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WUSTL Neuroscience Publications Archive - January 2014

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January 3, 2014

January 10, 2014

 January 24, 2014

January 24, 2014


Zeng, C.a d , Rothfuss, J.M.a , Zhang, J.a , Vangveravong, S.a , Chu, W.a , Li, S.a d , Tu, Z.a , Xu, J.a , Mach, R.H.a b c d
Functional assays to define agonists and antagonists of the sigma-2 receptor
(2014) Analytical Biochemistry, 448 (1), pp. 68-74. 

a Department of Radiology, Division of Radiological Sciences, Washington University School of Medicine, 510 S. Kingshighway Blvd., St. Louis, MO 63110, United States
b Department of Cell Biology and Physiology, Washington University School of Medicine, 510 S. Kingshighway Blvd., St. Louis, MO 63110, United States
c Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, 510 S. Kingshighway Blvd., St. Louis, MO 63110, United States
d Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States

The sigma-2 receptor has been identified as a biomarker in proliferating tumors. To date there is no well-established functional assay for defining sigma-2 agonists and antagonists. Many sigma-2 ligands with diverse structures have been shown to induce cell death in a variety of cancer cells by triggering caspase-dependent and independent apoptosis. Therefore, in the current study, we used the cell viability assay and the caspase-3 activity assay to determine sigma-2 agonists and antagonists. Three classes of sigma-2 ligands developed in our laboratory were evaluated for their potency to induce cell death in two tumor cell lines, mouse breast cancer cell line EMT-6 and human melanoma cell line MDA-MB-435. The data showed that the EC50 values of the sigma-2 ligands using the cell viability assay ranged from 11.4 μM to >200 μM, which were comparable with the EC50 values obtained using the caspase-3 assay. Based on the cytotoxicity of a sigma-2 ligand relative to that of siramesine, a commonly accepted sigma-2 agonist, we have categorized our sigma-2 ligands into agonists, partial agonists, and antagonists. The establishment of functional assays for defining sigma-2 agonists and antagonists will facilitate functional characterization of sigma-2 receptor ligands and sigma-2 receptors. © 2013 Elsevier Inc. All rights reserved.

Author Keywords
Agonist;  Antagonist;  Caspase-3;  Cell viability;  Functional assay;  Sigma-2 receptor

Document Type: Article
Source: Scopus

Zubcevic, L.a , Bavro, V.N.a b , Muniz, J.R.C.c , Schmidt, M.R.d , Wang, S.e , De Zorzi, R.f , Venien-Bryan, C.f g , Sansom, M.S.P.d h , Nichols, C.G.e , Tucker, S.J.a h
Control of KirBac3.1 potassium channel gating at the interface between cytoplasmic domains
(2014) Journal of Biological Chemistry, 289 (1), pp. 143-151. 

a Biological Physics Group, Clarendon Laboratory, University of Oxford, Oxford OX1 3PU, United Kingdom
b School of Immunity and Infection, University of Birmingham, Birmingham B15 2TT, United Kingdom
c Sao Carlos Institute of Physics, University of Sao Paulo, Sao Paulo SP 13560-970, Brazil
d Structural Bioinformatics and Computational Biochemistry Unit, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom
e Department of Cell Biology and Physiology, Center for the Investigation of Membrane Excitability Diseases, Washington University, St. Louis, MO 63110, United States
f Harvard Medical School, Boston, MA 02115, United States
g Institut de Minéralogie et de Physique des Milieux Condensés (IMPMC), CNRS-UMR 7590, Université Pierre et Marie Curie, 75005 Paris, France
h OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford OX1 3PT, United Kingdom

KirBac channels are prokaryotic homologs of mammalian inwardly rectifying potassium (Kir) channels, and recent structures of KirBac3.1 have provided important insights into the structural basis of gating in Kir channels. In this study, we demonstrate that KirBac3.1 channel activity is strongly pH-dependent, and we used x-ray crystallography to determine the structural changes that arise from an activatory mutation (S205L) located in the cytoplasmic domain (CTD). This mutation stabilizes a novel energetically favorable open conformation in which changes at the intersubunit interface in the CTD also alter the electrostatic potential of the inner cytoplasmic cavity. These results provide a structural explanation for the activatory effect of this mutation and provide a greater insight into the role of the CTD in Kir channel gating. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Document Type: Article
Source: Scopus

Swain, G.P.a , Prociuk, M.a , Bagel, J.H.a , O'Donnell, P.a , Berger, K.a , Drobatz, K.a , Gurda, B.L.a , Haskins, M.E.a , Sands, M.S.b , Vite, C.H.a
Adeno-associated virus serotypes 9 and rh10 mediate strong neuronal transduction of the dog brain
(2014) Gene Therapy, 21 (1), pp. 28-36. 

a Department of Clinical Studies and Pathobiology, School of Veterinary Medicine, University of Pennsylvania, 3900 Delancey Street, Philadelphia, PA, United States
b Departments of Internal Medicine and Genetics, Washington University School of Medicine, St Louis, MO, United States

Canine models have many advantages for evaluating therapy of human central nervous system (CNS) diseases. In contrast to nonhuman primate models, naturally occurring canine CNS diseases are common. In contrast to murine models, the dog's lifespan is long, its brain is large and the diseases affecting it commonly have the same molecular, pathological and clinical phenotype as the human diseases. We compared the ability of four intracerebrally injected adeno-associated virus vector (AAV) serotypes to transduce the dog brain with green fluorescent protein as the first step in using these vectors to evaluate both delivery and efficacy in naturally occurring canine homologs of human diseases. Quantitative measures of transduction, maximum diameter and area, identified both AAV2/9 and AAV2/rh10 as significantly more efficient than either AAV2/1 or AAV2/5 at transducing cerebral cortex, caudate nucleus, thalamus and internal capsule. Fluorescence co-labeling with cell-type-specific antibodies demonstrated that AAV2/9 and AAV2/rh10 were capable of primarily transducing neurons, although glial transduction was also identified and found to be more efficient with the AAV2/9 vector. These data are a prerequisite to evaluating the efficacy of recombinant AAV vectors carrying disease-modifying transgenes to treat naturally occurring canine models in preclinical studies of human CNS disease therapy. © 2014 Macmillan Publishers Limited.

Author Keywords
AAV;  animal model;  canine;  CNS

Document Type: Article
Source: Scopus

Anticevic, A.a b c d e f , Cole, M.W.g , Repovs, G.h , Savic, A.i , Driesen, N.R.a , Yang, G.a d , Cho, Y.T.a , Murray, J.D.j , Glahn, D.C.a e , Wang, X.-J.j , Krystal, J.H.a b c k
Connectivity, pharmacology, and computation: Toward a mechanistic understanding of neural system dysfunction in schizophrenia
(2013) Frontiers in Psychiatry, 4 (DEC), art. no. Article 169, . 

a Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States
b NIAAA Center for the Translational Neuroscience of Alcoholism, New Haven, CT, United States
c Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, CT, United States
d Interdepartmental Neuroscience Program, Yale University, New Haven, CT, United States
e Olin Neuropsychiatry Research Center, Institute of Living, Hartford Hospital, Hartford, CT, United States
f Department of Psychology, Yale University, New Haven, CT, United States
g Department of Psychology, Washington University in St. Louis, St. Louis, MO, United States
h Department of Psychology, University of Ljubljana, Ljubljana, Slovenia
i Department of Psychiatry, University of Zagreb School of Medicine, Zagreb, Croatia
j Center for Neural Science, New York University, New York, NY, United States
k Department of Neurobiology, Yale University School of Medicine, New Haven, CT, United States

Neuropsychiatric diseases such as schizophrenia and bipolar illness alter the structure and function of distributed neural networks. Functional neuroimaging tools have evolved sufficiently to reliably detect system-level disturbances in neural networks. This review focuses on recent findings in schizophrenia and bipolar illness using resting-state neuroimaging, an advantageous approach for biomarker development given its ease of data collection and lack of task-based confounds. These benefits notwithstanding, neuroimaging does not yet allow the evaluation of individual neurons within local circuits, where pharmacological treatments ultimately exert their effects. This limitation constitutes an important obstacle in translating findings from animal research to humans and from healthy humans to patient populations. Integrating new neuroscientific tools may help to bridge some of these gaps. We specifically discuss two complementary approaches. The first is pharmacological manipulations in healthy volunteers, which transiently mimic some cardinal features of psychiatric conditions. We specifically focus on recent neuroimaging studies using the NMDA receptor antagonist, ketamine, to probe glutamate synaptic dysfunction associated with schizophrenia. Second, we discuss the combination of human pharmacological imaging with biophysically informed computational models developed to guide the interpretation of functional imaging studies and to inform the development of pathophysiologic hypotheses. To illustrate this approach, we review clinical investigations in addition to recent findings of how computational modeling has guided inferences drawn from our studies involving ketamine administration to healthy subjects. Thus, this review asserts that linking experimental studies in humans with computational models will advance to effort to bridge cellular, systems, and clinical neuroscience approaches to psychiatric disorders. © 2013 Anticevic, Cole, Repovs, Savic, Driesen, Yang, Cho, Murray, Glahn, Wang and Krystal.

Author Keywords
Computational modeling;  Functional connectivity;  Glutamate;  NMDA receptors;  Pharmacology;  Schizophrenia;  Thalamus

Document Type: Review
Source: Scopus

Clifford, D.B., Ances, B.M.
HIV-associated neurocognitive disorder.
(2013) The Lancet infectious diseases, 13 (11), pp. 976-986. 

Department of Neurology and Medicine, Washington University in St Louis, St Louis, MO, USA. Electronic address:

Neurological involvement in HIV is often associated with cognitive impairment. Although severe and progressive neurocognitive impairment has become rare in HIV clinics in the era of potent antiretroviral therapy, most patients with HIV worldwide have poor outcomes on formal neurocognitive tests. In this Review, we describe the manifestations of HIV-associated neurocognitive disorder in the era of effective HIV therapy, outline diagnosis and treatment recommendations, and explore the research questions that remain. Although comorbid disorders, such as hepatitis C infection or epilepsy, might cause some impairment, their prevalence is insufficient to explain the frequency with which it is encountered. HIV disease markers, such as viral load and CD4 cell counts, are not strongly associated with ongoing impairment on treatment, whereas cardiovascular disease markers and inflammatory markers are. New cerebrospinal fluid and neuroimaging biomarkers are needed to detect and follow impairment. Ongoing research efforts to optimise HIV therapy within the CNS, and potentially to intervene in downstream mechanisms of neurotoxicity, remain important avenues for future investigation. Ultimately, the full control of virus in the brain is a necessary step in the goal of HIV eradication. Copyright © 2013 Elsevier Ltd. All rights reserved.

