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WUSTL Neuroscience Publications Archive - October 2014

Scopus Weekly Report

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October 22, 2014

Roberts, N.W.a , How, M.J.a , Porter, M.L.b , Temple, S.E.a , Caldwell, R.L.c , Powell, S.B.d , Gruev, V.d , Marshall, N.J.e , Cronin, T.W.f
Animal polarization imaging and implications for optical processing
(2014) Proceedings of the IEEE, 102 (10), art. no. 6880330, pp. 1427-1434. 

a School of Biological Sciences, University of BristolBristol BS8 1UG, United Kingdom
b Department of Biology, University of South DakotaVermillion, SD, United States
c Department of Integrative Biology, University of California at BerkeleyBerkeley, CA, United States
d Department of Computer Science and Engineering, Washington University in Saint LouisSaint Louis, MO, United States
e Queensland Brain Institute, University of QueenslandSt. Lucia, QLD, Australia
f Department of Biological Sciences, University of Maryland Baltimore CountyBaltimore, MD, United States

Biologically inspired solutions for modern-day sensory systems promise to deliver both higher capacity and faster, more efficient processing of information than current computational approaches. Many animals are able to perform remarkable sensing tasks despite only being able to process what would be considered modest data rates and bandwidths. The key biological innovations revolve around dedicated filter designs. By sacrificing some flexibility, specifically matched and hard-wired sensory systems, designed primarily for single roles, provide a blueprint for data and task-specific efficiency. In this paper, we examine several animal visual systems designed to use the polarization of light in spatial imaging. We investigate some implications for artificial optical processing based on models of polarization image processing in fiddler crabs, cuttlefish, octopus, and mantis shrimp.

Author Keywords
Animals;  Biophotonics;  Image processing;  Optical polarization;  Stokes parameters

Document Type: Article
Source: Scopus

York, T.a , Powell, S.B.a , Gao, S.a , Kahan, L.b , Charanya, T.c , Saha, D.d , Roberts, N.W.e , Cronin, T.W.f , Marshall, J.g , Achilefu, S.c , Lake, S.P.b , Raman, B.d , Gruev, V.a
Bioinspired polarization imaging sensors: From circuits and optics to signal processing algorithms and biomedical applications
(2014) Proceedings of the IEEE, 102 (10), art. no. 6880796, pp. 1450-1469. 

a Department of Computer Science and Engineering, Washington University in St. LouisSt. Louis, MO, United States
b Department of Mechanical Engineering and Materials Science, Washington UniversitySt. Louis, MO, United States
c Department of Radiology, Washington University School of MedicineSt. Louis, MO, United States
d Department of Biomedical Engineering, Washington UniversitySt. Louis, MO, United States
e School of Biological Sciences, University of BristolBristol BS8 1UG, United Kingdom
f Department of Biological Sciences, University of Maryland Baltimore CountyBaltimore, MD, United States
g Sensory Neurobiology Group, University of QueenslandBrisbane, QLD, Australia

In this paper, we present recent work on bioinspired polarization imaging sensors and their applications in biomedicine. In particular, we focus on three different aspects of these sensors. First, we describe the electro-optical challenges in realizing a bioinspired polarization imager, and in particular, we provide a detailed description of a recent low-power complementary metal-oxide-semiconductor (CMOS) polarization imager. Second, we focus on signal processing algorithms tailored for this new class of bioinspired polarization imaging sensors, such as calibration and interpolation. Third, the emergence of these sensors has enabled rapid progress in characterizing polarization signals and environmental parameters in nature, as well as several biomedical areas, such as label-free optical neural recording, dynamic tissue strength analysis, and early diagnosis of flat cancerous lesions in a murine colorectal tumor model. We highlight results obtained from these three areas and discuss future applications for these sensors.

Author Keywords
Bioinspired circuits;  Calibration;  Complementary metal-oxide-semiconductor (CMOS) image sensor;  Current-mode imaging;  Interpolation;  Neural recording;  Optical neural recording;  Polarization

Document Type: Article
Source: Scopus

Warren, D.E.a , Power, J.D.b , Bruss, J.a , Denburg, N.L.a c , Waldron, E.J.a , Sun, H.b , Petersen, S.E.b d e f g h , Tranel, D.a c
Network measures predict neuropsychological outcome after brain injury
(2014) Proceedings of the National Academy of Sciences of the United States of America, 111 (39), pp. 14247-14252. 

a Department of Neurology, University of Iowa, Carver College of MedicineIowa City, IA, United States
b Department of Neurology, Washington University, School of MedicineSt. Louis, MO, United States
c Department of Psychology, University of IowaIowa City, IA, United States
d Department of Radiology, Washington University, School of MedicineSt. Louis, MO, United States
e Department of Anatomy and Neurobiology, Washington University, School of MedicineSt. Louis, MO, United States
f Department of Neurosurgery, Washington University, School of MedicineSt. Louis, MO, United States
g Department of Psychology, Washington University in St. LouisSt. Louis, MO, United States
h Department of Biomedical Engineering, Washington University in St. LouisSt. Louis, MO, United States

Hubs are network components that hold positions of high importance for network function. Previous research has identified hubs in human brain networks derived from neuroimaging data; however, there is little consensus on the localization of such hubs. Moreover, direct evidence regarding the role of various proposed hubs in network function (e.g., cognition) is scarce. Regions of the default mode network (DMN) have been frequently identified as "cortical hubs" of brain networks. On theoretical grounds, we have argued against some of the methods used to identify these hubs and have advocated alternative approaches that identify different regions of cortex as hubs. Our framework predicts that our proposed hub locations may play influential roles in multiple aspects of cognition, and, in contrast, that hubs identified via other methods (including salient regions in the DMN) might not exert such broad influence. Here we used a neuropsychological approach to directly test these predictions by studying long-term cognitive and behavioral outcomes in 30 patients, 19 with focal lesions to six "target" hubs identified by our approaches (high system density and participation coefficient) and 11 with focal lesions to two "control" hubs (high degree centrality). In support of our predictions, we found that damage to target locations produced severe and widespread cognitive deficits, whereas damage to control locations produced more circumscribed deficits. These findings support our interpretation of how neuroimaging-derived network measures relate to cognition and augment classic neuroanatomically based predictions about cognitive and behavioral outcomes after focal brain injury.

