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Papers of the Week

  • 1) Neuropsychopharmacology. 2014 Jul 11. doi: 10.1038/npp.2014.172. [Epub ahead of print]

    Neural Signatures of Autism Spectrum Disorders: Insights into Brain Network Dynamics.

    Hernandez LM(1), Rudie JD(2), Green SA(3), Bookheimer S(4), Dapretto M(5).
    
    Author information: 
    (1)1] Interdepartmental Neuroscience Program [2] Department of Psychiatry and
    Biobehavioral Sciences.
    (2)UCLA David Geffen School of Medicine.
    (3)1] Department of Psychiatry and Biobehavioral Sciences [2] Department of
    Psychology, University of California, Los Angeles.
    (4)1] Department of Psychiatry and Biobehavioral Sciences [2] UCLA David Geffen
    School of Medicine [3] Department of Psychology, University of California, Los
    Angeles.
    (5)1] Department of Psychiatry and Biobehavioral Sciences [2] UCLA David Geffen
    School of Medicine.
    
    Neuroimaging investigations of Autism Spectrum Disorders (ASDs) have advanced our
    understanding of atypical brain function and structure, and have recently
    converged on a model of altered network-level connectivity. Traditional
    task-based functional magnetic resonance imaging (MRI) and volume-based
    structural MRI studies have identified widespread atypicalities in brain regions 
    involved in social behavior and other core ASD-related behavioral deficits. More 
    recent advances in MR-neuroimaging methods allow for quantification of brain
    connectivity using diffusion tensor imaging, functional connectivity, and graph
    theoretic methods. These newer techniques have moved the field toward a
    systems-level understanding of ASD etiology, integrating functional and
    structural measures across distal brain regions. Neuroimaging findings in ASD as 
    a whole have been mixed and at times contradictory, likely due to the vast
    genetic and phenotypic heterogeneity characteristic of the disorder. Future
    longitudinal studies of brain development will be crucial to yield insights into 
    mechanisms of disease etiology in ASD subpopulations. Advances in neuroimaging
    methods and large-scale collaborations will also allow for an integrated approach
    linking neuroimaging, genetics, and phenotypic data.Neuropsychopharmacology
    Reviews accepted article preview online, 11 July 2014; doi:10.1038/npp.2014.172.
    
    PMID: 25011468  [PubMed - as supplied by publisher]
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  • 2) PLoS Genet. 2014 Jul 10;10(7):e1004458. doi: 10.1371/journal.pgen.1004458. eCollection 2014.

    Age-associated sperm DNA methylation alterations: possible implications in offspring disease susceptibility.

    Jenkins TG(1), Aston KI(1), Pflueger C(2), Cairns BR(3), Carrell DT(4).
    
    Author information: 
    (1)Andrology and IVF Laboratories, Department of Surgery, University of Utah School 
    of Medicine, Salt Lake City, Utah, United States of America.
    (2)Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah
    School of Medicine, Salt Lake City, Utah, United States of America.
    (3)Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah
    School of Medicine, Salt Lake City, Utah, United States of America; Howard Hughes
    Medical Institute, Chevy Chase, Maryland, United States of America.
    (4)Andrology and IVF Laboratories, Department of Surgery, University of Utah School 
    of Medicine, Salt Lake City, Utah, United States of America; Department of
    Genetics, University of Utah School of Medicine, Salt Lake City, Utah, United
    States of America; Department of Obstetrics and Gynecology, University of Utah
    School of Medicine, Salt Lake City, Utah, United States of America.
    
    Recent evidence demonstrates a role for paternal aging on offspring disease
    susceptibility. It is well established that various neuropsychiatric disorders
    (schizophrenia, autism, etc.), trinucleotide expansion associated diseases
    (myotonic dystrophy, Huntington's, etc.) and even some forms of cancer have
    increased incidence in the offspring of older fathers. Despite strong
    epidemiological evidence that these alterations are more common in offspring
    sired by older fathers, in most cases the mechanisms that drive these processes
    are unclear. However, it is commonly believed that epigenetics, and specifically 
    DNA methylation alterations, likely play a role. In this study we have
    investigated the impact of aging on DNA methylation in mature human sperm. Using 
    a methylation array approach we evaluated changes to sperm DNA methylation
    patterns in 17 fertile donors by comparing the sperm methylome of 2 samples
    collected from each individual 9-19 years apart. With this design we have
    identified 139 regions that are significantly and consistently hypomethylated
    with age and 8 regions that are significantly hypermethylated with age. A
    representative subset of these alterations have been confirmed in an independent 
    cohort. A total of 117 genes are associated with these regions of methylation
    alterations (promoter or gene body). Intriguingly, a portion of the age-related
    changes in sperm DNA methylation are located at genes previously associated with 
    schizophrenia and bipolar disorder. While our data does not establish a causative
    relationship, it does raise the possibility that the age-associated methylation
    of the candidate genes that we observe in sperm might contribute to the increased
    incidence of neuropsychiatric and other disorders in the offspring of older
    males. However, further study is required to determine whether, and to what
    extent, a causative relationship exists.
    
    PMID: 25010591  [PubMed - in process]
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  • 3) Cerebrum. 2014 Feb 1;2014:3. eCollection 2014.

    Review: the reason I jump: the inner voice of a thirteen-year-old boy with autism.

    Grandin T.
    
    In Temple Grandin's review of The Reason I Jump by Naoki Higashida, she relates
    her own experience living with and studying autism to better understand the mind 
    of a remarkable 13-year-old Japanese boy with severe autism. Structured as a
    series of questions that a nonautistic person might ask an autistic one, Naoki's 
    book is translated by David Mitchell (author of the novel Cloud Atlas) and his
    wife, Keiko Yoshida, and contains an impassioned introduction in which Mitchell
    discusses his experience with his own autistic child.
    
