross-sectional study, three groups of children between ages 5
    and 8 years participated: SLI (n = 18), ALI (n = 22), and ALN (n = 20). A battery
    of cognitive, language, and ASD assessments was administered as well as a nonword
    repetition (NWR) test and measures of verbal memory, visual memory, and
    processing speed.
    RESULTS: NWR difficulties were more severe in SLI than in ALI, with the largest
    effect sizes in response to nonwords with the shortest syllable lengths. Among
    children with ASD, NWR difficulties were not associated with the presence of
    impairments in multiple ASD domains, as reported previously. Verbal memory
    difficulties were present in both SLI and ALI groups relative to children with
    ALN. Performance on measures related to verbal but not visual memory or
    processing speed were significantly associated with the relative degree of
    language impairment in children with ASD, supporting the role of verbal memory
    difficulties in language impairments among early school-age children with ASD.
    CONCLUSIONS: The primary difference between children with SLI and ALI was in NWR 
    performance, particularly in repeating two- and three-syllable nonwords,
    suggesting that shared difficulties in early language learning found in previous 
    studies do not necessarily reflect the same underlying mechanisms.
    PMID: 26097521  [PubMed]
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  • 12) Genes Brain Behav. 2015 Jun 19. doi: 10.1111/gbb.12227. [Epub ahead of print]

    Effects of advanced paternal age on trajectories of social behavior in offspring.

    Janecka M(1), Manduca A(2), Servadio M(2), Trezza V(2), Smith R(1), Mill
    J(1,)(3), Schalkwyk LC(1,)(4), Reichenberg A(5,)(6), Fernandes C(1).
    Author information: 
    (1)Social, Genetic and Developmental Psychiatry MRC Centre, Institute of
    Psychiatry, Psychology and Neuroscience, PO80 De Crespigny Park, King's College
    London, London, SE5 8AF, UK. (2)Department of Science, Roma Tre University, Viale
    Guglielmo Marconi 446, Rome, 00154, Italy. (3)University of Exeter Medical
    School, University of Exeter, Barrack Road, Exeter, EX2 5DW, UK. (4)School of
    Biological Sciences, University of Essex, Wivenhoe Park, Colchester, CO4 3SQ, UK.
    (5)Department of Child and Adolescent Psychiatry, Institute of Psychiatry,
    Psychology and Neuroscience, PO80 De Crespigny Park, King's College London,
    London, SE5 8AF, UK. (6)Department of Psychiatry, Icahn School of Medicine at
    Mount Sinai, One Gustave L. Levy Place Box 1230, New York, NY, 10029, USA.
    Our study is the first investigation of the effects of advanced paternal age
    (APA) on the developmental trajectory of social behavior in rodent offspring.
    Given the strong epidemiological association between APA and sexually-dimorphic
    neurodevelopmental disorders that are characterized by abnormalities in social
    behavior (autism, schizophrenia), we assessed sociability in male and female
    inbred mice (C57BL/6J) across postnatal development (N = 104) in relation to
    paternal age. We found differences in early social behavior in both male and
    female offspring of older breeders, with differences in this social domain
    persisting into adulthood in males only. We showed that these social deficits
    were not present in the fathers of these offspring, confirming a de novo origin
    of an altered social trajectory in the offspring generation. Our results, highly 
    novel in rodent research, support the epidemiological observations in humans and 
    provide evidence for a causal link between APA, age-related changes in the
    paternal sperm DNA and neurodevelopmental disorders in their offspring.
    This article is protected by copyright. All rights reserved.
    PMID: 26096767  [PubMed - as supplied by publisher]
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  • 13) Biochem Pharmacol. 2015 Jun 18. pii: S0006-2952(15)00328-7. doi: 10.1016/j.bcp.2015.06.012. [Epub ahead of print]

    The Human Clinical Phenotypes of Altered CHRNA7 Copy Number.

    Gillentine M(1), Schaaf C(2).
    Author information: 
    (1)Department of Molecular and Human Genetics, Baylor College of Medicine,
    Houston, TX. (2)Department of Molecular and Human Genetics, Baylor College of
    Medicine, Houston, TX; Jan and Dan Duncan Neurological Research Institute, Texas 
    Children's Hospital, 1250 Moursund St., Suite 1325, Houston, TX. Electronic
    address: Schaaf@bcm.edu.
    Copy number variants (CNVs) have been implicated in multiple neuropsychiatric
    conditions, including autism spectrum disorder (ASD), schizophrenia, and
    intellectual disability (ID). Chromosome 15q13 is a hotspot for such CNVs due to 
    the presence of low copy repeat (LCR) elements, which facilitate non-allelic
    homologous recombination (NAHR). Several of these CNVs have been overrepresented 
    in individuals with neuropsychiatric disorders; yet variable expressivity and
    incomplete penetrance are commonly seen. Dosage sensitivity of the CHRNA7 gene,
    which encodes for the α7 nicotinic acetylcholine receptor in the human brain, has
    been proposed to have a major contribution to the observed cognitive and
    behavioral phenotypes, as it represents the smallest region of overlap to all the
    15q13.3 deletions and duplications. Individuals with zero to four copies of
    CHRNA7 have been reported in the literature, and represent a range of clinical
    severity, with deletions causing generally more severe and more highly penetrant 
    phenotypes. Potential mechanisms to account for the variable expressivity within 
    each group of 15q13.3 CNVs will be discussed.
    Copyright © 2015. Published by Elsevier Inc.
    PMID: 26095975  [PubMed - as supplied by publisher]
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  • 14) Ann Hum Genet. 2015 Jun 19. doi: 10.1111/ahg.12121. [Epub ahead of print]

    Common Regulatory Variants of CYFIP1 Contribute to Susceptibility for Autism Spectrum Disorder (ASD) and Classical Autism.

    Wang J(1,)(2,)(3), Tao Y(4), Song F(4), Sun Y(1,)(2), Ott J(5), Saffen
    Author information: 
    (1)Institutes of Brain Science, Fudan University, Shanghai, China. (2)School of
    Life Sciences, Fudan University, Shanghai, China. (3)Key Laboratory of
    Exploration and Utilization of Aquatic Genetic Resources, Shanghai Ocean
    University, Shanghai, Ministry of Education, China. (4)Department of Cellular and
    Genetic Medicine, Fudan University, Shanghai, China. (5)Institute of Psychology, 
    Chinese Academy of Science, Beijing, China. (6)State Key Laboratory of Medical
    Neurobiology, Fudan University, Shanghai, China.
    Based on the analysis of mRNA expression and genotype data from the "Brain Cloud"
    database, we identified seven SNPs within or near the autism candidate gene
    CYFIP1 that show nominally significant correlations between genotype and CYFIP1
    mRNA expression in human dorsolateral prefrontal cortex. Analysis of transmission
    disequilibrium test (TDT) odds ratios (ORs) for these SNPs in a large Autism
    Genome Project (AGP) trio-based association study revealed the high-expression
    alleles of four of these SNPs (rs8028440, rs2289823, rs7403800 and rs3751566) to 
    be susceptibility alleles. Correlations between the regression coefficients for
    mRNA expression and log10 -transformed TDT ORs were statistically significant [P 
    = 0.008 (ASD); P = 0.002 (classical autism)]. Similarly, statistically
    significant correlations were obtained between levels of CYFIP1 mRNA expression
    predicted using the regression equations obtained from multiple linear regression
    analysis and log10 -transformed TDT ORs for specific combinations of genotypes
    for both ASD (rs2289823 + rs3751566: P = 0.008) and classical autism (rs2289823 +
    rs3751566: P = 0.008; rs2289823 + rs3751566 + rs765763: P = 0.0006) diagnoses.
    Together, these results support the hypothesis that high expression of CYFIP1
    mRNA increases susceptibility for both ASD and classical autism.
    © 2015 John Wiley & Sons Ltd/University College London.
    PMID: 26094621  [PubMed - as supplied by publisher]
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  • 15) Am J Hum Genet. 2015 Jun 17. pii: S0002-9297(15)00198-6. doi: 10.1016/j.ajhg.2015.05.012. [Epub ahead of print]

