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Papers of the Week

  • 1) Mol Autism. 2014 Aug 1;5:42. doi: 10.1186/2040-2392-5-42. eCollection 2014.

    The latent structure of cognitive and emotional empathy in individuals with autism, first-degree relatives and typical individuals.

    Grove R(1), Baillie A(1), Allison C(2), Baron-Cohen S(3), Hoekstra RA(4).
    Author information: 
    (1)Centre for Emotional Health, Department of Psychology, Macquarie University, 2109
    Sydney, NSW, Australia.
    (2)Autism Research Centre, Department of Psychiatry, Cambridge University,
    Cambridge, UK.
    (3)Autism Research Centre, Department of Psychiatry, Cambridge University,
    Cambridge, UK ; CLASS Clinic, Cambridgeshire and Peterborough NHS Foundation
    Trust, Cambridge, UK.
    (4)Autism Research Centre, Department of Psychiatry, Cambridge University,
    Cambridge, UK ; Faculty of Science, The Open University, Milton Keynes, UK.
    BACKGROUND: Empathy is a vital component for social understanding involving the
    ability to recognise emotion (cognitive empathy) and provide an appropriate
    affective response (emotional empathy). Autism spectrum conditions have been
    described as disorders of empathy. First-degree relatives may show some mild
    traits of the autism spectrum, the broader autism phenotype (BAP). Whether both
    cognitive and emotional empathy, rather than cognitive empathy alone, are
    impaired in autism and the BAP is still under debate. Moreover the association
    between various aspects of empathy is unclear. This study aims to examine the
    relationship between different components of empathy across individuals with
    varying levels of genetic vulnerability to autism.
    METHODS: Factor analyses utilising questionnaire and performance-based task data 
    were implemented among individuals with autism, parents of a child with autism
    and controls. The relationship between performance-based tasks and behavioural
    measures of empathy was also explored.
    RESULTS: A four-factor model including cognitive empathy, emotional empathy,
    social skills and a performance-based factor fitted the data best irrespective of
    genetic vulnerability. Individuals with autism displayed impairment on all four
    factors, with parents showing intermediate difficulties. Performance-based
    measures of empathy were related in almost equal magnitude to cognitive and
    emotional empathy latent factors and the social skills factor.
    CONCLUSIONS: This study suggests individuals with autism have difficulties with
    multiple facets of empathy, while parents show intermediate impairments,
    providing evidence for a quantitative BAP. Impaired scores on performance-based
    measures of empathy, often thought to be pure measures of cognitive empathy, were
    also related to much wider empathy difficulties than impairments in cognitive
    empathy alone.
    PMID: 25101164  [PubMed]
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  • 2) PLoS One. 2014 Aug 6;9(8):e103369. doi: 10.1371/journal.pone.0103369. eCollection 2014.

    Violations of personal space by individuals with autism spectrum disorder.

    Kennedy DP(1), Adolphs R(2).
    Author information: 
    (1)Department of Psychological and Brain Sciences, Indiana University, Bloomington, 
    Indiana, United States of America; Division of Humanities and Social Sciences,
    California Institute of Technology, Pasadena, California, United States of
    (2)Division of Humanities and Social Sciences, California Institute of Technology,
    Pasadena, California, United States of America; Division of Biology, California
    Institute of Technology, Pasadena, California, United States of America.
    The ability to maintain an appropriate physical distance (i.e., interpersonal
    distance) from others is a critical aspect of social interaction and contributes 
    importantly to real-life social functioning. In Study 1, using parent-report data
    that had been acquired on a large number of individuals (ages 4-18 years) for the
    Autism Genetic Resource Exchange and the Simons Simplex Collection, we found that
    those with Autism Spectrum Disorder (ASD; n = 766) more often violated the space 
    of others compared to their unaffected siblings (n = 766). This abnormality held 
    equally across ASD diagnostic categories, and correlated with clinical measures
    of communication and social functioning. In Study 2, laboratory experiments in a 
    sample of high-functioning adults with ASD demonstrated an altered relationship
    between interpersonal distance and personal space, and documented a complete
    absence of personal space in 3 individuals with ASD. Furthermore, anecdotal
    self-report from several participants confirmed that violations of social
    distancing conventions continue to occur in real-world interactions through
    adulthood. We suggest that atypical social distancing behavior offers a practical
    and sensitive measure of social dysfunction in ASD, and one whose psychological
    and neurological substrates should be further investigated.
    PMID: 25100326  [PubMed - in process]
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  • 3) JAMA Psychiatry. 2014 Aug 1;71(8):936-42. doi: 10.1001/jamapsychiatry.2014.476.

    Parental social responsiveness and risk of autism spectrum disorder in offspring.

