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WUSTL Neuroscience Publications Archive - April 2013

Scopus weekly reports:

April 24, 2013

April 10, 2013 


April 24, 2013

Laryea, G.a c , Arnett, M.G.b c , Wieczorek, L.d e , Muglia, L.J.b c
Site-specific modulation of brain glucocorticoid receptor and corticotropin-releasing hormone expression using lentiviral vectors
(2013) Molecular and Cellular Endocrinology, 371 (1-2), pp. 160-165. 
a Neuroscience Graduate Program, School of Medicine, Vanderbilt University, 465 21st. Avenue South, Nashville, TN 37232, United States
b Department of Pediatrics, University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, OH 45229, United States
c Center for Prevention of Preterm Birth, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, United States
d Program in Neuroscience, Washington University, 660 S. Euclid, St. Louis, MO 63110, United States
e UNC Chapel Hill, Center for Alcohol Studies, CB#7178, Chapel Hill, NC 27599-7178, United States

The glucocorticoid receptor (GR) and corticotropin-releasing hormone (CRH) are important molecular regulators of an individual's ability to respond to stressful stimuli in an adaptive manner. Impaired signaling of both GR and CRH often leads to dysfunction of the hypothalamic-pituitary-adrenal axis, which underlies the etiology of many affective disorders such as anxiety and depression. Studies focusing on how GR and CRH influence the stress response are limited as they generalize to broad brain regions, thus hindering identification of how specific CNS nuclei contribute to maladaptive stress responses. Our objective is to distinguish the site-specific involvement of GR and CRH in limbic regions involved in the stress response. With that intent, we use lentiviral (LV) vectors in combination with transgenic mouse lines, enabling us to modify expression of GR or CRH in a very localized manner. This paper describes the generation of several distinct LV vectors and transgenic mice models that will help further elucidate the site-specific actions of GR and CRH. © 2012 Elsevier Ireland Ltd.

Author Keywords
Corticotropin-releasing hormone;  Glucocorticoid receptor;  Hypothalamic-pituitary-adrenal axis; Lentiviral vectors;  Psychiatric disorders;  Stress

Document Type: Article
Source: Scopus

Olsen, J.E.a , Ross, S.A.b , Foreman, M.H.a , Engsberg, J.R.a 
Changes in muscle activation following ankle strength training in children with spastic cerebral palsy: An electromyography feasibility case report
(2013) Physical and Occupational Therapy in Pediatrics, 33 (2), pp. 230-242. 
a Human Performance Laboratory, Washington University, St. Louis School of Medicine Program in Occupational Therapy, 5240 Oakland Avenue, St. Louis, MO, 63110, United States
b Human Performance Laboratory, Maryville University Program in Physical Therapy, St. Louis, MO, United States

Children with cerebral palsy (CP) are likely to experience decreased participation in activities and less competence in activities of daily living. Studies of children with spastic CP have shown that strengthening programs produce positive results in strength, gait, and functional outcomes (measured by the Gross Motor Function Measure). No investigations have analyzed electromyography (EMG) activity before and after strength training to determine whether any changes occur in the GMFM. This feasibility case report quantified dorsiflexor and plantarflexor muscle activation changes during performance of 3-5 selected GMFM items following a plantarflexor strength training in two children with cerebral palsy. Increased plantarflexor strength and increased ability to selectively activate muscles were found. Little carryover to performance on GMFM items was observed. It is feasible to use EMG during performance on selected GMFM items to evaluate motor control changes following strength training in children with CP. © 2013 by Informa Healthcare USA, Inc.

Author Keywords
Cerebral palsy;  Electromyography;  Gross motor function measure;  Plantarflexor;  Strength training

Document Type: Review
Source: Scopus

Kessler, B.a , Pollo, T.C.a b , Treiman, R.a , Cardoso-Martins, C.c 
Frequency Analyses of Prephonological Spellings as Predictors of Success in Conventional Spelling
(2013) Journal of Learning Disabilities, 46 (3), pp. 252-259. 
a Washington University in St. Louis, St. Louis, MO, United States
b Universidade Federal de São João Del-Rei, Brazil
c Universidade Federal de Minas Gerais, Brazil

The present study explored how children's prephonological writing foretells differential learning outcomes in primary school. The authors asked Portuguese-speaking preschool children in Brazil (mean age 4 year 3 months) to spell 12 words. Monte Carlo tests were used to identify the 31 children whose writing was not based on spellings or sounds of the target words. Two and a half years later, the children took a standardized spelling test. The more closely the digram (two-letter sequence) frequencies in the preschool task correlated with those in children's books, the better scores the children had in primary school, and the more preschoolers used letters from their own name, the lower their subsequent scores. Thus, preschoolers whose prephonological writing revealed attentiveness to the statistical properties of text subsequently performed better in conventional spelling. These analytic techniques may help in the early identification of children at risk for spelling difficulties. © Hammill Institute on Disabilities 2012.

Author Keywords
dyslexia;  longitudinal;  precursors;  preschool;  spelling

Document Type: Article
Source: Scopus

Lind, P.A.a , Zhu, G.b , Montgomery, G.W.c , Madden, P.A.F.d , Heath, A.C.d , Martin, N.G.b , Slutske, W.S.e 
Genome-wide association study of a quantitative disordered gambling trait
(2013) Addiction Biology, 18 (3), pp. 511-522. 
a Quantitative Genetics, Queensland Institute of Medical Research, Brisbane, QLD, Australia
b Genetic Epidemiology, Queensland Institute of Medical Research, Brisbane, QLD, Australia
c Molecular Epidemiology, Queensland Institute of Medical Research, Brisbane, QLD, Australia
d Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
e Department of Psychological Sciences, University of Missouri, 210 McAlester Hall, Columbia, MO 65211, United States

Disordered gambling is a moderately heritable trait, but the underlying genetic basis is largely unknown. We performed a genome-wide association study (GWAS) for disordered gambling using a quantitative factor score in 1312 twins from 894 Australian families. Association was conducted for 2 381 914 single-nucleotide polymorphisms (SNPs) using the family-based association test in Merlin followed by gene and pathway enrichment analyses. Although no SNP reached genome-wide significance, six achieved P-values < 1 × 10 -5 with variants in three genes (MT1X, ATXN1 and VLDLR) implicated in disordered gambling. Secondary case-control analyses found two SNPs on chromosome 9 (rs1106076 and rs12305135 near VLDLR) and rs10812227 near FZD10 on chromosome 12 to be significantly associated with lifetime Diagnostic and Statistical Manual of Mental Disorders, fourth edition pathological gambling and South Oaks Gambling Screen classified probable pathological gambling status. Furthermore, several addiction-related pathways were enriched for SNPs associated with disordered gambling. Finally, gene-based analysis of 24 candidate genes for dopamine agonist-induced gambling in individuals with Parkinson's disease suggested an enrichment of SNPs associated with disordered gambling. We report the first GWAS of disordered gambling. While further replication is required, the identification of susceptibility loci and biological pathways will be important in characterizing the biological mechanisms that underpin disordered gambling. © 2012 The Authors. Addiction Biology © 2012 Society for the Study of Addiction.