Document Type: Review
Source: Scopus

Orestes, P.a c , Osuru, H.P.a , McIntire, W.E.d , Jacus, M.O.a , Salajegheh, R.a , Jagodic, M.M.a , Choe, W.J.a f , Lee, J.H.a g , Lee, S.-S.h i , Rose, K.E.a , Poiro, N.a , DiGruccio, M.R.a c , Krishnan, K.e , Covey, D.F.e , Lee, J.-H.h i , Barrett, P.Q.d , Jevtovic-Todorovic, V.a b c , Todorovic, S.M.a b c
Reversal of neuropathic pain in diabetes by targeting glycosylation of Cav3.2 T-type calcium channels
(2013) Diabetes, 62 (11), pp. 3828-3838. Cited 1 time.

a Department of Anesthesiology, University of Virginia Health System, Charlottesville, VA, United States
b Department of Neuroscience, University of Virginia Health System, Charlottesville, VA, United States
c Neuroscience Graduate Program, University of Virginia Health System, Charlottesville, VA, United States
d Department of Pharmacology, University of Virginia Health System, Charlottesville, VA, United States
e Department of Developmental Biology, Washington University, School of Medicine, St. Louis, MO, United States
f Department of Anesthesiology and Pain Medicine, InJe University, Ilsan Paik Hospital and College of Medicine, Goyang-City, South Korea
g Department of Anesthesiology and Pain Medicine, Busan Paik Hospital, InJe University, Busan, South Korea
h Department of Life Science, Sogang University, Seoul, South Korea
i Interdisciplinary Program of Biotechnology, Sogang University, Seoul, South Korea

It has been established that CaV3.2 T-type voltage-gated calcium channels (T-channels) play a key role in the sensitized (hyperexcitable) state of nociceptive sensory neurons (nociceptors) in response to hyperglycemia associated with diabetes, which in turn can be a basis for painful symptoms of peripheral diabetic neuropathy (PDN). Unfortunately, current treatment for painful PDN has been limited by nonspecific systemic drugs with significant side effects or potential for abuse. We studied in vitro and in vivo mechanisms of plasticity of CaV3.2 T-channel in a leptindeficient (ob/ob) mouse model of PDN. We demonstrate that posttranslational glycosylation of specific extracellular asparagine residues in CaV3.2 channels accelerates current kinetics, increases current density, and augments channel membrane expression. Importantly, deglycosylation treatment with neuraminidase inhibits native T-currents in nociceptors and in so doing completely and selectively reverses hyperalgesia in diabetic ob/ob mice without altering baseline pain responses in healthy mice. Our study describes a new mechanism for the regulation of CaV3.2 activity and suggests that modulating the glycosylation state of T-channels in nociceptors may provide a way to suppress peripheral sensitization. Understanding the details of this regulatory pathway could facilitate the development of novel specific therapies for the treatment of painful PDN. © 2013 by the American Diabetes Association.

Document Type: Article
Source: Scopus

Imai, S.
[The sirtuin family : regulators that connect metabolism, aging, and longevity].
(2013) Clinical calcium, 23 (1), pp. 29-38. 

Department of Developmental Biology, Washington University School of Medicine, WA, USA.

Recently, studies on the mechanisms of aging and longevity have been making significant progresses. Through those studies, the SIR2 (silent information regulator 2) family proteins, now called "sirtuins" , have drawn much attention as important regulators that connect metabolism, aging, and longevity. The general feature of sirtuin function is to maintain the robustness of the physiological system in response to or prevent its destruction from various internal and external perturbations. This particular function of sirtuins allows them to play critical roles in the regulation of many biological processes, including the regulation of aging and longevity. In this review article, recent findings in this quickly evolving field of sirtuin biology will be summarized, and the importance of sirtuins on the regulation of aging and longevity will be discussed.

Document Type: Review
Source: Scopus


January 10, 2014


Xu, X.a b , Jerskey, B.A.b c , Cote, D.M.c , Walsh, E.G.d , Hassenstab, J.J.e , Ladino, M.E.c f , Clark, U.S.b g , Labbe, D.R.b , Gunstad, J.J.h , Poppas, A.i , Cohen, R.A.b j , Hoge, R.D.k , Sweet, L.H.b c l
Cerebrovascular perfusion among older adults is moderated by strength training and gender
(2014) Neuroscience Letters, 560, pp. 26-30. 

a Idaho State University, Department of Psychology, Pocatello, ID 83209, United States
b Alpert Medical School of Brown University, Department of Psychiatry and Human Behavior, Providence, RI 02912, United States
c Butler Hospital Neuroimaging Center, Providence, RI 02906, United States
d Brown University, Department of Neuroscience, Providence, RI 02912, United States
e Washington University in Saint Louis School of Medicine, Departments of Neurology and Psychology, St. Louis, MO 63110, United States
f Columbia University Teachers College, Department of Clinical Psychology, New York, NY 10027-6696, United States
g Icahn School of Medicine at Mount Sinai, Department of Neurology, New York, NY 10029, United States
h Kent State University, Department of Psychology, Kent, OH 44242, United States
i Alpert Medical School of Brown University, Department of Medicine, Providence, RI 02912, United States
j University of Florida, Center for Cognitive Aging and Memory, Departments of Neurology, Psychiatry and Aging, Gainesville, FL 32611, United States
k Université de Montréal, Departments of Neuroscience and Radiology, Centre de recherche de l'institut universitaire de gériatrie, Succ. Centre-ville, Montréal, QC H3C 3J7, Canada
l University of Georgia, Department of Psychology, Athens, GA 30602-3013, United States

Cerebral perfusion is important in older adults as it is linked to cognitive declines. Physical activity can improve blood flow in the body but little is known about the relationship between physical activity and cerebral perfusion in older adults. In particular, no study has investigated the relation between strength training and cerebral perfusion. We examined whether different types of physical activity (assessed with the Rapid Assessment of Physical Activity questionnaire) were associated with MRI cerebrovascular perfusion in 59 older adults. There was a significant interaction between gender and strength training, such that women who engaged in strength training (weight lifting or calisthenics) at least once per week exhibited significantly greater cerebrovascular perfusion than women who did not. This interaction remained significant after controlling for other physical activity, demographics, and health variables. These findings suggest that regular strength training can be beneficial for cerebrovascular health in women. © 2013 Elsevier Ireland Ltd.

Author Keywords
ASL;  Cerebral perfusion;  Physical activity;  Sex;  Strength training

Document Type: Article
Source: Scopus

Madlinger-Lewis, L.a , Reynolds, L.b , Zarem, C.a , Crapnell, T.a , Inder, T.c d e , Pineda, R.a c
The effects of alternative positioning on preterm infants in the neonatal intensive care unit: A randomized clinical trial
(2014) Research in Developmental Disabilities, 35 (2), pp. 490-497. 

a Washington University School of Medicine, Program in Occupational Therapy, 4444 Forest Park Avenue, Saint Louis, MO 63110, United States
b Washington University School of Medicine, Department of Psychiatry, 660 South Euclid, Saint Louis, MO 63110, United States
c Washington University School of Medicine, Department of Pediatrics, 1 Children's Place, Saint Louis, MO 63110, United States
d Washington University School of Medicine, Department of Neurology, 1 Children's Place, Saint Louis, MO 63110, United States
e Washington University School of Medicine, Department of Radiology, 1 Children's Place, Saint Louis, MO 63110, United States

There is a paucity of studies that have investigated the developmental benefits of positioning in the neonatal intensive care unit. The purpose of this study was to investigate the effects of a new, alternative positioning device compared to traditional positioning methods used with preterm infants. In this randomized, blinded clinical trial, one hundred preterm infants (born ≤32 weeks gestation) from a level III neonatal intensive care unit in the United States were enrolled at birth. Participants were randomized to be positioned in the alternative positioning device or to traditional positioning methods for their length of stay in the neonatal intensive care unit. Infants were assessed using the NICU Network Neurobehavioral Scale between 35-40 weeks postmenstrual age. Clinical and feeding outcomes were also captured. Linear and logistic regressions were used to investigate differences in neurobehavioral outcome, feeding performance, and medical outcomes. Infants in the alternative positioning arm of the study demonstrated less asymmetry of reflex and motor responses on the NICU Network Neurobehavioral Scale (p= 0.04; adjusted mean difference = 0.90, 95% CI 0.05-1.75) than those positioned using traditional positioning methods. No other significant differences were observed. Reduction in asymmetry among preterm infants is an important benefit of alternative positioning, as symmetrical movement and responses are crucial for early development. However, it will be important to follow this sample of preterm infants to determine the effects of early positioning on neurodevelopmental outcome in childhood. © 2013 Elsevier Ltd.

Author Keywords
Development;  NICU;  Positioning;  Preterm infants

Document Type: Article
Source: Scopus

Frazier, T.W.a , Ratliff, K.R.b , Gruber, C.b , Zhang, Y.c , Law, P.A.d , Constantino, J.N.c
Confirmatory factor analytic structure and measurement invariance of quantitative autistic traits measured by the Social Responsiveness Scale-2
(2014) Autism, 18 (1), pp. 31-44. 

a Cleveland Clinic, United States
b Western Psychological Services, United States
c Washington University, School of Medicine in St Louis, Campus Box 8134, 660 South Euclid Avenue, St. Louis, MO 63110, United States
d Johns Hopkins University, School of Medicine, United States

Understanding the factor structure of autistic symptomatology is critical to the discovery and interpretation of causal mechanisms in autism spectrum disorder. We applied confirmatory factor analysis and assessment of measurement invariance to a large (N = 9635) accumulated collection of reports on quantitative autistic traits using the Social Responsiveness Scale, representing a broad diversity of age, severity, and reporter type. A two-factor structure (corresponding to social communication impairment and restricted, repetitive behavior) as elaborated in the updated Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5) criteria for autism spectrum disorder exhibited acceptable model fit in confirmatory factor analysis. Measurement invariance was appreciable across age, sex, and reporter (self vs other), but somewhat less apparent between clinical and nonclinical populations in this sample comprised of both familial and sporadic autism spectrum disorders. The statistical power afforded by this large sample allowed relative differentiation of three factors among items encompassing social communication impairment (emotion recognition, social avoidance, and interpersonal relatedness) and two factors among items encompassing restricted, repetitive behavior (insistence on sameness and repetitive mannerisms). Cross-trait correlations remained extremely high, that is, on the order of 0.66-0.92. These data clarify domains of statistically significant factoral separation that may relate to partially - but not completely - overlapping biological mechanisms, contributing to variation in human social competency. Given such robust intercorrelations among symptom domains, understanding their co-emergence remains a high priority in conceptualizing common neural mechanisms underlying autistic syndromes. © 2013 The Author(s).

Author Keywords
Asperger syndrome;  autism;  factor structure;  pervasive developmental disorder

Document Type: Article
Source: Scopus

Lohoff, F.W.a , Hodge, R.a , Narasimhan, S.a , Nall, A.a , Ferraro, T.N.a , Mickey, B.J.b , Heitzeg, M.M.b , Langenecker, S.A.b , Zubieta, J.-K.b , Bogdan, R.b , Nikolova, Y.S.c d , Drabant, E.c , Hariri, A.R.e , Bevilacqua, L.c , Goldman, D.f , Doyle, G.A.a
Functional genetic variants in the vesicular monoamine transporter 1 modulate emotion processing
(2014) Molecular Psychiatry, 19 (1), pp. 129-139. 

a Translational Research Laboratories, Department of Psychiatry, University of Pennsylvania School of Medicine, 125 South 31st Street, Room 2213, Philadelphia, PA 19104, United States
b Department of Psychiatry, Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, United States
c Department of Psychology and Neuroscience, Institute for Genome Sciences and Policy, Duke University, Durham, NC, United States
d Department of Psychology, Washington University in St Louis, St Louis, MO, United States
e 23andMe, Mountain View, CA, United States
f Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, Rockville, MD, United States

Emotional behavior is in part heritable and often disrupted in psychopathology. Identification of specific genetic variants that drive this heritability may provide important new insight into molecular and neurobiological mechanisms involved in emotionality. Our results demonstrate that the presynaptic vesicular monoamine transporter 1 (VMAT1) Thr136Ile (rs1390938) polymorphism is functional in vitro, with the Ile allele leading to increased monoamine transport into presynaptic vesicles. Moreover, we show that the Thr136Ile variant predicts differential responses in emotional brain circuits consistent with its effects in vitro. Lastly, deep sequencing of bipolar disorder (BPD) patients and controls identified several rare novel VMAT1 variants. The variant Phe84Ser was only present in individuals with BPD and leads to marked increase monoamine transport in vitro. Taken together, our data show that VMAT1 polymorphisms influence monoamine signaling, the functional response of emotional brain circuits and risk for psychopathology. © 2014 Macmillan Publishers Limited All rights reserved.

