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WUSTL Neuroscience Publications Archive - April 2016

Scopus weekly report.

April 22, 2016

Zhao, Y.a , Wen, J.b , Cross, A.H.c , Yablonskiy, D.A.b 
On the relationship between cellular and hemodynamic properties of the human brain cortex throughout adult lifespan
(2016) NeuroImage, 133, pp. 417-429. 

DOI: 10.1016/j.neuroimage.2016.03.022

a Department of Chemistry, Washington University in St. Louis, One Brookings Drive, Saint Louis, MO, United States
b Department of Radiology, Washington University in St. Louis, One Brookings Drive, Saint Louis, MO, United States
c Department of Neurology, Washington University in St. Louis, One Brookings Drive, Saint Louis, MO, United States

Abstract
Establishing baseline MRI biomarkers for normal brain aging is significant and valuable for separating normal changes in the brain structure and function from different neurological diseases. In this paper for the first time we have simultaneously measured a variety of tissue specific contributions defining R2* relaxation of the gradient recalled echo (GRE) MRI signal in human brains of healthy adults (ages 22 to 74 years) and related these measurements to tissue structural and functional properties. This was accomplished by separating tissue (R2t *) and extravascular BOLD contributions to the total tissue specific GRE MRI signal decay (R2*) using an advanced version of previously developed Gradient Echo Plural Contrast Imaging (GEPCI) approach and the acquisition and post-processing methods that allowed the minimization of artifacts related to macroscopic magnetic field inhomogeneities, and physiological fluctuations.Our data (20 healthy subjects) show that in most cortical regions R2t * increases with age while tissue hemodynamic parameters, i.e. relative oxygen extraction fraction (OEFrel), deoxygenated cerebral blood volume (dCBV) and tissue concentration of deoxyhemoglobin (Cdeoxy) remain practically constant. We also found the important correlations characterizing the relationships between brain structural and hemodynamic properties in different brain regions. Specifically, thicker cortical regions have lower R2t * and these regions have lower OEF.The comparison between GEPCI-derived tissue specific structural and functional metrics and literature information suggests that (a) regions in a brain characterized by higher R2t * contain higher concentration of neurons with less developed cellular processes (dendrites, spines, etc.), (b) regions in a brain characterized by lower R2t * represent regions with lower concentration of neurons but more developed cellular processes, and (c) the age-related increases in the cortical R2t * mostly reflect the age-related increases in the cellular packing density.The baseline GEPCI-based biomarkers obtain herein could serve to help distinguish age-related changes in brain cellular and hemodynamic properties from changes which occur due to the neurodegenerative diseases. © 2016 Elsevier Inc.

Author Keywords
Aging;  BOLD;  Cellular structure;  GEPCI;  Hemodynamic properties;  MRI

Document Type: Article
Source: Scopus
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Hayashi, Y.a b , Nishimune, H.c , Hozumi, K.d , Saga, Y.e f , Harada, A.g , Yuzaki, M.b , Iwatsubo, T.h , Kopan, R.i j , Tomita, T.a i 
A novel non-canonical Notch signaling regulates expression of synaptic vesicle proteins in excitatory neurons
(2016) Scientific Reports, 6, art. no. 23969, . 

DOI: 10.1038/srep23969

a Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan
b Department of Physiology, School of Medicine, Keio University, Tokyo, Japan
c Department of Anatomy and Cell Biology, University of Kansas Medical School, Kansas City, KS, United States
d Department of Immunology, Tokai University School of Medicine, Kanagawa, Japan
e Division of Mammalian Development, National Institute of Genetics, Shizuoka, Japan
f Department of Genetics, SOKENDAI, Shizuoka, Japan
g Department of Cell Biology, Graduate School of Medicine, Osaka University, Osaka, Japan
h Department of Neuropathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
i Department of Developmental Biology, Washington University, School of Medicine, St. Louis, MO, United States
j Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, College of Medicine, Cincinnati, OH, United States

Abstract
Notch signaling plays crucial roles for cellular differentiation during development through γ-secretase-dependent intramembrane proteolysis followed by transcription of target genes. Although recent studies implicate that Notch regulates synaptic plasticity or cognitive performance, the molecular mechanism how Notch works in mature neurons remains uncertain. Here we demonstrate that a novel Notch signaling is involved in expression of synaptic proteins in postmitotic neurons. Levels of several synaptic vesicle proteins including synaptophysin 1 and VGLUT1 were increased when neurons were cocultured with Notch ligands-expressing NIH3T3 cells. Neuron-specific deletion of Notch genes decreased these proteins, suggesting that Notch signaling maintains the expression of synaptic vesicle proteins in a cell-autonomous manner. Unexpectedly, cGMP-dependent protein kinase (PKG) inhibitor, but not γ-secretase inhibitor, abolished the elevation of synaptic vesicle proteins, suggesting that generation of Notch intracellular domain is dispensable for this function. These data uncover a ligand-dependent, but γ-secretase-independent, non-canonical Notch signaling involved in presynaptic protein expression in postmitotic neurons.

Document Type: Article
Source: Scopus
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Trela, C.J.a c , Piasecki, T.M.a c , Bartholow, B.D.a c , Heath, A.C.b c c , Sher, K.J.a c c 
The natural expression of individual differences in self-reported level of response to alcohol during ecologically assessed drinking episodes
(2016) Psychopharmacology, pp. 1-11. Article in Press. 

DOI: 10.1007/s00213-016-4270-5

a Department of Psychological Sciences, University of Missouri, 210 McAlester Hall, Columbia, MO, United States
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
c Alcoholism Research Center, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Rationale: Low sensitivity to alcohol is a well-established risk factor for alcohol use disorder (AUD). However, little is known about how the low sensitivity phenotype is expressed on a fine-grained, momentary level in drinkers’ daily experience. Objectives: The objective of the study is to evaluate individual differences in subjective states and appraisals of alcoholic beverages during the ascending limb of real-world drinking episodes. Methods: Social drinkers (N = 398) with varying degrees of alcohol sensitivity as indexed by the Self-Rating of the Effects of Alcohol form (SRE; Schuckit et al. in Addiction 92:979–988, 1997a) recorded diary entries over a 3-week monitoring period (2576 drinking episodes containing 6546 moments). Hierarchical linear modeling was used to evaluate whether individual differences in alcohol sensitivity predicted differing intra-episode estimated blood alcohol concentration (eBAC) trajectories, ratings of subjective states, and drink appraisals. Results: Lower self-reported alcohol sensitivity was associated with consuming “too much, too fast,” as indicated by a steeper slope of ascending eBAC. In models adjusted for momentary eBAC level, participants reporting lower alcohol sensitivity at baseline showed blunted subjective intoxication and drink-contingent punishment. Conclusions: The results suggest that low sensitivity to alcohol is associated with a blunting of some forms of subjective feedback (i.e., perceptions of intoxication and punishment) that might typically encourage drinking restraint. This may ‘tip the scales’ toward excess consumption and could help to explain why a low alcohol sensitivity forecasts AUD. © 2016 Springer-Verlag Berlin Heidelberg

Author Keywords
Alcohol sensitivity;  Alcohol use disorder;  Ecological momentary assessment;  Level of response to alcohol

Document Type: Article in Press
Source: Scopus
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Weidler, B.J., Bugg, J.M.
Transfer of location-specific control to untrained locations
(2016) Quarterly Journal of Experimental Psychology, pp. 1-16. Article in Press. 

DOI: 10.1080/17470218.2015.1111396

Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, USA

Abstract
Recent research highlights a seemingly flexible and automatic form of cognitive control that is triggered by potent contextual cues, as exemplified by the location-specific proportion congruence effect--reduced compatibility effects in locations associated with a high as compared to low likelihood of conflict. We investigated just how flexible location-specific control is by examining whether novel locations effectively cue control for congruency-unbiased stimuli. In two experiments, biased (mostly compatible or mostly incompatible) training stimuli appeared in distinct locations. During a final block, unbiased (50% compatible) stimuli appeared in novel untrained locations spatially linked to biased locations. The flanker compatibly effect was reduced for unbiased stimuli in novel locations linked to a mostly incompatible compared to a mostly compatible location, indicating transfer. Transfer was observed when stimuli appeared along a linear function (Experiment 1) or in rings of a bullseye (Experiment 2). The novel transfer effects imply that location-specific control is more flexible than previously reported and further counter the complex stimulus–response learning account of location-specific proportion congruence effects. We propose that the representation and retrieval of control settings in untrained locations may depend on environmental support and the presentation of stimuli in novel locations that fall within the same categories of space as trained locations. © 2016 The Experimental Psychology Society

Author Keywords
Cognitive control;  Context-specific proportion congruency effect;  Flanker;  Location-specific control;  Transfer

Document Type: Article in Press
Source: Scopus
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Rajagopal, R.a , Bligard, G.W.a , Zhang, S.a , Yin, L.b , Lukasiewicz, P.a , Semenkovich, C.F.b 
Functional deficits precede structural lesions in mice with high-fat diet-induced diabetic retinopathy
(2016) Diabetes, 65 (4), pp. 1072-1084. 

DOI: 10.2337/db15-1255

a Department of Ophthalmology and Visual Sciences, Washington University, School of Medicine in St. Louis, St. Louis, MO, United States
b Division of Endocrinology, Metabolism and Lipid Research, Washington University, School of Medicine in St. Louis, St. Louis, MO, United States

Abstract
Obesity predisposes to human type 2 diabetes, the most common cause of diabetic retinopathy. To determine if high-fat diet-induced diabetes in mice can model retinal disease, we weaned mice to chow or a high-fat diet and tested the hypothesis that diet-induced metabolic disease promotes retinopathy. Compared with controls, mice fed a diet providing 42% of energy as fat developed obesity-related glucose intolerance by 6 months. There was no evidence of microvascular disease until 12 months, when trypsin digests and dye leakage assays showed high fat-fed mice had greater atrophic capillaries, pericyte ghosts, and permeability than controls. However, electroretinographic dysfunction began at 6 months in high fat-fed mice, manifested by increased latencies and reduced amplitudes of oscillatory potentials compared with controls. These electroretinographic abnormalities were correlated with glucose intolerance. Unexpectedly, retinas from high fat-fed mice manifested striking induction of stress kinase and neural inflammasome activation at 3 months, before the development of systemic glucose intolerance, electroretinographic defects, or microvascular disease. These results suggest that retinal disease in the diabetic milieu may progress through inflammatory and neuroretinal stages long before the development of vascular lesions representing the classic hallmark of diabetic retinopathy, establishing a model for assessing novel interventions to treat eye disease. © 2016 by the American Diabetes Association.

Document Type: Article
Source: Scopus
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Carlozzi, N.E.a , Schilling, S.G.a b , Lai, J.-S.c d , Perlmutter, J.S.e f , Nance, M.A.g h , Waljee, J.F.i , Miner, J.A.a , Barton, S.K.e , Goodnight, S.M.a , Dayalu, P.j 
HDQLIFE: the development of two new computer adaptive tests for use in Huntington disease, Speech Difficulties, and Swallowing Difficulties
(2016) Quality of Life Research, pp. 1-11. Article in Press. 

DOI: 10.1007/s11136-016-1273-y

a Department of Physical Medicine and Rehabilitation, University of Michigan, North Campus Research Complex, 2800 Plymouth Road, Building NCRC B14, Room G216, Ann Arbor, MI, United States
b Institute for Social Research, University of Michigan, Ann Arbor, MI, United States
c Center on Outcomes, Research and Education, Evanston Northwestern Healthcare, Northwestern University, Evanston, IL, United States
d Institute for Health Services Research and Policy Studies, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
e Departments of Neurology, Radiology, and Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO, United States
f Program in Occupational Therapy and Program in Physical Therapy, Washington University School of Medicine, St. Louis, MO, United States
g Hennepin County Medical Center, Minneapolis, MN, United States
h Department of Medical and Molecular Genetics, Indiana University, Indianapolis, IN, United States
i Department of Surgery, University of Michigan, Ann Arbor, MI, United States
j Department of Neurology, University of Michigan, Ann Arbor, MI, United States

Abstract
Purpose: Huntington disease (HD) is an autosomal dominant neurodegenerative disease which results in several progressive symptoms, including bulbar dysfunction (i.e., speech and swallowing difficulties). Although difficulties in speech and swallowing in HD have a negative impact on health-related quality of life, no patient-reported outcome measure exists to capture these difficulties that are specific to HD. Thus, we developed a new patient-reported outcome measure for use in the Huntington Disease Health-Related Quality of Life (HDQLIFE) Measurement System that focused on the impact that difficulties with speech and swallowing have on HRQOL in HD. Methods: Five hundred and seven individuals with prodromal and/or manifest HD completed 47 newly developed items examining speech and swallowing difficulties. Unidimensional item pools were identified using exploratory factor analysis and confirmatory factor analysis (EFA and CFA, respectively). Item response theory (IRT) was used to calibrate the final measures. Results: EFA and CFA identified two separate unidimensional sets of items: Speech Difficulties (27 items) and Swallowing Difficulties (16 items). Items were calibrated separately for these two measures and resulted in item banks that can be administered as computer adaptive tests (CATs) and/or 6-item, static short forms. Reliability of both of these measures was supported through high correlations between the simulated CAT scores and the full item bank. Conclusions: CATs and 6-item calibrated short forms were developed for HDQLIFE Speech Difficulties and HDQLIFE Swallowing Difficulties. These measures both demonstrate excellent psychometric properties and may have clinical utility in other populations where speech and swallowing difficulties are prevalent. © 2016 Springer International Publishing Switzerland

Author Keywords
HDQLIFE;  Health-related quality of life;  Huntington disease;  Neuro-QoL;  Patient-reported outcome (PRO);  PROMIS;  Speech difficulties;  Swallowing difficulties

Document Type: Article in Press
Source: Scopus
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Rogers, C.
Here/In This Issue and There/Abstract Thinking: The Propensity for Revenge
(2016) Journal of the American Academy of Child and Adolescent Psychiatry, 55 (4), pp. 255-256. 