    PMID: 25009693  [PubMed]
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  • 4) J Neurol Neurosurg Psychiatry. 2014 Aug;85(8):e3. doi: 10.1136/jnnp-2014-308883.16.

    Research trends in british neuropsychiatry over the last decade.

    Cavanna AE.
    
    Author information: 
    The Barberry National Centre for Mental Health, Department of Neuropsychiatry, 25
    Vincent Drive Birmingham B15 2FG, United Kingdom.
    
    OBJECTIVE: Since its establishment in 1987, the British Neuropsychiatry
    Association (BNPA) has gathered clinicians and researchers with special interest 
    in neuropsychiatry and behavioural neurology. The association regularly invites
    abstract submissions on neuropsychiatry research topics to its yearly Annual
    General Meeting (AGM). These spontaneous contributions mainly reflect research
    interests of the BNPA members and their analysis can provide an overview on the
    recent research trends of British neuropsychiatry.
    METHOD: The author reviewed the BNPA-AGM Programmes and Abstract Books, as well
    as the Proceedings published in the Journal of Neurology, Neurosurgery and
    Psychiatry over the last ten years (2004-2013), in order to identify the research
    topics of all abstracts accepted for oral or poster presentation.
    RESULTS: A total of 186 research abstracts were presented at BNPA-AGM over the
    last decade. The mean number of abstracts was 19 per year. The year with the
    highest number of abstracts was 2011 (n=26), whilst the year with the lowest
    number was 2004 (n=7). The vast majority of abstracts (n=173, 93.0%) were
    presented by a corresponding author based in the United Kingdom. The overall
    distribution of research topics in these abstracts was as follows: Tourette
    syndrome (n=36, 20.4%), epilepsy (n=26, 14.8%), functional neurological symptoms 
    (n=19, 10.8%), dementias (n=11, 6.2%), acquired brain injury (n=10, 5.7%),
    Parkinson disease (n=9, 5.1%), amyotrophic lateral sclerosis (n=8, 4.5%),
    Huntington disease (n=6, 3.4%), multiple sclerosis (n=5, 2.8%), attention-deficit
    and hyperactivity disorder (n=3, 1.7%), catatonia (n=2, 1.1%), autistic spectrum 
    disorders (n=2, 1.1%), autoimmune limbic encephalitis (n=2, 1.1%), sleep
    disorders (n=2, 1.1%), plus systemic lupus erythematosus, chronic fatigue
    syndrome, headache and addiction (all n=1, 0.6%). Three of these abstracts
    focused on more than one neuropsychiatric conditions: n=2 on epilepsy and
    functional neurological symptoms; n=1 on epilepsy and Tourette syndrome. The
    remaining abstracts (n=31, 17.6%) did not focus on a particular neuropsychiatric 
    condition: these abstracts reported investigations of neurobiological
    mechanisms/cognitive processes in patients with common psychiatric disorders
    (n=10) and healthy subjects (n=10), neuropsychiatry service evaluations (n=5),
    single case reports/case series (n=3) and psychometric studies on the development
    of scales for behavioural/cognitive symptoms (n=2).
    CONCLUSION: The last decade has seen a considerable increase in the number of
    scientific abstracts presented at the BNPA by researchers based in UK, along with
    a diversification in the research topics. Specifically, in recent years there has
    been an increased interest in movement disorders, epilepsy and functional
    neurological symptoms, reflecting important advances in clinical research
    focusing on these neuropsychiatric conditions.
    
    Published by the BMJ Publishing Group Limited. For permission to use (where not
    already granted under a licence) please go to
    http://group.bmj.com/group/rights-licensing/permissions.
    
    PMID: 25009326  [PubMed - in process]
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  • 5) Autism. 2014 Jul 9. pii: 1362361314541012. [Epub ahead of print]

    A review of cultural adaptations of screening tools for autism spectrum disorders.

    Soto S(1), Linas K(2), Jacobstein D(2), Biel M(3), Migdal T(2), Anthony BJ(2).
    
    Author information: 
    (1)San Diego State University/University of California, USA
    sandra.soto@mail.sdsu.edu.
    (2)Georgetown Center for Child and Human Development, USA.
    (3)School of Medicine, Georgetown University, USA.
    
    Screening children to determine risk for Autism Spectrum Disorders has become
    more common, although some question the advisability of such a strategy. The
    purpose of this systematic review is to identify autism screening tools that have
    been adapted for use in cultures different from that in which they were
    developed, evaluate the cultural adaptation process, report on the psychometric
    properties of the adapted instruments, and describe the implications for further 
    research and clinical practice. A total of 21 articles met criteria for
    inclusion, reporting on the cultural adaptation of autism screening in 18
    countries and in nine languages. The cultural adaptation process was not always
    clearly outlined and often did not include the recommended guidelines.
    Cultural/linguistic modifications to the translated tools tended to increase with
    the rigor of the adaptation process. Differences between the psychometric
    properties of the original and adapted versions were common, indicating the need 
    to obtain normative data on populations to increase the utility of the translated
    tool.
    
    © The Author(s) 2014.
    
    PMID: 25008216  [PubMed - as supplied by publisher]
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  • 6) Sci Rep. 2014 Jul 10;4:5644. doi: 10.1038/srep05644.

    A mechanical model predicts morphological abnormalities in the developing human brain.

    Budday S(1), Raybaud C(2), Kuhl E(3).
    
    Author information: 
    (1)Department of Mechanical Engineering, Stanford University, Stanford, CA 94305,
    USA.
    (2)Division of Neuroradiology, Hospital for Sick Children, Toronto, ON M5G1X8,
    Canada.
    (3)Departments of Mechanical Engineering and Bioengineering, Stanford University,
    Stanford, CA 94305, USA.
    