    Lyall K(1), Constantino JN(2), Weisskopf MG(3), Roberts AL(4), Ascherio A(5),
    Santangelo SL(6).
    Author information: 
    (1)Department of Nutrition, Harvard School of Public Health, Boston,
    Massachusetts2Department of Public Health Sciences, University of California,
    (2)Department of Psychiatry, Washington University, St Louis, Missouri.
    (3)Department of Epidemiology, Harvard School of Public Health, Boston,
    Massachusetts5Department of Environmental Health, Harvard School of Public
    Health, Boston, Massachusetts.
    (4)Department of Social and Behavioral Sciences, Harvard School of Public Health,
    Boston, Massachusetts.
    (5)Department of Nutrition, Harvard School of Public Health, Boston,
    Massachusetts4Department of Epidemiology, Harvard School of Public Health,
    Boston, Massachusetts7Channing Division of Network Medicine, Department of
    Medicine, Brigham and Women's Hospital.
    (6)Department of Epidemiology, Harvard School of Public Health, Boston,
    Massachusetts8Department of Psychiatry, Maine Medical Center/Maine Medical Center
    Research Institute, Portland.
    IMPORTANCE: Although autism spectrum disorder (ASD) is known to be heritable,
    patterns of inheritance of subclinical autistic traits in nonclinical samples are
    poorly understood.
    OBJECTIVE: To examine the familiality of Social Responsiveness Scale (SRS) scores
    of individuals with and without ASD.
    DESIGN, SETTING, AND PARTICIPANTS: We performed a nested case-control study
    (pilot study: July 1, 2007, through June 30, 2009; full-scale study: September
    15, 2008, through September 14, 2012) within a population-based longitudinal
    cohort. Participants were drawn from the Nurses' Health Study II, a cohort of
    116 430 female nurses recruited in 1989. Case participants were index children
    with reported ASD; control participants were frequency matched by year of birth
    of case participants among those not reporting ASD. Of 3161 eligible
    participants, 2144 nurses (67.8%) returned SRS forms for a child and at least 1
    parent and were included in these analyses.
    EXPOSURE: The SRS scores, as reported by nurse mothers and their spouses, were
    examined in association with risk of ASD using crude and adjusted logistic
    regression analyses. The SRS scores of the children were examined in association 
    with SRS scores of the parents using crude and adjusted linear regression
    analyses stratified by case status.
    MAIN OUTCOMES AND MEASURES: Autism spectrum disorder, assessed by maternal
    report, validated in a subgroup with the Autism Diagnostic Interview-Revised.
    RESULTS: A total of 1649 individuals were included in these analyses, including
    256 ASD case participants, 1393 control participants, 1233 mothers, and 1614
    fathers. Risk of ASD was increased by 85.0% among children whose parents had
    concordantly elevated SRS scores (odds ratio [OR], 1.85; 95% CI, 1.08-3.16) and
    by 52.0% when the score of either parent was elevated (OR, 1.52; 95% CI,
    1.11-2.06). Elevated scores of the father significantly increased the risk of ASD
    in the child (OR, 1.94; 95% CI, 1.38-2.71), but no association was seen with
    elevated scores of the mother. Elevated parent scores significantly increased
    child scores in controls, corresponding to an increase in 23 points (P < .001).
    CONCLUSIONS AND RELEVANCE: These findings support the role of additive genetic
    influences in concentrating inherited ASD susceptibility in successive
    generations and the potential role of preferential mating, and suggest that
    typical variation in parental social functioning can produce clinically
    significant differences in offspring social traits.
    PMID: 25100167  [PubMed - in process]
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  • 4) Autism. 2014 Aug 5. pii: 1362361314542955. [Epub ahead of print]

    Measuring social communication behaviors as a treatment endpoint in individuals with autism spectrum disorder.

    Anagnostou E(1), Jones N(2), Huerta M(3), Halladay AK(4), Wang P(4), Scahill
    L(5), Horrigan JP(2), Kasari C(6), Lord C(3), Choi D(7), Sullivan K(8), Dawson
    Author information: 
    (1)Holland Bloorview Kids Rehabilitation Hospital, University of Toronto, Canada
    (2)Neuren Pharmaceuticals Limited, USA.
    (3)Weill Cornell Medical College, USA.
    (4)Autism Speaks, USA.
    (5)Emory University, USA.
    (6)University of California, Los Angeles, USA.
    (7)Stony Brook University, USA.
    (8)New York-Presbyterian Hospital/Weill Cornell Medical Center, USA.
    (9)Duke University, USA.
    Social communication impairments are a core deficit in autism spectrum disorder. 
    Social communication deficit is also an early indicator of autism spectrum
    disorder and a factor in long-term outcomes. Thus, this symptom domain represents
    a critical treatment target. Identifying reliable and valid outcome measures for 
    social communication across a range of treatment approaches is essential. Autism 
    Speaks engaged a panel of experts to evaluate the readiness of available measures
    of social communication for use as outcome measures in clinical trials. The panel
    held monthly conference calls and two face-to-face meetings over 14 months. Key
    criteria used to evaluate measures included the relevance to the clinical target,
    coverage of the symptom domain, and psychometric properties (validity and
    reliability, as well as evidence of sensitivity to change). In all, 38 measures
    were evaluated and 6 measures were considered appropriate for use, with some
    limitations. This report discusses the relative strengths and weaknesses of
    existing social communication measures for use in clinical trials and identifies 
    specific areas in need of further development.
    © The Author(s) 2014.
    PMID: 25096930  [PubMed - as supplied by publisher]
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  • 5) Cogn Neuropsychiatry. 2014 Aug 7:1-16. [Epub ahead of print]

    That looks familiar: attention allocation to familiar and unfamiliar faces in children with autism spectrum disorder.