DOI: 10.1016/j.jaac.2016.01.009

Washington University, School of Medicine, St. Louis, United States

Document Type: Article
Source: Scopus
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Cicero, T.J., Ellis, M.S.
Nonmedical prescription-opioid use and heroin use
(2016) New England Journal of Medicine, 374 (13), pp. 1295-1296. 

DOI: 10.1056/NEJMc1601875

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

Document Type: Letter
Source: Scopus
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Baranger, D.A.A.a b , Ifrah, C.a , Prather, A.A.c , Carey, C.E.a , Corral-Frías, N.S.d , Conley, E.D.e , Hariri, A.R.f , Bogdan, R.a b d 
PER1 rs3027172 genotype interacts with early life stress to predict problematic alcohol use, but not reward-related ventral striatum activity
(2016) Frontiers in Psychology, 7 (MAR), art. no. 464, . 

DOI: 10.3389/fpsyg.2016.00464

a Brain Laboratory, Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
b Division of Biology and Biomedical Sciences, Washington University in St. Louis, St. Louis, MO, United States
c Department of Psychiatry, University of California, San Francisco, San Francisco, CA, United States
d Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
e 23andMe, Mountain View, CA, United States
f Laboratory of NeuroGenetics, Department of Psychology and Neuroscience, Duke University, Durham, NC, United States

Abstract
Increasing evidence suggests that the circadian and stress regulatory systems contribute to alcohol use disorder (AUD) risk, which may partially arise through effects on reward-related neural function. The C allele of the PER1 rs3027172 single nucleotide polymorphism (SNP) reduces PER1 expression in cells incubated with cortisol and has been associated with increased risk for adult AUD and problematic drinking among adolescents exposed to high levels of familial psychosocial adversity. Using data from undergraduate students who completed the ongoing Duke Neurogenetics Study (DNS) (n = 665), we tested whether exposure to early life stress (ELS; Childhood Trauma Questionnaire) moderates the association between rs3027172 genotype and later problematic alcohol use (Alcohol Use Disorders Identification Test) as well as ventral striatum (VS) reactivity to reward (card-guessing task while functional magnetic resonance imaging data were acquired). Initial analyses found that PER1 rs3027172 genotype interacted with ELS to predict both problematic drinking and VS reactivity; minor C allele carriers, who were also exposed to elevated ELS reported greater problematic drinking and exhibited greater ventral striatum reactivity to reward-related stimuli. When gene × covariate and environment × covariate interactions were controlled for, the interaction predicting problematic alcohol use remained significant (p < 0.05, corrected) while the interaction predicting VS reactivity was no longer significant. These results extend our understanding of relationships between PER1 genotype, ELS, and problematic alcohol use, and serve as a cautionary tale on the importance of controlling for potential confounders in studies of moderation including gene × environment interactions. © 2016 Baranger, Ifrah, Prather, Carey, Corral-Frías, Drabant Conley, Hariri and Bogdan.

Author Keywords
Alcohol;  Circadian;  Early life stress;  GxE;  PER1;  Stress;  Ventral striatum

Document Type: Article
Source: Scopus
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Price, A.R.a b , Peelle, J.E.c , Bonner, M.F.a , Grossman, M.a b , Hamilton, R.H.a b 
Causal evidence for a mechanism of semantic integration in the angular Gyrus as revealed by high-definition transcranial direct current stimulation
(2016) Journal of Neuroscience, 36 (13), pp. 3829-3838. 

DOI: 10.1523/JNEUROSCI.3120-15.2016

a Center for Cognitive Neuroscience, University of Pennsylvania, Philadelphia, PA, United States
b Department of Neurology, University of Pennsylvania, Philadelphia, PA, United States
c Department of Otolaryngology, Washington University in St Louis, St Louis, MO, United States

Abstract
A defining aspect of human cognition is the ability to integrate conceptual information into complex semantic combinations. For example, we can comprehend “plaid” and “jacket” as individual concepts, but we can also effortlessly combine these concepts to form the semantic representation of “plaid jacket.” Many neuroanatomic models of semantic memory propose that heteromodal cortical hubs integrate distributed semantic features into coherent representations. However, little work has specifically examined these proposed integrative mechanisms and the causal role of these regions in semantic integration. Here, we test the hypothesis that the angular gyrus (AG) is critical for integrating semantic information by applying high-definition transcranial direct current stimulation (tDCS) to an fMRI-guided region-of-interest in the left AG. We found that anodal stimulation to the left AG modulated semantic integration but had no effect on a letter-string control task. Specifically, anodal stimulation to the left AG resulted in faster comprehension of semantically meaningful combinations like “tiny radish” relative to non-meaningful combinations, such as “fast blueberry,” when compared to the effects observed during sham stimulation and stimulation to a right-hemisphere control brain region. Moreover, the size of the effect from brain stimulation correlated with the degree of semantic coherence between the word pairs. These findings demonstrate that the left AG plays a causal role in the integration of lexical-semantic information, and that high-definition tDCS to an associative cortical hub can selectively modulate integrative processes in semantic memory. © 2016 the authors.

Author Keywords
Brain stimulation;  Compositionality;  Inferior parietal cortex;  Semantic integration;  Semantic memory;  tDCS

Document Type: Article
Source: Scopus
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Brier, M.R.a , Day, G.S.a , Snyder, A.Z.a b , Tanenbaum, A.B.a , Ances, B.M.a b 
N-methyl-D-aspartate receptor encephalitis mediates loss of intrinsic activity measured by functional MRI
(2016) Journal of Neurology, pp. 1-9. Article in Press. 

DOI: 10.1007/s00415-016-8083-6

a Department of Neurology, School of Medicine, Washington University in St. Louis, 660 S Euclid Ave, St. Louis, MO, United States
b Department of Radiology, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Spontaneous brain activity is required for the development and maintenance of normal brain function. Many disease processes disrupt the organization of intrinsic brain activity, but few pervasively reduce the amplitude of resting state blood oxygen level dependent (BOLD) fMRI fluctuations. We report the case of a female with anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis, longitudinally studied during the course of her illness to determine the contribution of NMDAR signaling to spontaneous brain activity. Resting state BOLD fMRI was measured at the height of her illness and 18 weeks following discharge from hospital. Conventional resting state networks were defined using established methods. Correlation and covariance matrices were calculated by extracting the BOLD time series from regions of interest and calculating either the correlation or covariance quantity. The intrinsic activity was compared between visits, and to expected activity from 45 similarly aged healthy individuals. Near the height of the illness, the patient exhibited profound loss of consciousness, high-amplitude slowing of the electroencephalogram, and a severe reduction in the amplitude of spontaneous BOLD fMRI fluctuations. The patient’s neurological status and measures of intrinsic activity improved following treatment. We conclude that NMDAR-mediated signaling plays a critical role in the mechanisms that give rise to organized spontaneous brain activity. Loss of intrinsic activity is associated with profound disruptions of consciousness and cognition. © 2016 Springer-Verlag Berlin Heidelberg

Author Keywords
fMRI;  Functional connectivity;  NMDA receptor encephalitis;  Resting-state

Document Type: Article in Press
Source: Scopus
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Martel, M.M.a , Levinson, C.A.b , Lee, C.A.a , Smith, T.E.a 
Impulsivity Symptoms as Core to the Developmental Externalizing Spectrum
(2016) Journal of Abnormal Child Psychology, pp. 1-8. Article in Press. 

DOI: 10.1007/s10802-016-0148-6

a Psychology Department, University of Kentucky, 207C Kastle Hall, Lexington, KY, United States
b Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Impulsivity is posited to be a key part of the externalizing spectrum during childhood, but this idea has received minimal empirical attention. The goal of the present investigation was to utilize network analysis to determine whether behavioral impulsivity symptoms are key components of the externalizing network across several developmental periods from preschool into adolescence. Participants were 109 preschoolers (64 % male) ages 3 to 6, 237 children (59 % male) ages 6 to 9, 372 children (59 % male) ages 10 to 13, and 357 adolescents (59 % male) ages 13 to 17 and their parents. Parents completed ratings of Attention-Deficit/Hyperactivity Disorder (ADHD) and Oppositional Defiant Disorder (ODD) symptoms on a well-validated rating scale. Network analyses indicated that ADHD and ODD were somewhat differentiated in preschool, becoming united by behavioral impulsivity symptoms during early childhood, and then differentiating into inattention versus externalizing clusters later during childhood and in adolescence. Behavioral impulsivity symptoms were core to the externalizing spectrum across most developmental periods, but core inattentive and ODD symptoms were also identified in line with progressive differentiation. These results suggest the increasing importance of impulsivity symptoms across development, explaining externalizing comorbidity and potentially serving as a viable target for childhood interventions for externalizing problems. © 2016 Springer Science+Business Media New York

Author Keywords
Adolescence;  Child development;  Externalizing disorder;  Impulsivity

Document Type: Article in Press
Source: Scopus
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Dubois, B.a ap , Hampel, H.a b , Feldman, H.H.c , Scheltens, P.d , Aisen, P.e , Andrieu, S.f , Bakardjian, H.g , Benali, H.h , Bertram, L.i j , Blennow, K.k , Broich, K.l , Cavedo, E.b m , Crutch, S.n , Dartigues, J.-F.o , Duyckaerts, C.p , Epelbaum, S.a , Frisoni, G.B.q r , Gauthier, S.s , Genthon, R.t , Gouw, A.A.f u , Habert, M.-O.v w , Holtzman, D.M.x y , Kivipelto, M.z aa , Lista, S.b , Molinuevo, J.-L.ab ac , O'Bryant, S.E.ad , Rabinovici, G.D.ae , Rowe, C.af , Salloway, S.ag ah ai , Schneider, L.S.aj , Sperling, R.ak al , Teichmann, M.a , Carrillo, M.C.am , Cummings, J.an , Jack, C.R., Jr.ao 
Preclinical Alzheimer's disease: Definition, natural history, and diagnostic criteria
(2016) Alzheimer's and Dementia, 12 (3), pp. 292-323. 