Author Keywords
association;  canonical pathways;  disordered gambling;  enrichment analysis;  genomewide;  MERLIN; quantitative

Document Type: Article
Source: Scopus

Brunner, P.a b c , Schalk, G.a b d e f 
Toward gaze-independent brain-computer interfaces
(2013) Clinical Neurophysiology, 124 (5), pp. 831-833. 
a Brain-Computer Interface R and D Program, Wadsworth Center, New York State Department of Health, Albany, NY, United States
b Department of Neurology, Albany Medical College, Albany, NY, United States
c Institute for Computer Graphics and Vision, Graz University of Technology, Graz, Austria
d Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
e Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY, United States
f Department of Biomedical Sciences, School of Public Health, State University of New York at Albany, Albany, NY, United States

Document Type: Editorial
Source: Scopus

Harms, M.B.a c , Cady, J.a , Zaidman, C.a , Cooper, P.a , Bali, T.a , Allred, P.a , Cruchaga, C.b c , Baughn, M.d , Libby, R.T.e , Pestronk, A.a c , Goate, A.b c , Ravits, J.d , Baloh, R.H.f 
Lack of C9ORF72 coding mutations supports a gain of function for repeat expansions in amyotrophic lateral sclerosis
(2013) Neurobiology of Aging, . Article in Press. 
a Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
c Hope Center for Neurological Disorders, Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
d Department of Neurosciences, University of California San Diego, La Jolla, CA, USA
e Benaroya Research Institute, Seattle, WA, USA
f Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA

Hexanucleotide repeat expansions in C9ORF72 are a common cause of familial and apparently sporadic amyotrophic lateral sclerosis (ALS) and frontal temporal dementia (FTD). The mechanism by which expansions cause neurodegeneration is unknown, but current evidence supports both loss-of-function and gain-of-function mechanisms. We used pooled next-generation sequencing of the C9ORF72 gene in 389 ALS patients to look for traditional loss-of-function mutations. Although rare variants were identified, none were likely to be pathogenic, suggesting that mutations other than the repeat expansion are not a common cause of ALS, and providing supportive evidence for a gain-of-function mechanism. We also show by repeat-primed PCR genotyping that the C9ORF72 expansion frequency varies by geographical region within the United States, with an unexpectedly high frequency in the Mid-West. Finally we also show evidence of somatic instability of the expansion size by Southern blot, with the largest expansions occurring in brain tissue. © 2013 Elsevier Inc. All rights reserved.

Author Keywords
Amyotrophic lateral sclerosis;  C9ORF72;  C9ORF72 hexanucleotide repeat;  Genetics

Document Type: Article in Press
Source: Scopus

Rosen, L.B.a , Freeman, A.F.a , Yang, L.M.a b , Jutivorakool, K.a c , Olivier, K.N.a , Angkasekwinai, N.d , Suputtamongkol, Y.d , Bennett, J.E.a , Pyrgos, V.a , Williamson, P.R.a , Ding, L.a , Holland, S.M.a , Browne, S.K.a 
Anti-GM-CSF autoantibodies in patients with cryptococcal meningitis
(2013) Journal of Immunology, 190 (8), pp. 3959-3966. 
a Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, 9000 Rock-ville Pike, MSC 1684, Bethesda, MD 20892-1684, United States
b Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
d Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand

Cryptococcal meningitis has been described in immunocompromised patients, as well as in those for whom no immune defect has been identified. GM-CSF regulates the function of phagocytes and pulmonary alveolar macrophages, critical elements in cryp-tococcal control. We performed clinical histories, immunological evaluation, and anticytokine autoantibody screening in four current patients with cryptococcal meningitis and identified and tested 103 archived plasma/cerebrospinal fluid samples from patients with cryptococcal meningitis. We assessed the ability of anti-GM-CSF autoantibody-containing plasmas to inhibit GM-CSF signaling. We recognized anti-GM-CSF autoantibodies in an otherwise healthy female with cryptococcal meningitis who later developed pulmonary alveolar proteinosis (PAP). Her diagnosis prompted screening of patients with cryptococcal meningitis for anticytokine autoantibodies. We identified seven HIV-negative patients with cryptococcal meningitis who tested positive for high-titer anti-GM-CSF autoantibodies. Two of the seven later developed evidence of PAP. Plasma from all patients prevented GM-CSF-induced STAT5 phosphorylation and MIP-1a production in normal PBMCs. This effect was limited to their IgG fraction. Anti-GM-CSF autoantibodies are associated with some cases of cryptococcal meningitis in otherwise immunocompetent patients. These cases need not have associated PAP. Copyright © 2013 by The American Association of Immunologists, Inc.

Document Type: Article
Source: Scopus

Schubert, T.a b , Hoon, M.a , Euler, T.b , Lukasiewicz, P.D.c , Wong, R.O.L.a 
Developmental Regulation and Activity-Dependent Maintenance of GABAergic Presynaptic Inhibition onto Rod Bipolar Cell Axonal Terminals
(2013) Neuron, 78 (1), pp. 124-137. 
a Department of Biological Structure, University of Washington, School of Medicine, 1959 Northeast Pacific Street, Seattle, WA 98195, United States
b Werner Reichardt Centre for Integrative Neuroscience, Institute for Ophthalmic Research, University of Tuebingen, 72076 Tuebingen, Germany
c Departments of Ophthalmology and Visual Sciences and Anatomy and Neurobiology, Washington University, St. Louis, MO 63110, United States

Presynaptic inhibition onto axons regulates neuronal output, but how such inhibitory synapses develop and are maintained in vivo remains unclear. Axon terminals of glutamatergic retinal rod bipolar cells (RBCs) receive GABAA and GABAC receptor-mediated synaptic inhibition. We found that perturbing GABAergic or glutamatergic neurotransmission does not prevent GABAergic synaptogenesis onto RBC axons. But, GABA release is necessary for maintaining axonal GABA receptors. This activity-dependent process is receptor subtype specific: GABAC receptors are maintained, whereas GABAA receptors containing α1, but not α3, subunits decrease over time in mice with deficient GABA synthesis. GABAA receptor distribution on RBC axons is unaffected in GABAC receptor knockout mice. Thus, GABAA and GABAC receptor maintenance are regulated separately. Although immature RBCs elevate their glutamate release when GABA synthesis is impaired, homeostatic mechanisms ensure that the RBC output operates within its normal range after eye opening, perhaps to regain proper visual processing within the scotopic pathway. Schubert et al. show that GABAergic transmission regulates maintenance of GABA receptors on retinal axon terminals in a receptor subtype-specific manner. © 2013 Elsevier Inc.