Author Keywords
amygdale;  bipolar disorder;  medial PFC;  schizophrenia;  SLC18A1

Document Type: Article
Source: Scopus

Selmeczy, D., Dobbins, I.G.
Relating the content and confidence of recognition judgments
(2014) Journal of Experimental Psychology: Learning Memory and Cognition, 40 (1), pp. 66-85. 

Department of Psychology, Washington University in St. Louis, United States

The Remember/Know procedure, developed by Tulving (1985) to capture the distinction between the conscious correlates of episodic and semantic retrieval, has spawned considerable research and debate. However, only a handful of reports have examined the recognition content beyond this dichotomous simplification. To address this, we collected participants' written justifications in support of ordinary old/new recognition decisions accompanied by confidence ratings using a 3-point scale (high/medium/ low). Unlike prior research, we did not provide the participants with any descriptions of Remembering or Knowing and thus, if the justifications mapped well onto theory, they would do so spontaneously. Word frequency analysis (unigrams, bigrams, and trigrams), independent ratings, and machine learning techniques (Support Vector Machine [SVM]) converged in demonstrating that the linguistic content of high and medium confidence recognition differs in a manner consistent with dual process theories of recognition. For example, the use of "I remember," particularly when combined with temporal or perceptual information (e.g., "when," "saw," "distinctly"), was heavily associated with high confidence recognition. Conversely, participants also used the absence of remembering for personally distinctive materials as support for high confidence new reports ("would have remembered"). Thus, participants afford a special status to the presence or absence of remembering and use this actively as a basis for high confidence during recognition judgments. Additionally, the pattern of classification successes and failures of a SVM was well anticipated by the dual process signal detection model of recognition and inconsistent with a single process, strictly unidimensional approach ©2013 American Psychological Association.

Author Keywords
Confidence;  Linguistics;  Recognition memory

Document Type: Article
Source: Scopus

Wahlheim, C.N., Maddox, G.B., Jacoby, L.L.
The role of reminding in the effects of spaced repetitions on cued recall: Sufficient but not necessary
(2014) Journal of Experimental Psychology: Learning Memory and Cognition, 40 (1), pp. 94-105. 

Department of Psychology, Washington University, St. Louis, United States

Three experiments examined the role of study-phase retrieval (reminding) in the effects of spaced repetitions on cued recall. Remindings were brought under task control to evaluate their effects. Participants studied 2 lists of word pairs containing 3 item types: single items that appeared once in List 2, within-list repetitions that appeared twice in List 2, and between-list repetitions that appeared once in List 1 and once in List 2. Our primary interest was in performance on between-list repetitions. Detection of between-list repetitions was encouraged in an n-back condition by instructing participants to indicate when a presented item was a repetition of any preceding item, including items presented in List 1. In contrast, detection of between-list repetitions was discouraged in a within-list back condition by instructing participants only to indicate repetitions occurring in List 2. Cued recall of between-list repetitions was enhanced when instructions encouraged detection of List 1 presentations. These results accord with those from prior experiments showing a role of study-phase retrieval in effects of spacing repetitions. Past experiments have relied on conditionalized data to draw conclusions, producing the possibility that performance benefits merely reflected effects of item selection. By bringing effects under task control, we avoided that problem. Our results provide evidence that reminding resulting from retrieval of earlier presentations plays a role in the effects of spaced repetitions on cued recall. However, our results also reveal that such retrievals are not necessary to produce an effect of spacing repetitions ©2013 American Psychological Association.

Author Keywords
Cognitive control;  Reminding;  Repetition effects;  Spacing effects;  Study-phase retrieval

Document Type: Article
Source: Scopus

Harms, K.J.
Applying cognitive load theory to generate effective programming tutorials
(2013) Proceedings of IEEE Symposium on Visual Languages and Human-Centric Computing, VL/HCC, art. no. 6645274, pp. 179-180. 

Department of Computer Science and Engineering, Washington University in St. Louis, St. Louis, MO, United States

Many programmers, including novices, often attempt to solve their coding problems by searching the web for example code [1]. Because these programmers are invested in their current project, they are motivated to discover a solution to their problem [2]. While searching the web for a solution, they may encounter source code that addresses their issue and also contains programming concepts that are new to user. Unfortunately, novice programmers often struggle to understand the source code and can fail to successfully integrate the code into their programs [3]. To help novice programmers understand unfamiliar source code, we propose automatically generating tutorials from source code to help these programmers acquire new programming skills in the course of working on their own chosen projects. © 2013 IEEE.

Document Type: Conference Paper
Source: Scopus

Donfrancesco, R.a , Di Trani, M.b , Gregori, P.c , Auguanno, G.c , Melegari, M.G.c , Zaninotto, S.d , Luby, J.e
Attention-deficit/hyperactivity disorder and alexithymia: A pilot study
(2013) ADHD Attention Deficit and Hyperactivity Disorders, 5 (4), pp. 361-367. 

a S. Pertini Hospital, ASL RM/B, Rome, Italy
b Department of Dynamic and Clinical Psychology, University of Rome Sapienza, Via dei Marsi 78, 00185 Rome, Italy
c La Scarpetta Hospital, ASL RM/A, Rome, Italy
d ICR Villa delle Querce, Nemi, Rome, Italy
e Washington University School of Medicine, St. Louis, MO, United States

Although the relationship between alexithymia and psychopathology has been studied extensively in adults, research is lacking on alexithymia in childhood psychopathology. The aim of this study was to investigate the relationship between alexithymia and attention-deficit/hyperactivity disorder (ADHD). The Italian version of the Alexithymia Questionnaire for Children was administered to a sample of 50 children with a DSM-IV diagnosis of ADHD, as assessed by means of the K-SADS PL, and to 100 healthy, age- and sex-matched children without ADHD. The total alexithymia score as well as the difficulty in identifying feelings (DIF) and externally oriented thinking factors were significantly associated with ADHD. The total alexithymia score, the DIF, and the difficulty in describing feelings factors were also significantly associated with symptoms of hyperactivity/impulsivity. No significant relationship between alexithymia and inattentiveness symptoms emerged. Results provide preliminary data on the relationship between alexithymia and ADHD. Findings point to an association between difficulty in identifying emotions and hyperactivity/impulsivity. Future studies conducted on larger patient samples, as well as longitudinal designs, are warranted to confirm our findings. © 2013 Springer-Verlag Wien.

Author Keywords
Alexithymia;  Attention-deficit/hyperactivity disorder;  Children

Document Type: Article
Source: Scopus

Bhave, S.R.a b , Dadey, D.Y.a b , Karvas, R.M.a , Ferraro, D.J.a , Kotipatruni, R.P.a , Jaboin, J.J.a , Hallahan, A.N.a b , DeWees, T.A.a , Linkous, A.G.c , Hallahan, D.E.a b d e f , Thotala, D.a d e
Autotaxin inhibition with PF-8380 enhances the radiosensitivity of human and murine glioblastoma cell lines
(2013) Frontiers in Oncology, 3 SEP, art. no. Article 236, . 

a Department of Radiation Oncology, Washington University, St. Louis, MO, United States
b School of Medicine, Washington University, St. Louis, MO, United States
c NYU Cancer Institute, New York University Langone Medical Center, New York, NY, United States
d Mallinckrodt Institute of Radiology, Washington University, St. Louis, MO, United States
e Siteman Cancer Center, Washington University, St. Louis, MO, United States
f The Hope Center, Washington University, St. Louis, MO, United States

Purpose: Glioblastoma multiforme (GBM) is an aggressive primary brain tumor that is radio-resistant and recurs despite aggressive surgery, chemo, and radiotherapy. Autotaxin (ATX) is over expressed in various cancers including GBM and is implicated in tumor progression, invasion, and angiogenesis. Using the ATX specific inhibitor, PF-8380, we studied ATX as a potential target to enhance radiosensitivity in GBM. Methods and Materials: Mouse GL261 and Human U87-MG cells were used as GBM cell models. Clonogenic survival assays and tumor transwell invasion assays were performed using PF-8380 to evaluate role of ATX in survival and invasion. Radiation dependent activation of Akt was analyzed by immunoblotting. Tumor induced angiogenesis was studied using the dorsal skin fold model in GL261. Heterotopic mouse GL261 tumors were used to evaluate the efficacy of PF-8380 as a radiosensitizer. Results: Pre-treatment of GL261 and U87-MG cells with 1 μM PF-8380 followed by 4 Gy irradiation resulted in decreased clonogenic survival, decreased migration (33% in GL261; P = 0.002 and 17.9% in U87-MG; P = 0.012), decreased invasion (35.6% in GL261; P = 0.0037 and 31.8% in U87-MG; P = 0.002), and attenuated radiation-induced Akt phosphorylation. In the tumor window model, inhibition of ATX abrogated radiation induced tumor neovascularization (65%; P = 0.011). In a heterotopic mouse GL261 tumors untreated mice took 11.2 days to reach a tumor volume of 7000 mm3, however combination of PF-8380 (10 mg/kg) Conclusion: Inhibition of ATX by PF-8380 led to decreased invasion and enhanced radiosensitization of GBM cells. Radiation-induced activation of Akt was abrogated by inhibition of ATX. Furthermore, inhibition of ATX led to diminished tumor vascularity and delayed tumor growth. These results suggest that inhibition of ATX may ameliorate GBM response to radiotherapy. © 2013 Bhave, Dadey, Karvas, Ferraro, Kotipatruni, Jaboin, Hallahan, DeWees, Linkous, Hallahan and Thotala.

Author Keywords
Autotaxin;  Glioblastoma;  Lysophosphatidic acid;  PF-8380;  Radiosensitizer

Document Type: Article
Source: Scopus

Luke, D.A., Wald, L.M., Carothers, B.J., Bach, L.E., Harris, J.K.
Network Influences on Dissemination of Evidence-Based Guidelines in State Tobacco Control Programs
(2013) Health Education and Behavior, 40 (1 SUPPL.), pp. 33S-42S. Cited 1 time.

Washington University in St. Louis, St. Louis, MO, United States

Little is known regarding the social network relationships that influence dissemination of evidence-based public health practices and policies. In public health, it is critical that evidence-based guidelines, such as the Centers for Disease Control and Prevention's Best Practices for Comprehensive Tobacco Control Programs, are effectively and efficiently disseminated to intended stakeholders. To determine the organizational and network predictors of dissemination among state tobacco control programs, interviews with members of tobacco control networks across eight states were conducted between August 2009 and September 2010. Measures included partner attributes (e.g., agency type) and relationships among network members (frequency of contact, extent of collaboration, and dissemination of Best Practices). Exponential random graph modeling was used to examine attribute and structural predictors of collaboration and dissemination among partners in each network. Although density and centralization of dissemination ties varied across states, network analyses revealed a consistent prediction pattern across all eight states. State tobacco control dissemination networks were less dense but more centralized compared with organizational contact and collaboration networks. Tobacco control partners in each state were more likely to disseminate the Best Practices guidelines if they also had existing contact and collaboration relationships with one another. Evidence-based guidelines in public health need to be efficiently and broadly disseminated if we hope to translate science into practice. This study suggests that funders, advocacy groups, and public health agencies can take advantage of existing public health organizational relationships to support the communication and dissemination of evidence-based practices and policies. © 2013 Society for Public Health Education.