DOI: 10.1016/j.jalz.2016.02.002

a Institute of Memory and Alzheimer's Disease (IM2A), Brain and Spine Institute (ICM), UMR S 1127 Frontlab, Department of Neurology, AP-HP, Pitié-Salpêtrière University Hospital, Sorbonne Universities, Pierre et Marie Curie University, Paris 06, Paris, France
b AXA Research Fund, UPMC Chair, Paris, France
c University of British Columbia, Canada
d Department of Neurology and Alzheimer Center, VU University Medical Center, Neuroscience Campus, Amsterdam, Netherlands
e University of Southern California, San Diego, CA, United States
f UMR1027, INSERM, Université Toulouse III, Toulouse University Hospital, France
g IHU-A-ICM, Institut des Neurosciences Translationnelles de Paris, Paris, France
h INSERM U1146, CNRS, UMR 7371, UPMC, UM CR2, Site Pitié-Salpêtrière, Paris, France
i Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), Institutes of Neurogenetics and Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany
j School of Public Health, Faculty of Medicine, Imperial College London, London, United Kingdom
k Clinical Neurochemistry Lab, Department of Neuroscience and Physiology, University of Gothenburg, Mölndal Hospital, Sahlgrenska University Hospital, Mölndal, Sweden
l Federal Institute for Drugs and Medical Devices, Bonn, Germany
m Laboratory of Alzheimer's Neuroimaging and Epidemiology, IRCCS Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
n Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, University College London, London, United Kingdom
o INSERM U 1219, Université de Bordeaux, France
p University Pierre et Marie Curie, Assistance Publique des Hôpitaux de Paris, Alzheimer-Prion Team, Institut du Cerveau et de la Moelle (ICM), Paris, France
q University Hospitals, University of Geneva, Geneva, Switzerland
r IRCCS Fatebenefratelli, Brescia, Italy
s McGill Center for Studies in Aging, Douglas Mental Health Research Institute, Montreal, Canada
t Fondation Pour la Recherche sur Alzheimer, Hôpital Pitié-Salpêtrière, Paris, France
u Department of Clinical Neurophysiology, MEG Center, VU University Medical Center, Amsterdam, Netherlands
v Sorbonne Universités, UPMC, Univ Paris 06, CNRS, INSERM, Laboratoire d'Imagerie Biomédicale, Paris, France
w AP-HP, Hôpital Pitié-Salpêtrière, Département de Médecine Nucléaire, Paris, France
x Department of Neurology, Washington University, Hope Center for Neurological Disorders, St. Louis, MO, United States
y Department of Neurology, Washington University, Knight Alzheimer's Disease Research Center, St. Louis, MO, United States
z Center for Alzheimer Research, Karolinska Institutet, Department of Geriatric Medicine, Karolinska University Hospital, Stockholm, Sweden
aa Institute of Clinical Medicine/ Neurology, University of Eastern Finland, Kuopio, Finland
ab Alzheimer's Disease and Other Cognitive Disorders Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
ac Barcelonaßeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain
ad Center for Alzheimer's and Neurodegenerative Disease Research, University of North Texas, Health Science CenterTX, United States
ae Memory and Aging Center, Department of Neurology, University of California San Francisco, San Francisco, CA, United States
af Department of Molecular Imaging, Austin Health, University of Melbourne, Australia
ag Memory and Aging Program, Butler Hospital, Alpert Medical School, Brown University, United States
ah Department of Neurology, Alpert Medical School, Brown University, United States
ai Department of Psychiatry, Alpert Medical School, Brown University, United States
aj Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
ak Harvard Medical School, Memory Disorders Unit, Center for Alzheimer Research and Treatment, Brigham and Women's Hospital, Boston, United States
al Harvard Medical School, Memory Disorders Unit, Center for Alzheimer Research and Treatment, Massachusetts General Hospital, Boston, United States
am Alzheimer's Association Division of Medical and Scientific Relations, Chicago, United States
an Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, United States
ao Department of Radiology, Mayo Clinic, Rochester, MN, United States

Abstract
During the past decade, a conceptual shift occurred in the field of Alzheimer's disease (AD) considering the disease as a continuum. Thanks to evolving biomarker research and substantial discoveries, it is now possible to identify the disease even at the preclinical stage before the occurrence of the first clinical symptoms. This preclinical stage of AD has become a major research focus as the field postulates that early intervention may offer the best chance of therapeutic success. To date, very little evidence is established on this "silent" stage of the disease. A clarification is needed about the definitions and lexicon, the limits, the natural history, the markers of progression, and the ethical consequence of detecting the disease at this asymptomatic stage. This article is aimed at addressing all the different issues by providing for each of them an updated review of the literature and evidence, with practical recommendations. © 2016 The Alzheimer's Association.

Author Keywords
Alzheimer's disease;  Amyloid PET;  Asymptomatic;  Biomarkers;  Blood biomarkers;  CSF biomarkers;  Diagnostic criteria;  Genetics;  MRI;  Pathophysiology;  Preclinical;  Tau PET

Document Type: Review
Source: Scopus
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Su, Y.a , Blazey, T.M.a , Owen, C.J.a , Christensen, J.J.a , Friedrichsen, K.a , Joseph-Mathurin, N.a , Wang, Q.a , Hornbeck, R.C.a , Ances, B.M.b, Snyder, A.Z.a b , Cash, L.A.a , Koeppe, R.A.c , Klunk, W.E.d , Galasko, D.e , Brickman, A.M.f , McDade, E.b , Ringman, J.M.g , Thompson, P.M.h, Saykin, A.J.i , Ghetti, B.i , Sperling, R.A.j , Johnson, K.A.j , Salloway, S.P.k , Schofield, P.R.l , Masters, C.L.m , Villemagne, V.L.m , Fox, N.C.n , Förster, S.o , Chen, K.p , Reiman, E.M.p , Xiong, C.q , Marcus, D.S.a , Weiner, M.W.r , Morris, J.C.b , Bateman, R.J.b , Benzinger, T.L.S.a 
Quantitative Amyloid imaging in autosomal Dominant Alzheimer's disease: Results from the DIAN study group
(2016) PLoS ONE, 11 (3), art. no. e0152082, . 

DOI: 10.1371/journal.pone.0152082

a Department of Radiology, Washington University, School of Medicine, Saint Louis, MO, United States
b Department of Neurology, Washington University, School of Medicine, Saint Louis, MO, United States
c Department of Radiology, University of Michigan, Ann Arbor, MI, United States
d University of Pittsburgh, School of Medicine, Pittsburgh, PA, United States
e University of California San Diego, San Diego, CA, United States
f Columbia University, New York, NY, United States
g Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
h Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
i Department of Radiology, Indiana University, Indianapolis, IN, United States
j Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
k Butler Hospital, Brown University, Providence, RI, United States
l Neuroscience Research Australia, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
m Florey Institute, University of Melbourne, Parkville, VIC, Australia
n Dememtia Research Centre, Institute of Neurology, London, United Kingdom
o Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) München/Tübingen, Dept. of Nuclear Medicine, Technische UniversitätMünchen, München, Germany
p Banner Alzheimer's Institute, Banner Health, 901 E. Willetta Street, Phoenix, AZ, United States
q Division of Biostatistics, Washington University, School of Medicine, Saint Louis, MO, United States
r Department of Radiology, University of California San Francisco, San Francisco, CA, United States

Abstract
Amyloid imaging plays an important role in the research and diagnosis of dementing disorders. Substantial variation in quantitative methods to measure brain amyloid burden exists in the field. The aim of this work is to investigate the impact of methodological variations to the quantification of amyloid burden using data from the Dominantly Inherited Alzheimer's Network (DIAN), an autosomal dominant Alzheimer's disease population. Cross-sectional and longitudinal [11C]-Pittsburgh Compound B (PiB) PET imaging data from the DIAN study were analyzed. Four candidate reference regions were investigated for estimation of brain amyloid burden. A regional spread function based technique was also investigated for the correction of partial volume effects. Cerebellar cortex, brain-stem, and white matter regions all had stable tracer retention during the course of disease. Partial volume correction consistently improves sensitivity to group differences and longitudinal changes over time. White matter referencing improved statistical power in the detecting longitudinal changes in relative tracer retention; however, the reason for this improvement is unclear and requires further investigation. Full dynamic acquisition and kinetic modeling improved statistical power although it may add cost and time. Several technical variations to amyloid burden quantification were examined in this study. Partial volume correction emerged as the strategy that most consistently improved statistical power for the detection of both longitudinal changes and across-group differences. For the autosomal dominant Alzheimer's disease population with PiB imaging, utilizing brainstem as a reference region with partial volume correction may be optimal for current interventional trials. Further investigation of technical issues in quantitative amyloid imaging in different study populations using different amyloid imaging tracers is warranted. © 2016 Su et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Document Type: Article
Source: Scopus
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Bundy, D.T.a , Pahwa, M.a , Szrama, N.a , Leuthardt, E.C.a b c d 
Decoding three-dimensional reaching movements using electrocorticographic signals in humans
(2016) Journal of Neural Engineering, 13 (2), art. no. 026021, . 

DOI: 10.1088/1741-2560/13/2/026021

a Department of Biomedical Engineering, Washington University in St. Louis, Campus Box 8057, 660 South Euclid, St Louis, MO, United States
b Department of Anatomy and Neurobiology, University in St. Louis, School of Medicine, St Louis, MO, United States
c Department of Neurological Surgery, Washington University in St. Louis, School of Medicine, Campus Box 8057, 660 South Euclid, St Louis, MO, United States
d Center for Innovation in Neuroscience and Technology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Objective. Electrocorticography (ECoG) signals have emerged as a potential control signal for brain-computer interface (BCI) applications due to balancing signal quality and implant invasiveness. While there have been numerous demonstrations in which ECoG signals were used to decode motor movements and to develop BCI systems, the extent of information that can be decoded has been uncertain. Therefore, we sought to determine if ECoG signals could be used to decode kinematics (speed, velocity, and position) of arm movements in 3D space. Approach. To investigate this, we designed a 3D center-out reaching task that was performed by five epileptic patients undergoing temporary placement of ECoG arrays. We used the ECoG signals within a hierarchical partial-least squares (PLS) regression model to perform offline prediction of hand speed, velocity, and position. Main Results. The hierarchical PLS regression model enabled us to predict hand speed, velocity, and position during 3D reaching movements from held-out test sets with accuracies above chance in each patient with mean correlation coefficients between 0.31 and 0.80 for speed, 0.27 and 0.54 for velocity, and 0.22 and 0.57 for position. While beta band power changes were the most significant features within the model used to classify movement and rest, the local motor potential and high gamma band power changes, were the most important features in the prediction of kinematic parameters. Significance. We believe that this study represents the first demonstration that truly three-dimensional movements can be predicted from ECoG recordings in human patients. Furthermore, this prediction underscores the potential to develop BCI systems with multiple degrees of freedom in human patients using ECoG. © 2016 IOP Publishing Ltd.

Author Keywords
BCI;  brain-computer interface;  ECoG;  electrocorticography;  neuroprosthetics

Document Type: Article
Source: Scopus
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Cameron, D.J.a , Pickett, K.A.b , Earhart, G.M.c , Grahn, J.A.a d 
The effect of dopaminergic medication on beat-based auditory timing in Parkinson's disease
(2016) Frontiers in Neurology, 7 (FEB), art. no. 19, . 

DOI: 10.3389/fneur.2016.00019

a Brain and Mind Institute, University of Western Ontario, London, ON, Canada
b Department of Kinesiology, University of Wisconsin-Madison, Madison, WI, United States
c Program in Physical Therapy, Department of Neuroscience, Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
d Department of Psychology, University of Western Ontario, London, ON, Canada

Abstract
Parkinson's disease (PD) adversely affects timing abilities. Beat-based timing is a mechanism that times events relative to a regular interval, such as the "beat" in musical rhythm, and is impaired in PD. It is unknown if dopaminergic medication influences beat-based timing in PD. Here, we tested beat-based timing over two sessions in participants with PD (OFF then ON dopaminergic medication) and in unmedicated control participants. People with PD and control participants completed two tasks. The first was a discrimination task in which participants compared two rhythms and determined whether they were the same or different. Rhythms either had a beat structure (metric simple rhythms) or did not (metric complex rhythms), as in previous studies. Discrimination accuracy was analyzed to test for the effects of beat structure, as well as differences between participants with PD and controls, and effects of medication (PD group only). The second task was the Beat Alignment Test (BAT), in which participants listened to music with regular tones superimposed, and responded as to whether the tones were "ON" or "OFF" the beat of the music. Accuracy was analyzed to test for differences between participants with PD and controls, and for an effect of medication in patients. Both patients and controls discriminated metric simple rhythms better than metric complex rhythms. Controls also improved at the discrimination task in the second vs. first session, whereas people with PD did not. For participants with PD, the difference in performance between metric simple and metric complex rhythms was greater (sensitivity to changes in simple rhythms increased and sensitivity to changes in complex rhythms decreased) when ON vs. OFF medication. Performance also worsened with disease severity. For the BAT, no group differences or effects of medication were found. Overall, these findings suggest that timing is impaired in PD, and that dopaminergic medication influences beat-based and non-beat-based timing differently. Judging the beat in music does not appear to be affected by PD or by dopaminergic medication. © 2016 Cameron, Pickett, Earhart and Grahn.

Author Keywords
Beat perception;  Dopamine;  Parkinson's disease;  Rhythm;  Timing

Document Type: Article
Source: Scopus
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Brace, E.J., DiAntonio, A.
Models of axon regeneration in Drosophila
(2016) Experimental Neurology, . Article in Press. 

DOI: 10.1016/j.expneurol.2016.03.014

Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA, 63110

Abstract
Maintaining neuronal connectivity in the face of injury and disease is a major challenge for the nervous system. The great length of axons makes them particularly vulnerable to insult with dire consequences for neuronal function. In the peripheral nervous system there is a program of axonal regeneration that can reestablish connectivity. In the mammalian central nervous system, however, injured axons have little or no capacity to regenerate. The molecular mechanisms that promote axon regeneration have begun to be identified and many of the implicated pathways are evolutionarily conserved. Here we discuss Drosophila models of axonal regrowth, describe insights derived from these studies, and highlight future directions in the use of the fly for dissecting the mechanisms of axonal regeneration. © 2016 Elsevier Inc.