Document Type: Article
Source: Scopus

Siglin, A.E.a , Sun, S.b , Moore, J.K.c , Tan, S.d , Poenie, M.d , Lear, J.D.e , Polenova, T.b , Cooper, J.A.c , Williams, J.C.a f 
Dynein and Dynactin Leverage Their Bivalent Character to Form a High-Affinity Interaction
(2013) PLoS ONE, 8 (4), art. no. e59453, . 
a Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, United States
b Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, United States
c Department of Cell Biology and Physiology, Washington University in Saint Louis, Saint Louis, MO, United States
d Department of Cell and Molecular Biology, University of Texas, Austin, TX, United States
e Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, United States
f Department of Molecular Medicine, Beckman Research Institute at City of Hope, Duarte, CA, United States

Cytoplasmic dynein and dynactin participate in retrograde transport of organelles, checkpoint signaling and cell division. The principal subunits that mediate this interaction are the dynein intermediate chain (IC) and the dynactin p150Glued; however, the interface and mechanism that regulates this interaction remains poorly defined. Herein, we use multiple methods to show the N-terminus of mammalian dynein IC, residues 10-44, is sufficient for binding p150Glued. Consistent with this mapping, monoclonal antibodies that antagonize the dynein-dynactin interaction also bind to this region of the IC. Furthermore, double and triple alanine point mutations spanning residues 6 to 19 in the yeast IC homolog, Pac11, produce significant defects in spindle positioning. Using the same methods we show residues 381 to 530 of p150Glued form a minimal fragment that binds to the dynein IC. Sedimentation equilibrium experiments indicate that these individual fragments are predominantly monomeric, but admixtures of the IC and p150Glued fragments produce a 2:2 complex. This tetrameric complex is sensitive to salt, temperature and pH, suggesting that the binding is dominated by electrostatic interactions. Finally, circular dichroism (CD) experiments indicate that the N-terminus of the IC is disordered and becomes ordered upon binding p150Glued. Taken together, the data indicate that the dynein-dynactin interaction proceeds through a disorder-to-order transition, leveraging its bivalent-bivalent character to form a high affinity, but readily reversible interaction. © 2013 Siglin et al.

Document Type: Article
Source: Scopus

Capotosto, P.a , Tosoni, A.a , Spadone, S.a , Sestieri, C.a , Perrucci, M.G.a , Romani, G.L.a , Penna, S.D.a , Corbetta, M.a b 
Anatomical segregation of visual selection mechanisms in human parietal cortex
(2013) Journal of Neuroscience, 33 (14), pp. 6225-6229. 
a Department of Neuroscience and Imaging, Institute of Advanced Biomedical Technologies, Gabriele D'Annunzio University, I-66110 Chieti, Italy
b Department of Neurology, Radiology, Anatomy, Neurobiology, Washington University School of Medicine, St. Louis, MO 63110, United States

Visual selection requires mechanisms for representing object salience and for shifting the focus of processing to novel objects. It is not clear from computational or neural models whether these operations are performed within the same or different brain regions. Here, we use repetitive transcranial magnetic stimulation to briefly interfere with neural activity in individually localized regions of human posterior parietal cortex (PPC) that are putatively involved in attending to contralateral locations or shifting attention between locations. Stimulation over right ventral intraparietal sulcus impaired target discrimination at contralateral locations, whereas stimulation over right medial superior parietal lobule impaired target discrimination after a shift of attention regardless of its location. This double dissociation is consistent with neuroimaging studies and indicates that mechanisms of visual selection are partly anatomically segregated in human PPC. © 2013 the authors.

Document Type: Article
Source: Scopus

Nguyen, T.-L.M.a , Khurana, S.S.c , Bellone, C.J.a , Capoccia, B.J.c , Sagartz, J.E.b , Kesman Jr., R.A.a , Mills, J.C.c , DiPaolo, R.J.a 
Autoimmune gastritis mediated by CD4+ T cells promotes the development of gastric cancer
(2013) Cancer Research, 73 (7), pp. 2117-2126. 
a Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, MO 63104, United States
b Department of Comparative Medicine, Saint Louis University School of Medicine, St. Louis, MO, United States
c Division of Gastroenterology, Washington University School of Medicine, St. Louis, MO, United States

Chronic inflammation is a major risk factor for cancer, including gastric cancers and other gastrointestinal cancers. For example, chronic inflammation caused by autoimmune gastritis (AIG) is associated with an increased risk of gastric polyps, gastric carcinoid tumors, and possibly adenocarcinomas. In this study, we characterized the progression of gastric cancer in a novel mouse model of AIG. In this model, disease was caused by CD4+ T cells expressing a transgenic T-cell receptor specific for a peptide from the H +/K+ ATPase proton pump, a protein expressed by parietal cells in the stomach. AIG caused epithelial cell aberrations that mimicked most of those seen in progression of human gastric cancers, including chronic gastritis followed by oxyntic atrophy, mucous neck cell hyperplasia, spasmolytic polypeptide-expressing metaplasia, dysplasia, and ultimately gastric intraepithelial neoplasias. Our work provides the first direct evidence that AIG supports the development of gastric neoplasia and provides a useful model to study how inflammation drives gastric cancer. © 2012 American Association for Cancer Research.

Document Type: Article
Source: Scopus

Powers, A.D., Oltmanns, T.F.
Borderline personality pathology and chronic health problems in later adulthood: The mediating role of obesity
(2013) Personality Disorders: Theory, Research, and Treatment, 4 (2), pp. 152-159.
Department of Psychology, Washington University, Campus Box 1125, One Brookings Drive, St. Louis, MO 63130-4899, United States

Borderline personality disorder (BPD) is associated with many negative physical health outcomes, including increased risk for serious chronic diseases such as diabetes, heart disease, and arthritis. BPD is also linked with obesity, a condition that is strongly related to many of the same physical health problems. Although research has shown that BPD is related to these physical conditions, there is limited evidence of whether body mass mediates the relation between BPD and serious physical health problems. The present study examined the associations among BPD features, body mass index (BMI), and six major physical health problems in an epidemiologically based sample (n = 1051) of Saint Louis residents, ages 55-64. Using interviewer-, self-, and informant-report of personality pathology, we found that BPD features were significantly related to reported presence of heart disease, arthritis, and obesity. BMI was also significantly related to heart disease and arthritis. Sobel mediation models showed that BMI fully mediated the relation between BPD features and arthritis. These results suggest that borderline pathology is an important risk factor for serious health problems in later adulthood. Obesity appears to be one pathway that leads to more health problems among individuals with BPD symptoms and may be a useful starting point when thinking about future intervention strategies. © 2012 American Psychological Association..

Author Keywords
body mass index;  borderline personality disorder;  obesity;  personality pathology;  physical health

Document Type: Article
Source: Scopus

Striley, C.W.a , Nattala, P.b , Ben Abdallah, A.c , Dennis, M.L.d , Cottler, L.B.e 
Enhanced case management versus substance abuse treatment alone among substance abusers with depression
(2013) Social Work Research, 37 (1), pp. 19-25. 
a University of Florida, Department of Epidemiology, Colleges of Medicine and Public Health and Health, 1225 Center Drive, Box 100231, Gainesville, FL 32610, United States
b Department of Nursing, National Institute for Mental Health and Neuro Science (NIMHANS), Bangalore, India
c Institute of Quality Improvement, Research and Informatics (INQUIRI), Department of Anesthesiology, Washington University School of Medicine, United States
d GAIN Coordinating Center, Chestnut Health Systems, Normal, IL, United States
e College of Public Health and Health Professions, Department of Epidemiology, University of Florida, United States

This pilot study evaluated the effectiveness of enhanced case management for substance abusers with comorbid major depression, which was an integrated approach to care. One hundred and 20 participants admitted to drug treatment who also met Computerized Diagnostic Interview Schedule criteria for major depression at baseline were randomized to enhanced case management (ECM) (n = 64) or treatment as usual (TAU) (n = 56). Both groups were followed up at six and 12 months. Participants' current clinical status across a broad range of domains in the past 90 days was assessed using the Global Appraisal of Individual Needs and included their Depressive Symptom Scale, Homicidal-Suicidal Thought Index, and Mental Health Treatment Index scores. The findings did not reveal any statistically significant effects of ECM on outcome measures. However, in view of the high rates of adverse treatment outcomes among comorbid groups, including suicide, the finding of a clinically significant reduction in homicidal and suicidal thoughts warrants further research; the comprehensive approach to treatment tested may be especially helpful to depressed substance abusers with such ideations. © 2013 National Association of Social Workers.