    Paired-Duplication Signatures Mark Cryptic Inversions and Other Complex Structural Variation.

    Brand H(1), Collins RL(2), Hanscom C(2), Rosenfeld JA(3), Pillalamarri V(2),
    Stone MR(2), Kelley F(4), Mason T(4), Margolin L(4), Eggert S(2), Mitchell E(5), 
    Hodge JC(6), Gusella JF(7), Sanders SJ(8), Talkowski ME(9).
    Author information: 
    (1)Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics
    Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, 
    MA 02114, USA; Department of Neurology, Harvard Medical School, Boston, MA 02114,
    USA. (2)Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental
    Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital,
    Boston, MA 02114, USA. (3)Signature Genomic Laboratories, PerkinElmer Inc.,
    Spokane, WA 99207, USA. (4)Program in Medical and Population Genetics and
    Genomics Platform, Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA. 
    (5)Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
    55905, USA. (6)Department of Laboratory Medicine and Pathology, Mayo Clinic,
    Rochester, MN 55905, USA; Department of Pathology and Laboratory Medicine,
    Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. (7)Molecular
    Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center
    for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114,
    USA; Program in Medical and Population Genetics and Genomics Platform, Broad
    Institute of Harvard and MIT, Cambridge, MA 02141, USA; Department of Genetics,
    Harvard Medical School, Boston, MA 02115, USA. (8)Department of Psychiatry,
    University of California, San Francisco, San Francisco, CA 94103, USA.
    (9)Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics
    Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, 
    MA 02114, USA; Department of Neurology, Harvard Medical School, Boston, MA 02114,
    USA; Program in Medical and Population Genetics and Genomics Platform, Broad
    Institute of Harvard and MIT, Cambridge, MA 02141, USA. Electronic address:
    Copy-number variants (CNVs) have been the predominant focus of genetic studies of
    structural variation, and chromosomal microarray (CMA) for genome-wide CNV
    detection is the recommended first-tier genetic diagnostic screen in
    neurodevelopmental disorders. We compared CNVs observed by CMA to the structural 
    variation detected by whole-genome large-insert sequencing in 259 individuals
    diagnosed with autism spectrum disorder (ASD) from the Simons Simplex Collection.
    These analyses revealed a diverse landscape of complex duplications in the human 
    genome. One remarkably common class of complex rearrangement, which we term
    dupINVdup, involves two closely located duplications ("paired duplications") that
    flank the breakpoints of an inversion. This complex variant class is cryptic to
    CMA, but we observed it in 8.1% of all subjects. We also detected other
    paired-duplication signatures and duplication-mediated complex rearrangements in 
    15.8% of all ASD subjects. Breakpoint analysis showed that the predominant
    mechanism of formation of these complex duplication-associated variants was
    microhomology-mediated repair. On the basis of the striking prevalence of
    dupINVdups in this cohort, we explored the landscape of all inversion variation
    among the 235 highest-quality libraries and found abundant complexity among these
    variants: only 39.3% of inversions were canonical, or simple, inversions without 
    additional rearrangement. Collectively, these findings indicate that dupINVdups, 
    as well as other complex duplication-associated rearrangements, represent
    relatively common sources of genomic variation that is cryptic to
    population-based microarray and low-depth whole-genome sequencing. They also
    suggest that paired-duplication signatures detected by CMA warrant further
    scrutiny in genetic diagnostic testing given that they might mark complex
    rearrangements of potential clinical relevance.
    Copyright © 2015 The American Society of Human Genetics. Published by Elsevier
    Inc. All rights reserved.
    PMID: 26094575  [PubMed - as supplied by publisher]
    read full article
  • 16) Int Rev Psychiatry. 2015 Jun 24:1-10. [Epub ahead of print]

    Parents' perspectives on care of children with autistic spectrum disorder in South Asia - Views from Pakistan and India.

    Minhas A(1), Vajaratkar V, Divan G, Hamdani SU, Leadbitter K, Taylor C, Aldred C,
    Tariq A, Tariq M, Cardoza P, Green J, Patel V, Rahman A.
    Author information: 
    (1)Institute of Psychiatry , Rawalpindi , Pakistan.
    Autism spectrum disorder (ASD) affects about 1.4% of the population in South Asia
    but very few have access to any form of health care service. The objective of
    this study was to explore the beliefs and practices related to the care of
    children with ASD to inform strategies for intervention. In Pakistan, primary
    data were collected through in-depth interviews of parents (N = 15), while in
    India a narrative review of existing studies was conducted. The results show that
    the burden of care is almost entirely on the mother, leading to high levels of
    stress. Poor awareness of the condition in both family members and front-line
    health-providers leads to delay in recognition and appropriate management. There 
    is considerable stigma and discrimination affecting children with autism and
    their families. Specialist services are rare, concentrated in urban areas, and
    inaccessible to the majority. Strategies for intervention should include building
    community and family support networks to provide respite to the main carer. In
    the absence of specialists, community members such as community health workers,
    traditional practitioners and even motivated family members could be trained in
    recognizing and providing evidence-based interventions. Such task-shifting
    strategies should be accompanied by campaigns to raise awareness so greater
    inclusivity can be achieved.
    PMID: 26107996  [PubMed - as supplied by publisher]
    read full article
  • 17) Codas. 2015 Mar-Apr;27(2):142-147.

    Comparative study of the imitation ability in Specific Language Impairment and Autism Spectrum Impairment.