Author Keywords
Axon injury;  Axon regeneration;  Degeneration;  Dendrite;  DLK;  Drosophila;  JNK;  Wallenda

Document Type: Article in Press
Source: Scopus
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Mazaika, P.K.a q , Weinzimer, S.A.b , Mauras, N.c n , Buckingham, B.d o , White, N.H.e p , Tsalikian, E.f m , Hershey, T.g h i p , Cato, A.j n , Aye, T.d o, Fox, L.c n , Wilson, D.M.d o , Tansey, M.J.f m , Tamborlane, W.b , Peng, D.a q , Raman, M.a , Marzelli, M.a k l q , Reiss, A.L.a d l q , Coffey, J.m , Cabbage, J.m , Salamati, S.m , Englert, K.n , Sikes, K.n , Ewen, T.n , Caswell, K.o , Steffen, A.b , Weyman, K.b , Zgorski, M.b , Ambrosino, J.b , Arbelaez, A.p , Levandoski, L.p , Starnes, A.p , Barnea-Goraly, N.q , Sperling, M.r , Becker, D.M.r , Cleary, P.r , Greenbaum, C.r , Moran, A.r 
Variations in brain volume and growth in young children with type 1 diabetes
(2016) Diabetes, 65 (2), pp. 476-485. Cited 1 time.

DOI: 10.2337/db15-1242

a Center for Interdisciplinary Brain Sciences Research, Department of Psychiatry and Behavioral Sciences, Stanford University, School of Medicine, Stanford, CA, United States
b Department of Pediatrics, Yale University, School of Medicine, New Haven, CT, United States
c Department of Pediatrics, Division of Endocrinology, Diabetes and Metabolism, Nemours Children's Health System, Jacksonville, FL, United States
d Department of Pediatrics, Stanford University, School of Medicine, Stanford, CA, United States
e Department of Pediatrics, Washington University in St. Louis, School of Medicine, St. Louis, MO, United States
f Department of Pediatric Endocrinology, University of Iowa, Iowa City, IA, United States
g Department of Psychiatry, Washington University in St. Louis, School of Medicine, St. Louis, MO, United States
h Department of Radiology, Washington University in St. Louis, School of Medicine, St. Louis, MO, United States
i Department of Neurology, Washington University in St. Louis, School of Medicine, St. Louis, MO, United States
j Division of Neurology, Nemours Children's Health System, Jacksonville, FL, United States
k Department of Bioengineering, Stanford University, School of Medicine, Stanford, CA, United States
l Department of Radiology, Stanford University, School of Medicine, Stanford, CA, United States
m Department of Pediatrics, University of Iowa, Carver College of Medicine, Iowa City, IA, United States
n Nemours Children's Health System, Jacksonville, FL, United States
o Division of Pediatric Endocrinology and Diabetes, Stanford University, Stanford, CA, United States
p Washington University in St. Louis, St. Louis, MO, United States
q Image Coordinating Center, Stanford University, Stanford, CA, United States
r Data and Safety Monitoring Board, United States

Abstract
Early-onset type 1 diabetes may affect the developing brain during a critical window of rapid brain maturation. Structural MRI was performed on 141 children with diabetes (4-10 years of age at study entry) and 69 age-matched control subjects at two time points spaced 18 months apart. For the children with diabetes, the mean (±SD) HbA1c level was 7.9 ± 0.9% (63 ± 9.8 mmol/mol) at both time points. Relative to control subjects, children with diabetes had significantly less growth of cortical gray matter volume and cortical surface area and significantly less growth of white matter volume throughout the cortex and cerebellum. For the population with diabetes, the change in the blood glucose level at the time of scan across longitudinal time points was negatively correlated with the change in gray and white matter volumes, suggesting that fluctuating glucose levels in children with diabetes may be associated with corresponding fluctuations in brain volume. In addition, measures of hyperglycemia and glycemic variation were significantly negatively correlated with the development of surface curvature. These results demonstrate that early-onset type 1 diabetes has widespread effects on the growth of gray and white matter in children whose blood glucose levels are well within the current treatment guidelines for the management of diabetes. © 2016 by the American Diabetes Association.

Document Type: Article
Source: Scopus
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Siddiqi, S.H.a , Abraham, N.K.b , Geiger, C.L.c , Karimi, M.d , Perlmutter, J.S.e , Black, K.J.f 
The human experience with intravenous levodopa
(2016) Frontiers in Pharmacology, 6 (JAN), art. no. 307, . Cited 1 time.

DOI: 10.3389/fphar.2015.00307

a Department of Psychiatry, Washington University, School of Medicine, St. Louis, MO, United States
b School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, Ottawa, ON, Canada
c Department of Internal Medicine, University of Washington, Seattle, WA, United States
d Department of Neurology, Washington University, School of Medicine, St. Louis, MO, United States
e Division of Biology and Biomedical Sciences, Washington University School of Medicine, Departments of Neurology, Radiology, and Anatomy and Neurobiology, St. Louis, MO, United States
f Division of Biology and Biomedical Sciences, Departments of Psychiatry, Neurology, Radiology, and Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Objective: To compile a comprehensive summary of published human experience with levodopa given intravenously, with a focus on information required by regulatory agencies. Background: While safe intravenous (IV) use of levodopa has been documented for over 50 years, regulatory supervision for pharmaceuticals given by a route other than that approved by the U.S. Food and Drug Administration (FDA) has become increasingly cautious. If delivering a drug by an alternate route raises the risk of adverse events, an investigational new drug (IND) application is required, including a comprehensive review of toxicity data. Methods: Over 200 articles referring to IV levodopa were examined for details of administration, pharmacokinetics, benefit, and side effects. Results: We identified 142 original reports describing IVLD use in humans, beginning with psychiatric research in 1959-1960 before the development of peripheral decarboxylase inhibitors. At least 2760 subjects have received IV levodopa, and reported outcomes include parkinsonian signs, sleep variables, hormone levels, hemodynamics, CSF amino acid composition, regional cerebral blood flow, cognition, perception and complex behavior. Mean pharmacokinetic variables were summarized for 49 healthy subjects and 190 with Parkinson's disease. Side effects were those expected from clinical experience with oral levodopa and dopamine agonists. No articles reported deaths or induction of psychosis. Conclusion: At least 2760 patients have received IV levodopa with a safety profile comparable to that seen with oral administration. © 2016 Siddiqi, Abraham, Geiger, Karimi, Perlmutter and Black.

Author Keywords
Carbidopa;  DOPA;  FDA;  IND;  Intravenous;  Levodopa;  Parkinson;  Pharmacokinetics

Document Type: Review
Source: Scopus
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Brier, M.R.a , McCarthy, J.E.b , Benzinger, T.L.S.c d , Stern, A.b , Su, Y.c , Friedrichsen, K.A.c , Morris, J.C.a d , Ances, B.M.a c d , Vlassenko, A.G.cd 
Local and distributed PiB accumulation associated with development of preclinical Alzheimer's disease
(2016) Neurobiology of Aging, 38, pp. 104-111. 

DOI: 10.1016/j.neurobiolaging.2015.10.025

a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Mathematics, 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 The Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Amyloid-beta plaques are a hallmark of Alzheimer's disease (AD) that can be assessed by amyloid imaging (e.g., Pittsburgh B compound [PiB]) and summarized as a scalar value. Summary values may have clinical utility but are an average over many regions of interest, potentially obscuring important topography. This study investigates the longitudinal evolution of amyloid topographies in cognitively normal older adults who had normal (N = 131) or abnormal (N = 26) PiB scans at baseline. At 3 years follow-up, 16 participants with a previously normal PiB scan had conversion to PiB scans consistent with preclinical AD. We investigated the multivariate relationship (canonical correlation) between baseline and follow-up PiB topographies. Furthermore, we used penalized regression to investigate the added information derived from PiB topography compared to summary measures. PiB accumulation can be local, that is, a topography predicting the same topography in the future, and/or distributed, that is, one topography predicting another. Both local and distributed PiB accumulation was associated with conversion of PiB status. Additionally, elements of the multivariate topography, and not the commonly used summary scalar, correlated with future PiB changes. Consideration of the entire multivariate PiB topography provides additional information regarding the development of amyloid-beta pathology in very early preclinical AD. © 2016 Elsevier Inc.

Author Keywords
Amyloid beta;  Canonical correlation;  Lasso;  Multivariate statistics

Document Type: Article
Source: Scopus
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Cavazos-Rehg, P.A.a , Housten, A.J.b , Krauss, M.J.a , Sowles, S.J.a , Spitznagel, E.L.c , Chaloupka, F.J.d , Grucza, R.a , Johnston, L.D.e , O'Malley, P.M.e , Bierut, L.J.a 
Selected State Policies and Associations With Alcohol Use Behaviors and Risky Driving Behaviors Among Youth: Findings from Monitoring the Future Study
(2016) Alcoholism: Clinical and Experimental Research, . Article in Press. 

DOI: 10.1111/acer.13041

a Department of Psychiatry Washington University School of Medicine St. Louis, Missouri
b Department of Surgery Washington University School of Medicine St. Louis, Missouri
c Division of Biostatistics Washington University School of Medicine St. Louis, Missouri
d Department of Economics University of Illinois at Chicago Chicago, Illinois
e Institute for Social Research University of Michigan Ann Arbor, Michigan

Abstract
Background: Effective policies that can reduce alcohol use behaviors and impaired driving among young people at a population level are needed. Graduated driver licensing (GDL) laws increase the driving privileges of young novice drivers as they age and gain more driving experience. In this study, we seek to determine the effects of GDLs on risky driving behaviors of youth and to assess if GDLs have an unintended effect on underage drinking behaviors. Methods: We utilized 2000 to 2013 data on 12th grade students from the Monitoring the Future (MTF) study, an ongoing, annual national survey (since 1975) that studies the substance use behaviors of adolescents, as well as data on GDL laws obtained via the Insurance Institute for Highway Safety (IIHS). We conducted a series of regular logistic regression models that included fixed effects for year and state, and adjusted for demographic characteristics, school characteristics, and other state alcohol policies. Results: Total weighted sample size was 129,289 12th graders. Past month alcohol use and binge drinking (i.e., ≥5 drinks on one occasion) in the past 2 weeks were 45 and 26%, respectively. Seventeen percent of respondents reported riding with a driver who drank alcohol. Nearly 12% reported driving in the past 2 weeks after drinking alcohol, and 7% reported driving after binge drinking. Over half of the students lived in a state with a "good" GDL law. The logistic regression models suggest a link between restrictive GDL policies and a reduction of alcohol use behaviors and risky driving behaviors among youth. Conclusions: Our findings indicate that the effects of GDLs extend beyond driving-related risks and into other drinking-related behaviors that pose immediate or delayed health risks for young people. We speculate that GDLs may dictate social norms and expectations for youth risk behaviors, and should be maximized throughout the United States. © 2016 Research Society on Alcoholism.

Author Keywords
Adolescent;  Automobile Driving;  Drinking and Driving;  Policy

Document Type: Article in Press
Source: Scopus
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Dashti, H.S.a , Follis, J.L.b , Smith, C.E.a , Tanaka, T.c , Garaulet, M.d , Gottlieb, D.J.e f g , Hruby, A.h , Jacques, P.F.i , Kiefte-De Jong, J.C.j k , Lamon-Fava, S.l , Scheer, F.A.J.L.e f , Bartz, T.M.m n , Kovanen, L.o , Wojczynski, M.K.p , Frazier-Wood, A.C.q , Ahluwalia, T.S.r s t , Perälä, M.-M.u , Jonsson, A.r , Muka, T.j , Kalafati, I.P.v , Mikkilä, V.w x , Ordovás, J.M.a y z 
Gene-environment interactions of circadian-related genes for cardiometabolic traits
(2015) Diabetes Care, 38 (8), pp. 1456-1466. 