Author Keywords
case management;  comorbidity;  depression;  integrated care;  suicide

Document Type: Article
Source: Scopus

Srinivasakumar, P.a b , Limbrick, D.b , Munro, R.b , Mercer, D.b , Rao, R.a , Inder, T.a , Mathur, A.a 
Posthemorrhagic ventricular dilatation-impact on early neurodevelopmental outcome
(2013) American Journal of Perinatology, 30 (3), pp. 207-213. 
a Division of Newborn Medicine, Washington University in St. Louis, St. Louis, MO, United States
b Department of Pediatrics, Washington University School of Medicine in Saint Louis, Saint Louis Children's Hospital, One Children's Place, Saint Louis, MO 63110, United States

Objective This study evaluates the impact of ventricular dilatation following severe (grades III or IV) intraventricular hemorrhage (IVH) in preterm neonates and the current practice of neurosurgical interventions in infants with posthemorrhagic ventricular dilatation (PHVD) and early neurodevelopmental outcome. Study Design Premature neonates born at ≤34 weeks' gestational ages with severe IVH were identified retrospectively over a 5-year period (2005 to 2009). Standard measures of ventricular dilatation on head ultrasound (HUS) were recorded. The treatment of PHVD, timing of surgery including the type of temporizing neurosurgical procedure (TNP)-either a ventricular reservoir or a subgaleal shunt-and the subsequent need for ventriculoperitoneal (VP) shunt were evaluated. Patients were retrospectively stratified to an "earlyo" versus "lateo" intervention group based on HUS measures. Early intervention was defined as TNP performed when the ventricular index (VI) was >97th percentile but <97th percentile + 4 mm. Late intervention was defined as TNP performed when VI was ≥97th percentile + 4 mm. Neurodevelopmental outcomes were evaluated at 18 to 24 months. Infants followed up for neurodevelopmental testing were stratified as group A (progressive PHVD with TNP), group B (PHVD without TNP), and group C (severe IVH without PHVD). Results One hundred seventy-three preterm neonates with severe IVH were identified during the study period, of whom 139/173 (80%) developed PHVD. Of these, 54 (54/139, 39%) received TNP either early (4/54, 7%) or late (50/54, 93%). Of those who received TNP, 32/54 (59%) required subsequent VP shunt placement. Neurodevelopmental testing was available in 39/109 (36%) infants who survived to discharge. The mean ± standard deviation cognitive, motor, and language composite scores were 77 ± 14.8, 67 ± 15.2, 70 ± 13.8 for group A (n = 16/39), 90 ± 7.8, 84 ± 9.6, 82 ± 18.2 for group B (n = 12/39), and 95 ± 14.3, 86 ± 10.7, 94 ± 15.8 for group C (n = 11/39), respectively (p < 0.006 for group A versus group B and p < 0.004 for group A versus group C across all domains). Increasing ventricular dilatation was associated with adverse motor, cognitive, and language outcomes (p = 0.002) and neonates with progressive PHVD requiring a TNP were most adversely affected (p = 0.0006). There were no differences in any outcome measures between the two types of TNPs. Clinical and demographic characteristics of infants lost to follow-up were not significantly different than those available for follow-up. Conclusion Increasing ventricular size adversely affects neurodevelopmental outcome in infants with PHVD. Copyright © 2013 by Thieme Medical Publishers, Inc.

Author Keywords
head ultrasound;  intraventricular hemorrhage;  posthemorrhagic ventricular dilatation;  subgaleal shunt;  temporizing neurosurgical procedure;  ventricular index;  ventricular reservoir


Document Type: Article
Source: Scopus

April 10, 2013


Granados-Fuentes, D., Herzog, E.D.
The clock shop: Coupled circadian oscillators
(2013) Experimental Neurology, 243, pp. 21-27. 
Department of Biology, Washington University, St. Louis, MO 63130, United States

Daily rhythms in neural activity underlie circadian rhythms in sleep-wake and other daily behaviors. The cells within the mammalian suprachiasmatic nucleus (SCN) are intrinsically capable of 24-h timekeeping. These cells synchronize with each other and with local environmental cycles to drive coherent rhythms in daily behaviors. Recent studies have identified a small number of neuropeptides critical for this ability to synchronize and sustain coordinated daily rhythms. This review highlights the roles of specific intracellular and intercellular signals within the SCN that underlie circadian synchrony. © 2012 Elsevier Inc.

Author Keywords
Neuropeptide;  Pacemaker;  Period gene;  Suprachiasmatic nucleus;  Vasoactive intestinal polypeptide

Document Type: Review
Source: Scopus

 Schwedt, T.J.a b , Schlaggar, B.L.c d e , Mar, S.d , Nolan, T.c , Coalson, R.S.c , Nardos, B.a , Benzinger, T.c , Larson-Prior, L.J.c 
Atypical Resting-State Functional Connectivity of Affective Pain Regions in Chronic Migraine
(2013) Headache, . Article in Press. 
a Department of Neurology Washington University School of Medicine St. Louis, MO USA
b Department of Anesthesiology Washington University School of Medicine St. Louis, MO USA
c Department of Radiology Washington University School of Medicine St. Louis, MO USA
d Department of Pediatrics Washington University School of Medicine St. Louis, MO USA
e Department of Anatomy and Neurobiology Washington University School of Medicine St. Louis, MO USA

Objective.-: Chronic migraineurs (CM) have painful intolerances to somatosensory, visual, olfactory, and auditory stimuli during and between migraine attacks. These intolerances are suggestive of atypical affective responses to potentially noxious stimuli. We hypothesized that atypical resting-state functional connectivity (rs-fc) of affective pain-processing brain regions may associate with these intolerances. This study compared rs-fc of affective pain-processing regions in CM with controls. Methods.-: Twelve minutes of resting-state blood oxygenation level-dependent data were collected from 20 interictal adult CM and 20 controls. Rs-fc between 5 affective regions (anterior cingulate cortex, right/left anterior insula, and right/left amygdala) with the rest of the brain was determined. Functional connections consistently differing between CM and controls were identified using summary analyses. Correlations between number of migraine years and the strengths of functional connections that consistently differed between CM and controls were calculated. Results.-: Functional connections with affective pain regions that differed in CM and controls included regions in anterior insula, amygdala, pulvinar, mediodorsal thalamus, middle temporal cortex, and periaqueductal gray. There were significant correlations between the number of years with CM and functional connectivity strength between the anterior insula with mediodorsal thalamus and anterior insula with periaqueductal gray. Conclusion.-: CM is associated with interictal atypical rs-fc of affective pain regions with pain-facilitating and pain-inhibiting regions that participate in sensory-discriminative, cognitive, and integrative domains of the pain experience. Atypical rs-fc with affective pain regions may relate to aberrant affective pain processing and atypical affective responses to painful stimuli characteristic of CM. © 2013 American Headache Society.