Author Keywords
Brain hubs;  FMRI;  Functional connectivity;  Neuropsychology

Document Type: Article
Source: Scopus

Slee, C.a , Lee, A.Y.b , Forooghian, F.c , Sbergstrom, C.a , Yan, J.a , Yeh, S.a
Fundus autofluorescence features in the inflammatory maculopathies
(2014) Clinical Ophthalmology, 8, pp. 2001-2012. 

a Section of Vitreoretinal Disease and Surgery, Department of Ophthalmology, Emory Eye Center, Emory UniversityAtlanta, GA, United States
b Department of Ophthalmology and Visual Sciences, Washington University in St LouisLouis, MO, United States
c Department of Ophthalmology and Visual Sciences, University of British ColumbiaVancouver, BC, Canada

Results: Thirty eyes of 15 patients were evaluated with both qualitative and quantitative FAF analysis. In acute macular neuroretinopathy, the active phase showed foveal hypoautofluorescence, which became hypoautofluorescent with resolution. In acute posterior multifocal placoid pigment epitheliopathy, multiple lesions with hypoautofluorescent centers with hyperautofluorescent borders were observed in active disease and became hypoautofluorescent with disease convalescence. In multifocal choroiditis and punctate inner choroiditis, the active hyperautofluorescent lesions progressed to inactive, hypoautofluorescent scars. Active serpiginous choroiditis showed hyperautofluorescent borders adjacent to a helicoid-shaped, hypoautofluorescent scar. Active unilateral acute idiopathic maculopathy (UAIM) showed a complex pattern of hypo- and hyperautoflourescence in the macula. The median foveal AF was the greatest in acute macular neuroretinopathy and UAIM among the maculopathies, while the greatest SD of foveal AF intensity was observed in UAIM.

Conclusion: The active phase of the majority of inflammatory maculopathies was characterized by hyperautofluorescent lesions. Increased SD of foveal AF correlated with a mixture of hypo- and hyperautoflourescence. Median and SD may be useful metrics in foveal AF and quantifiable values that may be assessed over time as a disease process evolves. Improvements in quantification methods of FAF imaging may allow us to objectively evaluate posterior uveitis.

Purpose: To describe the fundus autofluorescence (FAF) features of the inflammatory maculopathies and develop a quantification method for FAF analysis.

Methods: This is a retrospective, consecutive case series of patients with inflammatory maculopathies from two tertiary centers. The clinical findings, demographics, and FAF imaging characteristics were reviewed. Foveal autofluorescence (AF) was analyzed. Median and standard deviation (SD) of foveal AF intensity were measured.

Author Keywords
Foveal autofluorescence;  Fundus autofluorescence imaging;  Posterior uveitis;  Quantification

Document Type: Article
Source: Scopus

Bandt, S.K.a , Bundy, D.T.b , Hawasli, A.H.a , Ayoub, K.W.b c d , Sharma, M.b , Hacker, C.D.b c , Pahwa, M.b , Leuthardt, E.C.a b e
The role of resting state networks in focal neocortical seizures
(2014) PLoS ONE, 9 (9), art. no. e107401, . 

a Department of Neurological Surgery, Washington University, School of MedicineSt. Louis, MO, United States
b Department of Biomedical Engineering, Washington UniversitySt. Louis, MO, United States
c Washington University, School of MedicineSt. Louis, MO, United States
d Department of Biomedical Engineering, Oxford UniversityOxford, United Kingdom
e Center for Innovation in Neuroscience and Technology, Washington University, School of MedicineSt. Louis, MO, United States

Methods: Using data taken from invasively monitored patients with intractable focal neocortical epilepsy, we evaluated network connectivity (as determined by oscillatory covariance of the slow cortical potential (,0.5 Hz)) as it relates to neocortical seizure foci both in the interictal and ictal states.

Objective: The role of resting state functional networks in epilepsy is incompletely understood. While some pathologic diagnoses have been shown to have maintained but altered resting state connectivity, others have implicated resting state connectivity in disease progression. However little is known about how these resting state networks influence the behavior of a focal neocortical seizure.

Results: Similar to what has been shown in the past for sleep and anesthesia, electophysiologic resting state networks that are defined by this slow cortical potential covariance maintain their topographic correlation structure throughout an ictal event. Moreover, in the context of focal epilepsy in which the seizure has a specific site of onset, seizure propagation is not chaotic or random. Rather, the seizure (reflected by an elevation of high frequency power) preferentially propagates along the network that contains the seizure onset zone.

Significance: Taken together, these findings further undergird the fundamental role of resting state networks, provide novel insights into the network-influenced behavior of seizures, and potentially identify additional targets for surgical disconnection including informing the location for the completion of multiple subpial transections (MSPTs).