DOI: 10.2337/dc14-2709

a Jean MayerU.S. Department of Agriculture Human Nutrition Research Center on Aging, Nutrition and Genomics Laboratory, Tufts University, Boston, MA, United States
b Department of Mathematics, Computer Science and Cooperative Engineering, University of St. Thomas, Houston, TX, United States
c Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, United States
d Department of Physiology, University of Murcia, Murcia, Spain
e Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, United States
f Division of Sleep Medicine, Harvard Medical School, Boston, MA, United States
g Sleep Disorders Center, VA Boston Healthcare System, Boston, MA, United States
h Department of Nutrition, Harvard School of Public Health, Boston, MA, United States
i Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging, Nutritional Epidemiology Laboratory, Tufts University, Boston, MA, United States
j Erasmus Medical Center, Department of Epidemiology, Rotterdam, Netherlands
k Leiden University College, Global Public Health, Hague, Netherlands
l Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging, Cardiovascular Nutrition Laboratory, Tufts University, Boston, MA, United States
m Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, United States
n Department of Biostatistics, University of Washington, Seattle, WA, United States
o National Institute for Health and Welfare (THL), Department of Mental Health and Substance Abuse Services, Helsinki, Finland
p Department of Genetics, Washington University School of Medicine, St.Louis, MO, United States
q U.S. Department of Agriculture/Agricultural Research Service Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
r Novo Nordisk Foundation Centre for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
s Copenhagen Prospective Studies on Asthma in Childhood, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
t Danish Pediatric Asthma Centre, Gentofte Hospital, Copenhagen, Denmark
u Department of Chronic Disease Prevention, National Institute for Health and Welfare (THL), Helsinki, Finland
v Department OfNutrition and Dietetics, Harokopio University, Athens, Greece
w Department of Food and Environmental Sciences, Division of Nutrition, University of Helsinki, Helsinki, Finland
x Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland
y Department of Epidemiology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
z Instituto Madrileño de Estudios Avanzados en Alimentacion (IMDEA-FOOD), Madrid, Spain

Abstract
OBJECTIVE Common circadian-related gene variants associate with increased risk for metabolic alterations including type 2 diabetes. However, little is known about whether diet and sleep could modify associations between circadian-related variants (CLOCK-rs1801260, CRY2-rs11605924, MTNR1B-rs1387153, MTNR1B-rs10830963, NR1D1-rs2314339) and cardiometabolic traits (fasting glucose [FG], HOMA-insulin resistance, BMI, waist circumference, and HDL-cholesterol) to facilitate personalized recommendations. RESEARCH DESIGN AND METHODS We conducted inverse-variance weighted, fixed-effectmeta-analyses of results of adjusted associations and interactions between dietary intake/sleep duration and selected variants on cardiometabolic traits from 15 cohort studies including up to 28,190 participants of European descent from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. RESULTS We observed significant associations between relative macronutrient intakes and glycemic traits and short sleep duration (&lt;7 h) and higher FG and replicated known MTNR1B associations with glycemic traits. No interactions were evident after accounting for multiple comparisons. However, we observed nominally significant interactions (all P &lt; 0.01) between carbohydrate intake and MTNR1B-rs1387153 for FG with a 0.003 mmol/L higher FG with each additional 1% carbohydrate intake in the presence of the T allele, between sleep duration and CRY2-rs11605924 for HDL-cholesterol with a 0.010 mmol/L higher HDLcholesterol with each additional hour of sleep in the presence of the A allele, and between long sleep duration (≥9 h) and MTNR1B-rs1387153 for BMI with a 0.60 kg/m2 higher BMI with long sleep duration in the presence of the T allele relative to normal sleep duration (≥7 to &lt;9 h). CONCLUSIONS Our results suggest that lower carbohydrate intake and normal sleep duration may ameliorate cardiometabolic abnormalities conferred by common circadian-related genetic variants. Until further mechanistic examination of the nominally significant interactions is conducted, recommendations applicable to the general population regarding dietdspecifically higher carbohydrate and lower fat compositiondand normal sleep duration should continue to be emphasized among individuals with the investigated circadian-related gene variants. ©2015 by the American Diabetes Association.

Document Type: Article
Source: Scopus

April 14, 2016

Henn, C.M., Patel, A., Wall, L.B., Goldfarb, C.A.
Outcomes Following Cubital Tunnel Surgery in Young Patients: The Importance of Nerve Mobility
(2016) Journal of Hand Surgery, 41 (4), pp. e1-e7. 

DOI: 10.1016/j.jhsa.2016.01.014

Department of Orthopaedic Surgery, Washington University, School of Medicine, Campus Box 8233, 660 South Euclid Ave., Saint Louis, MO, United States

Abstract
Purpose To investigate the outcomes following surgical management of unstable and stable ulnar nerves at the elbow in young patients. Methods We retrospectively reviewed the charts of 67 patients who were 30 years old or younger when they underwent primary cubital tunnel surgery at our institution over a 10-year period. In 34 (45%) of these patients, the ulnar nerve either subluxated or perched on the medial epicondyle with elbow flexion and made up the "unstable" cohort. The remaining 42 patients made up the "stable" cohort. Preoperative, intraoperative, and postoperative data were obtained from the patients' charts. Thirty-nine patients completed the following outcome measures: Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH), visual analog scale (VAS) for pain and treatment satisfaction, return to sport or full activities, and the presence of persistent symptoms. Results At an average of 5.6 years following surgery, the unstable cohort had a significantly lower QuickDASH score (6.4 vs 18.6) and a significantly higher VAS for treatment satisfaction (8.7 vs 5.9) compared with the stable cohort. The unstable cohort was also significantly less likely to experience residual symptoms (43% vs 94%), persistent numbness (39% vs 44%), or persistent tingling (22% vs 56%) compared with the stable cohort. Within the stable cohort, patients who underwent simultaneous carpal tunnel release exhibited improved VAS and QuickDASH scores compared with patients who did not. There were no differences in time to return to sports or full activities or pain VAS between the two groups. Conclusions Surgical management of young patients with symptomatic, unstable ulnar nerves results in superior subjective outcomes compared with surgery in young patients with stable ulnar nerves. Type of study/level of evidence Therapeutic III. Copyright © 2016 American Society for Surgery of the Hand. All rights reserved.

Author Keywords
Cubital tunnel;  nerve instability;  subluxating ulnar nerve


Document Type: Article
Source: Scopus


 

Beare, R.J.a b , Chen, J.a b , Kelly, C.E.a , Alexopoulos, D.c , Smyser, C.D.c , Rogers, C.E.d , Loh, W.Y.a e , Matthews, L.G.a f g , Cheong, J.L.Y.a g h , Spittle, A.J.a g i , Anderson, P.J.a f , Doyle, L.W.a f g h , Inder, T.E.j , Seal, M.L.a f , Thompson, D.K.a e f 
Neonatal brain tissue classification with morphological adaptation and unified segmentation
(2016) Frontiers in Neuroinformatics, 10 (MAR), . 

DOI: 10.3389/fninf.2016.00012

a Murdoch Childrens Research Institute, The Royal Children's Hospital, Melbourne, VIC, Australia
b Department of Medicine, Monash Medical Centre, Monash University, Melbourne, VIC, Australia
c Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
d Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
e Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia
f Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia
g Royal Women's Hospital, Melbourne, VIC, Australia
h Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, VIC, Australia
i Department of Physiotherapy, University of Melbourne, Melbourne, VIC, Australia
j Department of Pediatric Newborn Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, United States

Abstract
Measuring the distribution of brain tissue types (tissue classification) in neonates is necessary for studying typical and atypical brain development, such as that associated with preterm birth, and may provide biomarkers for neurodevelopmental outcomes. Compared with magnetic resonance images of adults, neonatal images present specific challenges that require the development of specialized, population-specific methods. This paper introduces MANTiS (Morphologically Adaptive Neonatal Tissue Segmentation), which extends the unified segmentation approach to tissue classification implemented in Statistical Parametric Mapping (SPM) software to neonates. MANTiS utilizes a combination of unified segmentation, template adaptation via morphological segmentation tools and topological filtering, to segment the neonatal brain into eight tissue classes: cortical gray matter, white matter, deep nuclear gray matter, cerebellum, brainstem, cerebrospinal fluid (CSF), hippocampus and amygdala. We evaluated the performance of MANTiS using two independent datasets. The first dataset, provided by the NeoBrainS12 challenge, consisted of coronal T2-weighted images of preterm infants (born ≤30 weeks' gestation) acquired at 30 weeks' corrected gestational age (n = 5), coronal T2-weighted images of preterm infants acquired at 40 weeks' corrected gestational age (n = 5) and axial T2-weighted images of preterm infants acquired at 40 weeks' corrected gestational age (n = 5). The second dataset, provided by the Washington University NeuroDevelopmental Research (WUNDeR) group, consisted of T2-weighted images of preterm infants (born &lt;30 weeks' gestation) acquired shortly after birth (n = 12), preterm infants acquired at term-equivalent age (n = 12), and healthy term-born infants (born ≥38 weeks' gestation) acquired within the first 9 days of life (n = 12). For the NeoBrainS12 dataset, mean Dice scores comparing MANTiS with manual segmentations were all above 0.7, except for the cortical gray matter for coronal images acquired at 30 weeks. This demonstrates that MANTiS' performance is competitive with existing techniques. For the WUNDeR dataset, mean Dice scores comparing MANTiS with manually edited segmentations demonstrated good agreement, where all scores were above 0.75, except for the hippocampus and amygdala. The results show that MANTiS is able to segment neonatal brain tissues well, even in images that have brain abnormalities common in preterm infants. MANTiS is available for download as an SPM toolbox from http://developmentalimagingmcri.github.io/mantis © 2016 Beare, Chen, Kelly, Alexopoulos, Smyser, Rogers, Loh, Matthews, Cheong, Spittle, Anderson, Doyle, Inder, Seal and Thompson.

Author Keywords
Magnetic resonance imaging;  Neonate;  Preterm birth;  Statistical parametric mapping;  Tissue classification


Document Type: Article
Source: Scopus


 

Vaubel, R.A.a , Chen, S.G.b , Raleigh, D.R.c , Link, M.J.d , Chicoine, M.R.e , Barani, I.c , Jenkins, S.M.f , Aleff, P.A.g , Rodriguez, F.J.h , Burger, P.C.h , Dahiya, S.i , Perry, A.j , Giannini, C.a 
Meningiomas with rhabdoid features lacking other histologic features of malignancy: A study of 44 cases and review of the literature
(2016) Journal of Neuropathology and Experimental Neurology, 75 (1), pp. 44-52. 

DOI: 10.1093/jnen/nlv006

a Department of Anatomic Pathology, Mayo Clinic, Division of Anatomic Pathology, 200 First Street, SW, Rochester, MN, United States
b Department of Neurosurgery, Mayo Clinic, Jacksonville, FL, United States
c Department of Radiation Oncology, University of California, San Francisco, CA, United States
d Department of Neurosurgery, Mayo Clinic, Rochester, MN, United States
e Department of Neurologic Surgery, Washington University, St. Louis, MO, United States
f Departments of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, United States
g Departments of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, United States
h Department of Pathology, Johns Hopkins University, Baltimore, MD, United States
i Departments of Pathology and Immunology/Anatomic and Molecular Pathology, Washington University, St. Louis, MO, United States
j Department of Pathology, University of California, San Francisco, CA, United States

Abstract
The behavior of rhabdoid meningiomas otherwise lacking malignant features remains unknown as most of the originally reported aggressive cases showed anaplastic histologic features independently of rhabdoid phenotype. We studied 44 patients with rhabdoid meningiomas lacking anaplastic features. Median age at diagnosis was 48.6 years (range 10-79). Location was supratentorial in 28 (63.6%), skull base in 15 (34.1%), and spinal in 1 (2.3%). Tumor grade was otherwise World Health Organization grade I (n=22, 50%) or II (n=22, 50%). Rhabdoid cells represented <20% of the tumor in 12 cases (27.3%), 20% to 50% in 18 (40.9%), and >50% in 14 (31.8%). Median clinical follow-up, available for 38 patients, was 5.0 years (range 0.17-14.2). Recurrence occurred in 9 patients (5-year recurrence-free survival, 73.7%) with a significantly higher risk in subtotally resected tumors (p=0.043). Rhabdoid cell percentage was not associated with recurrence. Six patients died (4 of disease, 2 of unclear causes); 5-year overall survival was 86.7%, a mortality in excess of that expected in grade I-II meningiomas but much lower than originally reported. Review of 50 similar previously reported cases confirmed our findings. We suggest that rhabdoid meningiomas be graded analogously to nonrhabdoid tumors, with caution that some may still behave aggressively and close follow-up is recommended. © 2015 American Association of Neuropathologists, Inc. All rights reserved.

Author Keywords
Anaplastic meningioma;  Meningioma;  Rhabdoid meningioma;  WHO grade


Document Type: Review
Source: Scopus


 

Waters, M.F.a b , Hoh, B.L.c , Lynn, M.J.d , Kwon, H.-M.e f , Turan, T.N.e , Derdeyn, C.P.g , Fiorella, D.h , Khanna, A.a , Sheehan, T.O.a , Lane, B.F.d , Janis, S.i , Montgomery, J.d , Chimowitz, M.I.e 
Factors associated with recurrent ischemic stroke in the medical group of the SAMMPRIS Trial
(2016) JAMA Neurology, 73 (3), pp. 308-315. 