Author Keywords
Chronic migraine;  Functional connectivity;  Functional magnetic resonance imaging;  Headache;  Migraine;  Pain

Document Type: Article in Press
Source: Scopus

Constantino, J.N.a , Frazier, T.W.b 
Commentary: The observed association between autistic severity measured by the Social Responsiveness Scale (SRS) and general psychopathology - a response to Hus, Bishop, Gotham, Huerta and Lord (2013)
(2013) Journal of Child Psychology and Psychiatry and Allied Disciplines, . Article in Press. 
a Washington University School of Medicine - Psychiatry St. Louis, MO USA
b Cleveland Clinic Children's Hospital Center Center for Pediatric Behavioral Health Cleveland, OH USA

Author Keywords
Autistic disorder;  Child behavior check list;  Diagnosis;  Pervasive developmental disorder;  Social behavior

Document Type: Article in Press
Source: Scopus

Yeh, C.H.a , Chien, L.C.b , Balaban, D.a , Sponberg, R.a , Primavera, J.a , Morone, N.E.c , Glick, R.d , Albers, K.M.e , Cohen, S.M.a , Ren, D.a , Huang, L.C.f , Suen, L.K.-P.g 
A randomized clinical trial of auricular point acupressure for chronic low back pain: A feasibility study
(2013) Evidence-based Complementary and Alternative Medicine, 2013, art. no. 196978, . 
a School of Nursing, University of Pittsburgh, Victoria Building, 3500 Victoria Street 440, Pittsburgh, PA 15261, United States
b Department of Internal Medicine, Washington University, St. Louis, MO, United States
c Department of Medicine, University of Pittsburgh School of Medicine, Geriatric Research Education and Clinical Center, Pittsburgh, PA, United States
d School of Medicine, Departments of Psychiatry Physical Medicine, and Rehabilitation, and Family Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
e Department of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
f World Academy of Auricular Medicine, Hoover, AL, United States
g School of Nursing, Hong Kong Polytechnic University, Hong Kong

Objectives. This prospective, randomized clinical trial (RCT) was designed to investigate the feasibility and effects of a 4-week auricular point acupressure (APA) for chronic low back pain (CLBP). Methods. Participants were randomized to either true APA (true acupoints with taped seeds on the designated ear points for CLBP) or sham APA (sham acupoints with taped seeds but on different locations than those designated for CLBP). The duration of treatment was four weeks. Participants were assessed before treatment, weekly during treatment, and 1 month following treatment. Results. Participants in the true APA group who completed the 4-week APA treatment had a 70% reduction in worst pain intensity, a 75% reduction in overall pain intensity, and a 42% improvement in disability due to back pain from baseline assessment. The reductions of worst pain and overall pain intensity in the true APA group were statistically greater than participants in the sham group (P < 0.01) at the completion of a 4-week APA and 1 month followup. Discussion. The preliminary findings of this feasibility study showed a reduction in pain intensity and improvement in physical function suggesting that APA may be a promising treatment for patients with CLBP. © 2013 Chao Hsing Yeh et al.

Document Type: Article
Source: Scopus

 Perlman, S.J.a , Kulkarni, S.b , Manwaring, L.c , Shinawi, M.c 
Haploinsufficiency of ZNF238 is associated with corpus callosum abnormalities in 1q44 deletions
(2013) American Journal of Medical Genetics, Part A, 161 (4), pp. 711-716. 
a Neuromuscular Division, Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b Departments of Pathology and Immunology, Washington University, St. Louis, MO, United States
c Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States

A variety of candidate genes have been proposed to cause corpus callosum abnormalities (CCAs) in patients with terminal chromosome 1q deletions. Recent data excluded AKT3 and implicated ZNF238 and/or CEP170 as genes causative of corpus callosum anomalies in patients with 1q43-1q44 deletions. We report on a girl with dysmorphic features, seizures beginning in infancy, hypotonia, marked developmental delay, and dysgenesis of the corpus callosum. Chromosomal microarray analysis detected a de novo 1.47Mb deletion at 1q44. The deleted interval encompasses the ZNF238 gene but not the CEP170 or AKT3 genes, thus providing additional evidence for the former and against the latter as being causative of corpus callosum anomalies in patients with such deletions. © 2013 Wiley Periodicals, Inc.

Author Keywords
1q44 deletion;  Agenesis of corpus callosum;  AKT3;  CEP170;  Corpus callosal abnormalities;  ZNF238

Document Type: Article
Source: Scopus

Reidy, N.a b , Morgan, A.a b , Thompson, D.K.a b , Inder, T.E.a c , Doyle, L.W.a b d , Anderson, P.J.a b c 
Impaired language abilities and white matter abnormalities in children born very preterm and/or very low birth weight
(2013) Journal of Pediatrics, 162 (4), pp. 719-724. 
a Victorian Infant Brain Studies, Murdoch Children's Research Institute, Royal Children's Hospital, 50 Flemington Rd, Parkville, VIC 3052, Australia
b University of Melbourne, VIC, Australia
c School of Medicine, Washington University of St. Louis, St. Louis, MO, United States
d Royal Women's Hospital, VIC, Australia

Objectives: To investigate language abilities in children born very preterm (VPT; <32 weeks' gestational age) or very low birth weight (VLBW; <1500 g) at 7 years of age and compare their performances with children born at term, and to determine whether group differences could be explained by cerebral white matter abnormality on neonatal magnetic resonance imaging. Study design: A cohort of 198 children born <30 weeks' gestational age and/or <1250 g, and 70 term controls were examined. White matter abnormalities were rated quantitatively on brain magnetic resonance imaging at term-equivalent age. Language was assessed at age 7 years using standardized language tests. Differences between groups were tested in the 5 language subdomains of phonological awareness, semantics, grammar, discourse, and pragmatics. A mediation effect was tested between birth group, white matter abnormality, and language subdomains. Results: The VPT/VLBW group performed significantly worse than controls on all language subdomains (all P < .001). White matter abnormality mediated the effect of group differences on phonological awareness, and partly mediated this effect for semantics, grammar, and discourse. White matter abnormality was not significantly associated with pragmatics (P = .13). Conclusions: Language is an important area of concern in children born VPT/VLBW. Neonatal white matter abnormality is an important predictor of outcome; however, different language abilities are differentially associated with neonatal white matter abnormality. © 2013 Mosby Inc.

Document Type: Article
Source: Scopus

Carlson, E.N., Vazire, S., Oltmanns, T.F.
Self-Other Knowledge Asymmetries in Personality Pathology
(2013) Journal of Personality, 81 (2), pp. 155-170. 
Washington University in St. Louis, United States

Objective: Self-reports of personality provide valid information about personality disorders (PDs). However, informant reports provide information about PDs that self-reports alone do not provide. The current article examines whether and when one perspective is more valid than the other in identifying PDs. Method: Using a representative sample of adults 55 to 65 years of age (N=991; 45% males), we compared the validity of self- and informant (e.g., spouse, family, or friend) reports of the Five-Factor Model traits in predicting PD scores (i.e., composite of interviewer, self-, and informant reports of PDs). Results: Self-reports (particularly of Neuroticism) were more valid than informant reports for most internalizing PDs (i.e., PDs defined by high Neuroticism). Informant reports (particularly of Agreeableness and Conscientiousness) were more valid than self-reports for externalizing and/or antagonistic PDs (i.e., PDs defined by low Agreeableness and Conscientiousness). Neither report was consistently more valid for thought disorder PDs (i.e., PDs defined by low Extraversion). However, informant reports (particularly of Agreeableness) were more valid than self-reports for PDs that were both internalizing and externalizing (i.e., PDs defined by high Neuroticism and low Agreeableness). Conclusions: The intrapersonal and interpersonal manifestations of PDs differ, and these differences influence who knows more about pathology. © 2012,. Wiley Periodicals, Inc.