    The developing human brain remains one of the few unsolved mysteries of science. 
    Advancements in developmental biology, neuroscience, and medical imaging have
    brought us closer than ever to understand brain development in health and
    disease. However, the precise role of mechanics throughout this process remains
    underestimated and poorly understood. Here we show that mechanical stretch plays 
    a crucial role in brain development. Using the nonlinear field theories of
    mechanics supplemented by the theory of finite growth, we model the human brain
    as a living system with a morphogenetically growing outer surface and a
    stretch-driven growing inner core. This approach seamlessly integrates the two
    popular but competing hypotheses for cortical folding: axonal tension and
    differential growth. We calibrate our model using magnetic resonance images from 
    very preterm neonates. Our model predicts that deviations in cortical growth and 
    thickness induce morphological abnormalities. Using the gyrification index, the
    ratio between the total and exposed surface area, we demonstrate that these
    abnormalities agree with the classical pathologies of lissencephaly and
    polymicrogyria. Understanding the mechanisms of cortical folding in the
    developing human brain has direct implications in the diagnostics and treatment
    of neurological disorders, including epilepsy, schizophrenia, and autism.
    
    PMID: 25008163  [PubMed - in process]
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  • 7) Nat Rev Neurosci. 2014 Jul 9. doi: 10.1038/nrn3730. [Epub ahead of print]

    Mobile DNA elements in the generation of diversity and complexity in the brain.

    Erwin JA, Marchetto MC, Gage FH.
    
    Author information: 
    Salk Institute for Biological Studies, Laboratory of Genetics, 10010 North Torrey
    Pines Road, La Jolla, California 92037, USA.
    
    Mobile elements are DNA sequences that can change their position (retrotranspose)
    within the genome. Although its biological function is largely unappreciated, DNA
    derived from mobile elements comprises nearly half of the human genome. It has
    long been thought that neuronal genomes are invariable; however, recent studies
    have demonstrated that mobile elements actively retrotranspose during
    neurogenesis, thereby creating genomic diversity between neurons. In addition,
    mounting data demonstrate that mobile elements are misregulated in certain
    neurological disorders, including Rett syndrome and schizophrenia.
    
    PMID: 25005482  [PubMed - as supplied by publisher]
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  • 8) Pediatrics. 2014 Jul 14. pii: peds.2013-4285. [Epub ahead of print]

    Weighted Blankets and Sleep in Autistic Children-A Randomized Controlled Trial.

    Gringras P(1), Green D(2), Wright B(3), Rush C(4), Sparrowhawk M(5), Pratt K(4), 
    Allgar V(5), Hooke N(3), Moore D(3), Zaiwalla Z(6), Wiggs L(5).
    
    Author information: 
    (1)Children's Sleep Medicine, Evelina London Children's Hospital, St Thomas'
    Hospital, London, United Kingdom; paul.gringras@gstt.nhs.uk.
    (2)Centre for Rehabilitation and.
    (3)Lime Trees Child and Family Unit, York, England; and.
    (4)Children's Sleep Medicine, Evelina London Children's Hospital, St Thomas'
    Hospital, London, United Kingdom;
    (5)Department of Psychology, Oxford Brookes University, Oxford, United Kingdom;
    (6)Department of Clinical Neurophysiology, John Radcliffe Hospital, Oxford, United
    Kingdom.
    
    OBJECTIVE: To assess the effectiveness of a weighted-blanket intervention in
    treating severe sleep problems in children with autism spectrum disorder
    (ASD).METHODS: This phase III trial was a randomized, placebo-controlled
    crossover design. Participants were aged between 5 years and 16 years 10 months, 
    with a confirmed ASD diagnosis and severe sleep problems, refractory to
    community-based interventions. The interventions were either a commercially
    available weighted blanket or otherwise identical usual weight blanket (control),
    introduced at bedtime; each was used for a 2-week period before crossover to the 
    other blanket. Primary outcome was total sleep time (TST) recorded by actigraphy 
    over each 2-week period. Secondary outcomes included actigraphically recorded
    sleep-onset latency, sleep efficiency, assessments of child behavior, family
    functioning, and adverse events. Sleep was also measured by using parent-report
    diaries.RESULTS: Seventy-three children were randomized and analysis conducted on
    67 children who completed the study. Using objective measures, the weighted
    blanket, compared with the control blanket, did not increase TST as measured by
    actigraphy and adjusted for baseline TST. There were no group differences in any 
    other objective or subjective measure of sleep, including behavioral outcomes. On
    subjective preference measures, parents and children favored the weighted
    blanket.CONCLUSIONS: The use of a weighted blanket did not help children with ASD
    sleep for a longer period of time, fall asleep significantly faster, or wake less
    often. However, the weighted blanket was favored by children and parents, and
    blankets were well tolerated over this period.
    
    Copyright © 2014 by the American Academy of Pediatrics.
    
    PMID: 25022743  [PubMed - as supplied by publisher]
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  • 9) J Autism Dev Disord. 2014 Jul 15. [Epub ahead of print]

    Brief Report: Independent Validation of Autism Spectrum Disorder Case Status in the Utah Autism and Developmental Disabilities Monitoring (ADDM) Network Site.

    Bakian AV(1), Bilder DA, Carbone PS, Hunt TD, Petersen B, Rice CE.
    
    Author information: 
    (1)Department of Psychiatry, University of Utah, 650 Komas Drive Suite 206, Salt
    Lake City, UT, 84108, USA, amanda.bakian@hsc.utah.edu.
    