DOI: 10.1001/jamaneurol.2015.4315

a Department of Neurology, McKnight Brain Institute, University of Florida College of Medicine, PO Box 100296, Gainesville, FL, United States
b Department of Neuroscience, McKnight Brain Institute, University of Florida College of Medicine, Gainesville, United States
c Department of Neurosurgery, McKnight Brain Institute, University of Florida College of Medicine, Gainesville, United States
d Department of Biostatistics and Bioinformatics, Emory University Rollins School of Public Health, Atlanta, GA, United States
e Department of Neurosciences, Medical University of South Carolina, Charleston, United States
f Department of Neurology, Seoul Metropolitan Government-Seoul National University, Boramae Medical Center, Seoul, South Korea
g Mallinckrodt Institute of Radiology, Departments of Neurology and Neurosurgery, Washington University School of Medicine, St Louis, MO, United States
h Department of Neurosurgery, State University of New York, Stony Brook, United States
i National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States

Abstract
IMPORTANCE The Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) Trial showed that aggressive medical therapy was more effective than stenting for preventing stroke in patients with symptomatic intracranial stenosis. However, 15%of patients in the medical group still experienced a primary end point during a median follow-up of 32.7 months. OBJECTIVE To determine baseline features that were associated with a high rate of a primary end point in the medical arm of the SAMMPRIS Trial. DESIGN, SETTING, AND PARTICIPANTS A post hoc analysis of patients in the medical arm only of the SAMMPRIS trial. Enrollment occurred between October 2008 and April 2013 and included 227 patients randomized to medical management alone. Baseline demographic features, vascular risk factors, qualifying event, brain imaging, and angiographic features were analyzed. Bivariate and multivariable proportional hazard regression modeling was performed to relate baseline features to the time until a primary end point. The post hoc analysis was conducted from November 2014 to June 2015. INTERVENTIONS The SAMMPRIS Trial compared stenting with aggressive medical management in patients with a stroke or transient ischemic attack attributed to 70%to 99% stenosis of a major intracranial artery. MAIN OUTCOMES AND MEASURES The primary outcomewas any of the following: stroke or death within 30 days of enrollment, ischemic stroke in the territory of the symptomatic intracranial artery beyond 30 days after enrollment, or any stroke or death within 30 days after stenting a patient in the medical group during follow-up. RESULTS A total of 227 patients were included in the study, 82 of whom were female, and the mean (SD) age was 59.5 (11.8) years. Being female (hazard ratio [HR], 1.9; 95%CI, 0.96-3.7), having diabetes mellitus (HR, 1.8; 95%CI, 0.9-3.5), not taking a statin at enrollment (HR, 2.6; 95%CI, 1.2-5.7), stroke as the qualifying event (HR, 2.5; 95%CI, 1.03-6.0), Rankin grade of 1 or greater (HR, 2.3; 95%CI, 0.9-5.5), old infarct in the territory of the stenotic artery (HR, 2.6; 95%CI, 1.3-5.1), and greater than 80% stenosis (HR, 1.9; 95%CI, 0.9-3.7) were associated (P < .10) with higher risk on bivariate analysis. Factors that were significantly associated with a primary end point on multivariable analyses were old infarct in the territory (HR, 2.6; 95% CI, 1.3-5.3; P = .006), stroke as the qualifying event (HR, 3.0; 95%CI, 1.1-7.7; P = .03), and no statin use at enrollment (HR, 2.4; 95%CI, 1.1-5.2; P = .03). CONCLUSIONS AND RELEVANCE Old infarct in the territory of the stenosis, new stroke presentation, and absence of statin use at enrollment were independently associated with high rates of the primary end point in the medical group in the SAMMPRIS Trial. These featuresmay be useful for selecting high-risk patients for future clinical trials evaluating alternative therapies for intracranial stenosis.
 


Document Type: Article
Source: Scopus


 

Ceaser, A.E.a , Barch, D.M.a b c 
Striatal activity is associated with deficits of cognitive control and aberrant salience for patients with schizophrenia
(2016) Frontiers in Human Neuroscience, 9 (FEB2016), art. no. 687, . 

DOI: 10.3389/fnhum.2015.00687

a Cognitive Control and Psychopathology Laboratory, Department of Psychology, Washington University in St. Louis, St. Louis, MO, United States
b Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
c Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
A recent meta-analysis has shown that a large dopamine abnormality exists in the striatum when comparing patients with schizophrenia and controls, and this abnormality is thought to contribute to aberrant salience assignment (or a misattribution of relevance to irrelevant stimuli). This abnormality may also disrupt striatal contributions to cognitive control processing. We examined the relationship between striatal involvement in cognition and aberrant salience symptoms using a task of cognitive control that involves updating, interference control, and simple maintenance. The current study included a sample of 22 patients with schizophrenia and 20 healthy controls and used a slow event-related fMRI design. We predicted that (1) aberrant salience symptoms would be greater for patient's, (2) patients would demonstrate increased errors during interference control trials, given that patients may be inappropriately assigning salience to distracters, and (3) striatal activity during those errors would be correlated with aberrant salience symptoms. We found a trend toward a significant difference between patients and controls on aberrant salience symptoms, and a significant difference between groups on select task conditions. During interference control trials, patients were more likely to inappropriately encode distracters. For patients, both prefrontal and striatal activity was significantly greater when patients inappropriately identified the distracter as correct compared to activity during distracter rejection. During updating, patient prefrontal and striatal activity was significantly lower for incorrect than correct updating trials. Finally, as predicted, for patients the increase of activity during incorrect distracter trials was positively correlated with aberrant salience symptoms, but only for the striatal region. These relationships may have implications for treatments that improve cognitive function and reduce symptom expression. © 2016 Ceaser and Barch.

Author Keywords
Aberrant salience;  Basal ganglia;  Cognitive control;  fMRI;  Interference control;  Prefrontal cortex;  Psychosis;  Striatum


Document Type: Article
Source: Scopus


 

Lake, J.I.a , Avetisyan, M.a , Zimmermann, A.G.b , Heuckeroth, R.O.c 
Neural crest requires Impdh2 for development of the enteric nervous system, great vessels, and craniofacial skeleton
(2016) Developmental Biology, 409 (1), pp. 152-165. 

DOI: 10.1016/j.ydbio.2015.11.004

a Department of Pediatrics and Department of Developmental Regenerative and Stem Cell Biology, Washington University School of Medicine, 660 South Euclid Avenue, Box 8208, St. Louis, MO, United States
b Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, 125 Mason Farm Rd, Chapel Hill, NC, United States
c Department of Pediatrics, Perelman School of Medicine at the Univ. of Pennsylvania, The Children's Hospital of Philadelphia Research Inst., 3615 Civic Center Blvd, Philadelphia, PA, United States

Abstract
Mutations that impair the proliferation of enteric neural crest-derived cells (ENCDC) cause Hirschsprung disease, a potentially lethal birth defect where the enteric nervous system (ENS) is absent from distal bowel. Inosine 5' monophosphate dehydrogenase (IMPDH) activity is essential for de novo GMP synthesis, and chemical inhibition of IMPDH induces Hirschsprung disease-like pathology in mouse models by reducing ENCDC proliferation. Two IMPDH isoforms are ubiquitously expressed in the embryo, but only IMPDH2 is required for life. To further understand the role of IMPDH2 in ENS and neural crest development, we characterized a conditional Impdh2 mutant mouse. Deletion of Impdh2 in the early neural crest using the Wnt1-Cre transgene produced defects in multiple neural crest derivatives including highly penetrant intestinal aganglionosis, agenesis of the craniofacial skeleton, and cardiac outflow tract and great vessel malformations. Analysis using a Rosa26 reporter mouse suggested that some or all of the remaining ENS in Impdh2 conditional-knockout animals was derived from cells that escaped Wnt1-Cre mediated DNA recombination. These data suggest that IMPDH2 mediated guanine nucleotide synthesis is essential for normal development of the ENS and other neural crest derivatives. © 2015 Elsevier Inc.

Author Keywords
De novo purine synthesis;  Enteric nervous system;  Neural crest


Document Type: Article
Source: Scopus


 

Yagi, T.a b , Ito, D.a , Suzuki, N.a 
TFG-related neurologic disorders: New insights into relationships between endoplasmic reticulum and neurodegeneration
(2016) Journal of Neuropathology and Experimental Neurology, 75 (4), pp. 299-305. 

DOI: 10.1093/jnen/nlw009

a Department of Neurology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan
b Department of Medicine, Washington University, School of Medicine, St Louis, MO, United States

Abstract
The tropomyosin-receptor kinase fused gene (TFG), which is located on chromosome 3q12.2, was originally identified as a fusion partner that results in the formation of oncogenic products associated with multiple cancers. TFG protein interacts directly with Sec16, the scaffolding protein for coat protein II-coated vesicles that regulate endoplasmic reticulum (ER)-to-Golgi transport at ER exit sites. In 2012, a heterozygous mutation of TFG was identified as the causative gene for autosomal-dominant hereditary motor and sensory neuropathy with proximal dominant involvement. In 2013, a homozygous mutation of TFG was reported in a family with early onset spastic paraplegia, optic atrophy, and neuropathy. Another novel mutation in TFG was discovered in 2014 as a cause of dominant axonal Charcot-Marie-Tooth disease type 2. These findings suggest that mutations of TFG cause ER dysfunction and neurodegeneration in this disease spectrum, which is tightly associated with ER function. Here, we review the clinical phenotypes of these diseases and present recent insights that suggest causal roles of ER dysfunction in TFG-related neurologic disorders. Although the precise pathogenetic mechanisms underlying these TFG mutations remain to be elucidated, experimental manipulations suggest that the dysregulations of ER homeostasis that occur due to mutations in TFG lead to neurodegeneration. © 2016 American Association of Neuropathologists, Inc. All rights reserved.

Author Keywords
Charcot-Marie-Tooth disease;  Endoplasmic reticulum;  Neurodegeneration;  Spastic paraplegia;  Tropomyosin-receptor kinase fused gene (TFG)


Document Type: Review
Source: Scopus


 

Dorn, G.W.
Central Parkin: The evolving role of Parkin in the heart
(2016) Biochimica et Biophysica Acta - Bioenergetics, . Article in Press. 

DOI: 10.1016/j.bbabio.2016.03.014

Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Parkin is familiar to many because of its link to Parkinson's disease, and to others because of its well-characterized role as a central factor mediating selective mitophagy of damaged mitochondria for mitochondrial quality control. The genetic connection between Parkin and Parkinson's disease derives from clinical gene-association studies, whereas our mechanistic understanding of Parkin functioning in mitophagy is based almost entirely on work performed in cultured cells. Surprisingly, experimental evidence linking the disease and the presumed mechanism derives almost entirely from fruit flies; germline Parkin deficient mice do not develop Parkinson's disease phenotypes. Moreover, genetic manipulation of Parkin signaling in mouse hearts does not support a central role for Parkin in homeostatic mitochondrial quality control in this mitochondria-rich and -dependent organ. Here, I provide an overview of data suggesting that (in mouse hearts at least) Parkin functions more as a stress-induced and developmentally-programmed facilitator of cardiomyocyte mitochondrial turnover. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016. © 2016 Elsevier B.V.
 


Document Type: Article in Press
Source: Scopus


 

Wu, X.a , Eggebrecht, A.T.b , Ferradal, S.L.c , Culver, J.P.b d , Dehghani, H.a 
Fast and efficient image reconstruction for high density diffuse optical imaging of the human brain
(2015) Biomedical Optics Express, 6 (11), art. no. 247189, pp. 4567-4584. 

DOI: 10.1364/BOE.6.004567

a School of Computer Science, University of Birmingham, Birmingham, United Kingdom
b Department of Radiology, Washington University School of Medicine, 4525 Scott Avenue, St. Louis, MO, United States
c Division of Newborn Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States
d Department of Biomedical Engineering, Washington University, One Brookings Drive, St. Louis, MO, United States

Abstract
Real-time imaging of human brain has become an important technique within neuroimaging. In this study, a fast and efficient sensitivity map generation based on Finite Element Models (FEM) is developed which utilises a reduced sensitivitys matrix taking advantage of sparsity and parallelisation processes. Time and memory efficiency of these processes are evaluated and compared with conventional method showing that for a range of mesh densities from 50000 to 320000 nodes, the required memory is reduced over tenfold and computational time fourfold allowing for near real-time image recovery. © 2015 Optical Society of America.

Author Keywords
Functional monitoring and imaging;  Image reconstruction techniques;  Light propagation in tissues;  Tomography


Document Type: Article
Source: Scopus


 

Sorensen, C.J.a , George, S.Z.b , Callaghan, J.P.c , Van Dillen, L.R.d 
Psychological Factors Are Related to Pain Intensity in Back-Healthy People Who Develop Clinically Relevant Pain During Prolonged Standing: A Preliminary Study
(2016) PM and R, . Article in Press. 