Author Keywords
Accuracy;  Assessment;  Personality disorder;  Personality traits;  Self-knowledge

Document Type: Article
Source: Scopus

 Arbeláez, A.M.a , Su, Y.b , Thomas, J.B.c , Hauch, A.C.a , Hershey, T.b c d , Ances, B.M.c 
Comparison of Regional Cerebral Blood Flow Responses to Hypoglycemia Using Pulsed Arterial Spin Labeling and Positron Emission Tomography
(2013) PLoS ONE, 8 (3), art. no. e60085, . 
a Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
b Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
d Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States

Different brain regions sense and modulate the counterregulatory responses that can occur in response to declining plasma glucose levels. The aim of this study was to determine if changes in regional cerebral blood flow (rCBF) during hypoglycemia relative to euglycemia are similar for two imaging modalities-pulsed arterial spin labeling magnetic resonance imaging (PASL-MRI) and positron emission tomography (PET). Nine healthy non-diabetic participants underwent a hyperinsulinemic euglycemic (92±3 mg/dL) - hypoglycemic (53±1 mg/dL) clamp. Counterregulatory hormone levels were collected at each of these glycemic levels and rCBF measurements within the previously described network of hypoglycemia-responsive regions (thalamus, medial prefrontal cortex and globus pallidum) were obtained using PASL-MRI and [15O] water PET. In response to hypoglycemia, rCBF was significantly increased in the thalamus, medial prefrontal cortex, and globus pallidum compared to euglycemia for both PASL-MRI and PET methodologies. Both imaging techniques found similar increases in rCBF in the thalamus, medial prefrontal cortex, and globus pallidum in response to hypoglycemia. These brain regions may be involved in the physiologic and symptom responses to hypoglycemia. Compared to PET, PASL-MRI may provide a less invasive, less expensive method for assessing changes in rCBF during hypoglycemia without radiation exposure. © 2013 Arbeláez et al.

Document Type: Article
Source: Scopus

Ozturk, N.a , VanVickle-Chavez, S.J.b , Akileswaran, L.c , Van Gelder, R.N.b c , Sancar, A.a 
Ramshackle (Brwd3) promotes light-induced ubiquitylation of Drosophila Cryptochrome by DDB1-CUL4-ROC1 E3 ligase complex
(2013) Proceedings of the National Academy of Sciences of the United States of America, 110 (13), pp. 4980-4985. 
a Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, NC 27599, United States
b Department of Ophthalmology and Visual Sciences, Washington University Medical School, St. Louis, MO 63110, United States
c Department of Ophthalmology, University of Washington School of Medicine, Seattle, WA 98195, United States

Cryptochrome (CRY) is the primary circadian photoreceptor in Drosophila. It resets the circadian clock by promoting light-induced degradation of the clock proteins Timeless and Period, as well as its own proteolysis. The E3 ligases that ubiquitylate Timeless and Period before degradation are known and it is known that Drosophila (d) CRY is degraded by the ubiquitin-proteasome system as well. To identify the E3 ligase for dCRY we screened candidates in S2 cells by RNAi. Knockdown of each of the 25 putative F-box proteins identified by bioinformatics did not attenuate the light-induced degradation of dCRY. However, knockdown of a WD40 protein, Bromodomain and WD repeat domain containing 3 (Brwd3) (CG31132/Ramshackle) caused strong attenuation of dCRY degradation following light exposure. We found that BRWD3 functions as a Damage-specific DNA binding protein 1 (DDB1)- and CULLIN (CUL)4-associated factor in a Cullin4-RING Finger E3 Ligase (CRL4) that mediates light-dependent binding of dCRY to CUL4-ROC1-DDB1-BRWD3, inducing ubiquitylation of dCRY and its lightinduced degradation. Thus, this study identifies a light-activated E3 ligase complex essential for light-mediated CRY degradation in Drosophila cells. © PNAS 2013.

Author Keywords
Circadian rhythm;  Photocycle;  Sensory flavoprotein

Document Type: Article
Source: Scopus

 Markov, N.T.a b c , Ercsey-Ravasz, M.d e , Lamy, C.a b , Gomes, A.R.R.a b , Magrou, L.a b , Misery, P.a b , Giroud, P.a b , Barone, P.a b f , Dehay, C.a b , Toroczkai, Z.d , Knoblauch, K.a b , Van Essen, D.C.g , Kennedy, H.a b 
The role of long-range connections on the specificity of the macaque interareal cortical network
(2013) Proceedings of the National Academy of Sciences of the United States of America, 110 (13), pp. 5187-5192. 
a Stem Cell and Brain Research Institute, Institut National de la Santé et de la Recherche Médicale U846, 69500 Bron, France
b Université de Lyon, Université Lyon 1, 69003 Lyon, France
c Department of Neurobiology, Yale University, New Haven, CT 06520, United States
d Department of Physics, Interdisciplinary Center for Network Science and Applications, University of Notre Dame, Notre Dame, IN 46556, United States
e Faculty of Physics, Babes-Bolyai University, 400084 Cluj-Napoca, Romania
f Cerveau et Cognition, Unité Mixte de Recherche 5549, 31059 Toulouse, France
g Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO 63110, United States

We investigated the influence of interareal distance on connectivity patterns in a database obtained from the injection of retrograde tracers in 29 areas distributed over six regions (occipital, temporal, parietal, frontal, prefrontal, and limbic). One-third of the 1,615 pathways projecting to the 29 target areas were reported only recently and deemed new-found projections (NFPs). NFPs are predominantly long-range, low-weight connections. A minimum dominating set analysis (a graph theoretic measure) shows that NFPs play a major role in globalizing input to small groups of areas. Randomization tests show that (i) NFPs make important contributions to the specificity of the connectivity profile of individual cortical areas, and (ii) NFPs share key properties with known connections at the same distance. We developed a similarity index, which shows that intraregion similarity is high, whereas the interregion similarity declines with distance. For area pairs, there is a steep decline with distance in the similarity and probability of being connected. Nevertheless, the present findings reveal an unexpected binary specificity despite the high density (66%) of the cortical graph. This specificity is made possible because connections are largely concentrated over short distances. These findings emphasize the importance of long-distance connections in the connectivity profile of an area. We demonstrate that long-distance connections are particularly prevalent for prefrontal areas, where they may play a prominent role in large-scale communication and information integration. © PNAS 2013.