    [Article in English, Portuguese]
    Souza AC(1), Mazzega LC(1), Armonia AC(1), Pinto FC(1), Bevilacqua M(1),
    Nascimbeni RC(1), Tamanaha AC(1), Perissinoto J(1).
    Author information: 
    (1)School of Medicine, Universidade Federal de São Paulo, São Paulo, SP, Brazil.
    PURPOSE: To compare abilities of imitating generic and sequential motion gesture 
    schemes in family routines among children with Autism Spectrum Disorder (ASD) and
    Specific Language Impairment (SLI) and to analyze the relation between imitation 
    index and verbal production in the ASD group.
    METHODS: The sample was constituted by 2:1 pairing of 36 children, according to
    gender and age. All of them were diagnosed by a multidisciplinary team as
    belonging to the ASD group (n=24) or SLI group (n=12) and were under direct and
    indirect intervention in a school clinic. We have used the stage of imitation of 
    the Assessment of Symbolic Maturity, which entails the imitation of nine generic 
    and three sequential motion gesture schemes.
    RESULTS: There was a tendency to a better performance of the SLI group at
    imitating both generic and sequential gesture schemes. As we have related the
    ability of imitation to the verbal production in the ASD group, a direct relation
    between the production of phrases and the imitation of sequential schemes was
    CONCLUSION: The ability to imitate gesture and sequential schemes could be
    compared, and a more prominent impairment was identified in children with autism.
    Among them, a direct significant relationship between the ability of imitating
    sequential gesture schemes in family routine and verbal production of words and
    sentences was verified.
    PMID: 26107079  [PubMed - as supplied by publisher]
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  • 18) Cochrane Database Syst Rev. 2015;5:CD010766.

    Chelation for autism spectrum disorder (ASD).

    James S(1), Stevenson SW, Silove N, Williams K.
    Author information: 
    (1)Department of Research, Southwest AutismResearch and Resource Center, Phoenix,
    BACKGROUND: It has been suggested that the severity of autism spectrum disorder
    (ASD) symptoms is positively correlated with the level of circulating or stored
    toxic metals, and that excretion of these heavy metals, brought about by the use 
    of pharmaceutical chelating agents, results in improved symptoms.
    OBJECTIVES: To assess the potential benefits and adverse effects of
    pharmaceutical chelating agents (referred to as chelation therapy throughout this
    review) for autism spectrum disorder (ASD) symptoms.
    SEARCH METHODS: We searched the following databases on 6 November 2014: CENTRAL, 
    Ovid MEDLINE, Ovid MEDLINE In-Process, Embase,PsycINFO, Cumulative Index to
    Nursing and Allied Health Literature (CINAHL) and 15 other databases, including
    three trials registers. In addition we checked references lists and contacted
    SELECTION CRITERIA: All randomised controlled trials of pharmaceutical chelating 
    agents compared with placebo in individuals with ASD.
    DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, 
    assessed them for risk of bias and extracted relevant data. We did not conduct a 
    meta-analysis, as only one study was included.
    MAIN RESULTS: We excluded nine studies because they were non-randomised trials or
    were withdrawn before enrolment.We included one study, which was conducted in two
    phases. During the first phase of the study, 77 children with ASD were randomly
    assigned to receive seven days of glutathione lotion or placebo lotion, followed 
    by three days of oral dimercaptosuccinic acid (DMSA). Forty-nine children who
    were found to be high excreters of heavy metals during phase one continued on to 
    phase two to receive three days of oral DMSA or placebo followed by 11 days off, 
    with the cycle repeated up to six times. The second phase thus assessed the
    effectiveness of multiple doses of oral DMSA compared with placebo in children
    who were high excreters of heavy metals and who received a three-day course of
    oral DMSA. Overall, no evidence suggests that multiple rounds of oral DMSA had an
    effect on ASD symptoms.
    AUTHORS' CONCLUSIONS: This review included data from only one study, which had
    methodological limitations. As such, no clinical trial evidence was found to
    suggest that pharmaceutical chelation is an effective intervention for ASD. Given
    prior reports of serious adverse events, such as hypocalcaemia, renal impairment 
    and reported death, the risks of using chelation for ASD currently outweigh
    proven benefits. Before further trials are conducted, evidence that supports a
    causal link between heavy metals and autism and methods that ensure the safety of
    participants are needed.
    PMID: 26106752  [PubMed - in process]
    read full article
  • 19) Biomed Res Int. 2015;2015:341986. doi: 10.1155/2015/341986. Epub 2015 May 27.

    In Pursuit of New Imprinting Syndromes by Epimutation Screening in Idiopathic Neurodevelopmental Disorder Patients.

    Mayo S(1), Monfort S(1), Roselló M(1), Oltra S(1), Orellana C(1), Martínez F(1).
    Author information: 
    (1)Unidad de Genética y Diagnóstico Prenatal, Hospital Universitario y
    Politécnico La Fe, Avenida de Campanar 21, 46009 Valencia, Spain.
    Alterations of epigenetic mechanisms, and more specifically imprinting
    modifications, could be responsible of neurodevelopmental disorders such as
    intellectual disability (ID) or autism together with other associated clinical
    features in many cases. Currently only eight imprinting syndromes are defined in 
    spite of the fact that more than 200 genes are known or predicted to be
    imprinted. Recent publications point out that some epimutations which cause
    imprinting disorders may affect simultaneously different imprinted loci,
    suggesting that DNA-methylation may have been altered more globally. Therefore,
    we hypothesised that the detection of altered methylation patterns in known
    imprinting loci will indirectly allow identifying new syndromes due to
    epimutations among patients with unexplained ID. In a screening for imprinting
    alterations in 412 patients with syndromic ID/autism we found five patients with 
    altered methylation in the four genes studied: MEG3, H19, KCNQ1OT1, and SNRPN.
    Remarkably, the cases with partial loss of methylation in KCNQ1OT1 and SNRPN
    present clinical features different to those associated with the corresponding
    imprinting syndromes, suggesting a multilocus methylation defect in accordance
    with our initial hypothesis. Consequently, our results are a proof of concept
    that the identification of epimutations in known loci in patients with clinical
    features different from those associated with known syndromes will eventually
    lead to the definition of new imprinting disorders.
    PMID: 26106604  [PubMed - in process]
    read full article
  • 20) Neuroimage Clin. 2015 Apr 9;8:238-45. doi: 10.1016/j.nicl.2015.04.002. eCollection 2015.

    Diagnostic classification of intrinsic functional connectivity highlights somatosensory, default mode, and visual regions in autism.