    Gillespie-Smith K(1), Doherty-Sneddon G, Hancock PJ, Riby DM.
    Author information: 
    (1)a Department of Psychology, School of Natural Sciences , Stirling University ,
    Stirling , UK.
    Introduction. Existing eye-tracking literature has shown that both adults and
    children with autism spectrum disorders (ASD) show fewer and slower fixations on 
    faces. Despite this reduced saliency and processing of other faces, recognition
    of their own face is reported to be more "typical" in nature. This study uses
    eye-tracking to explore the typicality of gaze patterns when children with ASD
    attend their own faces compared to other familiar and unfamiliar faces. Methods. 
    Eye-tracking methodology was used to explore fixation duration and time taken to 
    fixate on the Eye and Mouth regions of familiar, unfamiliar and Self Faces.
    Twenty-one children with ASD (9-16 years) were compared to typically developing
    matched groups. Results. There were no significant differences between children
    with ASD and typically matched groups for fixation patterns to the Eye and Mouth 
    areas of all face types (familiar, unfamiliar and self). Correlational analyses
    showed that attention to the Eye area of unfamiliar and Self Faces was related to
    socio-communicative ability in children with ASD. Conclusions. Levels of
    socio-communicative ability in children with ASD were related to gaze patterns on
    unfamiliar and Self Faces, but not familiar faces. This lack of relationship
    between ability and attention to familiar faces may indicate that children across
    the autism spectrum are able to fixate these faces in a similar way. The
    implications for these findings are discussed.
    PMID: 25101966  [PubMed - as supplied by publisher]
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  • 6) J Neuropathol Exp Neurol. 2014 Aug 6. [Epub ahead of print]

    Neuropathology of the Anterior Midcingulate Cortex in Young Children With Autism.

    Uppal N(1), Wicinski B, Buxbaum JD, Heinsen H, Schmitz C, Hof PR.
    Author information: 
    (1)From the Fishberg Department of Neuroscience (NU, BW, PRH), Friedman Brain
    Institute (NU, BW, JDB, PRH), Seaver Autism Center for Research and Treatment
    (NU, JDB, PRH), Graduate School of Biomedical Sciences (NU, JDB, PRH), and
    Department of Psychiatry (JDB), Icahn School of Medicine at Mount Sinai, New
    York, New York; and Morphologic Brain Research Unit, Department of Psychiatry,
    University of Würzburg, Würzburg (HH); and Department of Neuroanatomy,
    Ludwig-Maximilians University of Munich, Munich (CS), Germany.
    The anterior cingulate cortex, which is involved in cognitive and affective
    functioning, is important in investigating disorders in which individuals exhibit
    impairments in higher-order functions. In this study, we examined the anterior
    midcingulate cortex (aMCC) at the cellular level in patients with autism and in
    controls. We focused our analysis on layer V of the aMCC because it contains von 
    Economo neurons, specialized cells thought to be involved in emotional expression
    and focused attention. Using a stereologic approach, we determined whether there 
    were neuropathologic changes in von Economo neuron number, pyramidal neuron
    number, or pyramidal neuron size between diagnostic groups. When the groups were 
    subdivided into young children and adolescents, pyramidal neuron and von Economo 
    neuron numbers positively correlated with autism severity in young children, as
    measured by the Autism Diagnostic Interview-Revised. Young children with autism
    also had significantly smaller pyramidal neurons than their matched controls.
    Because the aMCC is involved in decision-making during uncertain situations,
    decreased pyramidal neuron size may reflect a potential reduction in the
    functional connectivity of the aMCC.
    PMID: 25101703  [PubMed - as supplied by publisher]
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  • 7) Sci Rep. 2014 Aug 7;4:5985. doi: 10.1038/srep05985.

    Spatio-temporal processing of tactile stimuli in autistic children.