Document Type: Article
Source: Scopus

Huang, Y.-C.a e , Wei, K.-C.a e , Chang, C.-N.a e , Chen, P.-Y.a e , Hsu, P.-W.a e , Chen, C.P.d e , Lu, C.-S.b c e , Wang, H.-L.e , Gutmann, D.H.f , Yeh, T.-H.b c e
Transglutaminase 2 expression is increased as a function of malignancy grade and negatively regulates cell growth in meningioma
(2014) PLoS ONE, 9 (9), art. no. e108228, . 

a Department of Neurosurgery, Chang Gung Memorial Hospital at LinkouTaoyuan, Taiwan
b Department of Neurology, Chang Gung Memorial Hospital at LinkouTaoyuan, Taiwan
c Neuroscience Research Center, Chang Gung Memorial Hospital at LinkouTaoyuan, Taiwan
d Department of Rehabilitation, Chang Gung Memorial Hospital at LinkouTaoyuan, Taiwan
e Chang Gung University, College of MedicineTaoyuan, Taiwan
f Department of Neurology, Washington University, School of MedicineSt. Louis, MI, United States

Most meningiomas are benign, but some clinical-aggressive tumors exhibit brain invasion and cannot be resected without significant complications. To identify molecular markers for these clinically-aggressive meningiomas, we performed microarray analyses on 24 primary cultures from 21 meningiomas and 3 arachnoid membranes. Using this approach, increased transglutaminase 2 (TGM2) expression was observed, which was subsequently validated in an independent set of 82 meningiomas by immunohistochemistry. Importantly, the TGM2 expression level was associated with increasing WHO malignancy grade as well as meningioma recurrence. Inhibition of TGM2 function by siRNA or cystamine induced meningioma cell death, which was associated with reduced AKT phosphorylation and caspase-3 activation. Collectively, these findings suggest that TGM2 expression increases as a function of malignancy grade and tumor recurrence and that inhibition of TGM2 reduces meningioma cell growth.

Document Type: Article
Source: Scopus

Ramsey, A.a , Lord, S.b , Torrey, J.c , Marsch, L.b , Lardiere, M.d
Paving the Way to Successful Implementation: Identifying Key Barriers to Use of Technology-Based Therapeutic Tools for Behavioral Health Care
(2014) Journal of Behavioral Health Services and Research, 17 p. Article in Press. 

a Center for Mental Health Services Research, Brown School of Social Work, Washington University in St. Louis, One Brookings DriveSt. Louis, MO, United States
b Center for Technology and Behavioral Health, Dartmouth Psychiatric Research Center, 85 Mechanic Street, Suite B4-1Lebanon, NH, United States
c Dartmouth Psychiatric Research Center, 85 Mechanic Street, Suite B4-1Lebanon, NH, United States
d National Council for Behavioral Health, 1701 K St, NW Ste # 400Washington, DC, United States

This study aimed to identify barriers to use of technology for behavioral health care from the perspective of care decision makers at community behavioral health organizations. As part of a larger survey of technology readiness, 260 care decision makers completed an open-ended question about perceived barriers to use of technology. Using the Consolidated Framework for Implementation Research (CFIR), qualitative analyses yielded barrier themes related to characteristics of technology (e.g., cost and privacy), potential end users (e.g., technology literacy and attitudes about technology), organization structure and climate (e.g., budget and infrastructure), and factors external to organizations (e.g., broadband accessibility and reimbursement policies). Number of reported barriers was higher among respondents representing agencies with lower annual budgets and smaller client bases relative to higher budget, larger clientele organizations. Individual barriers were differentially associated with budget, size of client base, and geographic location. Results are discussed in light of implementation science frameworks and proactive strategies to address perceived obstacles to adoption and use of technology-based behavioral health tools.

Document Type: Article in Press
Source: Scopus

Schwetye, K.E.a , Gutmann, D.H.b
Cognitive and behavioral problems in children with neurofibromatosis type 1: Challenges and future directions
(2014) Expert Review of Neurotherapeutics, 14 (10), pp. 1139-1152. 

a Department of Pathology, Division of Neuropathology, Washington University School of Medicine, 660 S. Euclid AvenueSt. Louis, MO, United States
b Department of Neurology, Washington University School of Medicine, 660 S. Euclid AvenueSt. Louis, MO, United States

Cognitive and behavioral disorders affect nearly 80% of all children with the neurofibromatosis type 1 inherited cancer syndrome, and are among the most significant clinical manifestations for patients and their families. One of the barriers to successful therapeutic intervention is the wide spectrum of clinical phenotypic expression, ranging from visuospatial learning problems to social perceptual deficits (autism). Leveraging numerous small-Animal models of neurofibromatosis type 1, several promising targets have been identified to treat the learning, attention, and autism spectrum phenotypes in this at-risk population. In this review, we provide an up-to-date summary of our current understanding of these disorders in NF1, and propose future research directions aimed at designing more effective therapeutic approaches and clinical trials.

Author Keywords
Attention;  Autism;  Cognitive and behavioral;  Learning and memory;  Monogenic;  Mouse models;  Neurofibromatosis type 1;  NF1;  Preclinical;  Single gene

Document Type: Review
Source: Scopus

Nestojko, J.F.a , Bui, D.C.a , Kornell, N.c , Bjork, E.L.b
Expecting to teach enhances learning and organization of knowledge in free recall of text passages
(2014) Memory and Cognition, 42 (7), pp. 1038-1048. 

a Washington University in St. Louis, One Brookings Drive, Campus Box 1125St. Louis, MO, United States
b University of California, Los AngelesLos Angeles, CA, United States
c Williams CollegeWilliamstown, MA, United States

The present research assessed the potential effects of expecting to teach on learning. In two experiments, participants studied passages either in preparation for a later test or in preparation for teaching the passage to another student who would then be tested. In reality, all participants were tested, and no one actually engaged in teaching. Participants expecting to teach produced more complete and better organized free recall of the passage (Experiment 1) and, in general, correctly answered more questions about the passage than did participants expecting a test (Experiment 1), particularly questions covering main points (Experiment 2), consistent with their having engaged in more effective learning strategies. Instilling an expectation to teach thus seems to be a simple, inexpensive intervention with the potential to increase learning efficiency at home and in the classroom.