    Chen CP(1), Keown CL(2), Jahedi A(3), Nair A(4), Pflieger ME(5), Bailey BA(6),
    Müller RA(1).
    Author information: 
    (1)Department of Psychology, Brain Development Imaging Laboratory, San Diego
    State University, San Diego, CA, USA ; Computational Science Research Center, San
    Diego State University, San Diego, CA, USA. (2)Department of Psychology, Brain
    Development Imaging Laboratory, San Diego State University, San Diego, CA, USA ; 
    Department of Cognitive Science, University of California, San Diego, CA, USA.
    (3)Department of Psychology, Brain Development Imaging Laboratory, San Diego
    State University, San Diego, CA, USA ; Department of Mathematics and Statistics, 
    San Diego State University, San Diego, CA, USA. (4)Department of Psychology,
    Brain Development Imaging Laboratory, San Diego State University, San Diego, CA, 
    USA ; Joint Doctoral Program in Clinical Psychology, San Diego State University
    and University of California San Diego, San Diego, CA, United States.
    (5)Computational Science Research Center, San Diego State University, San Diego, 
    CA, USA ; Cortech Translational Solutions Center, La Mesa, CA, USA.
    (6)Computational Science Research Center, San Diego State University, San Diego, 
    CA, USA ; Department of Mathematics and Statistics, San Diego State University,
    San Diego, CA, USA.
    Despite consensus on the neurological nature of autism spectrum disorders (ASD), 
    brain biomarkers remain unknown and diagnosis continues to be based on behavioral
    criteria. Growing evidence suggests that brain abnormalities in ASD occur at the 
    level of interconnected networks; however, previous attempts using functional
    connectivity data for diagnostic classification have reached only moderate
    accuracy. We selected 252 low-motion resting-state functional MRI (rs-fMRI) scans
    from the Autism Brain Imaging Data Exchange (ABIDE) including typically
    developing (TD) and ASD participants (n = 126 each), matched for age, non-verbal 
    IQ, and head motion. A matrix of functional connectivities between 220
    functionally defined regions of interest was used for diagnostic classification, 
    implementing several machine learning tools. While support vector machines in
    combination with particle swarm optimization and recursive feature elimination
    performed modestly (with accuracies for validation datasets <70%), diagnostic
    classification reached a high accuracy of 91% with random forest (RF), a
    nonparametric ensemble learning method. Among the 100 most informative features
    (connectivities), for which this peak accuracy was achieved, participation of
    somatosensory, default mode, visual, and subcortical regions stood out. Whereas
    some of these findings were expected, given previous findings of default mode
    abnormalities and atypical visual functioning in ASD, the prominent role of
    somatosensory regions was remarkable. The finding of peak accuracy for 100
    interregional functional connectivities further suggests that brain biomarkers of
    ASD may be regionally complex and distributed, rather than localized.
    PMID: 26106547  [PubMed - in process]
    read full article
  • 21) Neuroimage Clin. 2015 Apr 15;8:170-9. doi: 10.1016/j.nicl.2015.04.008. eCollection 2015.

    The autism puzzle: Diffuse but not pervasive neuroanatomical abnormalities in children with ASD.

    Sussman D(1), Leung RC(1), Vogan VM(1), Lee W(1), Trelle S(1), Lin S(1), Cassel
    DB(1), Chakravarty MM(2), Lerch JP(3), Anagnostou E(4), Taylor MJ(1).
    Author information: 
    (1)Diagnostic Imaging Research, The Hospital for Sick Children, University of
    Toronto, 555 University Avenue, Toronto, ON M5G 1X8, Canada. (2)Cerebral Imaging 
    Centre, Douglas Mental Health University Institute, Verdun, QC, Canada ;
    Departments of Psychiatry and Biomedical Engineering, McGill University,
    Montreal, QC, Canada. (3)Mouse Imaging Centre (MICe), The Hospital for Sick
    Children, 25 Orde Street, Toronto, ON M5T 3H7, Canada ; Department of Medical
    Biophysics, University of Toronto, 101 College Street, Toronto, ON M5G 1L7,
    Canada. (4)Bloorview Research Institute, University of Toronto, 150 Kilgour Road,
    Toronto, ON M4G 1R8, Canada.
    Autism Spectrum Disorder (ASD) is a clinically diagnosed, heterogeneous,
    neurodevelopmental condition, whose underlying causes have yet to be fully
    determined. A variety of studies have investigated either cortical, subcortical, 
    or cerebellar anatomy in ASD, but none have conducted a complete examination of
    all neuroanatomical parameters on a single, large cohort. The current study
    provides a comprehensive examination of brain development of children with ASD
    between the ages of 4 and 18 years who are carefully matched for age and sex with
    typically developing controls at a ratio of one-to-two. Two hundred and ten
    magnetic resonance images were examined from 138 Control (116 males and 22
    females) and 72 participants with ASD (61 males and 11 females). Cortical
    segmentation into 78 brain-regions and 81,924 vertices was conducted with CIVET
    which facilitated a region-of-interest- (ROI-) and vertex-based analysis,
    respectively. Volumes for the cerebellum, hippocampus, striatum, pallidum, and
    thalamus and many associated subregions were derived using the MAGeT Brain
    algorithm. The study reveals cortical, subcortical and cerebellar differences
    between ASD and Control group participants. Diagnosis, diagnosis-by-age, and
    diagnosis-by-sex interaction effects were found to significantly impact total
    brain volume but not total surface area or mean cortical thickness of the ASD
    participants. Localized (vertex-based) analysis of cortical thickness revealed no
    significant group differences, even when age, age-range, and sex were used as
    covariates. Nonetheless, the region-based cortical thickness analysis did reveal 
    regional changes in the left orbitofrontal cortex and left posterior cingulate
    gyrus, both of which showed reduced age-related cortical thinning in ASD. Our
    finding of region-based differences without significant vertex-based results
    likely indicates non-focal effects spanning the entirety of these regions. The
    hippocampi, thalamus, and globus pallidus, were smaller in volume relative to
    total cerebrum in the ASD participants. Various sub-structures showed an
    interaction of diagnosis-by-age, diagnosis-by-sex, and diagnosis-by-age-range, in
    the case where age was divided into childhood (age < 12) and adolescence
    (12 < age < 18). This is the most comprehensive imaging-based neuro-anatomical
    pediatric and adolescent ASD study to date. These data highlight the
    neurodevelopmental differences between typically developing children and those
    with ASD, and support aspects of the hypothesis of abnormal neuro-developmental
    trajectory of the brain in ASD.
    PMID: 26106541  [PubMed - in process]
    read full article
  • 22) Front Cell Neurosci. 2015 Jun 8;9:217. doi: 10.3389/fncel.2015.00217. eCollection 2015.

    Emerging roles of Axin in cerebral cortical development.

    Ye T(1), Fu AK(1), Ip NY(1).
    Author information: 
    (1)Division of Life Science, Molecular Neuroscience Center and State Key
    Laboratory of Molecular Neuroscience, The Hong Kong University of Science and
    Technology Hong Kong, China.
    Proper functioning of the cerebral cortex depends on the appropriate production
    and positioning of neurons, establishment of axon-dendrite polarity, and
    formation of proper neuronal connectivity. Deficits in any of these processes
    greatly impair neural functions and are associated with various human
    neurodevelopmental disorders including microcephaly, cortical heterotopias, and
    autism. The application of in vivo manipulation techniques such as in utero
    electroporation has resulted in significant advances in our understanding of the 
    cellular and molecular mechanisms that underlie neural development in vivo. Axin 
    is a scaffold protein that regulates neuronal differentiation and morphogenesis
    in vitro. Recent studies provide novel insights into the emerging roles of Axin
    in gene expression and cytoskeletal regulation during neurogenesis, neuronal
    polarization, and axon formation. This review summarizes current knowledge on
    Axin as a key molecular controller of cerebral cortical development.
    PMID: 26106297  [PubMed]
    read full article
  • 23) J Autism Dev Disord. 2015 Jun 24. [Epub ahead of print]

    A Qualitative Study of Autism Policy in Canada: Seeking Consensus on Children's Services.