    Wada M(1), Suzuki M(2), Takaki A(3), Miyao M(4), Spence C(5), Kansaku K(6).
    Author information: 
    (1)1] Systems Neuroscience Section, Department of Rehabilitation for Brain
    Functions, Research Institute of National Rehabilitation Center for Persons with 
    Disabilities, Tokorozawa 359-8555, Japan [2] Developmental Disorders Section,
    Department of Rehabilitation for Brain Functions, Research Institute of National 
    Rehabilitation Center for Persons with Disabilities, Tokorozawa 359-8555, Japan.
    (2)Information Center for Persons with Developmental Disabilities, National
    Rehabilitation Center for Persons with Disabilities, Tokorozawa 359-8555, Japan.
    (3)Chichibu Gakuen, Rehabilitation Services Bureau, National Rehabilitation Center
    for Persons with Disabilities, Tokorozawa 359-8555, Japan.
    (4)Division of Developmental Neuropsychology, Department of Psychological Medicine, 
    National Center for Child Health and Development, Setagaya, Tokyo 157-8535,
    (5)Crossmodal Research Laboratory, Department of Experimental Psychology, Oxford
    University, Oxford OX1 3UD, UK.
    (6)1] Systems Neuroscience Section, Department of Rehabilitation for Brain
    Functions, Research Institute of National Rehabilitation Center for Persons with 
    Disabilities, Tokorozawa 359-8555, Japan [2] Brain Science Inspired Life Support 
    Research Center, The University of Electro-Communications, Tokyo 182-8585, Japan.
    Altered multisensory integration has been reported in autism; however, little is 
    known concerning how the autistic brain processes spatio-temporal information
    concerning tactile stimuli. We report a study in which a crossed-hands illusion
    was investigated in autistic children. Neurotypical individuals often experience 
    a subjective reversal of temporal order judgments when their hands are stimulated
    while crossed, and the illusion is known to be acquired in early childhood.
    However, under those conditions where the somatotopic representation is given
    priority over the actual spatial location of the hands, such reversals may not
    occur. Here, we showed that a significantly smaller illusory reversal was
    demonstrated in autistic children than in neurotypical children. Furthermore, in 
    an additional experiment, the young boys who had higher Autism Spectrum Quotient 
    (AQ) scores generally showed a smaller crossed hands deficit. These results
    suggest that rudimentary spatio-temporal processing of tactile stimuli exists in 
    autistic children, and the altered processing may interfere with the development 
    of an external frame of reference in real-life situations.
    PMID: 25100146  [PubMed - in process]
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  • 8) Psychol Med. 2014 Aug 11:1-11. [Epub ahead of print]

    White-matter relaxation time and myelin water fraction differences in young adults with autism.

    Deoni SC(1), Zinkstok JR(2), Daly E(2), Ecker C(2); MRC AIMS Consortium, Williams
    SC(3), Murphy DG(2).
    Author information: 
    (1)Advanced Baby Imaging Laboratory,School of Engineering, Brown
    University,Providence, RI,USA.
    (2)Department of Forensic and Neurodevelopmental Sciences,Institute of Psychiatry,
    King's College London,London,UK.
    (3)Department of Neuroimaging,Institute of Psychiatry, King's College
    BACKGROUND: Increasing evidence suggests that autism is associated with abnormal 
    white-matter (WM) anatomy and impaired brain 'connectivity'. While myelin plays a
    critical role in synchronized brain communication, its aetiological role in
    autistic symptoms has only been indirectly addressed by WM volumetric,
    relaxometry and diffusion tensor imaging studies. A potentially more specific
    measure of myelin content, termed myelin water fraction (MWF), could provide
    improved sensitivity to myelin alteration in autism.
    METHOD: We performed a cross-sectional imaging study that compared 14 individuals
    with autism and 14 age- and IQ-matched controls. T 1 relaxation times (T 1), T 2 
    relaxation times (T 2) and MWF values were compared between autistic subjects,
    diagnosed using the Autism Diagnostic Interview - Revised (ADI-R), with current
    symptoms assessed using the Autism Diagnostic Observation Schedule (ADOS) and
    typical healthy controls. Correlations between T 1, T 2 and MWF values with
    clinical measures [ADI-R, ADOS, and the Autism Quotient (AQ)] were also assessed.
    RESULTS: Individuals with autism showed widespread WM T 1 and MWF differences
    compared to typical controls. Within autistic individuals, worse current social
    interaction skill as measured by the ADOS was related to reduced MWF although not
    T 1. No significant differences or correlations with symptoms were observed with 
    respect to T 2.
    CONCLUSIONS: Autistic individuals have significantly lower global MWF and higher 
    T 1, suggesting widespread alteration in tissue microstructure and biochemistry. 
    Areas of difference, including thalamic projections, cerebellum and cingulum,
    have previously been implicated in the disorder; however, this is the first study
    to specifically indicate myelin alteration in these regions.
    PMID: 25111948  [PubMed - as supplied by publisher]
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  • 9) PLoS One. 2014 Aug 11;9(8):e104433. doi: 10.1371/journal.pone.0104433. eCollection 2014.

    Gender-Dependent Effects of Maternal Immune Activation on the Behavior of Mouse Offspring.