Author Keywords
Memory;  Recall;  Text processing

Document Type: Article
Source: Scopus

Eisenstein, S.A.a , Koller, J.M.a , Black, K.D.b , Campbell, M.C.c d , Lugar, H.M.a , Ushe, M.c , Tabbal, S.D.e , Karimi, M.c , Hershey, T.a c d f , Perlmutter, J.S.c d f g h , Black, K.J.a c d f g
Functional anatomy of subthalamic nucleus stimulation in Parkinson disease
(2014) Annals of Neurology, 76 (2), pp. 279-295. 

a Department of Psychiatry, Washington University in St Louis, St Louis, MO, United States
b School of Arts and Sciences, University of Rochester, Rochester, NY, United States
c Department of Neurology, Washington University in St Louis, St Louis, MO, United States
d Department of Radiology, Washington University in St Louis, St Louis, MO, United States
e Department of Neurology, American University of Beirut, Beirut, Lebanon
f Division of Biology and Biomedical Sciences, Washington University in St Louis, St Louis, MO, United States
g Department of Anatomy and Neurobiology, Washington University in St Louis, St Louis, MO, United States
h Programs in Physical Therapy and Occupational Therapy, Washington University in St Louis, St Louis, MO, United States

Objective We developed a novel method to map behavioral effects of deep brain stimulation (DBS) across a 3-dimensional brain region and to assign statistical significance after stringent type I error correction. This method was applied to behavioral changes in Parkinson disease (PD) induced by subthalamic nucleus (STN) DBS to determine whether these responses depended on anatomical location of DBS. Methods Fifty-one PD participants with STN DBS were evaluated off medication, with DBS off and during unilateral STN DBS with clinically optimized settings. Dependent variables included DBS-induced changes in Unified Parkinson Disease Rating Scale (UPDRS) subscores, kinematic measures of bradykinesia and rigidity, working memory, response inhibition, mood, anxiety, and akathisia. Weighted t tests at each voxel produced p images showing where DBS most significantly affected each dependent variable based on outcomes of participants with nearby DBS. Finally, a permutation test computed the probability that this p image indicated significantly different responses based on stimulation site. Results Most motor variables improved with DBS anywhere in the STN region, but several motor, cognitive, and affective responses significantly depended on precise location stimulated, with peak p values in superior STN/zona incerta (quantified bradykinesia), dorsal STN (mood, anxiety), and inferior STN/substantia nigra (UPDRS tremor, working memory). Interpretation Our method identified DBS-induced behavioral changes that depended significantly on DBS site. These results do not support complete functional segregation within STN, because movement improved with DBS throughout, and mood improved with dorsal STN DBS. Rather, findings support functional convergence of motor, cognitive, and limbic information in STN. © 2014 American Neurological Association.

Document Type: Article
Source: Scopus

Thomas, J.B.a , Brier, M.R.a , Bateman, R.J.a , Snyder, A.Z.b , Benzinger, T.L.b , Xiong, C.c , Raichle, M.a b d , Holtzman, D.M.a , Sperling, R.A.e , Mayeux, R.f , Ghetti, B.g , Ringman, J.M.h , Salloway, S.i , McDade, E.j , Rossor, M.N.k , Ourselin, S.k , Schofield, P.R.l m , Masters, C.L.n , Martins, R.N.o , Weiner, M.W.p q r , Thompson, P.M.s , Fox, N.C.t , Koeppe, R.A.u , Jack, C.R., Jr.v , Mathis, C.A.w , Oliver, A.a , Blazey, T.M.b , Moulder, K.x , Buckles, V.a , Hornbeck, R.b , Chhatwal, J.y , Schultz, A.P.y , Goate, A.M.r , Fagan, A.M.a , Cairns, N.J.a , Marcus, D.S.b , Morris, J.C.a , Ances, B.M.a
Functional connectivity in autosomal dominant and late-onset Alzheimer disease
(2014) JAMA Neurology, 71 (9), pp. 1111-1122. 

a Department of Neurology, Washington University in St. Louis, 660 S Euclid Ave, PO Box 8111St Louis, MO, United States
b Department of Radiology, Washington University in St. LouisSt Louis, MO, United States
c Division of Biostatistics, Washington University in St. LouisSt Louis, MO, United States
d Department of Anatomy and Neurobiology, Washington University in St. LouisSt Louis, MO, United States
e Department of Neurology, Massachusetts General Hospital, Harvard Medical SchoolBoston, MA, United States
f Department of Neurology, Columbia University Medical CenterNew York, NY, United States
g Department of Pathology and Laboratory Medicine, Indiana UniversityBloomington, IN, United States
h Department of Neurology, David Geffen School of Medicine, University of CaliforniaLos Angeles, CA, United States
i Departments of Neurology and Psychiatry, Warren Alpert Medical School, Brown UniversityProvidence, RI, United States
j Department of Neurology, University of PittsburghPittsburgh, PA, United States
k Dementia Research Centre, Institute of Neurology, University College LondonLondon, United Kingdom
l Neuroscience Research AustraliaSydney, NSW, Australia
m School of Medical Sciences, University of New SouthWalesSydney, NSW, Australia
n Mental Health Research Institute, University of MelbourneMelbourne, VIC, Australia
o School of Medical Sciences, Edith Cowan UniversityJoondalup, WA, Australia
p Department of Medicine, University of CaliforniaSan Francisco, CA, United States
q Department of Radiology, University of CaliforniaSan Francisco, CA, United States
r Department of Psychiatry, University of CaliforniaSan Francisco, CA, United States
s Departments of Neurology and Psychiatry, Imaging Genetics Center, University of CaliforniaLos Angeles, CA, United States
t Department of Neurodegeneration, Institute of Neurology, University College of LondonLondon, United Kingdom
u Department of Radiology, University of MichiganAnn Arbor, MI, United States
v Department of Radiology, Mayo ClinicRochester, MN, United States
w Department of Radiology, University of PittsburghPittsburgh, PA, United States
x Department of Psychiatry, Washington University in St. LouisSt Louis, MO, United States
y Department of Neurology, Martinos Center for Biomedical Imaging, Massachusetts General HospitalBoston, MA, United States