    Shepherd CA(1), Waddell C.
    Author information: 
    (1)Faculty of Health Sciences, Children's Health Policy Centre, Simon Fraser
    University, 2435-515 West Hastings Street, Vancouver, BC, V6B 5K3, Canada.
    Canadian autism policy has been unusually contentious, with parents resorting to 
    litigation to secure services for their children in several provinces. To
    ascertain whether consensus was possible on improving services, we conducted an
    in-depth qualitative interview study with 39 parents, policymakers and
    researchers across the country. Parents vividly described the stresses of caring 
    for their children, with considerable sympathy from researchers. Policymakers in 
    turn struggled to balance the needs of all children. Yet participants agreed on
    the need for more comprehensive services across the spectrum and throughout the
    lifespan, and on the need to "do more for all" children. Our findings suggest
    that there is an emerging consensus on improving autism services in Canada-which 
    should greatly benefit children.
    PMID: 26105592  [PubMed - as supplied by publisher]
    read full article
  • 24) Neurotherapeutics. 2015 Jun 24. [Epub ahead of print]

    Discovery of Rare Mutations in Autism: Elucidating Neurodevelopmental Mechanisms.

    Gamsiz ED(1), Sciarra LN, Maguire AM, Pescosolido MF, van Dyck LI, Morrow EM.
    Author information: 
    (1)Department of Molecular Biology, Cell Biology and Biochemistry (MCB), and
    Institute for Brain Science, Brown University, Providence, RI, USA.
    Autism spectrum disorder (ASD) is a group of highly genetic neurodevelopmental
    disorders characterized by language, social, cognitive, and behavioral
    abnormalities. ASD is a complex disorder with a heterogeneous etiology. The
    genetic architecture of autism is such that a variety of different rare mutations
    have been discovered, including rare monogenic conditions that involve autistic
    symptoms. Also, de novo copy number variants and single nucleotide variants
    contribute to disease susceptibility. Finally, autosomal recessive loci are
    contributing to our understanding of inherited factors. We will review the
    progress that the field has made in the discovery of these rare genetic variants 
    in autism. We argue that mutation discovery of this sort offers an important
    opportunity to identify neurodevelopmental mechanisms in disease. The hope is
    that these mechanisms will show some degree of convergence that may be amenable
    to treatment intervention.
    PMID: 26105128  [PubMed - as supplied by publisher]
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  • 25) CNS Drugs. 2015 Jun 24. [Epub ahead of print]

    Developing Medications Targeting Glutamatergic Dysfunction in Autism: Progress to Date.

    Fung LK(1), Hardan AY.
    Author information: 
    (1)Division of Child and Adolescent Psychiatry, Department of Psychiatry and
    Behavioral Sciences, Stanford University School of Medicine, 401 Quarry Road,
    Stanford, CA, 94305-5717, USA, lkfung@stanford.edu.
    Pharmacologic treatments targeting specific molecular mechanisms relevant for
    autism spectrum disorder (ASD) are beginning to emerge in early drug development.
    This article reviews the evidence for the disruption of glutamatergic
    neurotransmission in animal models of social deficits and summarizes key
    pre-clinical and clinical efforts in developing pharmacologic interventions based
    on modulation of glutamatergic systems in individuals with ASD. Understanding the
    pathobiology of the glutamatergic system has led to the development of new
    investigational treatments for individuals with ASD. Specific examples of
    medications that modulate the glutamatergic system in pre-clinical and clinical
    studies are described. Finally, we discuss the limitations of current strategies 
    and future opportunities in developing medications targeting the glutamatergic
    system for treating individuals with ASD.
    PMID: 26104862  [PubMed - as supplied by publisher]
    read full article
  • 26) Dev Med Child Neurol. 2015 Jun 22. doi: 10.1111/dmcn.12837. [Epub ahead of print]

    Validity, reliability, and usability of the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test for autism spectrum disorders.

    Kramer JM(1), Liljenquist K(2), Coster WJ(1).
    Author information: 
    (1)Department of Occupational Therapy, Boston University, Boston, MA, USA.
    (2)Rehabilitation Sciences Program, Boston University, Boston, MA, USA.
    AIM: This study aimed to explore the test-retest reliability of the Pediatric
    Evaluation of Disability Inventory-Computer Adaptive Test for autism spectrum
    disorders (PEDI-CAT [ASD]), the concurrent validity of this test with the
    Vineland Adaptive Behavior Scales (VABS-II), and parents' perceptions of
    METHOD: A convenience sample of participants (n=39) was recruited nationally
    through disability organizations. Parents of young people aged 10 to 18 years
    (mean age 14y 10mo, SD 2y 8mo; 34 males, five females) who reported a diagnosis
    of autism were eligible to participate. Parents completed the VABS-II
    questionnaire once and the PEDI-CAT (ASD) twice (n=29) no more than 3 weeks apart
    (mean 12d) using computer-simulated administration. Parents also answered
    questions about the usability of these instruments. We examined score reliability
    using intraclass correlation coefficients (ICCs) and we explored the relationship
    between instruments using Spearman's rank correlation coefficients. Parent
    responses were grouped by common content; content categories were triangulated by
    an additional reviewer.
    RESULTS: Intraclass correlation coefficients indicate excellent reliability for
    all PEDI-CAT (ASD) domain scores (ICC≥0.86). PEDI-CAT (ASD) and VABS-II domain
    scores correlated as expected or stronger than expected (0.57-0.81). Parents
    reported that the computer-based PEDI-CAT (ASD) was easy to use and included
    fewer irrelevant questions than the VABS-II instrument.
    INTERPRETATION: These findings suggest that the PEDI-CAT (ASD) is a reliable
    assessment that parents can easily use. The PEDI-CAT (ASD) operationalizes the
    International Classification of Function, Disability and Health for Children and 
    Youth constructs of 'activity' and 'participation', and this preliminary research
    suggests that the instrument's constructs are related to those of VABS-II.
    © 2015 Mac Keith Press.
    PMID: 26104112  [PubMed - as supplied by publisher]
    read full article
  • 27) Magn Reson Med Sci. 2015 Jun 23. [Epub ahead of print]

    Correlation between Morphologic Changes and Autism Spectrum Tendency in Obsessive-Compulsive Disorder.

    Kobayashi T(1), Hirano Y, Nemoto K, Sutoh C, Ishikawa K, Miyata H, Matsumoto J,
    Matsumoto K, Masuda Y, Nakazato M, Shimizu E, Nakagawa A.
    Author information: 
    (1)Research Center for Child Mental Development, Chiba University.
    OBJECTIVES: Obsessive-compulsive disorder (OCD) is one of the most debilitating
    psychiatric disorders, with some speculating that a reason for difficulty in its 
    treatment might be its coexistence with autism spectrum. We investigated the
    tendency for autistic spectrum disorders (ASD) in patients with OCD from a
    neuroimaging point of view using voxel-based morphometry.
    METHODS: We acquired T1-weighted images from 20 patients with OCD and 30 healthy 
    controls and investigated the difference in regional volume between the groups as
    well as the correlation between Autism-Spectrum Quotient (AQ) scores and regional
    cerebral volumes of patients with OCD.
    RESULTS: Volumes in the bilateral middle frontal gyri were significantly
    decreased in patients with OCD compared to controls. Correlational analysis
    showed significant positive correlations between AQ scores and regional gray
    matter (GM) volumes in the left dorsolateral prefrontal cortex (DLPFC) and left
    amygdala. Furthermore, GM volumes of these regions were positively correlated
    with each other.
    CONCLUSIONS: The positive correlation of ASD traits in patients with OCD with
    regional GM volumes in the left DLPFC and amygdala could reflect the
    heterogeneity of patient symptoms. Our results suggest that differences in GM
    volume might allow classification of patients with OCD for appropriate therapy
    based on their particular traits.
    PMID: 26104070  [PubMed - as supplied by publisher]
    read full article
  • 28) Issues Law Med. 2015 Spring;30(1):25-46.