DOI: 10.1016/j.pmrj.2016.02.013

a Program in Physical Therapy, Washington University School of Medicine in St. Louis, Saint Louis, MO
b Department of Physical Therapy, Brooks-PHHP Research Collaboration, University of Florida, Gainesville, FL
c Department of Kinesiology, University of Waterloo, Waterloo, Ontario, Canada
d Program in Physical Therapy, Washington University School of Medicine in St. Louis, 4444 Forest Park Blvd., Box 8502, Saint Louis, MO

Abstract
Background: An induced-pain paradigm has been used to examine risk factors for the development of low back pain (LBP) during prolonged standing in back-healthy people (standing paradigm). Previous studies that used induced-pain methods suggest that pain intensity may be related to psychologic factors. It is not currently known, however, whether pain intensity reported during the standing paradigm is related to psychologic factors. Objective: To examine the relationship between LBP symptom intensity and psychological factors (fear of pain and pain catastrophizing) in back-healthy people who develop LBP during prolonged standing. We hypothesized that symptom intensity during standing would be positively related to initial levels of fear of pain and pain catastrophizing in people who developed LBP during standing. Design: Cross-sectional. Setting: Movement science research center at an academic medical center. Participants: Fifty seven back-healthy participants. Methods: Participants completed the Fear of Pain Questionnaire-III (FPQ-III) and Pain Catastrophizing Scale (PCS) before a 2-hour standing protocol. Participants rated LBP intensity on a 100-mm visual analogue scale (VAS) throughout standing and were classified as pain developers (PDs) or nonpain developers (NPDs). Relationships between LBP intensity and psychological measures were examined in PDs that did and did not have a ≥20 mm maximum VAS score. Main Outcome Measurements: FPQ-III and PCS total scores, maximum and average VAS scores during standing. Results: There were 24 (42%) PDs. Five PDs reported a maximum VAS score ≥20 mm. For PDs with a maximum VAS score <20 mm, correlations between average VAS scores and each psychological measure were small and nonsignificant (FPQ-III: r = 0.16, P = .50; PCS: r = 0.27, P = .26). For PDs with a maximum VAS score ≥20 mm, correlation between average VAS scores and FPQ-III was large and significant (r = 0.91, P = .03), and large for PCS but nonsignificant (r = 0.87, P = .06). Conclusion: These preliminary data suggest that if pain exceeds a clinically meaningful threshold (20 mm) during standing, pain intensity is related to psychological factors. Understanding factors that modulate acute pain response can inform early intervention strategies. © 2016 American Academy of Physical Medicine and Rehabilitation.
 


Document Type: Article in Press
Source: Scopus

April 7, 2016

Armstrong, E.L.a , te Nijenhuis, J.b , Woodley of Menie, M.A.c d , Fernandes, H.B.F.e , Must, O.f , Must, A.g
A NIT-picking analysis: Abstractness dependence of subtests correlated to their Flynn effect magnitudes
(2016) Intelligence, 57, pp. 1-6. 

DOI: 10.1016/j.intell.2016.02.009


a Washington University in St. Louis, United States
b National Research Center for Dementia, Chosun University, Gwangju, South Korea
c Department of Psychology, Technische Universität Chemnitz, Germany
d Center Leo Apostel for Interdisciplinary Research, Vrije Universiteit Brussel, Belgium
e Department of Psychology, Federal University of Rio Grande do Sul Department of Psychology, Brazil
f Department of Psychology, University of Tartu, Estonia
g Estonian National Defense College, Estonia


Abstract
We examine the association between the strength of the Flynn effect in Estonia and highly convergent panel-ratings of the 'abstractness' of nine subtests on the National Intelligence Test, in order to test the theory that the Flynn effect results in part from an increase in the use of abstract reference frames in solving cognitive problems. The vectors of abstractness ratings and Flynn effect gains, controlled for guessing) exhibit a near-zero correlation (r = -02); however, abstractness correlates positively with (and is therefore confounded by) g-loadings (r = .61). A General Linear Model is used to determine the degree to which the abstractness vector predicts the Flynn effect vector, independently of subtest g-loadings and the portion of the secular IQ gain due to guessing (the Brand effect). Consistent with the abstract reasoning model of the Flynn effect, abstractness positively predicts Flynn effect magnitudes, once controlled for confounds (sr = .44), which indicates an increasing tendency to utilize factors external to the items in order to abstract their solutions. © 2016 Elsevier Inc.


Author Keywords
Abstract thinking;  Estonia;  Flynn effect;  G loading;  Intelligence;  National Intelligence Test


Document Type: Article
Source: Scopus




Johnson, K.J.a , Zoellner, N.L.a , Gutmann, D.H.b
Peri-gestational risk factors for pediatric brain tumors in Neurofibromatosis Type 1
(2016) Cancer Epidemiology, 42, pp. 53-59. 

DOI: 10.1016/j.canep.2016.03.005


a Brown School, Washington University, St. Louis, MO, United States
b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States


Abstract
Background: Individuals with Neurofibromatosis Type 1 (NF1) are strongly predisposed to developing pediatric brain tumors (PBTs), especially optic pathway gliomas (OPGs). Although developmental factors have been implicated in the origins of PBTs in both human and animal studies, associations between early-life factors and PBTs have not been evaluated in individuals with NF1. Our objective was to evaluate associations between peri-gestational characteristics and PBTs in this population. Methods: We conducted a cross-sectional study, ascertaining questionnaire and medical record data for 606 individuals <18 years old who enrolled in the NF1 Patient Registry Initiative (NPRI) from 6/9/2011-6/29/2015. One hundred eighty-four individuals had reported PBT diagnoses, including 65 who were identified with OPG diagnoses. Cox proportional hazards regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between PBT and OPG diagnoses and peri-gestational characteristics (prematurity, birth weight, parental age, plurality, family history of NF1, assisted reproductive technology, maternal vitamin supplementation, and parental smoking). Results: We observed no significant associations between any of the assessed characteristics and PBTs overall or OPGs with the exception of birth weight. After controlling for potential confounding variables, we observed a significant positive association between birth weight quartile and OPGs with a HR of 3.32 (95% CI 1.39-7.94) for the fourth (≥3915.5 g) compared to the first (≤3020 g) quartile (p for trend = 0.001). Conclusions: Consistent with results for PBTs in the general population, these results suggest that higher birth weights increase OPG risk in individuals with NF1. © 2016 Elsevier Ltd.


Author Keywords
Birth weight;  Brain neoplasms;  Glioma;  Neurofibromatosis 1


Document Type: Article
Source: Scopus




Tang, M.a b , Wu, G.a c , Wang, Z.a , Yang, N.a , Shi, H.a , He, Q.b , Zhu, C.a , Yang, Y.a , Yu, G.a , Wang, C.a , Yuan, X.a , Liu, Q.d , Guan, Y.e , Dong, X.f , Tang, Z.a
Voltage-gated potassium channels involved in regulation of physiological function in MrgprA3-specific itch neurons
(2016) Brain Research, 1636, pp. 161-171. 

DOI: 10.1016/j.brainres.2016.02.014


a College of Basic Medicine, Nanjing University of Chinese Medicine, Nanjing, China
b College of Biology and Environmental Sciences, Jishou University, Jishou, China
c College of Basic Medicine, Guangxi University of Chinese Medicine, Nanning, China
d Department of Anesthesiology, Washington University, St. Louis, United States
e Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Schools of Medicine, Baltimore, MD, United States
f Howard Hughes Medical Institute, Johns Hopkins University, School of Medicine, Baltimore, MD, United States


Abstract
Itch is described as an unpleasant or irritating skin sensation that elicits the desire or reflex to scratch. MrgprA3, one of members of the Mrgprs family, is specifically expressed in a subpopulation of dorsal root ganglion (DRG) in the peripheral nervous system (PNS). These MrgprA3-expressing DRG neurons have been identified as itch-specific neurons. They can be activated by the compound, chloroquine, which is used as a drug to treat malaria. In the present study, we labeled these itch-specific neurons using the method of molecular genetic markers, and then studied their electrophysiological properties. We also recorded the cutaneous MrgprA3- neurons retrogradely labeled by Dil dye (MrgprA3--Dil). We first found that MrgprA3+ neurons have a lower excitability than MrgprA3- neurons (MrgprA3--non-Dil and MrgprA3--Dil). The number of action potential (AP) was reduced more obviously in MrgprA3+ neurons than that of in MrgprA3- neurons. In most cases, MrgprA3+ neurons only generated single AP; however, in MrgprA3- neurons, the same stimulation could induce multiple AP firing due to the greater voltage-gated potassium (Kv) current existence in MrgprA3+ than in MrgprA3- neurons. Thus, Kv current plays an important role in the regulation of excitability in itch-specific neurons. © 2016 Elsevier B.V. All rights reserved.


Author Keywords
DRG;  Itch;  Kv current;  MrgprA3


Document Type: Article
Source: Scopus




Cooley, S.A.a , Paul, R.H.a b , Fennema-Notestine, C.c , Morgan, E.E.c , Vaida, F.c , Deng, Q.c , Chen, J.A.c , Letendre, S.c , Ellis, R.c , Clifford, D.B.d , Marra, C.M.e , Collier, A.C.e , Gelman, B.B.f , McArthur, J.C.g , McCutchan, J.A.c , Simpson, D.M.h , Morgello, S.h , Grant, I.c , Ances, B.M.d , For The Cns Hiv Anti-Retroviral Therapy Effects Research (Charter) Groupi
Apolipoprotein E ε4 genotype status is not associated with neuroimaging outcomes in a large cohort of HIV+ individuals
(2016) Journal of NeuroVirology, pp. 1-8. Article in Press. 

DOI: 10.1007/s13365-016-0434-7


a University of Missouri – St. Louis, St. Louis, MO, United States
b Missouri Institute of Mental Health, St. Louis, MO, United States
c University of California, San Diego, San Diego, CA, United States
d Washington University in St. Louis, Box 8111 660 South Euclid Ave, Saint Louis, MO, United States
e University of Washington, Seattle, Seattle, WA, United States
f University of Texas Medical Branch, Galveston, TX, United States
g Johns Hopkins University, Baltimore, MD, United States
h Icahn School of Medicine at Mount Sinai, New York, NY, United States


Abstract
Previous neuroimaging studies suggest a negative relationship between the apolipoprotein (ApoE) ε4 allele and brain integrity in human immunodeficiency virus (HIV)-infected (HIV+) individuals, although the presence of this relationship across adulthood remains unclear. The purpose of this study is to clarify the discrepancies using a large, diverse group of HIV+ individuals and multiple imaging modalities sensitive to HIV. The association of ApoE ε4 with structural neuroimaging and magnetic resonance spectroscopy (MRS) was examined in 237 HIV+ individuals in the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) study. Cortical and subcortical gray matter, abnormal and total white matter, ventricles, sulcal cerebrospinal fluid (CSF), and cerebellar gray matter, white matter, and CSF volumes, and MRS concentrations of myo-inositol, creatine, N-acetyl-aspartate, and choline in the frontal white matter (FWM), frontal gray matter (FGM), and basal ganglia were examined. Secondary analyses explored this relationship separately in individuals ≥50 years old (n = 173) and <50 years old (n = 63). No significant differences were observed between ApoE ε4+ (ApoE ε3/ε4 and ApoE ε4/ε4) individuals (n = 69) and ApoE ε4− (ApoE ε2/ε3 and ApoE ε3/ε3) individuals (n = 167). When individuals were further divided by age, no significant genotype group differences were identified in individuals <50 or ≥50 years of age on any neuroimaging outcome. The ApoE ε4 allele did not affect brain integrity in this large, diverse sample of HIV+ individuals. The effects of ApoE ε4 may not be apparent until more advanced ages and may be more prominent when present along with other risk factors for neuronal damage. © 2016 Journal of NeuroVirology, Inc.


Author Keywords
Brain volumetrics;  Genetics;  HIV/AIDS;  Magnetic resonance spectroscopy


Document Type: Article in Press
Source: Scopus




Nitzan, E.a b , Avraham, O.a c , Kahane, N.a , Ofek, S.a , Kumar, D.a , Kalcheim, C.a
Dynamics of BMP and Hes1/Hairy1 signaling in the dorsal neural tube underlies the transition from neural crest to definitive roof plate
(2016) BMC Biology, 14 (1), art. no. 23, . 