IMPORTANCE: Autosomal dominant Alzheimer disease (ADAD) is caused by rare genetic mutations in 3 specific genes in contrast to late-onset Alzheimer disease (LOAD), which has a more polygenetic risk profile. OBJECTIVE: To assess the similarities and differences in functional connectivity changes owing to ADAD and LOAD. DESIGN, SETTING, AND PARTICIPANTS: We analyzed functional connectivity in multiple brain resting state networks (RSNs) in a cross-sectional cohort of participants with ADAD (n = 79) and LOAD (n = 444), using resting-state functional connectivitymagnetic resonance imaging at multiple international academic sites. MAIN OUTCOMES AND MEASURES: For both types of AD, we quantified and compared functional connectivity changes in RSNs as a function of dementia severity measured by the Clinical Dementia Rating Scale. In ADAD, we qualitatively investigated functional connectivity changes with respect to estimated years from onset of symptoms within 5 RSNs. RESULTS: A decrease in functional connectivity with increasing Clinical Dementia Rating scores were similar for both LOAD and ADAD in multiple RSNs. Ordinal logistic regression models constructed in one type of Alzheimer disease accurately predicted clinical dementia rating scores in the other, further demonstrating the similarity of functional connectivity loss in each disease type. Among participants with ADAD, functional connectivity in multiple RSNs appeared qualitatively lower in asymptomatic mutation carriers near their anticipated age of symptom onset compared with asymptomatic mutation noncarriers. CONCLUSIONS AND RELEVANCE: Resting-state functional connectivity magnetic resonance imaging changes with progressing AD severity are similar between ADAD and LOAD. Resting-state functional connectivitymagnetic resonance imagingmay be a useful end point for LOAD and ADAD therapy trials. Moreover, the disease process of ADAD may be an effective model for the LOAD disease process.

Document Type: Article
Source: Scopus

Schramm, E.C.a , Clark, S.J.b , Triebwasser, M.P.a , Raychaudhuri, S.c d e f , Seddon, J.M.g h , Atkinson, J.P.a
Genetic variants in the complement system predisposing to age-related macular degeneration: A review
(2014) Molecular Immunology, 61 (2), pp. 118-125. 

a Division of Rheumatology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO, United States
b Centre for Hearing and Vision Research, Institute of Human Development, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom
c Divisions of Rheumatology and Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA, United States
d Partners Center for Personalized Genetic Medicine, Boston, MA, United States
e Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, United States
f Faculty of Medical and Human Sciences, University of Manchester, Manchester, United Kingdom
g Department of Ophthalmology, Tufts University School of Medicine, Boston, MA, United States
h Ophthalmic Epidemiology and Genetics Service, Tufts Medical Center, Boston, MA, United States

Age-related macular degeneration (AMD) is a major cause of visual impairment in the western world. It is characterized by the presence of lipoproteinaceous deposits (drusen) in the inner layers of the retina. Immunohistochemistry studies identified deposition of complement proteins in the drusen as well as in the choroid. In the last decade, genetic studies have linked both common and rare variants in genes of the complement system to increased risk of development of AMD. Here, we review the variants described to date and discuss the functional implications of dysregulation of the alternative pathway of complement in AMD. © 2014 Elsevier Ltd.

Author Keywords
Age-related macular degeneration;  Alternative pathway;  Complement system;  Genetic variants

Document Type: Review
Source: Scopus

Putnam, A.L., Wahlheim, C.N., Jacoby, L.L.
Memory for flip-flopping: Detection and recollection of political contradictions
(2014) Memory and Cognition, 42 (7), pp. 1198-1210. 

Department of Psychology, Washington University in St. Louis, One Brookings Drive, Campus Box 1125St. Louis, MO, United States

During political campaigns, candidates often change their positions on controversial issues. Does changing positions create confusion and impair memory for a politician’s current position? In 3 experiments, two political candidates held positions on controversial issues in two debates. Across the debates, their positions were repeated, changed, or held only in the second debate (control). Relative to the control condition, recall of the most recent position on issues was enhanced when change was detected and recollected, whereas recall was impaired when change was not recollected. Furthermore, examining the errors revealed that subjects were more likely to intrude a Debate 1 response than to recall a blend of the two positions, and that recollecting change decreased Debate 1 intrusions. We argue that detecting change produces a recursive representation that embeds the original position in memory along with the more recent position. Recollecting change then enhances memory for the politician’s positions and their order of occurrence by accessing the recursive trace.

Author Keywords
Change detection;  Contradiction;  Politics;  Proactive interference;  Recursive reminding

Document Type: Article
Source: Scopus

Stein, K.C., True, H.L.
Prion Strains and Amyloid Polymorphism Influence Phenotypic Variation
(2014) PLoS Pathogens, 10 (9), 4 p. 

Department of Cell Biology and Physiology, Washington University School of MedicineSt. Louis, MO, United States

Document Type: Article
Source: Scopus

Cutler, A.J.a b , Brams, M.c , Bukstein, O.d , Mattingly, G.e , McBurnett, K.f , White, C.g , Rubin, J.h
Response/remission with guanfacine extended-release and psychostimulants in children and adolescents with attention-deficit/hyperactivity disorder
(2014) Journal of the American Academy of Child and Adolescent Psychiatry, 53 (10), pp. 1092-1101. 

a Florida Clinical Research Center, LLC, 8043 Cooper Creek BlvdBradenton, FL, United States
b University of FloridaGainesville, FL, United States
c Baylor College of MedicineHouston, United States
d DePelchin Children's Center, Houston and Baylor College of Medicine, United States
e Washington University School of MedicineSt. Charles, MO, United States
f University of California, San FranciscoSan Francisco, United States
g Shire Pharmaceutical Development LtdBasingstoke, United Kingdom
h Alcobra Inc., Plymouth MeetingPA, United States

Objective: In this post hoc analysis, we assessed whether guanfacine extended-release (GXR) adjunctive to a psychostimulant resulted in greater response and remission rates than placebo + psychostimulant in children and adolescents with attention-deficit/hyperactivity disorder (ADHD).