Author Keywords
dissemination;  evidence-based public health;  network analysis;  systems science;  tobacco control

Document Type: Article
Source: Scopus

Beirowski, B.
Concepts for regulation of axon integrity by enwrapping glia
(2013) Frontiers in Cellular Neuroscience, 7 (DEC), art. no. 256, . 

Department of Genetics, Washington University School of Medicine, Saint Louis, MO, United States

Long axons and their enwrapping glia (EG; Schwann cells (SCs) and oligodendrocytes (OLGs)) form a unique compound structure that serves as conduit for transport of electric and chemical information in the nervous system. The peculiar cytoarchitecture over an enormous length as well as its substantial energetic requirements make this conduit particularly susceptible to detrimental alterations. Degeneration of long axons independent of neuronal cell bodies is observed comparatively early in a range of neurodegenerative conditions as a consequence of abnormalities in SCs and OLGs. This leads to the most relevant disease symptoms and highlights the critical role that these glia have for axon integrity, but the underlying mechanisms remain elusive. The quest to understand why and how axons degenerate is now a crucial frontier in disease-oriented research. This challenge is most likely to lead to significant progress if the inextricable link between axons and their flanking glia in pathological situations is recognized. In this review I compile recent advances in our understanding of the molecular programs governing axon degeneration, and mechanisms of EG's non-cell autonomous impact on axon-integrity. A particular focus is placed on emerging evidence suggesting that EG nurture long axons by virtue of their intimate association, release of trophic substances, and neurometabolic coupling. The correction of defects in these functions has the potential to stabilize axons in a variety of neuronal diseases in the peripheral nervous system and central nervous system (PNS and CNS). © 2013 Beirowski.

Author Keywords
Amyotrophic lateral sclerosis;  Axon;  Charcot-marie-tooth disease;  Multiple sclerosis;  Neurodegeneration;  Oligodendrocyte;  Schwann cell;  Wallerian degeneration

Document Type: Review
Source: Scopus


January 3, 2014


Markov, N.T.a b c , Ercsey-Ravasz, M.M.d g , Ribeiro Gomes, A.R.a b , Lamy, C.a b , Magrou, L.a b , Vezoli, J.a b h , Misery, P.a b , Falchier, A.a b i , Quilodran, R.a b j , Gariel, M.A.a b k , Sallet, J.a b l , Gamanut, R.a b , Huissoud, C.a b m , Clavagnier, S.a b n , Giroud, P.a b o , Sappey-Marinier, D.e , Barone, P.a b , Dehay, C.a b , Toroczkai, Z.d , Knoblauch, K.a b , Van Essen, D.C.f , Kennedy, H.a b

A weighted and directed interareal connectivity matrix for macaque cerebral cortex
(2014) Cerebral Cortex, 24 (1), pp. 17-36. 

a Stem Cell and Brain Research Institute, INSERM U846, 69500 Bron, France
b Université de Lyon, Université Lyon i, 69003, Lyon, France
c Department of Neurobiology, University of Yale, 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 CERMEP, Hôpital Neurologique, 69394 Lyon Cedex 03, France
f Washington University, School of Medicine, St Louis, MO, United States
g Physics Department, Babes-Bolyai University, Cluj-Napoca, Romania
h Ernst Strüngmann Institute (ESI) for Neuroscience in Cooperation with the Max Planck Society, Frankfurt, Germany
i Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY, United States
j Escuela de Medicina, Departamento de Pre-clínicas, Universidad de Valparaíso, Valparaíso, Chile
k Department of Vision and Cognition, Netherlands Institute for Neuroscience, Amsterdam, Netherlands
l Decision and Action Laboratory, University of Oxford, Oxford, United Kingdom
m Service de Gynécologie-obstétrique, Hospices Civils de Lyon, France
n McGill Vision Research, Montreal, Canada
o Cerveau et Cognition, UMR 5549, Toulouse, France

Retrograde tracer injections in 29 of the 91 areas of the macaque cerebral cortex revealed 1,615 interareal pathways, a third of which have not previously been reported. A weight index (extrinsic fraction of labeled neurons [FLNe]) was determined for each area-to-area pathway. Newly found projections were weaker on average compared with the known projections; nevertheless, the 2 sets of pathways had extensively overlapping weight distributions. Repeat injections across individuals revealed modest FLNe variability given the range of FLNe values (standard deviation <1 log unit, range 5 log units). The connectivity profile for each area conformed to a lognormal distribution, where a majority of projections are moderate or weak in strength. In the G29 × 29 interareal subgraph, two-thirds of the connections that can exist do exist. Analysis of the smallest set of areas that collects links from all 91 nodes of the G29 × 91 subgraph (dominating set analysis) confirms the dense (66%) structure of the cortical matrix. The G29 × 29 subgraph suggests an unexpectedly high incidence of unidirectional links. The directed and weighted G29 × 91 connectivity matrix for the macaque will be valuable for comparison with connectivity analyses in other species, including humans. It will also inform future modeling studies that explore the regularities of cortical networks. © The Author 2012.

Author Keywords
Connection;  Cortex;  Graph;  Monkey;  Network

Document Type: Article
Source: Scopus

Pineda, R.G.a b , Neil, J.b c d , Dierker, D.e , Smyser, C.D.b c , Wallendorf, M.f , Kidokoro, H.b , Reynolds, L.C.a , Walker, S.a , Rogers, C.g , Mathur, A.M.b , Van Essen, D.C.e , Inder, T.b c d
Alterations in brain structure and neurodevelopmental outcome in preterm infants hospitalized in different neonatal intensive care unit environments
(2014) Journal of Pediatrics, 164 (1), pp. 52-60.e2. 

a Department of Occupational Therapy, Washington University School of Medicine, 10-109 Northwest Tower, 1 Children's Place, St Louis, MO 63110, United States
b Department of Pediatrics, 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 Radiology, Washington University School of Medicine, St Louis, MO, United States
e Department of Anatomy and Neurobiology, Washington University School of Medicine, St Louis, MO, United States
f Department of Biostatistics, Washington University School of Medicine, St Louis, MO, United States
g Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States

Objective To evaluate associations between neonatal intensive care unit (NICU) room type (open ward and private room) and medical outcomes; neurobehavior, electrophysiology, and brain structure at hospital discharge; and developmental outcomes at 2 years of age. Study design In this prospective longitudinal cohort study, we enrolled 136 preterm infants born <30 weeks gestation from an urban, 75-bed level III NICU from 2007-2010. Upon admission, each participant was assigned to a bedspace in an open ward or private room within the same hospital, based on space and staffing availability, where they remained for the duration of hospitalization. The primary outcome was developmental performance at 2 years of age (n = 86 infants returned for testing, which was 83% of survivors) measured using the Bayley Scales of Infant and Toddler Development, 3rd Edition. Secondary outcomes were: (1) medical factors throughout the hospitalization; (2) neurobehavior; and (3) cerebral injury and maturation (determined by magnetic resonance imaging and electroencephalography). Results At term equivalent age, infants in private rooms were characterized by a diminution of normal hemispheric asymmetry and a trend toward having lower amplitude integrated electroencephalography cerebral maturation scores (P =.02; β = -0.52 [CI -0.95, -0.10]). At age 2 years, infants from private rooms had lower language scores (P =.006; β = -8.3 [CI -14.2, -2.4]) and a trend toward lower motor scores (P =.02; β = -6.3 [CI -11.7, -0.99]), which persisted after adjustment for potential confounders. Conclusion These findings raise concerns that highlight the need for further research into the potential adverse effects of different amounts of sensory exposure in the NICU environment. © Copyright 2014 Mosby Inc. All rights reserved.

Document Type: Article
Source: Scopus

Thompson, D.K.a b , Thai, D.a , Kelly, C.E.a , Leemans, A.c , Tournier, J.-D.b , Kean, M.J.d , Lee, K.J.a e , Inder, T.E.f , Doyle, L.W.a g h , Anderson, P.J.a e , Hunt, R.W.a e i
Alterations in the optic radiations of very preterm children - Perinatal predictors and relationships with visual outcomes
(2014) NeuroImage: Clinical, 4, pp. 145-153. 

a Murdoch Childrens Research Institute, Melbourne, Australia
b Florey Institute of Neuroscience and Mental Health, Melbourne, Australia
c Image Sciences Institute, University Medical Center Utrecht, Netherlands
d Department of Medical Imaging, Royal Children's Hospital, Melbourne, Australia
e Department of Paediatrics, University of Melbourne, Melbourne, Australia
f St. Louis Children's Hospital, Washington University in St. Louis, St. Louis, United States
g Royal Women's Hospital, Melbourne, Australia
h Department of Obstetrics and Gynaecology, University of Melbourne, Australia
i Department of Neonatal Medicine, Royal Children's Hospital, Melbourne, Australia

Children born very preterm (VPT) are at risk for visual impairments, the main risk factors being retinopathy of prematurity and cerebral white matter injury, however these only partially account for visual impairments in VPT children. This study aimed to compare optic radiation microstructure and volume between VPT and term-born children, and to investigate associations between 1) perinatal variables and optic radiations; 2) optic radiations and visual function in VPT children. We hypothesized that optic radiation microstructure would be altered in VPT children, predicted by neonatal cerebral white matter abnormality and retinopathy of prematurity, and associated with visual impairments. 142 VPT children and 32 controls underwent diffusion-weighted magnetic resonance imaging at 7 years of age. Optic radiations were delineated using constrained spherical deconvolution tractography. Tract volume and average diffusion tensor values for the whole optic radiations and three sub-regions were compared between the VPT and control groups, and correlated with perinatal variables and 7-year visual outcome data. Total tract volumes and average diffusion values were similar between VPT and control groups. On regional analysis of the optic radiation, mean and radial diffusivity were higher within the middle sub-regions in VPT compared with control children. Neonatal white matter abnormalities and retinopathy of prematurity were associated with optic radiation diffusion values. Lower fractional anisotropy in the anterior sub-regions was associated with poor visual acuity and increased likelihood of other visual defects. This study presents evidence for microstructural alterations in the optic radiations of VPT children, which are largely predicted by white matter abnormality or severe retinopathy of prematurity, and may partially explain the higher rate of visual impairments in VPT children. © 2013 The Authors.