    Sociological Environmental Causes are Insufficient to Explain Autism Changepoints of Incidence.

    Deisher TA, Doan NV.
    The Environmental Protection Agency (EPA) recently published a study analyzing
    time trends in the cumulative incidence of autistic disorder (AD) in the U.S.,
    Denmark, and worldwide. A birth year changepoint (CP) around 1988 was identified.
    It has been argued that the epidemic rise in autism over the past three decades
    is partly due to a combination of sociologic factors along with the potential
    contribution of thimerosal containing vaccines. Our work conducted an expanded
    analysis of AD changepoints in CA and U.S., and determined whether changepoints
    in time trends of AD rates temporally coincide with changepoints for the proposed
    causative sociologic and environmental factors. Birth year changepoints were
    identified for 1980.9 [95% CI, 1978.6-1983.1], 1988.4 [95% CI, 1987.8-1989.0] and
    1995.6 [95% CI, 1994.6-1996.6] for CA and U.S. data, confirming and expanding the
    EPA results. AD birth year changepoints significantly precede the changepoints
    calculated for indicators of increased social awareness of AD. Furthermore, the
    1981 and 1996 AD birth year changepoints don't coincide with any predicted
    changepoints based on altered thimerosal content in vaccines nor on revised
    editions of the Diagnostic and Statistical Manual of Mental Disorders (DSM).
    PMID: 26103707  [PubMed - in process]
    read full article
  • 29) J Abnorm Psychol. 2015 Jun 29. [Epub ahead of print]

    Impaired Recollection of Visual Scene Details in Adults With Autism Spectrum Conditions.

    Cooper RA, Plaisted-Grant KC, Hannula DE, Ranganath C, Baron-Cohen S, Simons JS.
    Subtle memory deficits observed in autism spectrum conditions (ASC) have often
    been characterized as reflecting impaired recollection and it has been proposed
    that a relational binding deficit may underlie the recollection impairment.
    However, subjective recollection and relational binding have not been measured
    within the same task in ASC to date and it is unclear whether a relational
    binding deficit can provide a full account of recollection impairments in ASC.
    Relational memory has also not been compared with item memory when the demands of
    the 2 tasks are comparable. To assess recollection, relational memory, and item
    memory within a single task in ASC, 24 adults with ASC and 24 typically developed
    adults undertook a change detection memory task that assessed recollection of
    item-specific and spatial details. Participants studied rendered indoor and
    outdoor scenes and, in a subsequent recognition memory test, distinguished scenes
    that had not changed from those that had either undergone an item change (a
    different item exemplar) or a relational (spatial) change, which was followed by 
    a subjective recollection judgment. The ASC group identified fewer item changes
    and spatial changes, to a similar degree, which was attributable to a specific
    reduction in recollection-based recognition relative to the control group. These 
    findings provide evidence that recollection deficits in ASC may not be driven
    entirely by a relational binding deficit. (PsycINFO Database Record
    (c) 2015 APA, all rights reserved).
    PMID: 26120966  [PubMed - as supplied by publisher]
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  • 30) J Nat Sci. 2015;1(7):e125.

    Melatonin in Children with Autism Spectrum Disorders: How Does the Evidence Fit Together?

    Veatch OJ(1), Goldman SE(2), Adkins KW(1), Malow BA(1).
    Author information: 
    (1)Sleep Disorders Division, Department of Neurology, Vanderbilt University
    Medical Center, Nashville, TN, USA. (2)South Sound Pulmonary & Sleep Medicine,
    Olympia, WA, USA.
    Autism spectrum disorders (ASD) are prevalent neurodevelopmental conditions,
    affecting 1 in 68 children in the United States alone. Sleep disturbance,
    particularly insomnia, is very common in children diagnosed with ASD, with
    evidence supporting overlapping neurobiological and genetic underpinnings. One of
    the most well studied mechanisms related to ASD and insomnia is dysregulation of 
    the melatonin pathway, which has been observed in many individuals with ASD
    compared to typically developing controls. Furthermore, variation in genes whose 
    products regulate endogenous melatonin modify sleep patterns in humans and have
    also been implicated in some cases of ASD. However, the relationship between
    comorbid insomnia, melatonin processing, and genes that regulate endogenous
    melatonin levels in ASD is complex and requires further study to fully elucidate.
    The aim of this review is to provide an overview of the current findings related 
    to the effects of genetic variation in the melatonergic pathway on risk for
    expression of sleep disorders in children with ASD. In addition, functional
    findings related to endogenous levels of melatonin and pharmacokinetic profiles
    in this patient population are evaluated.
    PMID: 26120597  [PubMed]
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  • 31) Child Adolesc Psychiatry Ment Health. 2015 Jun 20;9:22. doi: 10.1186/s13034-015-0054-7. eCollection 2015.

    The effectiveness of psychosocial interventions for anxiety in children and adolescents with autism spectrum disorder: a systematic review and meta-analysis.

    Kreslins A(1), Robertson AE(1), Melville C(1).
    Author information: 
    (1)Institute of Health and Wellbeing, University of Glasgow, 1st Floor Admin
    Building Gartnavel Royal Hospital, 1055 Great Western Road, Glasgow, G12 0XH,
    Anxiety is a common problem in children and adolescents with autism spectrum
    disorder (ASD). This meta-analysis aimed to systematically evaluate the evidence 
    for the use of psychosocial interventions to manage anxiety in this population.
    Cognitive behavioural therapy (CBT) was the primary intervention modality
    studied. A comprehensive systematic search and study selection process was
    conducted. Separate statistical analyses were carried out for clinician-,
    parent-, and self-reported outcome measures. Sensitivity analyses were conducted 
    by removing any outlying studies and any studies that did not use a CBT
    intervention. A subgroup analysis was performed to compare individual and group
    delivery of treatment. Ten randomised control trials involving a total of 470
    participants were included. The overall SMD was d = 1.05 (95 % CI 0.45, 1.65;
    z = 3.45, p = 0.0006) for clinician- reported outcome measures; d = 1.00 (95%CI
    0.21, 1.80; z = 2.47, p = 0.01) for parent-reported outcome measures; and
    d = 0.65 (95%CI -0.10, 1.07; z = 1.63, p = 0.10) for self-reported outcome
    measures. Clinician- and parent-reported outcome measures showed that
    psychosocial interventions were superior to waitlist and treatment-as-usual
    control conditions at post-treatment. However, the results of self-reported
    outcome measures failed to reach significance. The sensitivity analyses did not
    significantly change these results and the subgroup analysis indicated that
    individual treatment was more effective than group treatment. The main
    limitations of this review were the small number of included studies as well as
    the clinical and methodological variability between studies.
    PMID: 26120361  [PubMed]
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  • 32) J Autism Dev Disord. 2015 Jun 28. [Epub ahead of print]

    Autism Symptoms Across Adulthood in Men with Fragile X Syndrome: A Cross-Sectional Analysis.