    Xuan IC(1), Hampson DR(2).
    Author information: 
    (1)Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University
    of Toronto, Toronto, Canada.
    (2)Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University
    of Toronto, Toronto, Canada; Department of Pharmacology and Toxicology, Faculty
    of Medicine, University of Toronto, Toronto, Canada.
    Autism spectrum disorders are neurodevelopmental disorders characterized by two
    core symptoms; impaired social interactions and communication, and ritualistic or
    repetitive behaviors. Both epidemiological and biochemical evidence suggests that
    a subpopulation of autistics may be linked to immune perturbations that occurred 
    during fetal development. These findings have given rise to an animal model,
    called the "maternal immune activation" model, whereby the offspring from female 
    rodents who were subjected to an immune stimulus during early or mid-pregnancy
    are studied. Here, C57BL/6 mouse dams were treated mid-gestation with saline,
    lipopolysaccharide (LPS) to mimic a bacterial infection, or
    polyinosinic:polycytidylic acid (Poly IC) to mimic a viral infection.
    Autism-associated behaviors were examined in the adult offspring of the treated
    dams. Behavioral tests were conducted to assess motor activity, exploration in a 
    novel environment, sociability, and repetitive behaviors, and data analyses were 
    carried independently on male and female mice. We observed a main treatment
    effect whereby male offspring from Poly IC-treated dams showed reduced motor
    activity. In the marble burying test of repetitive behavior, male offspring but
    not female offspring from both LPS and Poly IC-treated mothers showed increased
    marble burying. Our findings indicate that offspring from mothers subjected to
    immune stimulation during gestation show a gender-specific increase in
    stereotyped repetitive behavior.
    PMID: 25111339  [PubMed - as supplied by publisher]
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  • 10) J Neurodev Disord. 2014;6(1):24. doi: 10.1186/1866-1955-6-24. Epub 2014 Jul 30.

    AGG interruptions and maternal age affect FMR1 CGG repeat allele stability during transmission.

    Yrigollen CM(1), Martorell L(2), Durbin-Johnson B(3), Naudo M(2), Genoves J(2),
    Murgia A(4), Polli R(4), Zhou L(5), Barbouth D(6), Rupchock A(6), Finucane B(7), 
    Latham GJ(8), Hadd A(8), Berry-Kravis E(5), Tassone F(9).
    Author information: 
    (1)Department of Biochemistry and Molecular Medicine, University of California,
    Davis, School of Medicine, 2700 Stockton Blvd., Suite 2102, Sacramento, CA 95817,
    (2)Molecular Genetics Section, Hospital Sant Joan de Déu, Barcelona, Spain.
    (3)Department of Public Health Sciences, University of California, Davis, Davis, CA,
    (4)Laboratory of Molecular Genetics of Neurodevelopment, Department of Women's and
    Children's Health, University of Padova, Padova, Italy.
    (5)Department of Pediatrics, Neurological Sciences, and Biochemistry, Rush
    University Medical Center, Chicago, IL, USA.
    (6)Dr. John T. Macdonald Foundation, Department of Human Genetics, Miller School of 
    Medicine, University of Miami, Miami, FL, USA.
    (7)Geisinger Autism and Developmental Medicine Institute, Lewisburg, PA, USA.
    (8)Asuragen, Inc., Austin, TX, USA.
    (9)Department of Biochemistry and Molecular Medicine, University of California,
    Davis, School of Medicine, 2700 Stockton Blvd., Suite 2102, Sacramento, CA 95817,
    USA ; MIND Institute, University of California, Davis, School of Medicine, Davis,
    CA, USA.
    BACKGROUND: The presence of AGG interruptions in the CGG repeat locus of the
    fragile X mental retardation 1 (FMR1) gene decreases the instability of the
    allele during transmission from parent to child, and decreases the risk of
    expansion of a premutation allele to a full mutation allele (the predominant
    cause of fragile X syndrome) during maternal transmission.
    METHODS: To strengthen recent findings on the utility of AGG interruptions in
    predicting instability or expansion to a full mutation of FMR1 CGG repeat
    alleles, we assessed the outcomes of 108 intermediate (also named gray zone) and 
    710 premutation alleles that were transmitted from parent to child, and collected
    from four international clinical sites. We have used the results to revise our
    initial model that predicted the risk of a maternal premutation allele expanding 
    to a full mutation during transmission and to test the effect of AGG
    interruptions on the magnitude of expanded allele instability of intermediate or 
    premutation alleles that did not expand to a full mutation.
    RESULTS: Consistent with previous studies, the number of AGG triplets that
    interrupts the CGG repeat locus was found to influence the risk of allele
    instability, including expansion to a full mutation. The total length of the CGG 
    repeat allele remains the best predictor of instability or expansion to a full
    mutation, but the number of AGG interruptions and, to a much lesser degree,
    maternal age are also factors when considering the risk of transmission of the
    premutation allele to a full mutation.
    CONCLUSIONS: Our findings demonstrate that a model with total CGG length, number 
    of AGG interruptions, and maternal age is recommended for calculating the risk of
    expansion to a full mutation during maternal transmission. Taken together, the
    results of this study provide relevant information for the genetic counseling of 
    female premutation carriers, and improve the current predictive models which
    calculate risk of expansion to a full mutation using only total CGG repeat
    PMID: 25110527  [PubMed]
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  • 11) Brain Res. 2014 Aug 7. pii: S0006-8993(14)01023-3. doi: 10.1016/j.brainres.2014.07.050. [Epub ahead of print]

    Interactions of innate and adaptive immunity in brain development and function.