Author Keywords
Diffusion weighted imaging;  Magnetic resonance imaging;  Prematurity;  Tractography;  Visual system

Document Type: Article
Source: Scopus

Nelson, E.C.a , Lynskey, M.T.a , Heath, A.C.a , Wray, N.b , Agrawal, A.a , Shand, F.L.c , Henders, A.K.b , Wallace, L.b , Todorov, A.A.a , Schrage, A.J.a , Madden, P.A.F.a , Degenhardt, L.c d , Martin, N.G.b , Montgomery, G.W.b
Association of OPRD1 polymorphisms with heroin dependence in a large case-control series
(2014) Addiction Biology, 19 (1), pp. 111-121. 

a Department of Psychiatry, Washington University School of Medicine, 4560 Clayton Avenue, St. Louis, MO 63110, United States
b Queensland Institute of Medical Research, Australia
c National Drug and Alcohol Research Centre, University of New South Wales, Australia
d Centre for Health Policy, Programs and Economics, School of Population Health, University of Melbourne, Australia

Genes encoding the opioid receptors (OPRM1, OPRD1 and OPRK1) are obvious candidates for involvement in risk for heroin dependence. Prior association studies commonly had samples of modest size, included limited single nucleotide polymorphism (SNP) coverage of these genes and yielded inconsistent results. Participants for the current investigation included 1459 heroin-dependent cases ascertained from maintenance clinics in New South Wales, Australia, 1495 unrelated individuals selected from an Australian sample of twins and siblings as not meeting DSM-IV criteria for lifetime alcohol or illicit drug dependence (non-dependent controls) and 531 controls ascertained from economically disadvantaged neighborhoods in proximity to the maintenance clinics. A total of 136 OPRM1, OPRD1 and OPRK1 SNPs were genotyped in this sample. After controlling for admixture with principal components analysis, our comparison of cases to non-dependent controls found four OPRD1 SNPs in fairly high linkage disequilibrium for which adjusted P values remained significant (e.g. rs2236857; OR 1.25; P = 2.95 × 10-4) replicating a previously reported association. A post hoc analysis revealed that the two SNP (rs2236857 and rs581111) GA haplotype in OPRD1 is associated with greater risk (OR 1.68; P = 1.41 × 10-5). No OPRM1 or OPRK1 SNPs reached more than nominal significance. Comparisons of cases to neighborhood controls reached only nominal significance. Our results replicate a prior report providing strong evidence implicating OPRD1 SNPs and, in particular, the two SNP (rs2236857 and rs581111) GA haplotype in liability for heroin dependence. Support was not found for similar association involving either OPRM1 or OPRK1 SNPs. Genes encoding the opioid receptors (OPRM1, OPRD1 and OPRK1) are obvious candidates for involvement in risk for heroin dependence. Participants for the current investigation included 1459 heroin-dependent cases ascertained from maintenance clinics in New South Wales, Australia, 1495 unrelated individuals selected from an Australian sample of twins and siblings as not meeting DSM-IV criteria for lifetime alcohol or illicit drug dependence (non-dependent controls) and 531 controls ascertained from economically disadvantaged neighborhoods in proximity to the maintenance clinics. © 2012 Society for the Study of Addiction.

Author Keywords
Association study;  case-control;  heroin dependence;  OPRD1;  OPRK1;  OPRM1

Document Type: Article
Source: Scopus

Theim, K.R.a b , Wilfley, D.E.a , Beach, E.a , Tanofsky-Kraff, M.b , Goldschmidt, A.B.c
Content of children's loss of control eating episodes assessed by self-report and laboratory test meal
(2014) European Eating Disorders Review, 22 (1), pp. 72-76. 

a Washington University School of Medicine, St. Louis, MO, United States
b Uniformed Services University of the Health Sciences, Bethesda, MD, United States
c Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Eating Disorders Program, 5841 S. Maryland Ave., MC 3077, Chicago, IL 60637, United States

Pediatric loss of control (LOC) eating heightens risk for excessive weight gain and further disordered eating. Assessment of LOC typically involves self-report interview or laboratory test meal, although no study has concurrently examined data from both methods. We gathered eating episode data via interview (Child Eating Disorder Examination; ChEDE) and a laboratory test meal, among 22 overweight girls (aged 7-12 years) reporting LOC eating. Children consumed more energy during ChEDE episodes, although ChEDE and test meal episodes did not differ in macronutrient content. Episodes' correlation for amount consumed (grams) did not reach significance, p =.076. In exploratory analyses among the seven children reporting LOC during the test meal, episodes were significantly correlated for grams consumed. Findings provide preliminary data to suggest that semi-structured interviews accurately capture children's LOC episode quantity. Episodes did not qualitatively differ, although children reported consuming more energy during self-reported episodes. Replication is warranted in larger studies. Copyright © 2013 John Wiley & Sons, Ltd and Eating Disorders Association. Copyright © 2013 John Wiley & Sons, Ltd and Eating Disorders Association.

Author Keywords
assessment;  child;  loss of control eating

Document Type: Article
Source: Scopus

Stout, M.J., Epplin, K., Wood, A., Trudell, A.
Discussion: 'Sleep-disordered breathing and adverse pregnancy outcomes' by Pamidi et al
(2014) American Journal of Obstetrics and Gynecology, 210 (1), pp. e10-e12. 

Department of Obstetrics and Gynecology, Washington University in St. Louis, St. Louis, MO, United States

Document Type: Note
Source: Scopus

Chang, S.D.a b c , Bruchas, M.R.a b
Functional selectivity at GPCRs: New opportunities in psychiatric drug discovery
(2014) Neuropsychopharmacology, 39 (1), pp. 248-249. 

a Department of Anesthesiology, Washington University, St Louis, MO, United States
b Department of Neurobiology, Washington University, St Louis, MO, United States
c Department of Psychiatry, Washington University, St Louis, MO, United States

Document Type: Short Survey
Source: Scopus

Paganetti, P.a , Antoniello, K.a , Devraj, K.b , Toni, N.a f , Kieran, D.a g , Madani, R.a , Pihlgren, M.a , Adolfsson, O.a , Froestl, W.a , Schrattenholz, A.c , Liebner, S.b , Havas, D.d , Windisch, M.d , Cirrito, J.R.e , Pfeifer, A.a , Muhs, A.a
Increased efflux of amyloid-β peptides through the blood-brain barrier by muscarinic acetylcholine receptor inhibition reduces pathological phenotypes in mouse models of brain amyloidosis
(2014) Journal of Alzheimer's Disease, 38 (4), pp. 767-786. 

a AC Immune SA, EPLF Building PSE-B, CH-1015 Lausanne, Switzerland
b Institute of Neurology, Medical School Goethe University, Frankfurt am Main, Germany
c ProteoSys AG, Mainz, Germany
d QPS Austria, Grambach, Austria
e Department of Neurology, Knight AD Research Center, Washington University School of Medicine, St. Louis, MO, United States
f Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland
g Quintiles Outcome, St-Prex, Switzerland

The formation and accumulation of toxic amyloid-β peptides (Aβ) in the brain may drive the pathogenesis of Alzheimer's disease. Accordingly, disease-modifying therapies for Alzheimer's disease and related disorders could result from treatments regulating Aβ homeostasis. Examples are the inhibition of production, misfolding, and accumulation of Aβ or the enhancement of its clearance. Here we show that oral treatment with ACI-91 (Pirenzepine) dose-dependently reduced brain Aβ burden in AβPPPS1, hAβPPSL, and AβPP/PS1 transgenic mice. A possible mechanism of action of ACI-91 may occur through selective inhibition of muscarinic acetylcholine receptors (AChR) on endothelial cells of brain microvessels and enhanced Aβ peptide clearance across the blood-brain barrier. One month treatment with ACI-91 increased the clearance of intrathecally-injected Aβ in plaque-bearing mice. ACI-91 also accelerated the clearance of brain-injected Aβ in blood and peripheral tissues by favoring its urinal excretion. A single oral dose of ACI-91 reduced the half-life of interstitial Aβ peptide in pre-plaque mhAβPP/PS1d mice. By extending our studies to an in vitro model, we showed that muscarinic AChR inhibition by ACI-91 and Darifenacin augmented the capacity of differentiated endothelial monolayers for active transport of Aβ peptide. Finally, ACI-91 was found to consistently affect, in vitro and in vivo, the expression of endothelial cell genes involved in Aβ transport across the Blood Brain Brain (BBB). Thus increased Aβ clearance through the BBB may contribute to reduced Aβ burden and associated phenotypes. Inhibition of muscarinic AChR restricted to the periphery may present a therapeutic advantage as it avoids adverse central cholinergic effects. © 2014 - IOS Press and the authors. All rights reserved.

Author Keywords
Aβ brain efflux;  Aβ clearance;  Aβ homeostasis;  AβPP transgenic mice;  Amyloid-β peptides;  Drug treatment;  Muscarinic receptors;  Plaque deposition

Document Type: Article
Source: Scopus

Sukstanskii, A.L., Yablonskiy, D.A.
On the role of neuronal magnetic susceptibility and structure symmetry on gradient echo MR signal formation
(2014) Magnetic Resonance in Medicine, 71 (1), pp. 345-353. 

Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States

Purpose Phase images obtained by gradient-recalled echo (GRE) MRI provide new contrast in the brain that is distinct from that obtained with conventional T1-weighted and T2-weighted images. The results are especially intriguing in white matter where both signal amplitude and phase display anisotropic properties. However, the biophysical origins of these phenomena are not well understood. The goal of this article is to provide a comprehensive theory of GRE signal formation based on a realistic model of neuronal structure. Methods We use Maxwell equations to find the distribution of magnetic field induced by myelin sheath and axon. We account for both anisotropy of neuronal tissue "magnetic micro-architecture" and anisotropy of myelin sheath magnetic susceptibility. Results Model describes GRE signal comprising of three compartments - axonal, myelin, and extracellular. Both axonal and myelin water signals have frequency shifts that are affected by the magnetic susceptibility anisotropy of long molecules forming lipid bilayer membranes. These parts of frequency shifts reach extrema for axon oriented perpendicular to the magnetic field and are zeros in a parallel case. Myelin water signal is substantially non-monoexponential. Conclusions Both, anisotropy of neuronal tissue "magnetic micro-architecture" and anisotropy of myelin sheath magnetic susceptibility, are important for describing GRE signal phase and magnitude. © 2013 Wiley Periodicals, Inc.

Author Keywords
gradient echo;  magnetic susceptibility;  phase contrast;  tissue anisotropy;  white matter

Document Type: Article
Source: Scopus

Udan-Johns, M.a , Bengoechea, R.a , Bell, S.b , Shao, J.a , Diamond, M.I.a , True, H.L.c , Weihl, C.C.a , Baloh, B.H.b
Prion-like nuclear aggregation of TDP-43 during heat shock is regulated by HSP40/70 chaperones
(2014) Human Molecular Genetics, 23 (1), art. no. ddt408, pp. 157-170. 

a Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, United States
b Department of Neurology, Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8730 Alden Drive, Los Angeles, CA 90048, United States
c Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, United States

TDP-43 aggregation in the cytoplasm or nucleusis a key feature of the pathology of amyotrophic lateral sclerosis and frontotemporal dementia and is observed in numerous other neurodegenerative diseases, including Alzheimer's disease. Despite this fact, the inciting events leading to TDP-43 aggregation remain unclear. We observed that endogenous TDP-43 undergoes reversible aggregation in the nucleus after the heat shock and that this behavior is mediated by the C-terminal prion domain. Substitution of the prion domain from TIA-1 or an authentic yeast prion domain from RNQ1 into TDP-43 can completely recapitulate heat shock-induced aggregation. TDP-43 is constitutively bound to members of the Hsp40/Hsp70 family, and we found that heat shockinduced TDP-43 aggregation is mediated by the availability of these chaperones interacting with the inherently disordered C-terminal prion domain. Finally, we observed that the aggregation of TDP-43 during heat shock led to decreased binding tohnRNPA1, and a change in TDP-43 RNA-binding partners suggesting that TDP-43 aggregation alters its function in response to misfolded protein stress. These findings indicate that TDP-43 shares properties with physiologic prions from yeast, in that self-aggregation is mediated by a Q/N-rich disordered domain, is modulated by chaperone proteins and leads to altered function of the protein. Furthermore, they indicate that TDP-43 aggregation is regulated by chaperone availability, explaining the recurrent observation of TDP-43 aggregates in degenerative diseases of both the brain and muscle where protein homeostasis is disrupted. © The Author 2013. Published by Oxford University Press. All rights reserved.