    Hartley SL(1), Wheeler AC, Mailick MR, Raspa M, Mihaila I, Bishop E, Bailey DB.
    Author information: 
    (1)Human Development and Family Studies and Waisman Center, University of
    Wisconsin-Madison, 1500 Highland Ave., Madison, WI, 53705, USA,
    A cross-sectional analysis was used to examine age-related differences in ASD
    symptoms and corresponding differences in disruptive behavior and social skills
    in 281 adult men with fragile X syndrome. Four age groups were created: 18-21,
    22-29, 30-39, and 40-49 years. The 18-21 year-old group was reported to have more
    impairments in verbal communication than the 22-29 year-old group and more
    restricted and repetitive behaviors than the 40-49 year-old group. There was not 
    an age-group difference in the percentage of men who met criteria for an ASD
    diagnosis based on respondent-reported, current symptoms. There was a trend for
    an age-related difference in disruptive behavior. Findings add to understanding
    of the developmental trajectory of ASD symptoms in adulthood.
    PMID: 26123010  [PubMed - as supplied by publisher]
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  • 33) J Autism Dev Disord. 2015 Jun 28. [Epub ahead of print]

    The New DSM-5 Impairment Criterion: A Challenge to Early Autism Spectrum Disorder Diagnosis?

    Zander E(1), Bölte S.
    Author information: 
    (1)Pediatric Neuropsychiatry Unit, Department of Children's and Women's Health,
    Center of Neurodevelopmental Disorders (KIND), Karolinska Institutet, Gävlegatan 
    22B, 113 30, Stockholm, Sweden, eric.zander@ki.se.
    The possible effect of the DSM-5 impairment criterion on diagnosing autism
    spectrum disorder (ASD) in young children was examined in 127 children aged
    20-47 months with a DSM-IV-TR clinical consensus diagnosis of ASD. The composite 
    score of the Vineland Adaptive Behavior Scales (VABS) served as a proxy for the
    DSM-5 impairment criterion. When applying a mild level of impairment (cutoff: 1
    SD below the mean on the VABS), 88 % of the cases fulfilled the impairment
    criterion. Sixty-nine percent fulfilled the impairment criterion at a moderate
    level (1.5 SDs) and 33 % at a severe level (2 SDs). Findings indicate that a
    strict application of the new DSM-5 impairment criterion might compromise early
    diagnosis of ASD.
    PMID: 26123009  [PubMed - as supplied by publisher]
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  • 34) J Autism Dev Disord. 2015 Jun 28. [Epub ahead of print]

    Preschoolers with Autism Spectrum Disorder Followed for 2 Years: Those Who Gained and Those Who Lost the Most in Terms of Adaptive Functioning Outcome.

    Hedvall Å(1), Westerlund J, Fernell E, Norrelgen F, Kjellmer L, Olsson MB,
    Carlsson LH, Eriksson MA, Billstedt E, Gillberg C.
    Author information: 
    (1)Gillberg Neuropsychiatry Centre, Sahlgrenska Academy, University of
    Gothenburg, 411 19, Gothenburg, Sweden, asa.lundholm-hedvall@gnc.gu.se.
    Clinical predictors of 2-year outcome in preschoolers with ASD were studied in a 
    population-based group of very young children with ASD (n = 208). Children who
    gained the most (n = 30) and lost the most (n = 23), i.e., increased or decreased
    their adaptive functioning outcome according to the Vineland Composite Score
    between study entry (T1) and follow-up (T2), 2 years later were compared.
    Individual factors that differed significantly between the two outcome groups
    were cognitive level, age at referral, not passing expected milestones at
    18 months, autistic type behavior problems and regression. However, logistic
    regression analysis showed that only cognitive level at T1 (dichotomized into
    IQ < 70 and IQ ≥ 70) made a unique statistically significant contribution to
    outcome prediction (p = <.001) with an odds ratio of 18.01. The findings have
    significant clinical implications in terms of information at diagnosis regarding 
    clinical prognosis in ASD.
    PMID: 26123008  [PubMed - as supplied by publisher]
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  • 35) Autism. 2015 Jun 29. pii: 1362361315592378. [Epub ahead of print]

    Estimation of the prevalence of autism spectrum disorder in South Korea, revisited.

    Pantelis PC(1), Kennedy DP(2).
    Author information: 
    (1)Indiana University, USA pcpantel@indiana.edu. (2)Indiana University, USA.
    Two-phase designs in epidemiological studies of autism prevalence introduce
    methodological complications that can severely limit the precision of resulting
    estimates. If the assumptions used to derive the prevalence estimate are invalid 
    or if the uncertainty surrounding these assumptions is not properly accounted for
    in the statistical inference procedure, then the point estimate may be inaccurate
    and the confidence interval may not be a true reflection of the precision of the 
    estimate. We examine these potential pitfalls in the context of a recent
    high-profile finding by Kim et al. (2011, Prevalence of autism spectrum disorders
    in a total population sample. American Journal of Psychiatry 168: 904-912), who
    estimated that autism spectrum disorder affects 2.64% of children in a South
    Korean community. We reconstructed the study's methodology and used Monte Carlo
    simulations to analyze whether their point estimate and 95% confidence interval
    (1.91%, 3.37%) were reasonable, given what was known about their screening
    instrument and sample. We find the original point estimate to be highly
    assumption-dependent, and after accounting for sources of uncertainty unaccounted
    for in the original article, we demonstrate that a more reasonable confidence
    interval would be approximately twice as large as originally reported. We argue
    that future studies should give serious consideration to the additional sources
    of uncertainty introduced by a two-phase design, which may easily outstrip any
    expected gains in efficiency.
    © The Author(s) 2015.
    PMID: 26122467  [PubMed - as supplied by publisher]
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  • 36) J Comp Neurol. 2015 Jul 1. doi: 10.1002/cne.23842. [Epub ahead of print]

    Differential Effects of Social and Physical Environmental Enrichment on Brain Plasticity, Cognition, and Ultrasonic Communication In Rats.