Method: In this 9-week, double-blind, placebo-controlled dose-optimization study, participants (N = 461) aged 6 to 17 years with suboptimal response to psychostimulants were randomized to GXR on awakening (AM) + psychostimulant, GXR at bedtime (PM) + psychostimulant, or placebo + psychostimulant. Results At the final on-treatment assessment, more participants in both GXR + psychostimulant groups versus the placebo + psychostimulant group achieved response as assessed by 2 criteria: reduction from baseline in ADHD Rating Scale IV (ADHD-RS-IV) total score (1) ≥40% (GXR AM + psychostimulant = 69.8%, GXR PM + psychostimulant = 70.3%, versus placebo + psychostimulant = 57.9%; p =.032 and p =.026, respectively), or (2) ≥50% (63.1%, 64.9%, versus 43.4%; p <.001 for both). Results were similar for symptomatic remission (ADHD-RS-IV total score ≤18; 61.1%, 62.2%, versus 46.1%; p =.010 and p =.005, respectively) and syndromal remission (symptomatic remission plus Clinical Global Impressions of Severity of Illness score ≤2). The most common treatment-emergent adverse events in participants receiving GXR + psychostimulant were headache (21.2%) and somnolence (13.6%).

Conclusion GXR + psychostimulant treatment resulted in a greater percentage of participants meeting stringent criteria for response and remission compared with placebo + psychostimulant. The adverse event profile of adjunctive therapy was consistent with known effects of either treatment alone. Clinical trial registration information - Efficacy and Safety of SPD503 in Combination With Psychostimulants;; NCT00734578.

Author Keywords
α2A-agonist guanfacine XR ADHD response remission

Document Type: Article
Source: Scopus

Barch, D.M.
Risk for mood pathology: Neural and psychological markers of abnormal negative information processing
(2014) Journal of the American Academy of Child and Adolescent Psychiatry, 53 (5), pp. 579-588.e9. 

Washington University, Psychology, Psychiatry, One Brookings DriveSt. Louis, MO, United States

Document Type: Article
Source: Scopus

McCreedy, D.A., Wilems, T.S., Xu, H., Butts, J.C., Brown, C.R., Smith, A.W., Sakiyama-Elbert, S.E.
Survival, differentiation, and migration of high-purity mouse embryonic stem cell-derived progenitor motor neurons in fibrin scaffolds after sub-acute spinal cord injury
(2014) Biomaterials Science, 2 (11), pp. 1672-1682. 

Department of Biomedical Engineering, Washington University in St. LouisSt. Louis, MO, United States

Embryonic stem (ES) cells can be differentiated into many neural cell types that hold great potential in cell replacement therapies following spinal cord injury (SCI). Coupling stem cell transplantation with biomaterial scaffolds can produce a unified combination therapy with several potential advantages including enhanced cell survival, greater transplant retention, reduced scarring, and improved integration at the transplant/host interface. Undesired cell types, however, are commonly present in ES-cell derived cultures due to the limited efficiency of most ES cell induction protocols. Heterogeneous cell populations can confound the interaction between the biomaterial and specific neural populations leading to undesired outcomes. In particular, biomaterial scaffolds may enhance tumor formation by promoting survival and proliferation of undifferentiated ES cells that can persist after induction. Methods for purification of specific ES cell-derived neural populations are necessary to recognize the full potential of combination therapies involving biomaterials and ES cell-derived neural populations. We previously developed a method for enriching ES cell-derived progenitor motor neurons (pMNs) induced from mouse ES cells via antibiotic selection and showed that the enriched cell populations are depleted of pluripotent stem cells. In this study, we demonstrate the survival and differentiation of enriched pMNs within three dimensional (3D) fibrin scaffolds in vitro and when transplanted into a sub-acute dorsal hemisection model of SCI into neurons, oligodendrocytes and astrocytes. This journal is

Document Type: Article
Source: Scopus

Lilienthal, L., Hale, S., Myerson, J.
The effects of environmental support and secondary tasks on visuospatial working memory
(2014) Memory and Cognition, 42 (7), pp. 1118-1129. 

Psychology Department, Washington University in St. Louis, 1 Brookings DriveSaint Louis, MO, United States

In the present experiments, we examined the effects of environmental support on participants’ ability to rehearse locations and the role of such support in the effects of secondary tasks on memory span. In Experiment 1, the duration of interitem intervals and the presence of environmental support for visuospatial rehearsal (i.e., the array of possible memory locations) during the interitem intervals were both manipulated across four tasks. When support was provided, memory spans increased as the interitem interval durations increased, consistent with the hypothesis that environmental support facilitates rehearsal. In contrast, when environmental support was not provided, spans decreased as the duration of the interitem intervals increased, consistent with the hypothesis that visuospatial memory representations decay when rehearsal is impeded. In Experiment 2, the ratio of interitem interval duration to intertrial interval duration was kept the same on all four tasks, in order to hold temporal distinctiveness constant, yet forgetting was still observed in the absence of environmental support, consistent with the decay hypothesis. In Experiment 3, the effects of impeding rehearsal were compared to the effects of verbal and visuospatial secondary processing tasks. Forgetting of locations was greater when presentation of to-be-remembered locations alternated with the performance of a secondary task than when rehearsal was impeded by the absence of environmental support. The greatest forgetting occurred when a secondary task required the processing visuospatial information, suggesting that in addition to decay, both domain-specific and domain-general effects contribute to forgetting on visuospatial working memory tasks.