    An independent validation was conducted of the Utah Autism and Developmental
    Disabilities Monitoring Network's (UT-ADDM) classification of children with
    autism spectrum disorder (ASD). UT-ADDM final case status (n = 90) was compared
    with final case status as determined by independent external expert reviewers
    (EERs). Inter-rater reliability (ICC = 0.84), specificity [0.83 (95 % CI
    0.74-0.90)], and sensitivity [0.99 (95 % CI 0.96-1.00)] were high for ASD case
    versus non-case classification between UT-ADDM and EER. At least one EER
    disagreed with UT-ADDM on ASD final case status on nine out of 30 records;
    however, all three EERs disagreed with UT-ADDM for only one record. Findings
    based on limited data suggest that children with ASD as identified by UT-ADDM are
    consistently classified as ASD cases by independent autism experts.
    
    PMID: 25022251  [PubMed - as supplied by publisher]
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  • 10) J Autism Dev Disord. 2014 Jul 15. [Epub ahead of print]

    Observation of Spontaneous Expressive Language (OSEL): A New Measure for Spontaneous and Expressive Language of Children with Autism Spectrum Disorders and Other Communication Disorders.

    Kim SH(1), Junker D, Lord C.
    
    Author information: 
    (1)Yale Child Study Center, Yale University School of Medicine, 40 Temple St. Suite 
    7-D, New Haven, CT, 06510, USA, so-hyun.kim@yale.edu.
    
    A new language measure, the Observation of Spontaneous Expressive Language
    (OSEL), is intended to document spontaneous use of syntax, pragmatics, and
    semantics in 2-12-year-old children with Autism Spectrum Disorder (ASD) and other
    communication disorders with expressive language levels comparable to typical
    2-5 year olds. Because the purpose of the OSEL is to provide developmental norms 
    for use of language, the first step involves assessment of the scale's
    feasibility, validity, and reliability using a sample of 180 2-5 year-old
    typically developing children. Pilot data from the OSEL shows strong internal
    consistency, high reliabilities and validity. Once replicated with a large
    population-based sample and in special populations, the scale should be helpful
    in designing appropriate interventions for children with ASD and other
    communication disorders.
    
    PMID: 25022249  [PubMed - as supplied by publisher]
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  • 11) Cell Rep. 2014 Jul 9. pii: S2211-1247(14)00491-4. doi: 10.1016/j.celrep.2014.06.022. [Epub ahead of print]

    Neurexin Dysfunction in Adult Neurons Results in Autistic-like Behavior in Mice.

    Rabaneda LG(1), Robles-Lanuza E(1), Nieto-González JL(2), Scholl FG(3).
    
    Author information: 
    (1)Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del
    Rocío/CSIC/Universidad de Sevilla and Departamento de Fisiología Médica y
    Biofísica, Universidad de Sevilla, Campus del Hospital Universitario Virgen del
    Rocío, Avenida Manuel Siurot s/n, Sevilla 41013, Spain.
    (2)Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del
    Rocío/CSIC/Universidad de Sevilla and Departamento de Fisiología Médica y
    Biofísica, Universidad de Sevilla, Campus del Hospital Universitario Virgen del
    Rocío, Avenida Manuel Siurot s/n, Sevilla 41013, Spain; Centro de Investigación
    Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Campus del
    Hospital Universitario Virgen del Rocío, Avenida Manuel Siurot s/n, Sevilla
    41013, Spain.
    (3)Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del
    Rocío/CSIC/Universidad de Sevilla and Departamento de Fisiología Médica y
    Biofísica, Universidad de Sevilla, Campus del Hospital Universitario Virgen del
    Rocío, Avenida Manuel Siurot s/n, Sevilla 41013, Spain. Electronic address:
    fgs@us.es.
    
    Autism spectrum disorders (ASDs) comprise a group of clinical phenotypes
    characterized by repetitive behavior and social and communication deficits.
    Autism is generally viewed as a neurodevelopmental disorder where insults during 
    embryonic or early postnatal periods result in aberrant wiring and function of
    neuronal circuits. Neurexins are synaptic proteins associated with autism. Here, 
    we generated transgenic βNrx1ΔC mice in which neurexin function is selectively
    impaired during late postnatal stages. Whole-cell recordings in cortical neurons 
    show an impairment of glutamatergic synaptic transmission in the βNrx1ΔC mice.
    Importantly, mutant mice exhibit autism-related symptoms, such as increased
    self-grooming, deficits in social interactions, and altered interaction for
    nonsocial olfactory cues. The autistic-like phenotype of βNrx1ΔC mice can be
    reversed after removing the mutant protein in aged animals. The defects resulting
    from disruption of neurexin function after the completion of embryonic and early 
    postnatal development suggest that functional impairment of mature circuits can
    trigger autism-related phenotypes.
    
    Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
    
    PMID: 25017069  [PubMed - as supplied by publisher]
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  • 12) PLoS One. 2014 Jul 16;9(7):e102251. doi: 10.1371/journal.pone.0102251. eCollection 2014.

    Attenuation of Typical Sex Differences in 800 Adults with Autism vs. 3,900 Controls.

    Baron-Cohen S(1), Cassidy S(2), Auyeung B(3), Allison C(2), Achoukhi M(2),
    Robertson S(2), Pohl A(2), Lai MC(4).
    
    Author information: 
    (1)Autism Research Centre, Department of Psychiatry, University of Cambridge,
    Cambridge, United Kingdom; Cambridge Lifespan Asperger Syndrome Service (CLASS)
    Clinic, Cambridgeshire and Peterborough National Health Service Foundation Trust,
    Cambridge, United Kingdom.
    (2)Autism Research Centre, Department of Psychiatry, University of Cambridge,
    Cambridge, United Kingdom.
    (3)Autism Research Centre, Department of Psychiatry, University of Cambridge,
    Cambridge, United Kingdom; Department of Psychology, University of Edinburgh,
    Edinburgh, United Kingdom.
    (4)Autism Research Centre, Department of Psychiatry, University of Cambridge,
    Cambridge, United Kingdom; Cambridge Lifespan Asperger Syndrome Service (CLASS)
    Clinic, Cambridgeshire and Peterborough National Health Service Foundation Trust,
    Cambridge, United Kingdom; Department of Psychiatry, National Taiwan University
    Hospital and College of Medicine, Taipei, Taiwan.
    