    Brenes JC(1,)(2,)(3), Lackinger M(4), Höglinger GU(5), Schratt G(4), Schwarting
    RK(1), Wöhr M(1).
    Author information: 
    (1)Behavioral Neuroscience, Experimental and Biological Psychology,
    Philipps-University of Marburg, Gutenbergstr. 18, 35032, Marburg, Germany.
    (2)Institute for Psychological Research, University of Costa Rica, Rodrigo Facio 
    Campus, 2060 San Pedro, Costa Rica. (3)Neuroscience Research Center, University
    of Costa Rica, Rodrigo Facio Campus, 2060 San Pedro, Costa Rica. (4)Biochemical
    and Pharmacological Center, Institute of Physiological Chemistry,
    Philipps-University of Marburg, Karl-von-Frisch-Str. 1, 35032, Marburg, Germany. 
    (5)Technical University München & German Center for Neurodegenerative Diseases
    (DZNE) München, Department for Translational Neurodegeneration, Max-Lebsche-Platz
    30, 81377, München, Germany.
    Environmental enrichment (EE) exerts beneficial effects on brain plasticity,
    cognition, and anxiety/depression, leading to a brain that can counteract
    deficits underlying various brain disorders. Since the complexity of EE commonly 
    used makes it difficult to identify causal aspects, we examined possible factors 
    using a 2x2 design with social EE (2 vs. 6 rats) and physical EE (physically
    enriched vs. non-enriched). For the first time, we demonstrate that social and
    physical EE have differential effects on brain plasticity, cognition, and
    ultrasonic communication. Expectedly, physical EE promoted neurogenesis in the
    dentate gyrus of the hippocampal formation, but not in the subventricular zone,
    and, as a novel finding, affected microRNA expression levels, with the
    activity-dependent miR-124 and miR-132 being upregulated. Concomitant
    improvements in cognition were observed, yet social deficits were seen in the
    emission of pro-social 50-kHz ultrasonic vocalizations (USV) and paralleled by a 
    lack of social approach in response to them, consistent with the intense world
    syndrome/theory of autism. In contrast, social EE had only minor effects on brain
    plasticity and cognition, but led to increased pro-social 50-kHz USV emission
    rates and enhanced social approach behavior. Importantly, social deficits
    following physical EE were prevented by additional social EE. The finding that
    social EE has positive while physical EE has negative effects on social behavior 
    indicates that preclinical studies focusing on EE as potential treatment in
    models for neuropsychiatric disorders characterized by social deficits, such as
    autism, should include social EE in addition to physical EE, since its lack might
    worsen social deficits. This article is protected by copyright. All rights
    © 2015 Wiley Periodicals, Inc.
    PMID: 26132842  [PubMed - as supplied by publisher]
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  • 37) Clin Pediatr (Phila). 2015 Jun 29. pii: 0009922815592607. [Epub ahead of print]

    Prevalence of Autism Spectrum Disorder in Children Referred for Diagnostic Autism Evaluation.

    Monteiro SA(1), Spinks-Franklin A(2), Treadwell-Deering D(2), Berry L(2),
    Sellers-Vinson S(2), Smith E(2), Proud M(2), Voigt RG(2).
    Author information: 
    (1)Baylor College of Medicine, Houston, TX, USA samontei@texaschildrens.org.
    (2)Baylor College of Medicine, Houston, TX, USA.
    Increased public awareness of autism spectrum disorders (ASD) and routine
    screening in primary care have contributed to increased requests for diagnostic
    ASD evaluations. However, given the scarcity of subspecialty autism diagnostic
    resources, overreferral of children suspected of having ASD may be contributing
    to long waiting lists at tertiary care autism centers and delaying diagnosis for 
    those children who truly have ASD. To determine whether children are being
    excessively referred to ASD-specific diagnostic clinics, our objective was to
    determine the prevalence of true ASD diagnoses in children referred for
    diagnostic ASD evaluation. Charts of all patients referred to a regional autism
    center between April 2011 and August 2012 for suspicion of a possible ASD were
    retrospectively reviewed and demographic and clinical diagnoses abstracted. Only 
    214 of 348 patients evaluated (61%) received an ASD diagnosis. Thus, concerns
    about autism are not confirmed by an ASD diagnosis in a significant number of
    © The Author(s) 2015.
    PMID: 26130396  [PubMed - as supplied by publisher]
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  • 38) BMC Psychiatry. 2015 Jul 1;15:138. doi: 10.1186/s12888-015-0522-x.

    The effect of the video game Mindlight on anxiety symptoms in children with an Autism Spectrum Disorder.

    Wijnhoven LA(1,)(2), Creemers DH(3,)(4), Engels RC(5,)(6), Granic I(7).
    Author information: 
    (1)Behavioural Science Institute, Radboud University Nijmegen, P.O. Box 9104,
    6500 HE, Nijmegen, The Netherlands. l.wijnhoven@pwo.ru.nl. (2)GGZ Oost-Brabant,
    P.O. Box 3, 5427 ZG, Boekel, The Netherlands. l.wijnhoven@pwo.ru.nl.
    (3)Behavioural Science Institute, Radboud University Nijmegen, P.O. Box 9104,
    6500 HE, Nijmegen, The Netherlands. d.creemers@ggzoostbrabant.nl. (4)GGZ
    Oost-Brabant, P.O. Box 3, 5427 ZG, Boekel, The Netherlands.
    d.creemers@ggzoostbrabant.nl. (5)Behavioural Science Institute, Radboud
    University Nijmegen, P.O. Box 9104, 6500 HE, Nijmegen, The Netherlands.
    rengels@trimbos.nl. (6)Trimbos Institute, Da Costakade 45, 3521 VS, Utrecht, The 
    Netherlands. rengels@trimbos.nl. (7)Behavioural Science Institute, Radboud
    University Nijmegen, P.O. Box 9104, 6500 HE, Nijmegen, The Netherlands.
    BACKGROUND: In the clinical setting, a large proportion of children with an
    autism spectrum disorder (ASD) experience anxiety symptoms. Because anxiety is an
    important cause of impairment for children with an ASD, it is necessary that
    effective anxiety interventions are implemented for these children. Recently, a
    serious game called Mindlight has been developed that is focused on decreasing
    anxiety in children. This approach is based on recent research suggesting that
    video games might be suitable as an intervention vehicle to enhance mental health
    in children. In the present study it will be investigated whether Mindlight is
    effective in decreasing (sub) clinical anxiety symptoms in children who are
    diagnosed with an ASD.
    METHODS/DESIGN: The present study involves a randomized controlled trial (RCT)
    with two conditions (experimental versus control), in which it is investigated
    whether Mindlight is effective in decreasing (sub) clinical anxiety symptoms in
    children with an ASD. For this study, children of 8-16 years old with a diagnosis
    of an ASD and (sub) clinical anxiety symptoms will be randomly assigned to the
    experimental (N = 60) or the control (N = 60) condition. Children in the
    experimental condition will play Mindlight for one hour per week, for six
    consecutive weeks. Children in the control condition will play the puzzle game
    Triple Town, also for one hour per week and for six consecutive weeks. All
    children will complete assessments at baseline, post-intervention and 3-months
    follow-up. Furthermore, parents and teachers will also complete assessments at
    the same time points. The primary outcome will be child report of anxiety
    symptoms. Secondary outcomes will be parent report of child anxiety, child/parent
    report of depressive symptoms, and parent/teacher report of social functioning
    and behavior problems.
    DISCUSSION: This paper aims to describe a study that will examine the effect of
    the serious game Mindlight on (sub) clinical anxiety symptoms of children with an
    ASD in the age of 8-16 years old. It is expected that children in the
    experimental condition will show lower levels of anxiety symptoms at 3-months
    follow-up, compared to children in the control condition. If Mindlight turns out 
    to be effective, it could be an important contribution to the already existing
    interventions for anxiety in children with an ASD. Mindlight could then be
    implemented as an evidence-based treatment for anxiety symptoms in children with 
    an ASD in mental health institutes and special education schools.
    TRIAL REGISTRATION: Dutch Trial Register NTR5069 . Registered 20 April 2015.
    PMID: 26129831  [PubMed - in process]
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