    Filiano AJ(1), Gadani SP(2), Kipnis J(2).
    Author information: 
    (1)Center for Brain Immunology and Glia (BIG), Department of Neuroscience, School of
    Medicine, University of Virginia, Charlottesville, VA 22908, USA. Electronic
    address: ajf5v@virginia.edu.
    (2)Center for Brain Immunology and Glia (BIG), Department of Neuroscience, School of
    Medicine, University of Virginia, Charlottesville, VA 22908, USA; Graduate
    Program in Neuroscience and Medical Scientist Training Program, School of
    Medicine, University of Virginia, Charlottesville, VA 22908, USA.
    It has been known for decades that the immune system has a tremendous impact on
    behavior. Most work has described the negative role of immune cells on the
    central nervous system. However, we and others have demonstrated over the last
    decade that a well-regulated immune system is needed for proper brain function.
    Here we discuss several neuro-immune interactions, using examples from brain
    homeostasis and disease states. We will highlight our understanding of the
    consequences of malfunctioning immunity on neurodevelopment and will discuss the 
    roles of the innate and adaptive immune system in neurodevelopment and how T
    cells maintain a proper innate immune balance in the brain surroundings and
    within its parenchyma. Also, we describe how immune imbalance impairs higher
    order brain functioning, possibly leading to behavioral and cognitive impairment.
    Lastly, we propose our hypothesis that some behavioral deficits in
    neurodevelopmental disorders, such as in autism spectrum disorder, are the
    consequence of malfunctioning immunity.
    Copyright © 2014. Published by Elsevier B.V.
    PMID: 25110235  [PubMed - as supplied by publisher]
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  • 12) Brain Connect. 2014 Aug 10. [Epub ahead of print]

    Alpha-to-Gamma Phase-amplitude Coupling Methods and Application to Autism Spectrum Disorder.

    Berman J(1), Liu S, Bloy L, Blaskey L, Roberts TP, Edgar JC.
    Author information: 
    (1)Children's Hospital of Philadelphia, Radiology, Philadelphia, Pennsylvania,
    United States, University of Pennsylvania, Perelman School of Medicine,
    Radiology, Philadelphia, Pennsylvania, United States ; bermanj@email.chop.edu.
    Adult studies have shown that a basic property of resting-state (RS) brain
    activity is the coupling of posterior alpha oscillations (alpha phase) to
    posterior gamma oscillations (gamma amplitude). The present study examined
    whether this basic RS process is present in children. Given reports of abnormal
    parietal-occipital RS alpha in children with autism spectrum disorder (ASD), the 
    present study examined whether RS alpha-to-gamma phase-amplitude coupling (PAC)
    is disrupted in ASD. Simulations presented in this study showed limitations with 
    traditional PAC analyses. In particular, to avoid false-positive PAC findings,
    simulations showed the need to use a unilateral passband to filter the upper
    frequency band as well as the need for longer epochs of data. For the human
    study, eyes-closed RS magnetoencephalography data were analyzed from 25 children 
    with ASD and 18 typically developing (TD) children with at least 60 seconds of
    artifact free data. Source modeling provided continuous time course data at a
    midline parietal-occipital source for PAC analyses. Greater alpha-to-gamma PAC
    was observed in ASD than TD (p<0.005). Although children with ASD had higher PAC 
    values, in both groups gamma activity increased at the peak of the alpha
    oscillation. In addition, an association between alpha power and alpha-to-gamma
    PAC was observed in both groups, although this relationship was stronger in ASD
    than TD (p <0.05). Present results demonstrated that although alpha-to-gamma PAC 
    is present in children, this basic RS process is abnormal in children with ASD.
    Finally, simulations and the human data highlighted the need to consider the
    interplay between alpha power, epoch length, and choice of signal processing
    methods on PAC estimates.
    PMID: 25109843  [PubMed - as supplied by publisher]
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  • 13) Brain Cogn. 2014 Aug 7;90C:157-164. doi: 10.1016/j.bandc.2014.07.003. [Epub ahead of print]

    Neural mechanisms of savant calendar calculating in autism: An MEG-study of few single cases.