Author Keywords
Anatomy;  Monkey;  Neocortex

Document Type: Article
Source: Scopus

 Berghorst, L.H.a b , Bogdan, R.c , Frank, M.J.d , Pizzagalli, D.A.b 
Acute stress selectively reduces reward sensitivity
(2013) Frontiers in Human Neuroscience, (MAR),
a Department of Psychology, Harvard University, Cambridge, MA, United States
b Center for Depression, Anxiety and Stress Research, McLean Hospital, Harvard Medical School, Belmont, MA, United States
c BRAIN Laboratory, Department of Psychology, Washington University in St. Louis, St. Louis, MO, United States
d Brown Institute for Brain Science, Departments of Psychiatry and Cognitive, Linguistic, and Psychological Sciences, Brown University, Providence, RI, United States

Stress may promote the onset of psychopathology by disrupting reward processing. However, the extent to which stress impairs reward processing, rather than incentive processing more generally, is unclear. To evaluate the specificity of stress-induced reward processing disruption, 100 psychiatrically healthy females were administered a probabilistic stimulus selection task enabling comparison of sensitivity to reward-driven (Go) and punishment-driven (NoGo) learning under either 'no stress' or 'stress' (threat- of-shock) conditions. Cortisol samples and self-report measures were collected. Contrary to hypotheses, the groups did not differ significantly in task performance or cortisol reactivity. However, further analyses focusing only on individuals under 'stress' who were high responders with regard to both cortisol reactivity and self-reported negative affect revealed reduced reward sensitivity relative to individuals tested in the 'no stress' condition; importantly, these deficits were reward-specific. Overall, findings provide preliminary evidence that stress-reactive individuals show diminished sensitivity to reward but not punishment under stress. While such results highlight the possibility that stress-induced anhedonia might be an important mechanism linking stress to affective disorders, future studies are necessary to confirm this conjecture. © 2013 Berghorst, Bogdan, Frank and Pizzagalli.

Author Keywords
Affect-cognition interactions;  Anhedonia;  Cortisol;  Depression;  Emotion;  Punishment;  Reward;  Stress

Document Type: Article
Source: Scopus

 Dorsey, E.R.a , Willis, A.W.b 
Caring for the majority
(2013) Movement Disorders, 28 (3), pp. 261-262. 
a Department of Neurology, Johns Hopkins Medicine, Baltimore, MD, United States
b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States

Document Type: Editorial
Source: Scopus

 Lenze, E.J., Host, H.H., Hildebrand, M., Morrow-Howell, N., Carpenter, B., Freedland, K.E., Baum, C.M., Binder, E.F.
Enhanced medical rehabilitation is feasible in a skilled nursing facility: Preliminary data on a novel treatment for older adults with depression
(2013) American Journal of Geriatric Psychiatry, 21 (3), p. 307. 
Washington University, St. Louis, MO, United States

Document Type: Letter
Source: Scopus

 Gamazon, E.R.a , Badner, J.A.b , Cheng, L.c , Zhang, C.c , Zhang, D.d , Cox, N.J.a , Gershon, E.S.b , Kelsoe, J.R.e , Greenwood, T.A.e , Nievergelt, C.M.e , Chen, C.c , McKinney, R.e , Shilling, P.D.e , Schork, N.J.f , Smith, E.N.f , Bloss, C.S.f , Nurnberger, J.I.g , Edenberg, H.J.h , Foroud, T.f , Koller, D.L.g , Scheftner, W.A.i , Coryell, W.j , Rice, J.k , Lawson, W.B.l , Nwulia, E.A.l , Hipolito, M.l , Byerley, W.m , McMahon, F.J.n , Schulze, T.G.n o , Berrettini, W.H.p , Potash, J.B.q , Zandi, P.P.q , Mahon, P.B.q , McInnis, M.G.r , Zöllner, S.r , Zhang, P.r , Craig, D.W.s , Szelinger, S.s , Barrett, T.B.t , Liu, C.c 
Enrichment of cis-regulatory gene expression SNPs and methylation quantitative trait loci among bipolar disorder susceptibility variants
(2013) Molecular Psychiatry, 18 (3), pp. 340-346. Cited 1 time.
a Department of Medicine, University of Chicago, Chicago, IL, United States
b Department of Psychiatry, University of Chicago, Chicago, IL, United States
c Department of Psychiatry, University of Illinois at Chicago, 900 S Ashland Ave, Chicago, IL 60607-7173, United States
d School of Medicine, University of Zhejiang, Hanzhou, Zhejiang, China
e Department of Psychiatry, University of California, San Diego, CA, United States
f Scripps Genomic Medicine and Scripps Translational Science Institute, San Diego, CA, United States
g Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, United States
h Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
i Department of Psychiatry, Rush University, Chicago, IL, United States
j Department of Psychiatry, University of Iowa, Iowa City, IA, United States
k Division of Biostatistics, Washington University, St Louis, MO, United States
l Department of Psychiatry, Howard University, Washington, DC, United States
m Department of Psychiatry, University of California, San Francisco, CA, United States
n Genetic Basis of Mood and Anxiety Disorders Unit, National Institute of Mental Health Intramural Research Program, National Institutes of Health, Bethesda, MD, United States
o Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany
p Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, United States
q Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, MD, United States
r Department of Psychiatry, University of Michigan, Ann Arbor, MI, United States
s Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, United States
t Department of Psychiatry, Portland VA Medical Center, Portland, OR, United States

We conducted a systematic study of top susceptibility variants from a genome-wide association (GWA) study of bipolar disorder to gain insight into the functional consequences of genetic variation influencing disease risk. We report here the results of experiments to explore the effects of these susceptibility variants on DNA methylation and mRNA expression in human cerebellum samples. Among the top susceptibility variants, we identified an enrichment of cis regulatory loci on mRNA expression (eQTLs), and a significant excess of quantitative trait loci for DNA CpG methylation, hereafter referred to as methylation quantitative trait loci (mQTLs). Bipolar disorder susceptibility variants that cis regulate both cerebellar expression and methylation of the same gene are a very small proportion of bipolar disorder susceptibility variants. This finding suggests that mQTLs and eQTLs provide orthogonal ways of functionally annotating genetic variation within the context of studies of pathophysiology in brain. No lymphocyte mQTL enrichment was found, suggesting that mQTL enrichment was specific to the cerebellum, in contrast to eQTLs. Separately, we found that using mQTL information to restrict the number of single-nucleotide polymorphisms studied enhances our ability to detect a significant association. With this restriction a priori informed by the observed functional enrichment, we identified a significant association (rs12618769, P bonferroni <0.05) from two other GWA studies (TGen+GAIN; 2191 cases and 1434 controls) of bipolar disorder, which we replicated in an independent GWA study (WTCCC). Collectively, our findings highlight the importance of integrating functional annotation of genetic variants for gene expression and DNA methylation to advance the biological understanding of bipolar disorder. © 2013 Macmillan Publishers Limited.

Author Keywords
bipolar disorder;  eQTL;  GWAS;  mQTL

Document Type: Article
Source: Scopus

Diggs-Andrews, K.A.a , Tokuda, K.b , Izumi, Y.b , Zorumski, C.F.b , Wozniak, D.F.b , Gutmann, D.H.a 
Dopamine deficiency underlies learning deficits in neurofibromatosis-1 mice
(2013) Annals of Neurology, 73 (2), pp. 309-315. 
a Departments of Neurology, Washington University School of Medicine, St Louis, MO, United States
b Departments of Psychiatry, Washington University School of Medicine, St Louis, MO, United States

Children with neurofibromatosis type 1 (NF1) are prone to learning and behavioral abnormalities, including problems with spatial learning and attention. The molecular etiology for these deficits is unclear, as previous studies have implicated defective dopamine, cyclic adenosine monophosphate (cAMP), and Ras homeostasis. Using behavioral, electrophysiological, and primary culture, we now demonstrate that reduced dopamine signaling is responsible for cAMP-dependent defects in neuron function and learning. Collectively, these results establish defective dopaminergic function as a contributing factor underlying impaired spatial learning and memory in children and adults with NF1, and support the use of treatments that restore normal dopamine homeostasis for select individuals. ANN NEUROL 2013;73:309-315 Copyright © 2012 American Neurological Association.