    Sex differences have been reported in autistic traits and systemizing (male
    advantage), and empathizing (female advantage) among typically developing
    individuals. In individuals with autism, these cognitive-behavioural profiles
    correspond to predictions from the "extreme male brain" (EMB) theory of autism
    (extreme scores on autistic traits and systemizing, below average on
    empathizing). Sex differences within autism, however, have been
    under-investigated. Here we show in 811 adults (454 females) with autism and
    3,906 age-matched typical control adults (2,562 females) who completed the
    Empathy Quotient (EQ), the Systemizing Quotient-Revised (SQ-R), and the Autism
    Spectrum Quotient (AQ), that typical females on average scored higher on the EQ, 
    typical males scored higher on the SQ-R and AQ, and both males and females with
    autism showed a shift toward the extreme of the "male profile" on these measures 
    and in the distribution of "brain types" (the discrepancy between standardized EQ
    and SQ-R scores). Further, normative sex differences are attenuated but not
    abolished in adults with autism. The findings provide strong support for the EMB 
    theory of autism, and highlight differences between males and females with
    autism.
    
    PMID: 25029203  [PubMed - as supplied by publisher]
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  • 13) Front Syst Neurosci. 2014 Jun 27;8:118. doi: 10.3389/fnsys.2014.00118. eCollection 2014.

    Twenty-four hour quantitative-EEG and in-vivo glutamate biosensor detects activity and circadian rhythm dependent biomarkers of pathogenesis in Mecp2 null mice.

    Johnston MV(1), Ammanuel S(2), O'Driscoll C(3), Wozniak A(4), Naidu S(5), Kadam
    SD(6).
    
    Author information: 
    (1)Neuroscience Laboratory, Departments of Neurology and Pediatrics, Hugo Moser
    Research Institute at Kennedy Krieger, Johns Hopkins University School of
    Medicine Baltimore, MD, USA.
    (2)Neuroscience Laboratory, Hugo Moser Research Institute at Kennedy Krieger
    Baltimore, MD, USA.
    (3)Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of
    Public Health, Hugo Moser Research Institute at Kennedy Krieger, Johns Hopkins
    University School of Medicine Baltimore, MD, USA.
    (4)Biostatistics Center, Johns Hopkins Bloomberg School of Public Health, Johns
    Hopkins University School of Medicine Baltimore, MD, USA.
    (5)Departments of Neurology and Pediatrics, Hugo Moser Research Institute at Kennedy
    Krieger Baltimore, MD, USA.
    (6)Neuroscience Laboratory, Departments of Neurology, Hugo Moser Research Institute 
    at Kennedy Krieger and Johns Hopkins University School of Medicine Baltimore, MD,
    USA.
    
    Mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (Mecp2)
    cause most cases of Rett syndrome (RTT). Currently there is no cure for RTT.
    Abnormal EEGs are found in 100% of RTT cases and are associated with severe sleep
    dysfunction, the cause of which is not well understood. Mice deficient in MeCP2
    protein have been studied and characterized for their neuropathological and
    behavioral deficits to better understand RTT. With the goal to study the
    non-ictal EEG correlates in symptomatic Mecp2 KO mice (Mecp2(tm1.1Bird/y)), and
    determine novel EEG biomarkers of their reported progressive neurodegeneration,
    we used 24 h video-EEG/EMG with synchronous in-vivo cortical glutamate biosensor 
    in the frontal cortex. We scored the EEG for activity states and spectral
    analysis was performed to evaluate correlations to the synchronous extracellular 
    glutamate fluctuations underlying Mecp2 inactivation as compared to WT.
    Significant alterations in sleep structure due to dark cycle-specific long wake
    states and poor quality of slow-wave sleep were associated with a significant
    increase in glutamate loads per activity cycle. The dynamics of the
    activity-state-dependent physiological rise and fall of glutamate indicative of
    glutamate homeostasis were significantly altered in the KO mice. Colorimetric
    quantitation of absolute glutamate levels in frontal cortex also indicated the
    presence of significantly higher levels in KO. This study for the first time
    found evidence of uncompensated sleep deprivation-like EEG biomarkers that were
    associated with glutamate homeostatic dysfunction in the Mecp2 KO mice.
    
    PMID: 25018705  [PubMed]
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  • 14) J Autism Dev Disord. 2014 Jul 17. [Epub ahead of print]

    Restricted and Repetitive Behaviors in Individuals with a History of ASDs Who Have Achieved Optimal Outcomes.

    Troyb E(1), Orinstein A, Tyson K, Eigsti IM, Naigles L, Fein D.
    
    Author information: 
    (1)Department of Psychology, University of Connecticut, 406 Babbidge Road, Storrs,
    CT, 06269, USA, etroyb@gmail.com.
    
    Studies of autism spectrum disorders (ASDs) suggest that restricted and
    repetitive behaviors (RRBs) are particularly difficult to remediate. We examined 
    present and past RRBs in 34 individuals who achieved optimal outcomes (OOs; lost 
    their ASD diagnosis), 45 high-functioning individuals with ASD (HFA) and 34
    typically developing (TD) peers. The OO group exhibited minimal residual RRBs at 
    the time of the study. All OO participants were reported to have at least one RRB
    in early childhood and almost 90 % met the RRB cutoff for ASD in early childhood,
    but RRBs were not more present in the OO than the TD group at the time of the
    study. History of RRBs in the HFA and OO groups differed only in oversensitivity 
    to noise and insistence on sameness. Reports of current behavior indicated that
    RRB's had almost totally disappeared in the OO group. Thus, although RRB's were
    present in the OO group in childhood, they resolved along with social and
    communication deficits.
    