    Dubischar-Krivec AM(1), Bölte S(2), Braun C(3), Poustka F(4), Birbaumer N(5),
    Neumann N(6).
    Author information: 
    (1)Institute of Medical Psychology and Behavioral Neurobiology, University of
    Tübingen, Silcherstr. 5, 72076 Tübingen, Germany.
    (2)Department of Women's and Children's Health, Karolinska Institute, Center of
    Neurodevelopmental Disorders (KIND), 17177 Stockholm, Sweden.
    (3)MEG-Center, University of Tübingen, Otfried-Müller-Str. 47, 72076 Tübingen,
    (4)Department of Child and Adolescent Psychiatry and Psychotherapy, J.W. Goethe
    University of Frankfurt, Deutschordenstr. 50, 60528 Frankfurt/M., Germany.
    (5)Institute of Medical Psychology and Behavioral Neurobiology, University of
    Tübingen, Silcherstr. 5, 72076 Tübingen, Germany; Ospedale San Camillo, Istituto 
    Ricovero e Cura a Carattere Scientifico (IRCCS), Via Alberoni 70, 30126 Venezia, 
    (6)Institute of Medical Psychology and Behavioral Neurobiology, University of
    Tübingen, Silcherstr. 5, 72076 Tübingen, Germany; Center for Diagnostic Radiology
    and Neuroradiology, Functional Imaging Unit, University of Greifswald,
    Walther-Rathenau-Str. 46, 17475 Greifswald, Germany. Electronic address:
    This study contrasted the neurological correlates of calendar calculating (CC)
    between those individuals with autism spectrum disorder (ASD) and typically
    developing individuals. CC is the ability to correctly and quickly state the day 
    of the week of a given date. Using magnetoencephalography (MEG), we presented 126
    calendar tasks with dates of the present, past, and future. Event-related
    magnetic fields (ERF) of 3000ms duration and brain activation patterns were
    compared in three savant calendar calculators with ASD (ASDCC) and three
    typically developing calendar calculators (TYPCC). ASDCC outperformed TYPCC in
    correct responses, but not in answering speed. Comparing amplitudes of their
    ERFs, there was a main effect of group between 1000 and 3000ms, but no further
    effects of hemisphere or sensor location. We conducted CLARA source analysis
    across the entire CC period in each individual. Both ASDCC and TYPCC exhibited
    activation maxima in prefrontal areas including the insulae and the left superior
    temporal gyrus. This is in accordance with verbal fact retrieval and working
    memory as well as monitoring and coordination processes. In ASDCC, additional
    activation sites at the right superior occipital gyrus, the right precuneus, and 
    the right putamen point to visual-spatial strategies and are in line with the
    preference of autistic individuals for engaging posterior regions relatively more
    strongly in various reasoning and problem solving tasks.
    Copyright © 2014 Elsevier Inc. All rights reserved.
    PMID: 25108822  [PubMed - as supplied by publisher]
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  • 14) Psychol Med. 2014 Aug 11:1-13. [Epub ahead of print]

    The epidemiology and global burden of autism spectrum disorders.

    Baxter AJ(1), Brugha TS(2), Erskine HE(1), Scheurer RW(3), Vos T(1), Scott JG(3).
    Author information: 
    (1)School of Population Health,University of Queensland,Herston,Australia.
    (2)Department of Health Sciences,University of Leicester,Leicester General
    (3)Queensland Centre for Mental Health Research,Wacol,Australia.
    BACKGROUND: Autism spectrum disorders (ASDs) are persistent disabling
    neurodevelopmental disorders clinically evident from early childhood. For the
    first time, the burden of ASDs has been estimated for the Global Burden of
    Disease Study 2010 (GBD 2010). The aims of this study were to develop global and 
    regional prevalence models and estimate the global burden of disease of ASDs.
    Method A systematic review was conducted for epidemiological data (prevalence,
    incidence, remission and mortality risk) of autistic disorder and other ASDs.
    Data were pooled using a Bayesian meta-regression approach while adjusting for
    between-study variance to derive prevalence models. Burden was calculated in
    terms of years lived with disability (YLDs) and disability-adjusted life-years
    (DALYs), which are reported here by world region for 1990 and 2010.
    RESULTS: In 2010 there were an estimated 52 million cases of ASDs, equating to a 
    prevalence of 7.6 per 1000 or one in 132 persons. After accounting for
    methodological variations, there was no clear evidence of a change in prevalence 
    for autistic disorder or other ASDs between 1990 and 2010. Worldwide, there was
    little regional variation in the prevalence of ASDs. Globally, autistic disorders
    accounted for more than 58 DALYs per 100��000 population and other ASDs accounted
    for 53 DALYs per 100��000.
    CONCLUSIONS: ASDs account for substantial health loss across the lifespan.
    Understanding the burden of ASDs is essential for effective policy making. An
    accurate epidemiological description of ASDs is needed to inform public health
    policy and to plan for education, housing and financial support services.
    PMID: 25108395  [PubMed - as supplied by publisher]
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  • 15) J Autism Dev Disord. 2014 Aug 9. [Epub ahead of print]

    Mapping the Developmental Trajectory and Correlates of Enhanced Pitch Perception on Speech Processing in Adults with ASD.