Author Keywords
Decay;  Environmental support;  Interference;  Secondary tasks;  Visuospatial working memory

Document Type: Article
Source: Scopus

Mamah, D.a , Owoso, A.a , Sheffield, J.M.b , Bayer, C.a
The WERCAP Screen and the WERC Stress Screen: Psychometrics of self-rated instruments for assessing bipolar and psychotic disorder risk and perceived stress burden
(2014) Comprehensive Psychiatry, 55 (7), pp. 1757-1771. 

a Department of Psychiatry, Washington University, School of Medicine, (Box 8134), 660 S. EuclidSt. Louis, MO, United States
b Department of Psychology, Washington UniversitySt. Louis, United States

Methods Prevalence rates of the WERCAP Screen were evaluated among 171 community youth (aged 13-24 years); internal consistency was assessed and k-means cluster analysis was used to identify symptom groups. In 33 participants, test-retest reliability coefficients were assessed, and ROC curve analysis was used to determine the validity of the psychosis section of the WERCAP Screen (pWERCAP) against the Structured Interview of Psychosis-Risk Symptoms (SIPS). Correlations of the pWERCAP, the affectivity section of the WERCAP Screen (aWERCAP) and the WERC Stress Screen were examined to determine the relatedness of scores with cognition and clinical measures.

Background Identification of individuals in the prodromal phase of bipolar disorder and schizophrenia facilitates early intervention and promises an improved prognosis. There are no current assessment tools for clinical risk symptoms of bipolar disorder, and psychosis-risk assessment generally involves semi-structured interviews, which are time consuming and rater dependent. We present psychometric data on two novel quantitative questionnaires: the Washington Early Recognition Center Affectivity and Psychosis (WERCAP) Screen for assessing bipolar and psychotic disorder risk traits, and the accompanying WERC Stress Screen for assessing individual and total psychosocial stressor severities.

Results Cluster analysis identified three groups of participants: a normative (47%), a psychosis-affectivity (18%) and an affectivity only (35%) group. Internal consistency of the aWERCAP and pWERCAP resulted in alphas of 0.87 and 0.92, and test-retest reliabilities resulted in intraclass correlation coefficients of 0.76 and 0.86 respectively. ROC curve analysis showed the optimal cut-point on the pWERCAP as a score of >30 (sensitivity: 0.89; specificity: 1.0). There was a significant negative correlation between aWERCAP scores and total cognition (R = -0.42), and between pWERCAP scores and sensorimotor processing speed. Total stress scores correlated significantly with scores on the aWERCAP (R = 0.88), pWERCAP (R = 0.62) and total cognition (R = -0.44).

Conclusions Our results show that the WERCAP Screen and the WERC Stress Screen are easy to administer and derived scores are related to cognitive and clinical traits. This suggests that their use could have particular benefits for epidemiologic studies and in busy clinical settings. Longitudinal studies would be required to evaluate clinical outcomes with high questionnaire scores.


Document Type: Article
Source: Scopus


October 8, 2014

York, T.a , Gruev, V.a , Saha, D.b , Raman, B.b
A 220 × 128 120 mW 60 frames/s current mode polarization imager for in vivo optical neural recording
(2014) Proceedings - IEEE International Symposium on Circuits and Systems, art. no. 6865518, pp. 1849-1852. 

a Dept. of Computer Science and Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States
b Dept. of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States

A 220 by 128 current mode imaging sensor with polarization sensitivity is used to image intrinsic neural activity in vivo from the antenna lobe of a locust. The polarization sensitivity is achieved via post-CMOS fabrication deposition of pixelated aluminum nanowire polarization filters at four different orientations offset by 45 degrees. The measured change in polarization response from the neural cells baseline for hexanol is 0.38%, for octanol is 0.15%, and for the combined odor is 0.45%. © 2014 IEEE.

Document Type: Conference Paper
Source: Scopus

Bennett, R.E., Brody, D.L.
Acute reduction of microglia does not alter axonal injury in a mouse model of repetitive concussive traumatic brain injury
(2014) Journal of Neurotrauma, 31 (19), pp. 1647-1663. 

Department of Neurology, Washington University, 660 South Euclid Avenue, Campus Box 8111St. Louis, MO, United States

The pathological processes that lead to long-term consequences of multiple concussions are unclear. Primary mechanical damage to axons during concussion is likely to contribute to dysfunction. Secondary damage has been hypothesized to be induced or exacerbated by inflammation. The main inflammatory cells in the brain are microglia, a type of macrophage. This research sought to determine the contribution of microglia to axon degeneration after repetitive closed-skull traumatic brain injury (rcTBI) using CD11b-TK (thymidine kinase) mice, a valganciclovir-inducible model of macrophage depletion. Low-dose (1 mg/mL) valganciclovir was found to reduce the microglial population in the corpus callosum and external capsule by 35% after rcTBI in CD11b-TK mice. At both acute (7 days) and subacute (21 days) time points after rcTBI, reduction of the microglial population did not alter the extent of axon injury as visualized by silver staining. Further reduction of the microglial population by 56%, using an intermediate dose (10 mg/mL), also did not alter the extent of silver staining, amyloid precursor protein accumulation, neurofilament labeling, or axon injury evident by electron microscopy at 7 days postinjury. Longer treatment of CD11b-TK mice with intermediate dose and treatment for 14 days with high-dose (50 mg/mL) valganciclovir were both found to be toxic in this injury model. Altogether, these data are most consistent with the idea that microglia do not contribute to acute axon degeneration after multiple concussive injuries. The possibility of longer-term effects on axon structure or function cannot be ruled out. Nonetheless, alternative strategies directly targeting injury to axons may be a more beneficial approach to concussion treatment than targeting secondary processes of microglial-driven inflammation.