    PMID: 25030967  [PubMed - as supplied by publisher]
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  • 15) J Autism Dev Disord. 2014 Jul 18. [Epub ahead of print]

    Autism Spectrum Disorder: FRAXE Mutation, a Rare Etiology.

    Correia F(1), Café C, Almeida J, Mouga S, Oliveira G.
    
    Author information: 
    (1)Serviço de Pediatria, Centro Hospitalar do Alto Ave, Rua dos Cutileiros,
    Creixomil, 4835-044, Guimarães, Portugal.
    
    Autism spectrum disorder (ASD) is characterized by impaired social interaction
    and communication, restricted interests and repetitive behaviors. Fragile X E is 
    associated with X-linked non-specific mild intellectual disability (ID) and with 
    behavioral problems. Most of the known genetic causes of ASD are also causes of
    ID, implying that these two identities share common genetic bases. We present a
    child with an ASD with a normal range of intelligence quotient, that later
    evolved to compulsive behavior. FRAXE locus analysis by polymerase chain reaction
    revealed a complete mutation of the FMR 2 gene. This report stresses the
    importance of clinicians being aware of the association between a full mutation
    of FMR2 and ASD associated with compulsive behavior despite normal intellectual
    level.
    
    PMID: 25035088  [PubMed - as supplied by publisher]
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  • 16) Biol Psychiatry. 2014 Jun 12. pii: S0006-3223(14)00422-3. doi: 10.1016/j.biopsych.2014.05.024. [Epub ahead of print]

    An Autism Case History to Review the Systematic Analysis of Large-Scale Data to Refine the Diagnosis and Treatment of Neuropsychiatric Disorders.

    Kohane IS.
    
    Author information: 
    Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts.
    Electronic address: isaac_kohane@harvard.edu.
    
    Analysis of large-scale systems of biomedical data provides a perspective on
    neuropsychiatric disease that may be otherwise elusive. Described here is an
    analysis of three large-scale systems of data from autism spectrum disorder (ASD)
    and of ASD research as an exemplar of what might be achieved from study of such
    data. First is the biomedical literature that highlights the fact that there are 
    two very successful but quite separate research communities and findings
    pertaining to genetics and the molecular biology of ASD. There are those studies 
    positing ASD causes that are related to immunological dysregulation and those
    related to disorders of synaptic function and neuronal connectivity. Second is
    the emerging use of electronic health record systems and other large clinical
    databases that allow the data acquired during the course of care to be used to
    identify distinct subpopulations, clinical trajectories, and pathophysiological
    substructures of ASD. These systems reveal subsets of patients with distinct
    clinical trajectories, some of which are immunologically related and others which
    follow pathologies conventionally thought of as neurological. The third is
    genome-wide genomic and transcriptomic analyses which show molecular pathways
    that overlap neurological and immunological mechanisms. The convergence of these 
    three large-scale data perspectives illustrates the scientific leverage that
    large-scale data analyses can provide in guiding researchers in an approach to
    the diagnosis of neuropsychiatric disease that is inclusive and comprehensive.
    
    Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All
    rights reserved.
    
    PMID: 25034947  [PubMed - as supplied by publisher]
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  • 17) Ann Epidemiol. 2014 May 23. pii: S1047-2797(14)00191-4. doi: 10.1016/j.annepidem.2014.05.010. [Epub ahead of print]

    Mediators of the association between parental severe mental illness and offspring neurodevelopmental problems.

    McCoy BM(1), Rickert ME(1), Class QA(1), Larsson H(2), Lichtenstein P(2),
    D'Onofrio BM(3).
    
    Author information: 
    (1)Department of Psychological and Brain Sciences, Indiana University Bloomington,
    Bloomington.
    (2)Department of Medical Epidemiology and Biostatistics, Karolinska Institutet,
    Stockholm, Sweden.
    (3)Department of Psychological and Brain Sciences, Indiana University Bloomington,
    Bloomington. Electronic address: bmdonofr@indiana.edu.
    
    PURPOSE: Parental severe mental illness (SMI) is associated with an increased
    risk of offspring autism spectrum disorder (ASD) and attention deficit
    hyperactivity disorder (ADHD). We conducted a study to examine the extent to
    which risk of preterm birth, low birth weight, and small for gestational age
    mediated this association.
    METHODS: We obtained data on offspring born 1992-2001 in Sweden (n = 870,017)
    through the linkage of multiple population-based registers. We used logistic and 
    Cox regression to assess the associations between parental SMI, adverse pregnancy
    outcomes, and offspring ASD and ADHD, as well as tested whether adverse pregnancy
    outcomes served as mediators.
    RESULTS: After controlling for measured covariates, maternal and paternal SMI
    were associated with an increased risk for preterm birth, low birth weight, and
    gestational age, and for offspring ASD and ADHD. These pregnancy outcomes were
    also associated with an increased risk of ASD and ADHD. We found that pregnancy
    outcomes did not mediate the association between parental SMI and offspring ASD
    and ADHD, as there was no substantial change in magnitude of the risk estimates
    after controlling for pregnancy outcomes.
    CONCLUSIONS: Parental SMI and adverse pregnancy outcomes appear to be independent
    risk factors for offspring ASD and ADHD.
    
    Copyright © 2014 Elsevier Inc. All rights reserved.
    
    PMID: 25037304  [PubMed - as supplied by publisher]
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  • 18) Nat Genet. 2014 Jul 20. doi: 10.1038/ng.3039. [Epub ahead of print]

    Most genetic risk for autism resides with common variation.