DOI: 10.1186/s12915-016-0245-6


a Hebrew University of Jerusalem-Hadassah Medical School, Department of Medical Neurobiology, IMRIC and ELSC, PO Box 12272, Jerusalem, Israel
b Weizmann Institute of Science, Department of Molecular Cell Biology, Rehovot, Israel
c Washington University, Present address: Department of Genetics, St. Louis, MO, United States


Abstract
Background: The dorsal midline region of the neural tube that results from closure of the neural folds is generally termed the roof plate (RP). However, this domain is highly dynamic and complex, and is first transiently inhabited by prospective neural crest (NC) cells that sequentially emigrate from the neuroepithelium. It only later becomes the definitive RP, the dorsal midline cells of the spinal cord. We previously showed that at the trunk level of the axis, prospective RP progenitors originate ventral to the premigratory NC and progressively reach the dorsal midline following NC emigration. However, the molecular mechanisms underlying the end of NC production and formation of the definitive RP remain virtually unknown. Results: Based on distinctive cellular and molecular traits, we have defined an initial NC and a subsequent RP stage, allowing us to investigate the mechanisms responsible for the transition between the two phases. We demonstrate that in spite of the constant production of BMP4 in the dorsal tube at both stages, RP progenitors only transiently respond to the ligand and lose competence shortly before they arrive at their final location. In addition, exposure of dorsal tube cells at the NC stage to high levels of BMP signaling induces premature RP traits, such as Hes1/Hairy1, while concomitantly inhibiting NC production. Reciprocally, early inhibition of BMP signaling prevents Hairy1 mRNA expression at the RP stage altogether, suggesting that BMP is both necessary and sufficient for the development of this RP-specific trait. Furthermore, when Hes1/Hairy1 is misexpressed at the NC stage, it inhibits BMP signaling and downregulates BMPR1A/Alk3 mRNA expression, transcription of BMP targets such as Foxd3, cell-cycle progression, and NC emigration. Reciprocally, Foxd3 inhibits Hairy1, suggesting that repressive cross-interactions at the level of, and downstream from, BMP ensure the temporal separation between both lineages. Conclusions: Together, our data suggest that BMP signaling is important both for NC and RP formation. Given that these two structures develop sequentially, we speculate that the longer exposure of RP progenitors to BMP compared with that of premigratory NC cells may be translated into a higher signaling level in the former. This induces changes in responsiveness to BMP, most likely by downregulating the expression of Alk3 receptors and, consequently, of BMP-dependent downstream transcription factors, which exhibit spatial complementary expression patterns and mutually repress each other to generate alternative fates. This molecular dynamic is likely to account for the transition between the NC and definitive RP stages and thus be responsible for the segregation between central and peripheral lineages during neural development. © 2016 Nitzan et al.


Author Keywords
Avian embryo;  BMP;  Dorsal interneurons;  Dorso-ventral patterning;  Epithelial-to-mesenchymal transition;  Foxd3;  Hairy1;  HES1;  Neural tube


Document Type: Article
Source: Scopus




Cabrera-Nguyen, E.P.a , Cavazos-Rehg, P.a , Krauss, M.a , Bierut, L.J.a , Moreno, M.A.b
Young adults’ exposure to alcohol- and marijuana-related content on twitter
(2016) Journal of Studies on Alcohol and Drugs, 77 (2), pp. 349-353. 

DOI: 10.15288/jsad.2016.77.349


a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
b Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, United States


Abstract
Objective: Twitter is among the most popular social media platforms used by young adults, yet it has been underutilized in substance use research compared with older platforms (e.g., MySpace and Facebook). We took a first step toward studying the associations between exposure to pro–alcohol- and marijuana-related content among young adults via Twitter and current heavy episodic drinking and current marijuana use, respectively. Method: We conducted an online survey of 587 (254 men, 333 women) Twitter users between ages 18 and 25 years in February 2014 using an online survey system that has been previously used in research on health behaviors and attitudes. Results: Current heavy episodic drinking was significantly associated with higher levels of exposure to pro-alcohol content. Similarly, current marijuana use was significantly associated with higher levels of exposure to pro-marijuana content. Conclusions: Our findings suggest that in-depth research regarding young adults’ exposure to pro–alcohol-and marijuana-related content via Twitter may provide a foundation for developing effective prevention messages on this social media platform to counter the pro–alcohol and marijuana messages. © 2016, Alcohol Research Documentation Inc. All Rights Reserved.


Document Type: Article
Source: Scopus




Salas, J.a , Scherrer, J.F.a , Lustman, P.J.b c , Schneider, F.D.a
Racial differences in the association between nonmedical prescription opioid use, abuse/dependence, and major depression
(2016) Substance Abuse, 37 (1), pp. 25-30. 

DOI: 10.1080/08897077.2015.1129523


a Department of Family and Community Medicine, Saint Louis University School of Medicine, 1402 South Grand Boulevard, Saint Louis, MO, United States
b Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, United States
c Bell Street Clinic, John Cochran Hospital, St. Louis VA Medical Center, St. Louis, MO, United States


Abstract
Background: African Americans (AAs) have lower rates of depressive disorders and are less likely to receive opioid analgesics for chronic pain than whites. Given the evidence that prescription opioid use is associated with depression, we hypothesized that the opioid abuse/dependence and depression comorbidity would be less common among AAs compared with whites. Methods: A cross-sectional secondary analysis of the public use files for the 2012 (n = 55,268) and 2013 (n = 55,160) National Survey on Drug Use and Health (NSDUH) was used to obtain past-year, DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) criteria diagnoses of nonmedical prescription opioid use (NMPOU), abuse/dependence, and major depressive episode (MDE). Covariates included anxiety disorder, alcohol and illicit drug abuse/dependence, smoking, age, gender, education, marital status, health insurance, county urbanicity, and income. Logistic regression models estimating the association between opioid use and MDE were computed before and after adjusting for covariates and separately for AAs and whites. Results: AAs and whites had similar past-year prevalence of NMPOU (3.5% vs. 3.7%) and abuse/dependence (0.7% vs. 0.9%). MDE was significantly more prevalent among whites (7.4% vs. 5.5%; P <.0001). Among whites, NMPOU and abuse/dependence were associated with MDE (odds ratio [OR] = 1.36, 95% confidence interval [CI] = 1.12-1.64 and OR = 2.22, 95% CI = 1.67-2.94, respectively). Among AAs, there were no significant associations between NMPOU, abuse/dependence, and MDE (OR range: 0.80-0.95). Conclusions: In a nationally representative sample, co-occurrence of past-year depression, NMPOU, and abuse/dependence was determined in whites but not AAs. Additional research is needed to establish the contribution of pain and temporal relationships. © Taylor & Francis Group, LLC.


Author Keywords
Depression;  epidemiology;  opioids;  racial disparities


Document Type: Article
Source: Scopus




Luby, J.L.
The Importance of Early Nurturance for Social Development
(2015) Journal of the American Academy of Child and Adolescent Psychiatry, 54 (12), pp. 972-973. 

DOI: 10.1016/j.jaac.2015.09.008


Early Emotional Development Program, Washington University School of Medicine, St. Louis, United States


Document Type: Editorial
Source: Scopus




Walkup, J.T.a , Wagner, K.D.b , Miller, L.c , Yenokyan, G.d , Luby, J.L.e , Joshi, P.T.f , Axelson, D.A.g , Robb, A.f , Salpekar, J.A.f , Wolf, D.b , Sanyal, A.d , Birmaher, B.h , Vitiello, B.i , Riddle, M.A.c
Treatment of Early-Age Mania: Outcomes for Partial and Nonresponders to Initial Treatment
(2015) Journal of the American Academy of Child and Adolescent Psychiatry, 54 (12), pp. 1008-1019. 

DOI: 10.1016/j.jaac.2015.09.015


a Weill Cornell Medical College, New York Presbyterian Hospital, 525 E 68th Street, Box 140, New York, NY, United States
b University of Texas Medical Branch, Galveston, United States
c Johns Hopkins University School of Medicine, Baltimore, United States
d Johns Hopkins Bloomberg School of Public Health, United States
e Washington University in St. Louis, United States
f Children's National Medical Center, George Washington University School of Medicine, Washington, DC, United States
g Nationwide Children's Hospital, Ohio State University, Wexner Medical Center, Columbus, United States
h University of Pittsburgh Medical Center, Western Psychiatric Institute and Clinic, Pittsburgh, United States
i National Institute of Mental Health (NIMH), Bethesda, MD, United States


Abstract
Objective The Treatment of Early Age Mania (TEAM) study evaluated lithium, risperidone, and divalproex sodium (divalproex) in children with bipolar I disorder who were naive to antimanic medication, or were partial or nonresponders to 1 of 3 study medications. This report evaluates the benefit of either an add-on or a switch of antimanic medications for an 8-week trial period in partial responders and nonresponders, respectively. Method TEAM is a randomized, controlled trial of individuals (N = 379) aged 6 to 15 years (mean ± SD = 10.2 ± 2.7 years) with DSM-IV bipolar I disorder (mixed or manic phase). Participants (n = 154) in this report were either nonresponders or partial responders to 1 of the 3 study medications. Nonresponders (n = 89) were randomly assigned to 1 of the other 2 antimanic medications and cross-tapered. Partial responders (n = 65) were randomly assigned to 1 of 2 other antimanic medications as an add-on to their initial medication. Adverse event (AE) rates are reported only for the add-on group. Results Response rate for children switched to risperidone (47.6%) was higher than for those switched to either lithium (12.8%; p =.005; number needed to treat [NNT] = 3; 95% CI = 1.71-9.09) or divalproex (17.2%; p =.03; NNT = 3; 95% CI = 1.79-20.10); response rate for partial responders who added risperidone (53.3%) was higher than for those who added divalproex (0%; p =.0002; NNT = 2; 95% CI = 1.27-3.56) and trended higher for lithium (26.7%; p =.07; NNT = 4). Reported AEs in the add-on group were largely consistent with the known AE profile for the second medication. Weight gain (kg) was observed for all add-on medications: lithium add-on (n = 29 of 30) = 1.66 ± 1.97; risperidone add-on (n = 15 of 15) = 2.8 ± 1.34; divalproex add-on (n = 19 of 20) = 1.42 ± 1.96. There was no evidence at the 5% significance level that the average weight gain was different by study medication for partial responders (p =.07, 1-way analysis of variance). Conclusion Risperidone appears to be more useful than lithium or divalproex for children with bipolar I disorder and other comorbid conditions who are nonresponders or partial responders to an initial antimanic medication trial.


Author Keywords
bipolar;  mania;  nonresponders;  pharmacology;  treatment

 


Document Type: Article
Source: Scopus

April 4, 2016

McMillen, J.C.a , Hawley, K.M.b , Proctor, E.K.c 
Mental Health Clinicians’ Participation in Web-Based Training for an Evidence Supported Intervention: Signs of Encouragement and Trouble Ahead
(2015) Administration and Policy in Mental Health and Mental Health Services Research, 12 p. Article in Press. 

DOI: 10.1007/s10488-015-0645-x

a School of Social Service Administration, University of Chicago, 969 E. 60th, Chicago, IL, United States
b Department of Psychological Sciences, University of Missouri, 210 McAlester Hall, Columbia, MO, United States
c George Warren Brown School of Social Work, Washington University in St. Louis, 1 Brookings Drive, Box 1196, St. Louis, MO, United States

Abstract
Comprehensive scalable clinician training is needed to increase the impact of evidence-supported psychotherapies. This study was designed to ascertain clinician participation in different low-cost training activities, what predicts their training participation, and how participation can be increased. The study enrolled 163 clinicians. Of these, 105 completed a follow-up survey and 20 completed a more in-depth qualitative interview. Some activities (web training) attracted greater participation than others (e.g., discussion boards, role playing). Key findings include the desirability of self-paced learning and the flexibility it afforded practicing clinicians. However, some found the lack of accountability insurmountable. Many desired in-person training as a way to introduce accountability and motivation. While low-cost, relevant, self-paced learning appeals to practicing clinicians, it may need to be combined with opportunities for in-person training and accountability mechanisms in order to encourage large numbers of clinicians to complete training. © 2015 Springer Science+Business Media New York

Author Keywords
Dissemination;  Evidence-based practice;  Technology;  Training


Document Type: Article in Press
Source: Scopus


 

Pe, M.L.a , Kircanski, K.b , Thompson, R.J.c , Bringmann, L.F.a , Tuerlinckx, F.a , Mestdagh, M.a , Mata, J.d , Jaeggi, S.M.e , Buschkuehl, M.f , Jonides, J.g , Kuppens, P.a , Gotlib, I.H.b 
Emotion-Network Density in Major Depressive Disorder
(2015) Clinical Psychological Science, 3 (2), pp. 292-300. 

DOI: 10.1177/2167702614540645

a Department of Psychology, KU Leuven, Belgium
b Department of Psychology, Stanford University, United States
c Department of Psychology, Washington University in St. Louis, United States
d Max Planck Institute for Human Development, Germany
e School of Education, University of California, Irvine, United States
f MIND Research Institute, Irvine, CA, United States
g Department of Psychology, University of Michigan, Ann Arbor, United States

Abstract
Major depressive disorder (MDD) is a prevalent disorder involving disturbances in mood. There is still much to understand regarding precisely how emotions are disrupted in individuals with MDD. In this study, we used a network approach to examine the emotional disturbances underlying MDD. We hypothesized that compared with healthy control individuals, individuals diagnosed with MDD would be characterized by a denser emotion network, thereby indicating that their emotion system is more resistant to change. Indeed, results from a 7-day experience sampling study revealed that individuals with MDD had a denser overall emotion network than did healthy control individuals. Moreover, this difference was driven primarily by a denser negative, but not positive, network in MDD participants. These findings suggest that the disruption in emotions that characterizes depressed individuals stems from a negative emotion system that is resistant to change. © 2014, © The Author(s) 2014.

Author Keywords
affective disorders;  depression;  emotion


Document Type: Article
Source: Scopus