Document Type: Article
Source: Scopus

Langer, J.K.a , Rodebaugh, T.L.a b , Menatti, A.R.b , Weeks, J.W.b , Schneier, F.R.c
Psychometric Properties of the Gaze Anxiety Rating Scale: Convergent, Discriminant, and Factorial Validity
(2014) Cognitive Behaviour Therapy, 43 (1), pp. 49-59. 

a Department of Psychology, Washington University in St. Louis, St. Louis, United States
b Department of Psychology, Ohio University, Athens, United States
c Columbia University Medical Center, New York, United States

Fear and avoidance of gaze are two features thought to be associated with problematic social anxiety. Avoidance of eye contact has been linked with such undesirable traits as deceptiveness, insincerity, and lower self-esteem. The Gaze Anxiety Rating Scale (GARS) is a self-report measure designed to assess gaze anxiety and avoidance, but its psychometric properties have only been assessed in one preliminary study. We further investigated psychometric properties of the GARS by assessing convergent and factorial validity. We obtained a two-factor solution: gaze anxiety and avoidance across situations (1) in general (GARS-General) and (2) related to dominance communication (GARS-Dominance). The GARS-General factor related more strongly to social anxiety than the GARS-Dominance, and convergent validity of the factors was supported by expected relationships with personality and social anxiety variables. Our results indicate that the GARS subscales are psychometrically valid measures of gaze aversion, supporting their use in future study of the relationship between social anxiety and eye contact behavior. © 2014 Swedish Association for Behaviour Therapy.

Author Keywords
dominance;  eye contact;  factor analysis;  Gaze Anxiety Rating Scale;  social anxiety

Document Type: Article
Source: Scopus

Stout, M.J., Epplin, K., Wood, A., Trudell, A.
Sleep-disordered breathing and adverse pregnancy outcomes: Pamidi et al
(2014) American Journal of Obstetrics and Gynecology, 210 (1), pp. 87-88. 

Department of Obstetrics and Gynecology, Washington University in St. Louis, St. Louis, MO, United States

Document Type: Note
Source: Scopus

Deutsch, A.R.a b , Slutske, W.S.a b , Heath, A.C.b c , Madden, P.A.F.b c , Martin, N.G.d
Substance use and sexual intercourse onsets in adolescence: A genetically informative discordant twin design
(2014) Journal of Adolescent Health, 54 (1), pp. 114-116. Cited 1 time.

a Department of Psychological Sciences, University of Missouri-Columbia, 122 Psychology Building, Columbia, MO 65211, United States
b Midwest Alcohol Research Center, Columbia, MO, United States
c Department of Psychiatry, Washington University, St. Louis, MO, United States
d Queensland Institute of Medical Research, Brisbane, Australia

Purpose Using a genetically informed, discordant twin analysis, the objective of this study was to examine whether earlier onset of drinking and smoking behaviors predicted early sexual intercourse onset. Methods Over 3,400 adult same-sex twins from the Australian Twin Registry completed a structured interview that included retrospective reports on onsets of smoking, drinking, intoxication, and sexual intercourse and conduct disorder symptoms. A two-level frailty model estimated within-twin-pair and between-twin-pair comparisons. Onsets of smoking, drinking, drunkenness, and conduct disorder symptoms were estimated as sexual intercourse onset predictors. Results After controlling for conduct disorder, smoking and drinking onset did not predict sexual intercourse onset for either within-twin-pair or between-twin-pair comparisons. Drunkenness onset had a significant effect on sexual intercourse onset, such that twins who first experienced alcohol intoxication at a younger age than their co-twins were also more likely to have sex earlier than their co-twins. Conclusions Relationships between substance use and sexual intercourse onsets may be due mostly to shared underlying factors; there was only a small relation between intoxication onset and sexual intercourse onset, and no direct relation between smoking and drinking onset and sexual intercourse onset. © 2014 Society for Adolescent Health and Medicine. All rights reserved.

Author Keywords
Problem behavior theory;  Sexual intercourse onset;  Substance use onset;  Twin study

Document Type: Article
Source: Scopus

Jin, X.a , Bermudez, I.b , Steinbach, J.H.a
The Nicotinic α5 Subunit Can Replace Either an Acetylcholine-Binding or Nonbinding Subunit in the α4β2* Neuronal Nicotinic Receptor
(2014) Molecular Pharmacology, 85 (1), pp. 11-17. 

a Department of Anesthesiology, Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, United States
b Department of Biological and Medical Sciences, Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, United Kingdom

Heteropentameric neuronal nicotinic receptors assemble so that the canonical acetylcholine-binding sites are located at the interfaces between two pairs of subunits, while the fifth subunit does not participate in a canonical transmitter-binding site. Several subunits are considered to be unable to participate in forming a functional receptor when they occupy a position that would contribute to such a site, including the α5 subunit. The α5 subunit is of interest because of its apparent involvement in nicotine dependence and in the control of dopamine release. We have examined this question using α4 and β2 subunits in concatemeric constructs with the α5 subunit, expressed in Xenopus oocytes. Using dimeric constructs of a4 and β2 subunits expressed with free α5 and pentameric constructs incorporating a single copy of α5, we find that the α5 subunit can occupy the position of a nonbinding subunit, or replace a β2 subunit participating in a canonical binding site. The resulting receptors functionally resemble pentamers assembled with two copies of α4 and three copies of β2. Functional receptors apparently cannot be formed with α5 subunits in both canonical binding sites. These observations extend the present ideas on the possible positions in the pentamer that may be occupied by the α5 subunit, and suggest that additional physiologic or pharmacological subtypes of neuronal nicotinic receptors may be present in neurons. Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics.

Document Type: Article
Source: Scopus

O'Neill, P.R.a , Giri, L.a , Karunarathne, W.K.A.a , Patel, A.K.b , Venkatesh, K.V.b , Gautam, N.a c
The structure of dynamic GPCR signaling networks
(2014) Wiley Interdisciplinary Reviews: Systems Biology and Medicine, 6 (1), pp. 115-123. 

a Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Chemical Engineering, Indian Institute of Technology, Mumbai, India
c Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States

G-protein-coupled receptors (GPCRs) stimulate signaling networks that control a variety of critical physiological processes. Static information on the map of interacting signaling molecules at the basis of many cellular processes exists, but little is known about the dynamic operation of these networks. Here we focus on two questions. First, Is the network architecture underlying GPCR-activated cellular processes unique in comparison with others such as transcriptional networks? We discuss how spatially localized GPCR signaling requires uniquely organized networks to execute polarized cell responses. Second, What approaches overcome challenges in deciphering spatiotemporally dynamic networks that govern cell behavior? We focus on recently developed microfluidic and optical approaches that allow GPCR signaling pathways to be triggered and perturbed with spatially and temporally variant input while simultaneously visualizing molecular and cellular responses. When integrated with mathematical modeling, these approaches can help identify design principles that govern cell responses to extracellular signals. We outline why optical approaches that allow the behavior of a selected cell to be orchestrated continually are particularly well suited for probing network organization in single cells. © 2013 Wiley Periodicals, Inc.

Document Type: Article
Source: Scopus

Gronski, M.
Balance and Motor Deficits and the Role of Occupational Therapy in Children Who Are Deaf and Hard of Hearing: A Critical Appraisal of the Topic
(2013) Journal of Occupational Therapy, Schools, and Early Intervention, 6 (4), pp. 356-371. 

Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO, United States

Children who are deaf and hard of hearing (d/hh) have an increased risk of developing balance and gross-motor deficits compared to children with normal hearing. However, postural control and motor assessments are not routinely administered to children who are d/hh unless the child presents with easily observable deficits. The objective of this review is to analyze the literature regarding vestibular function, postural control and balance, and motor skills in children who are d/hh to determine the role for occupational therapy. Information was found using PubMed, OVID, Cochrane, EBSCO, and CINAHL with search terms "occupational therapy," "children," "deaf/hard of hearing," "hearing loss," "hearing impairment," "participation," "motor skills," "postural control," "vestibular," and "balance." Two reviewers independently screened titles and abstracts to identify the clinical use of each and identified randomized controlled trials, observational studies, and systematic reviews for full-text review. The reviewers each assessed study characteristics and rated study quality and indication-wide strength of evidence. Research on children who are d/hh often focuses on communication and social deficits. However, these children also demonstrate reduced levels of function in postural control, balance, and motor skills. Children who are d/hh often exhibit concurrent vestibular dysfunction; however, screening for these impairments is not a standard of practice. This literature review highlights the essential role of early intervention occupational therapy to prevent motor delays resulting in decreased participation for children who are d/hh. © 2013 Copyright Taylor and Francis Group, LLC.

Author Keywords
balance;  children;  deaf/hard of hearing;  hearing impairment;  hearing loss;  motor skills;  Occupational therapy;  participation;  postural control;  vestibular

Document Type: Article
Source: Scopus

Reynolds, L.C.a , Pineda, R.G.b c , Mathur, A.c , Vavasseur, C.d , Shah, D.K.e , Liao, S.c , Inder, T.c f g
Cerebral maturation on amplitude-integrated electroencephalography and perinatal exposures in preterm infants
(2013) Acta Paediatrica, International Journal of Paediatrics, . Article in Press. 

a Department of Psychiatry Washington University School of Medicine St. Louis, MO USA
b Program in Occupational Therapy Washington University School of Medicine St. Louis, MO USA
c Department of Pediatrics Washington University School of Medicine St. Louis, MO USA
d Department of Newborn Medicine National Maternity Hospital Dublin Ireland
e Department of Neonatology Barts and the London Childrens Hospital London UK
f Department of Neurology Washington University School of Medicine St. Louis, MO USA
g Department of Radiology Washington University School of Medicine St. Louis, MO USA

Aim: To determine the associations between perinatal exposures, cerebral maturation on amplitude-integrated encephalography (aEEG) and outcome. Methods: During this prospective cohort study, 136 infants ≤30 weeks estimated gestational age received 4 h of aEEG at four time points (between the first 2 weeks of life and term-equivalent age) during hospitalisation. Perinatal factors were documented. Associations between perinatal exposures and Burdjalov-scores were investigated. Neurodevelopmental outcome was assessed at the age of two. Results: Immature cyclicity on the initial aEEG recording was associated with higher CRIB score (p = 0.01), vaginal delivery (p = 0.02), male gender (p < 0.01) and death (p = 0.01). Perinatal factors associated with lower Burdjalov-scores included cerebral injury (p < 0.01), sepsis (p < 0.01), lower caffeine dose (p = 0.006), prolonged mechanical ventilation (p = 0.002) and death (p < 0.01). Burdjalov-scores at 30 (β = 2.62, p < 0.01) and 34 weeks postmenstrual age (β = 2.89, p = 0.05) predicted motor scores. Conclusion: aEEG measures of cyclicity and Burdjalov-scores in the first 6 weeks of life, with an emphasis on 30 and 34 weeks postmenstrual age, demonstrated associations with perinatal factors known to predict adverse neurodevelopmental outcome. © 2013 Foundation Acta Pædiatrica.

Author Keywords
Amplitude-integrated electroencephalography;  Cerebral maturation;  Neonatal intensive care;  Perinatal exposure;  Preterm infant

Document Type: Article in Press
Source: Scopus

Dribben, W.H.a , Creeley, C.E.b , Farber, U.b
Corrigendum to Low-level lead exposure triggers neuronal apoptosis in the developing mouse brain [Neurotoxicol Teratol 33 (2011) 473-480]
(2013) Neurotoxicology and Teratology, 35 (1), p. 54. 

a Division of Emergency Medicine, Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8072, St. Louis, MO 63110, United States
b Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8314, St. Louis, MO 63110, United States

Document Type: Erratum
Source: Scopus

Ju, Y.-E.S., Lucey, B.P., Holtzman, D.M.
Sleep and Alzheimer disease pathology-a bidirectional relationship
(2013) Nature Reviews Neurology, . Article in Press. 