Document Type: Article
Source: Scopus

D'Ambrosio, R.a b c , Eastman, C.L.a , Darvas, F.a , Fender, J.S.a , Verley, D.R.a h , Farin, F.M.c d , Wilkerson, H.-W.c d , Temkin, N.R.a e , Miller, J.W.a b , Ojemann, J.a b c , Rothman, S.M.f i , Smyth, M.D.g 
Mild passive focal cooling prevents epileptic seizures after head injury in rats
(2013) Annals of Neurology, 73 (2), pp. 199-209. 
a Department of Neurological Surgery, Seattle, WA, United States
b Department of Neurology and Regional Epilepsy Center, Seattle, WA, United States
c Center for Human Development and Disability, Seattle, WA, United States
d Department of Environmental and Occupational Health Sciences, Seattle, WA, United States
e Department of Biostatistics, University of Washington, Seattle, WA, United States
f Department of Neurology, University of Minnesota, Minneapolis, MN, United States
g Department of Neurological Surgery, Washington University in St Louis, St Louis, MO, United States
h University of California at Los Angeles, Los Angeles, CA, United States
i Mercy Clinic Child Neurology, St Louis, MO, United States

Objective Post-traumatic epilepsy is prevalent, often difficult to manage, and currently cannot be prevented. Although cooling is broadly neuroprotective, cooling-induced prevention of chronic spontaneous recurrent seizures has never been demonstrated. We examined the effect of mild passive focal cooling of the perilesional neocortex on the development of neocortical epileptic seizures after head injury in the rat. Methods Rostral parasagittal fluid percussion injury in rats reliably induces a perilesional, neocortical epileptic focus within weeks after injury. Epileptic seizures were assessed by 5-electrode video-electrocorticography (ECoG) 2 to 16 weeks postinjury. Focal cooling was induced with ECoG headsets engineered for calibrated passive heat dissipation. Pathophysiology was assessed by glial fibrillary acidic protein immunostaining, cortical sclerosis, gene expression of inflammatory cytokines interleukin (IL)-1α and IL-1β, and ECoG spectral analysis. All animals were formally randomized to treatment groups, and data were analyzed blind. Results Cooling by 0.5 to 2°C inhibited the onset of epileptic seizures in a dose-dependent fashion. The treatment induced no additional pathology or inflammation, and normalized the power spectrum of stage N2 sleep. Cooling by 2°C for 5.5 weeks beginning 3 days after injury virtually abolished ictal activity. This effect persisted through the end of the study, >10 weeks after cessation of cooling. Rare remaining seizures were shorter than in controls. Interpretation These findings demonstrate potent and persistent prevention and modification of epileptic seizures after head injury with a cooling protocol that is neuroprotective, compatible with the care of head injury patients, and conveniently implemented. The required cooling can be delivered passively without Peltier cells or electrical power. ANN NEUROL 2013;73:199-209 Copyright © 2012 American Neurological Association.

Document Type: Article
Source: Scopus

 Pong, W.W., Higer, S.B., Gianino, S.M., Emnett, R.J., Gutmann, D.H.
Reduced microglial CX3CR1 expression delays neurofibromatosis-1 glioma formation
(2013) Annals of Neurology, 73 (2), pp. 303-308. 
Department of Neurology, Washington University School of Medicine, Box 8111, 660 South Euclid Avenue, St Louis, MO 63110, United States

Although traditional models of carcinogenesis have largely focused on neoplastic cells, converging data have revealed the importance of non-neoplastic stromal cells in influencing tumor growth and progression. Leveraging a genetically engineered mouse model of neurofibromatosis type 1 (NF1)-associated optic glioma, we now demonstrate that stromal microglia express the CX3CR1 chemokine receptor, such that reduced CX3CR1 expression decreases optic nerve microglia. Moreover, genetic reduction of Cx3cr1 expression in Nf1 optic glioma mice delays optic glioma formation. Coupled with previous findings demonstrating that microglia maintain optic glioma growth, these new findings provide a strong preclinical rationale for the development of future stroma-directed glioma therapies in children. ANN NEUROL 2013;73:303-308 Copyright © 2013 American Neurological Association.

Document Type: Article
Source: Scopus

 Wolf, T.J.a b , Rognstad, M.C.a 
Changes in cognition following mild stroke
(2013) Neuropsychological Rehabilitation, 23 (2), pp. 256-266. 
a Programme in Occupational Therapy, Washington University, School of Medicine, 4444 Forest Park, St. Louis, MO 63108, United States
b Department of Neurology, Washington University, School of Medicine, Saint Louis, MO, United States

The objective of the study was to determine how performance on cognitive assessments administered in the subacute phase of mild stroke change or remain stable over time. A prospective longitudinal cohort pilot study was used to assess the cognitive status of participants with mild stroke (n = 20) at two time points: (1) within 3 weeks post-discharge from the acute care setting following mild stroke, and (2) approximately 6 months post-mild stroke. Participants were given a battery of cognitive assessments at both time points that included the following measures: (1) Short Blessed Test, (2) California Verbal Learning Test (CVLT), (3) Connor's Continuous Performance Task (CPT), and (4) The Delis-Kaplan Executive Function System (DKEFS) Trail Making subtest. The only significant differences between the test administrations was on the CVLT Short Delay Free Recall (p = .027) and Long Delay Free Recall (p = .002) which was likely due to practice effects associated with this measure. The results of the study show that performance on standardised cognitive testing in the early phases of mild stroke remained stable over a 6 month period. These results help justify the necessity and ability to assess cognition immediately post-mild stroke in order to make accurate and appropriate rehabilitation recommendations. © 2013 Taylor & Francis.

Author Keywords
Cognition;  Executive function;  Neuropsychological tests;  Rehabilitation;  Stroke

Document Type: Article
Source: Scopus

Ozaydin, F.a , Ozdemir, S.K.b , Koashi, M.c , Imoto, N.d 
Superadditivity of quantum channel capacity

(2012) AIP Conference Proceedings, 1476, pp. 346-350. 
a Department of Computer Engineering, Okan University, Istanbul, Turkey
b Department of Electrical and Systems Engineering, Washington University, St. Louis, United States
c Photon Science Center, Tokyo University, Tokyo, Japan
d Department of Materials Engineering Science, Graduate School of Engineering Science, Osaka University, Toyonaka, Osaka, Japan

Superadditivity of quantum capacity of communication channels is one of the most interesting findings of the field. Yard and Smith, finding a relation between the private capacity and the assisted quantum capacity, showed a striking example of superadditivity, i.e. two channels of zero quantum capacity could achieve a positive quantum capacity when used together [1]. The four dimensional channels they used are a 50% erasure channel (therefore zero quantum capacity, due to no-cloning theorem) and a Horodecki channel (again zero quantum capacity due to incapability of sharing free entanglement). In this work we present the more general cases of superadditivity. Directly calculating the lower bounds of joint quantum capacities without using the relation between private capacity and assisted quantum capacity, we examine scenarios considering erasure channels of arbitrary probabilities and different Horodecki channels, and discuss the roles of degradability and anti-degradability as well as the role of the private capacity in superadditivity. We also derive an upper bound for the joint quantum capacity for the superactivation case. © 2012 American Institute of Physics.

Author Keywords
quantum capacity;  Superactivation;  superadditivity


Document Type: Conference Paper
Source: Scopus