    Gaugler T(1), Klei L(2), Sanders SJ(3), Bodea CA(1), Goldberg AP(4), Lee AB(1),
    Mahajan M(5), Manaa D(5), Pawitan Y(6), Reichert J(7), Ripke S(8), Sandin S(6),
    Sklar P(9), Svantesson O(6), Reichenberg A(10), Hultman CM(6), Devlin B(2),
    Roeder K(11), Buxbaum JD(12).
    
    Author information: 
    (1)Department of Statistics, Carnegie Mellon University, Pittsburgh, Pennsylvania,
    USA.
    (2)Department of Psychiatry, University of Pittsburgh School of Medicine,
    Pittsburgh, Pennsylvania, USA.
    (3)1] Department of Psychiatry, University of California, San Francisco, San
    Francisco, California, USA. [2] Department of Genetics, Yale University School of
    Medicine, New Haven, Connecticut, USA.
    (4)1] Seaver Autism Center for Research and Treatment, Icahn School of Medicine at
    Mount Sinai, New York, New York, USA. [2] Department of Psychiatry, Icahn School 
    of Medicine at Mount Sinai, New York, New York, USA. [3] Icahn Institute for
    Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New
    York, New York, USA.
    (5)Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount
    Sinai, New York, New York, USA.
    (6)Department of Medical Epidemiology and Biostatistics, Karolinska Institutet,
    Stockholm, Sweden.
    (7)1] Seaver Autism Center for Research and Treatment, Icahn School of Medicine at
    Mount Sinai, New York, New York, USA. [2] Department of Psychiatry, Icahn School 
    of Medicine at Mount Sinai, New York, New York, USA.
    (8)Center for Human Genetic Research, Massachusetts General Hospital, Boston,
    Massachusetts, USA.
    (9)1] Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York,
    New York, USA. [2] Icahn Institute for Genomics and Multiscale Biology, Icahn
    School of Medicine at Mount Sinai, New York, New York, USA. [3] Department of
    Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York,
    New York, USA. [4] Friedman Brain Institute, Icahn School of Medicine at Mount
    Sinai, New York, New York, USA. [5] Division of Psychiatric Genomics, Icahn
    School of Medicine at Mount Sinai, New York, New York, USA.
    (10)1] Seaver Autism Center for Research and Treatment, Icahn School of Medicine at
    Mount Sinai, New York, New York, USA. [2] Department of Psychiatry, Icahn School 
    of Medicine at Mount Sinai, New York, New York, USA. [3] Department of Preventive
    Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
    (11)1] Department of Statistics, Carnegie Mellon University, Pittsburgh,
    Pennsylvania, USA. [2] Ray and Stephanie Lane Center for Computational Biology,
    Carnegie Mellon University, Pittsburgh, Pennsylvania, USA.
    (12)1] Seaver Autism Center for Research and Treatment, Icahn School of Medicine at
    Mount Sinai, New York, New York, USA. [2] Department of Psychiatry, Icahn School 
    of Medicine at Mount Sinai, New York, New York, USA. [3] Department of Genetics
    and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New
    York, USA. [4] Friedman Brain Institute, Icahn School of Medicine at Mount Sinai,
    New York, New York, USA. [5] Department of Neuroscience, Icahn School of Medicine
    at Mount Sinai, New York, New York, USA. [6] The Mindich Child Health and
    Development Institute, Icahn School of Medicine at Mount Sinai, New York, New
    York, USA.
    
    A key component of genetic architecture is the allelic spectrum influencing trait
    variability. For autism spectrum disorder (herein termed autism), the nature of
    the allelic spectrum is uncertain. Individual risk-associated genes have been
    identified from rare variation, especially de novo mutations. From this evidence,
    one might conclude that rare variation dominates the allelic spectrum in autism, 
    yet recent studies show that common variation, individually of small effect, has 
    substantial impact en masse. At issue is how much of an impact relative to rare
    variation this common variation has. Using a unique epidemiological sample from
    Sweden, new methods that distinguish total narrow-sense heritability from that
    due to common variation and synthesis of results from other studies, we reach
    several conclusions about autism's genetic architecture: its narrow-sense
    heritability is ∼52.4%, with most due to common variation, and rare de novo
    mutations contribute substantially to individual liability, yet their
    contribution to variance in liability, 2.6%, is modest compared to that for
    heritable variation.
    
    PMID: 25038753  [PubMed - as supplied by publisher]
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  • 19) Autism Res Treat. 2014;2014:935686. doi: 10.1155/2014/935686. Epub 2014 Jun 22.

    Computer vision tools for low-cost and noninvasive measurement of autism-related behaviors in infants.

    Hashemi J(1), Tepper M(1), Vallin Spina T(2), Esler A(3), Morellas V(4),
    Papanikolopoulos N(4), Egger H(5), Dawson G(6), Sapiro G(7).
    
    Author information: 
    (1)Department of Electrical and Computer Engineering, Duke University, Durham, NC
    27708, USA.
    (2)Institute of Computing, University of Campinas, 13083 Campinas, SP, Brazil.
    (3)Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA.
    (4)Department of Computer Science and Engineering, University of Minnesota,
    Minneapolis, MN 55455, USA.
    (5)Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC
    22708, USA.
    (6)Department of Psychiatry and Behavioral Sciences and School of Medicine, Duke
    University, Durham, NC 27708, USA.
    (7)Department of Electrical and Computer Engineering, Department of Computer
    Science, and Department of Biomedical Engineering, Duke University, Durham, NC
    27708, USA.
    