Washington University School of Medicine, Department of Neurology, Washington University, 660 South Euclid Avenue, Box 8111, St Louis, MO 63110, USA

Factors other than age and genetics may increase the risk of developing Alzheimer disease (AD). Accumulation of the amyloid-β (Aβ) peptide in the brain seems to initiate a cascade of key events in the pathogenesis of AD. Moreover, evidence is emerging that the sleep-wake cycle directly influences levels of Aβ in the brain. In experimental models, sleep deprivation increases the concentration of soluble Aβ and results in chronic accumulation of Aβ, whereas sleep extension has the opposite effect. Furthermore, once Aβ accumulates, increased wakefulness and altered sleep patterns develop. Individuals with early Aβ deposition who still have normal cognitive function report sleep abnormalities, as do individuals with very mild dementia due to AD. Thus, sleep and neurodegenerative disease may influence each other in many ways that have important implications for the diagnosis and treatment of AD.

Document Type: Article in Press
Source: Scopus

Laurens, J.a , Meng, H.b , Angelaki, D.b
Neural representation of orientation relative to gravity in the macaque cerebellum
(2013) Neuron, 80 (6), pp. 1508-1518. 

a Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, United States

A fundamental challenge for maintaining spatial orientation and interacting with the world is knowledge of our orientation relative to gravity, i.e., head tilt. Sensing gravity is complicated because of Einstein's equivalence principle, in which gravitational and translational accelerations are physically indistinguishable. Theory has proposed that this ambiguity is solved by tracking head tilt through multisensory integration. Here we identify a group of Purkinje cells in the caudal cerebellar vermis with responses that reflect an estimate of head tilt. These tilt-selective cells are complementary to translation-selective Purkinje cells, such that their population activities sum to the net gravitoinertial acceleration encoded by the otolith organs, as predicted by theory. These findings reflect the remarkable ability of the cerebellum for neural computation and provide quantitative evidence for a neural representation of gravity, whose calculation relies on long-postulated theoretical concepts such as internal models and Bayesian priors. © 2013 Elsevier Inc.

Document Type: Article
Source: Scopus

Zu, T.a b , Liu, Y.a b , Bañez-Coronel, M.a b , Reid, T.a b , Pletnikova, O.c , Lewis, J.d , Miller, T.M.e , Harms, M.B.e , Falchook, A.E.f , Subramony, S.H.a f , Ostrow, L.W.g , Rothstein, J.D.g , Troncoso, J.C.c , Ranum, L.P.W.a b f h
RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia
(2013) Proceedings of the National Academy of Sciences of the United States of America, 110 (51), pp. E4968-E4977. 

a Center for NeuroGenetics, College of Medicine, University of Florida, Gainesville, FL 32610, United States
b Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, FL 32610, United States
c Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
d Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL 32610, United States
e Department of Neurology, Washington University in St. Louis, St. Louis, MO 63110, United States
f Department of Neurology, College of Medicine, University of Florida, Gainesville, FL 32610, United States
g Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
h Genetics Institute, College of Medicine, University of Florida, Gainesville, FL 32610, United States

The finding that a GGGGCC (G4C2) hexanucleotide repeat expansion in the chromosome 9 ORF 72 (C9ORF72) gene is a common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) links ALS/FTD to a large group of unstable microsatellite diseases. Previously, we showed that microsatellite expansion mutations can be bidirectionally transcribed and that these mutations express unexpected proteins by a unique mechanism, repeat-associated non-ATG (RAN) translation. In this study, we show that C9ORF72 antisense transcripts are elevated in the brains of C9ORF72 expansion-positive [C9(+)] patients, and antisense GGCCCC (G2C 4) repeat-expansion RNAs accumulate in nuclear foci in brain. Additionally, sense and antisense foci accumulate in blood and are potential biomarkers of the disease. Furthermore, we show that RAN translation occurs from both sense and antisense expansion transcripts, resulting in the expression of six RAN proteins (antisense: Pro-Arg, Pro-Ala, Gly-Pro; and sense: Gly-Ala, Gly-Arg, Gly-Pro). These proteins accumulate in cytoplasmic aggregates in affected brain regions, including the frontal and motor cortex, hippocampus, and spinal cord neurons, with some brain regions showing dramatic RAN protein accumulation and clustering. The finding that unique antisense G 2C4 RNA foci and three unique antisense RAN proteins accumulate in patient tissues indicates that bidirectional transcription of expanded alleles is a fundamental pathologic feature of C9ORF72 ALS/FTD. Additionally, these findings suggest the need to test therapeutic strategies that target both sense and antisense RNAs and RAN proteins in C9ORF72 ALS/FTD, and to more broadly consider the role of antisense expression and RAN translation across microsatellite expansion diseases.

Author Keywords
Clustered aggregates;  Cytoplasmic inclusions;  Noncoding RNA

Document Type: Article
Source: Scopus

Hanley, D.F.a , Chabot, R.b , Mould, W.A.a , Morgan, T.c , Naunheim, R.d , Sheth, K.N.e , Chiang, W.f , Prichep, L.S.b
Use of brain electrical activity for the identification of hematomas in mild traumatic brain injury
(2013) Journal of Neurotrauma, 30 (24), pp. 2051-2056. 

a Division of Brain Injury Outcomes, Johns Hopkins University School of Medicine, Baltimore, MD, United States
b Department of Psychiatry, NYU School of Medicine, Brain Research Laboratories, 462 First Avenue, New York, NY, 10016, United States
c Department of Clinical Research, Johns Hopkins University, Baltimore, MD, United States
d Department of Emergency Medicine, Washington University School of Medicine, St. Louis, MO, United States
e Division of Neuro-Critical Care and Stroke, University of Maryland School of Medicine, R. Adams Cowley Shock Trauma Center, Baltimore, MD, United States
f Department of Emergency Medicine, NYU School of Medicine and Bellevue Hospital Center, New York, NY, United States

This study investigates the potential clinical utility in the emergency department (ED) of an index of brain electrical activity to identify intracranial hematomas. The relationship between this index and depth, size, and type of hematoma was explored. Ten minutes of brain electrical activity was recorded from a limited montage in 38 adult patients with traumatic hematomas (CT scan positive) and 38 mild head injured controls (CT scan negative) in the ED. The volume of blood and distance from recording electrodes were measured by blinded independent experts. Brain electrical activity data were submitted to a classification algorithm independently developed traumatic brain injury (TBI) index to identify the probability of a CT+traumatic event. There was no significant relationship between the TBI-Index and type of hematoma, or distance of the bleed from recording sites. A significant correlation was found between TBI-Index and blood volume. The sensitivity to hematomas was 100%, positive predictive value was 74.5%, and positive likelihood ratio was 2.92. The TBI-Index, derived from brain electrical activity, demonstrates high accuracy for identification of traumatic hematomas. Further, this was not influenced by distance of the bleed from the recording electrodes, blood volume, or type of hematoma. Distance and volume limitations noted with other methods, (such as that based on near-infrared spectroscopy) were not found, thus suggesting the TBI-Index to be a potentially important adjunct to acute assessment of head injury. Because of the life-Threatening risk of undetected hematomas (false negatives), specificity was permitted to be lower, 66%, in exchange for extremely high sensitivity. © Copyright 2013, Mary Ann Liebert, Inc. 2013.

Author Keywords
hematoma;  mild traumatic brain injury;  neuroimaging;  quantitative EEG

Document Type: Article
Source: Scopus

Firszt, J.B.a , Reeder, R.M.a , Holden, T.A.a , Burton, H.b c , Chole, R.A.a d
Changes in auditory perceptions and cortex resulting from hearing recovery after extended congenital unilateral hearing loss
(2013) Frontiers in Systems Neuroscience, 7 (DEC), art. no. 108, . 

a Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO, United States
b Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
d Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States

Monaural hearing induces auditory system reorganization. Imbalanced input also degrades time-intensity cues for sound localization and signal segregation for listening in noise. While there have been studies of bilateral auditory deprivation and later hearing restoration (e.g., cochlear implants), less is known about unilateral auditory deprivation and subsequent hearing improvement. We investigated effects of long-term congenital unilateral hearing loss on localization, speech understanding, and cortical organization following hearing recovery. Hearing in the congenitally affected ear of a 41 year old female improved significantly after stapedotomy and reconstruction. Pre-operative hearing threshold levels showed unilateral, mixed, moderately-severe to profound hearing loss. The contralateral ear had hearing threshold levels within normal limits. Testing was completed prior to, and 3 and 9 months after surgery. Measurements were of sound localization with intensity-roved stimuli and speech recognition in various noise conditions. We also evoked magnetic resonance signals with monaural stimulation to the unaffected ear. Activation magnitudes were determined in core, belt, and parabelt auditory cortex regions via an interrupted single event design. Hearing improvement following 40 years of congenital unilateral hearing loss resulted in substantially improved sound localization and speech recognition in noise. Auditory cortex also reorganized. Contralateral auditory cortex responses were increased after hearing recovery and the extent of activated cortex was bilateral, including a greater portion of the posterior superior temporal plane. Thus, prolonged predominant monaural stimulation did not prevent auditory system changes consequent to restored binaural hearing. Results support future research of unilateral auditory deprivation effects and plasticity, with consideration for length of deprivation, age at hearing correction and degree and type of hearing loss. © 2013 Firszt, Reeder, Holden, Burton and Chole.

Author Keywords
Brain imaging;  Conductive;  Congenital;  Sound localization;  Speech recognition;  Stapedotomy;  Unilateral hearing loss

Document Type: Article
Source: Scopus

Bugg, J.M.a , Scullin, M.K.a b
Controlling Intentions: The Surprising Ease of Stopping After Going Relative to Stopping After Never Having Gone
(2013) Psychological Science, 24 (12), pp. 2463-2471. 

a Department of Psychology, Washington University in St. Louis, United States
b Department of Neurology, Emory University School of Medicine, United States

Decades of cognitive-control research have highlighted the difficulty of controlling a prepotent response. We examined whether having prepotent prospective-memory intentions similarly heightens the difficulty associated with stopping an intention once a prospective-memory task is finished. In three experiments, participants encoded a prospective-memory intention (e.g., press Q in response to the targets corn and dancer) and subsequently encountered either four targets or zero targets. Instructions then indicated that the prospective-memory task was finished. In a follow-up task, the targets appeared, and commission errors were recorded. Surprisingly, it was easier for participants to stop the intention when it had been fulfilled (four-target condition) than when it had gone unfulfilled (zero-target condition; Experiments 1 and 2). This was true even after intention cancellation (Experiment 2). Although repeatedly performing an intention strengthens target-action links, it appears to enable deactivation of the intention, a process that is largely target specific (Experiment 3). We relate these findings to the Zeigarnik effect, target-action deactivation, and reconsolidation theories. © The Author(s) 2013.