    Mayer JL(1), Hannent I, Heaton PF.
    Author information: 
    (1)Department of Psychology, Whitelands College, University of Roehampton, Holyborne
    Avenue, London, SW15 4JD, UK, jennifer.mayer@roehampton.ac.uk.
    Whilst enhanced perception has been widely reported in individuals with Autism
    Spectrum Disorders (ASDs), relatively little is known about the developmental
    trajectory and impact of atypical auditory processing on speech perception in
    intellectually high-functioning adults with ASD. This paper presents data on
    perception of complex tones and speech pitch in adult participants with
    high-functioning ASD and typical development, and compares these with
    pre-existing data using the same paradigm with groups of children and adolescents
    with and without ASD. As perceptual processing abnormalities are likely to
    influence behavioural performance, regression analyses were carried out on the
    adult data set. The findings revealed markedly different pitch discrimination
    trajectories and language correlates across diagnostic groups. While pitch
    discrimination increased with age and correlated with receptive vocabulary in
    groups without ASD, it was enhanced in childhood and stable across development in
    ASD. Pitch discrimination scores did not correlate with receptive vocabulary
    scores in the ASD group and for adults with ASD superior pitch perception was
    associated with sensory atypicalities and diagnostic measures of symptom
    severity. We conclude that the development of pitch discrimination, and its
    associated mechanisms markedly distinguish those with and without ASD.
    PMID: 25106823  [PubMed - as supplied by publisher]
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  • 16) J Med Genet. 2014 Aug 8. pii: jmedgenet-2014-102588. doi: 10.1136/jmedgenet-2014-102588. [Epub ahead of print]

    The clinical significance of small copy number variants in neurodevelopmental disorders.

    Asadollahi R(1), Oneda B(1), Joset P(1), Azzarello-Burri S(1), Bartholdi D(1),
    Steindl K(1), Vincent M(1), Cobilanschi J(1), Sticht H(2), Baldinger R(1),
    Reissmann R(1), Sudholt I(1), Thiel CT(3), Ekici AB(3), Reis A(3), Bijlsma EK(4),
    Andrieux J(5), Dieux A(6), FitzPatrick D(7), Ritter S(8), Baumer A(1), Latal
    B(8), Plecko B(9), Jenni OG(8), Rauch A(1).
    Author information: 
    (1)Institute of Medical Genetics, University of Zurich, Schlieren-Zurich,
    (2)Institute of Biochemistry, University of Erlangen-Nuremberg, Erlangen, Germany.
    (3)Institute of Human Genetics, University of Erlangen-Nuremberg, Erlangen, Germany.
    (4)Department of Clinical Genetics, Leiden University Medical Center (LUMC), Leiden,
    The Netherlands.
    (5)Institut de Génétique Médicale, Hôpital Jeanne de Flandre, CHRU de Lille, Lille, 
    (6)Clinique de Génétique Guy Fontaine, Hôpital Jeanne de Flandre, CHRU de Lille,
    Lille, France.
    (7)MRC Human Genetics Unit, MRC Institute for Genetic and Molecular Medicine,
    University of Edinburgh, Edinburgh, UK.
    (8)Child Development Center, University Children's Hospital Zurich, Zurich,
    (9)Division of Child Neurology, University Children's Hospital Zurich, Zurich,
    BACKGROUND: Despite abundant evidence for pathogenicity of large copy number
    variants (CNVs) in neurodevelopmental disorders (NDDs), the individual
    significance of genome-wide rare CNVs <500 kb has not been well elucidated in a
    clinical context.
    METHODS: By high-resolution chromosomal microarray analysis, we investigated the 
    clinical significance of all rare non-polymorphic exonic CNVs sizing 1-500 kb in 
    a cohort of 714 patients with undiagnosed NDDs.
    RESULTS: We detected 96 rare CNVs <500 kb affecting coding regions, of which 58
    (60.4%) were confirmed. 6 of 14 confirmed de novo, one of two homozygous and four
    heterozygous inherited CNVs affected the known microdeletion regions 17q21.31,
    16p11.2 and 2p21 or OMIM morbid genes (CASK, CREBBP, PAFAH1B1, SATB2; AUTS2,
    NRXN3, GRM8). Two further de novo CNVs affecting single genes (MED13L, CTNND2)
    were instrumental in delineating novel recurrent conditions. For the first time, 
    we here report exonic deletions of CTNND2 causing low normal IQ with learning
    difficulties with or without autism spectrum disorder. Additionally, we
    discovered a homozygous out-of-frame deletion of ACOT7 associated with features
    comparable to the published mouse model. In total, 24.1% of the confirmed small
    CNVs were categorised as pathogenic or likely pathogenic (median size 130 kb),
    17.2% as likely benign, 3.4% represented incidental findings and 55.2% remained
    CONCLUSIONS: These results verify the diagnostic relevance of genome-wide rare
    CNVs <500 kb, which were found pathogenic in ∼2% (14/714) of cases (1.1% de novo,
    0.3% homozygous, 0.6% inherited) and highlight their inherent potential for
    discovery of new conditions.
    Published by the BMJ Publishing Group Limited. For permission to use (where not
    already granted under a licence) please go to
    PMID: 25106414  [PubMed - as supplied by publisher]
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