    The early detection of developmental disorders is key to child outcome, allowing 
    interventions to be initiated which promote development and improve prognosis.
    Research on autism spectrum disorder (ASD) suggests that behavioral signs can be 
    observed late in the first year of life. Many of these studies involve extensive 
    frame-by-frame video observation and analysis of a child's natural behavior.
    Although nonintrusive, these methods are extremely time-intensive and require a
    high level of observer training; thus, they are burdensome for clinical and large
    population research purposes. This work is a first milestone in a long-term
    project on non-invasive early observation of children in order to aid in risk
    detection and research of neurodevelopmental disorders. We focus on providing
    low-cost computer vision tools to measure and identify ASD behavioral signs based
    on components of the Autism Observation Scale for Infants (AOSI). In particular, 
    we develop algorithms to measure responses to general ASD risk assessment tasks
    and activities outlined by the AOSI which assess visual attention by tracking
    facial features. We show results, including comparisons with expert and nonexpert
    clinicians, which demonstrate that the proposed computer vision tools can capture
    critical behavioral observations and potentially augment the clinician's
    behavioral observations obtained from real in-clinic assessments.
    
    PMID: 25045536  [PubMed]
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  • 20) Ann Neurol. 2014 Jul 14. doi: 10.1002/ana.24225. [Epub ahead of print]

    Genetic and phenotypic diversity of NHE6 mutations in Christianson syndrome.

    Pescosolido MF(1), Stein DM, Schmidt M, Moufawad El Achkar C, Sabbagh M, Rogg JM,
    Tantravahi U, McLean RL, Liu JS, Poduri A, Morrow EM.
    
    Author information: 
    (1)Department of Molecular Biology, Cell Biology and Biochemistry; and Institute for
    Brain Science, Brown University, Lab for Molecular Medicine, 70 Ship Street,
    Providence, RI, 02912; Developmental Disorders Genetics Research Program, Emma
    Pendleton Bradley Hospital and Department of Psychiatry and Human Behavior, The
    Warren Alpert Medical School of Brown University, 1011 Veteran Memorial Pkwy.,
    East Providence, RI, 02915.
    
    Objective: Recently, Christianson syndrome (CS) has been determined to be caused 
    by mutations in the X-linked Na(+) /H(+) Exchanger 6 (NHE6). We aimed to
    determine the diagnostic criteria and mutational spectrum for CS. Methods: Twelve
    independent pedigrees (14 boys, ages 4 to 19) with mutations in NHE6 were
    administered standardized research assessments and mutations were characterized. 
    Results: The mutational spectrum was composed of 9 single nucleotide variants
    (SNVs), 2 indels and 1 CNV deletion. All mutations were protein-truncating or
    splicing mutations. We identified two recurrent mutations (c.1498 c>t, p.R500X;
    and c.1710 g>a, p.W570X). Otherwise, all mutations were unique. In our study,
    seven of 12 mutations (58%) were de novo, in contrast to prior literature wherein
    mutations were largely inherited. We also report prominent neurological, medical 
    and behavioral symptoms. All CS participants were non-verbal and had intellectual
    disability, epilepsy and ataxia. Many had prior diagnoses of autism and/or
    Angelman syndrome. Other neurologic symptoms included eye movement abnormalities 
    (79%), postnatal microcephaly (92%) and MRI evidence of cerebellar atrophy (33%).
    Regression was noted in 50%, with recurrent presentations involving loss of words
    and/or the ability to walk. Medical symptoms, particularly gastrointestinal
    symptoms, were common. Height and body mass index measures were below normal
    ranges in most participants. Behavioral symptoms included hyperkinetic behavior
    (100%) and a majority exhibited high pain threshold. Interpretation: This is the 
    largest cohort of independent CS pedigrees reported. We propose diagnostic
    criteria for CS. CS represents a novel neurogenetic disorder with general
    relevance to autism, intellectual disability, Angelman syndrome, epilepsy and
    regression. ANN NEUROL 2014. © 2014 American Neurological Association.
    
    Copyright © 2014 American Neurological Association.
    
    PMID: 25044251  [PubMed - as supplied by publisher]
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  • 21) J Child Psychol Psychiatry. 2014 Jul 16. doi: 10.1111/jcpp.12242. [Epub ahead of print]

    The peer relationships of girls with ASD at school: comparison to boys and girls with and without ASD.

    Dean M(1), Kasari C, Shih W, Frankel F, Whitney R, Landa R, Lord C, Orlich F,
    King B, Harwood R.
    
    Author information: 
    (1)Center for Autism Research and Treatment, University of California, Los Angeles, 
    CA, USA.
    
    BACKGROUND: This study examines the social relationships of elementary school
    children with high-functioning autism, focusing on how gender relates to social
    preferences and acceptance, social connections, reciprocal friendships, and
    rejection.
    METHOD: Peer nomination data were analyzed for girls with and without ASD
    (n = 50) and boys with and without ASD (n = 50). Girls and boys with ASD were
    matched by age, gender, and IQ. Each child with ASD was matched by age and gender
    to a typically developing classmate.
    RESULTS: Consistent with typically developing populations, children with ASD
    preferred, were accepted by, and primarily socialized with same-gender friends.
    With fewer nominations and social relationships, girls and boys with ASD appear
    more socially similar to each other than to the same-gender control group.
    Additionally, girls and boys with ASD showed higher rates of social exclusion
    than their typically developing peers. However, boys with ASD were more overtly
    socially excluded compared to girls with ASD, who seemed to be overlooked, rather
    than rejected.
    CONCLUSIONS: Our data suggest a number of interesting findings in the social
    relationships of children with ASD in schools. Like typically developing
    populations, children with ASD identify with their own gender when socializing
    and choosing friends. But given the social differences between genders, it is
    likely that girls with ASD are experiencing social challenges that are different 
    from boys with ASD. Therefore, gender is an important environmental factor to
    consider when planning social skills interventions at school.
    
    © 2014 The Authors. Journal of Child Psychology and Psychiatry. © 2014
    Association for Child and Adolescent Mental Health.
    
    PMID: 25039696  [PubMed - as supplied by publisher]
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