Author Keywords
cognitive processes;  prospective memory;  response inhibition

Document Type: Article
Source: Scopus

Ching, J.K.a , Ju, J.S.a , Pittman, S.K.a , Margeta, M.b , Weihl, C.C.a
Increased autophagy accelerates colchicine-induced muscle toxicity
(2013) Autophagy, 9 (12), pp. 2115-2125. 

a Department of Neurology, Hope Center for Neurological Diseases, Washington University School of Medicine, St. Louis, MO, United States
b Department of Pathology, University of California San Francisco School of Medicine, San Francisco, CA, United States

Colchicine treatment is associated with an autophagic vacuolar myopathy in human patients. The presumed mechanism of colchicine-induced myotoxicity is the destabilization of the microtubule system that leads to impaired autophagosome-lysosome fusion and the accumulation of autophagic vacuoles. Using the MTOR inhibitor rapamycin we augmented colchicine's myotoxic effect by increasing the autophagic flux; this resulted in an acute myopathy with muscle necrosis. In contrast to myonecrosis induced by cardiotoxin, myonecrosis induced by a combination of rapamycin and colchicine was associated with accumulation of autophagic substrates such as LC3-II and SQSTM1; as a result, autophagic vacuoles accumulated in the center of myofibers, where LC3-positive autophagosomes failed to colocalize with the lysosomal protein marker LAMP2. A similar pattern of central LC3 accumulation and myonecrosis is seen in human patients with colchicine myopathy, many of whom have been treated with statins (HMGCR/HMG-CoA reductase inhibitors) in addition to colchicine. In mice, cotreatment with colchicine and simvastatin also led to muscle necrosis and LC3 accumulation, suggesting that, like rapamycin, simvastatin activates autophagy. Consistent with this, treatment of mice with four different statin medications enhanced autophagic flux in skeletal muscle in vivo. Polypharmacy is a known risk factor for toxic myopathies; our data suggest that some medication combinations may simultaneously activate upstream autophagy signaling pathways while inhibiting the degradation of these newly synthesized autophagosomes, resulting in myotoxicity. © 2013 Landes Bioscience.

Author Keywords
Autophagy;  Colchicine;  HMG-CoA reductase inhibitor;  Toxic myopathy;  Vacuolar myopathy

Document Type: Article
Source: Scopus

Sorscher, S.
Metastatic pancreatic poorly differentiated neuroendocrine carcinoma: Current treatment considerations
(2013) Clinical Advances in Hematology and Oncology, 11 (12), pp. 748-749. Cited 1 time.

Department of Internal Medicine, Oncology Division, Washington University, St Louis, MO, United States

Document Type: Note
Source: Scopus

Zaidman, C.M.a , Harms, M.B.a b , Pestronk, A.a
Ultrasound of inherited vs. acquired demyelinating polyneuropathies
(2013) Journal of Neurology, 260 (12), pp. 3115-3121. 

a Department of Neurology, Washington University, School of Medicine, 660 S. Euclid Ave, Box 8111, St. Louis, MO 63110, United States
b Department of Neurology, Hope Center for Neurological Disorders, St. Louis, MO 63110, United States

We compared features of nerve enlargement in inherited and acquired demyelinating neuropathies using ultrasound. We measured median and ulnar nerve cross-sectional areas in proximal and distal regions in 128 children and adults with inherited [Charcot-Marie-Tooth-1 (CMT-1) (n = 35)] and acquired [chronic inflammatory demyelinating polyneuropathy (CIDP) (n = 55), Guillaine-Barre syndrome (GBS) (n = 21) and multifocal motor neuropathy (MMN) (n = 17)] demyelinating neuropathies. We classified nerve enlargement by degree and number of regions affected. We defined patterns of nerve enlargement as: none, no enlargement; mild, nerves enlarged but never more than twice normal; regional, nerves normal in at least one region and enlarged more than twice normal in at least one region; diffuse, nerves enlarged at all four regions with at least one region more than twice normal size. Nerve enlargement was commonly diffuse (89 %) and generally more than twice normal size in CMT-1, but not (p < 0.001) in acquired disorders which mostly had either no, mild or regional nerve enlargement [CIDP (64 %), GBS (95 %), and MMN (100 %)]. In CIDP, subjects treated within 3 months of disease onset had less nerve enlargement than those treated later. Ultrasound identified patterns of diffuse nerve enlargement can be used to screen patients suspected of having CMT-1. Normal, mildly, or regionally enlarged nerves in demyelinating polyneuropathy suggests an acquired etiology. Early treatment in CIDP may impede nerve enlargement. © 2013 Springer-Verlag Berlin Heidelberg.

Author Keywords
Charcot-Marie-Tooth (CMT);  Chronic inflammatory demyelinating polyneuropathy (CIDP);  Guillaine-Barre syndrome (GBS);  Multifocal motor neuropathy (MMN);  Nerve;  Ultrasound

Document Type: Article
Source: Scopus

Rajagopal, A.a , Shimony, J.S.e , McKinstry, R.C.e , Altaye, M.b d , Maloney, T.a , Mangano, F.T.c d , Limbrick, D.D.f , Holland, S.K.a d , Jones, B.V.a d , Simpson, S.a , Mercer, D.f , Yuan, W.a d
White matter microstructural abnormality in children with hydrocephalus detected by probabilistic diffusion tractography
(2013) American Journal of Neuroradiology, 34 (12), pp. 2379-2385. 

a Pediatric Neuroimaging Research Consortium, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
b Department of Radiology, Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
c Division of Pediatric Neurosurgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
d University of Cincinnati College of Medicine, Cincinnati, OH, United States
e Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
f Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States

BACKGROUND AND PURPOSE: Hydrocephalus is a severe pathologic condition in which WM damage is a major factor associated with poor outcomes. The goal of the study was to investigate tract-based WM connectivity and DTI measurements in children with hydrocephalus by using the probabilistic diffusion tractography method. MATERIALS AND METHODS: Twelve children with hydrocephalus and 16 age-matched controls were included in the study. Probabilistic diffusion tractography was conducted to generate tract-based connectivity distribution and DTI measures for the genu of the corpus callosum and the connectivity index. Tract-based summary measurements, including the connectivity index and DTI measures (fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity), were calculated and compared between the 2 study groups. RESULTS: Tract-based summary measurement showed a higher percentage of voxels with lower normalized connectivity index values in the WM tracts in children with hydrocephalus. In the genu of the corpus callosum, the left midsegment of the corticospinal tract, and the right midsegment of the corticospinal tract, the normalized connectivity index value in children with hydrocephalus was found to be significantly lower (P < .05, corrected). The tract-based DTI measures showed that the children with hydrocephalus had significantly higher mean diffusivity, axial diffusivity, and radial diffusivity in the genu of the corpus callosum, left midsegment of the corticospinal tract, and right midsegment of corticospinal tract and lower fractional anisotropy in the genu of the corpus callosum (P < .05, corrected). CONCLUSIONS: The analysis of WM connectivity showed that the probabilistic diffusion tractography method is a sensitive tool to detect the decreased continuity in WM tracts that are under the direct influence of mechanical distortion and increased intracranial pressure in hydrocephalus. This voxel-based connectivity method can provide quantitative information complementary to the standard DTI summary measures.

Document Type: Article
Source: Scopus

Sadowsky, C.L.a b , Hammond, E.R.a , Strohl, A.B.c , Commean, P.K.d , Eby, S.A.e , Damiano, D.L.f , Wingert, J.R.g , Bae, K.T.h , McDonald III, J.W.a i
Lower extremity functional electrical stimulation cycling promotes physical and functional recovery in chronic spinal cord injury
(2013) Journal of Spinal Cord Medicine, 36 (6), pp. 623-631. 

a International Center for Spinal Cord Injury, Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD, United States
b Department of Physical Medicine and Rehabilitation, Department of Neurology (JWM), John Hopkins, Baltimore, MD, United States
c Division of Plastic and Reconstructive Surgery, Mount Sinai Medical Center, New York, NY, United States
d Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO, United States
e Department of Physical Medicine and Rehabilitation, Sinai Hospital, Baltimore, MD, United States
f National Institutes of Health, Bethesda, MD, United States
g Department of Health and Wellness, University of North Carolina, Asheville, NC, United States
h Department of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
i Department of Neurology, Neurological Surgery, Anatomy and Neurobiology, Washington University School of Medicine, St Louis, MO, United States

Objective: To examine the effect of long-termlower extremity functional electrical stimulation (FES) cycling on the physical integrity and functional recovery in people with chronic spinal cord injury (SCI). Design: Retrospective cohort, mean follow-up 29.1 months, and cross-sectional evaluation. Setting: Washington University Spinal Cord Injury Neurorehabilitation Center, referral center. Participants: Twenty-five people with chronic SCI who received FES during cycling were matched by age, gender, injury level, and severity, and duration of injury to 20 people with SCI who received range of motion and stretching. Intervention: Lower extremity FES during cycling as part of an activity-based restorative treatment regimen. Main outcome measure: Change in neurological function: motor, sensory, and combined motor-sensory scores (CMSS) assessed by the American Spinal Injury Association Impairment scale. Response was defined as ≥1 point improvement. Results: FES was associated with an 80% CMSS responder rate compared to 40% in controls. An average 9.6 CMSS point loss among controls was offset by an average 20-point gain among FES subjects. Quadriceps muscle mass was on average 36% higher and intra/inter-muscular fat 44% lower, in the FES group. Hamstring and quadriceps muscle strength was 30 and 35% greater, respectively, in the FES group. Quality of life and daily function measures were significantly higher in FES group. Conclusion: FES during cycling in chronic SCI may provide substantial physical integrity benefits, including enhanced neurological and functional performance, increased muscle size and force-generation potential, reduced spasticity, and improved quality of life. © The Academy of Spinal Cord Injury Professionals, Inc. 2013.

Author Keywords
Activity-based restorative therapy;  Assistive technology;  Cycle ergometry;  Functional electrical stimulation;  Paraplegia;  Physical muscle strength;  Quality of life;  Rehabilitation;  Spasticity;  Spinal cord injury;  Tetraplegia

Document Type: Article
Source: Scopus

Eggebrecht, A.T.a , White, B.R.a b , Ferradal, S.L.a c , Zhan, Y.d , Snyder, A.Z.a e , Dehghani, H.d , Culver, J.P.a b c
A quantitative spatial comparison of high-density diffuse optical tomography and fMRI cortical mapping
(2012) Biomedical Optics, BIOMED 2012, pp. BSu4A.2. 

a Department of Radiology, Washington University School of Medicine, 4525 Scott Ave, East Bldg. CB 8225, St Louis, MO, 63110, United States
b Department of Physics, Washington University, One Brookings Dr., St Louis, MO, 63110, United States
c Department of Biomedical Engineering, Washington University School of Engineering and Applied Science, Whittaker Hall, One Brookings Dr., St Louis, MO, 63130, United States
d School of Computer Science, University of Birmingham, B15 2TT, United Kingdom
e Department of Neurology, Washington University School of Medicine, 660 S. Euclid Ave, St Louis, MO, 63110, United States

Image-quality of high-density diffuse optical tomography is evaluated against fMRI using functional maps of visual cortex as a benchmark. Co-registered subject-specific light models have an average localization error of 4.4 +/- 1 mm. © OSA 2012.

Document Type: Conference Paper
Source: Scopus

Ferradal, S.L.a b , Liao, S.M.c , Eggebrecht, A.T.b , Inder, T.E.b c , Culver, J.P.a b
Functional connectivity mapping in hospitalized infants using diffuse optical tomography
(2012) Biomedical Optics, BIOMED 2012, pp. BSu4A.7. 

a Department of Biomedical Engineering, Washington University, St. Louis, MO, United States
b Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Pediatrics Washington University, St. Louis, MO, United States

Resting-state functional connectivity is an attractive tool for studying brain function in neonates. Here, we present fcDOT maps of multiple networks detected in premature infants at the bedside. © 2012.

Document Type: Conference Paper
Source: Scopus