Author Keywords
axon injury;  concussion;  microglia

Document Type: Article
Source: Scopus

Anticevic, A.a b c d e , Tang, Y.f , Cho, Y.T.a , Repovs, G.g , Cole, M.W.h , Savic, A.a i , Wang, F.a j , Krystal, J.H.a b c , Xu, K.j
Amygdala connectivity differs among chronic, early course, and individuals at risk for developing schizophrenia
(2014) Schizophrenia Bulletin, 40 (5), pp. 1105-1116. 

a Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States
b NIAAA Center for the Translational Neuroscience of Alcoholism, New Haven, CT, United States
c Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, CT, United States
d Department of Psychology, Yale University, 2 Hillhouse Avenue, New Haven, CT, United States
e Interdepartmental Neuroscience Program, Yale University, New Haven, CT, United States
f Department of Psychiatry, First Affiliated Hospital, China Medical University, Shenyang, Liaoning, China
g Department of Psychology, University of Ljubljana, Ljubljana, Slovenia
h Department of Psychology, Washington University in St Louis, St Louis, MO, United States
i University Psychiatric Hospital Vrapce, University of Zagreb, Zagreb, Croatia
j Department of Radiology, First Affiliated Hospital, China Medical University, 155 Nanjing North Street, Shenyang 110001, Liaoning, China

Alterations in circuits involving the amygdala have been repeatedly implicated in schizophrenia neuropathology, given their role in stress, affective salience processing, and psychosis onset. Disturbances in amygdala whole-brain functional connectivity associated with schizophrenia have yet to be fully characterized despite their importance in psychosis. Moreover, it remains unknown if there are functional alterations in amygdala circuits across illness phases. To evaluate this possibility, we compared whole-brain amygdala connectivity in healthy comparison subjects (HCS), individuals at high risk (HR) for schizophrenia, individuals in the early course of schizophrenia (EC-SCZ), and patients with chronic schizophrenia (C-SCZ). We computed whole-brain resting-state connectivity using functional magnetic resonance imaging at 3T via anatomically defined individual-specific amygdala seeds. We identified significant alterations in amygdala connectivity with orbitofrontal cortex (OFC), driven by reductions in EC-SCZ and C-SCZ (effect sizes of 1.0 and 0.97, respectively), but not in HR for schizophrenia, relative to HCS. Reduced amygdala- OFC coupling was associated with schizophrenia symptom severity (r = .32, P < .015). Conversely, we identified a robust increase in amygdala connectivity with a brainstem region around noradrenergic arousal nuclei, particularly for HR individuals relative to HCS (effect size = 1.54), but not as prominently for other clinical groups. These results suggest that deficits in amygdala-OFC coupling could emerge during the initial episode of schizophrenia (EC-SCZ) and may present as an enduring feature of the illness (C-SCZ) in association with symptom severity but are not present in individuals with elevated risk for developing schizophrenia. Instead, in HR individuals, there appears to be increased connectivity in a circuit implicated in stress response. © The Author 2013.

Author Keywords
Amygdala;  Connectivity;  First episode;  Prefrontal cortex;  Risk for schizophrenia;  Schizophrenia

Document Type: Article
Source: Scopus

Macauley, S.L.a b , Wong, A.M.S.e , Shyng, C.b , Augner, D.P.e , Dearborn, J.T.b , Pearse, Y.e , Roberts, M.S.b , Fowler, S.C.d , Cooper, J.D.e , Watterson, D.M.f , Sands, M.S.b c
An anti-neuroinflammatory that targets dysregulated glia enhances the efficacy of CNS-directed gene therapy in murine infantile neuronal ceroid lipofuscinosis
(2014) Journal of Neuroscience, 34 (39), pp. 13077-13082. 

a Department of Neurology, Washington University School of MedicineSt. Louis, MO, United States
b Department of Internal Medicine, Washington University School of MedicineSt. Louis, MO, United States
c Department of Genetics, Washington University School of MedicineSt. Louis, MO, United States
d Departments of Pharmacology and Toxicology, University of KansasLawrence, KS, United States
e Department of Neuroscience, Centre for the Cellular Basis of Behaviour, MRC Centre for Neurodegeneration Research, Institute of Psychiatry, King’s College LondonLondon, United Kingdom
f Department of Pharmacology, Feinberg School of Medicine, Northwestern UniversityChicago, IL, United States

Infantile neuronal ceroid lipofuscinosis (INCL) is an inherited neurodegenerative lysosomal storage disease (LSD) caused by a deficiency in palmitoyl protein thioesterase-1 (PPT1). Studies in Ppt1−/− mice demonstrate that glial activation is central to the pathogenesis of INCL. Astrocyte activation precedes neuronal loss, while cytokine upregulation associated with microglial reactivity occurs before and concurrent with neurodegeneration. Therefore, we hypothesized that cytokine cascades associated with neuroinflammation are important therapeutic targets for the treatment of INCL. MW01–2-151SRM (MW151) is a blood–brain barrier penetrant, small-molecule anti-neuroinflammatory that attenuates glial cytokine upregulation in models of neuroinflammation such as traumatic brain injury, Alzheimer's disease, and kainic acid toxicity. Thus, we used MW151, alone and in combination with CNS-directed, AAV-mediated gene therapy, as a possible treatment for INCL. MW151 alone decreased seizure susceptibility. When combined with AAV-mediated gene therapy, treated INCL mice had increased life spans, improved motor performance, and eradication of seizures. Combination-treated INCL mice also had decreased brain atrophy, astrocytosis, and microglial activation, as well as intermediary effects on cytokine upregulation. These data suggest that MW151 can attenuate seizure susceptibility but is most effective when used in conjunction with a therapy that targets the primary genetic defect.

Author Keywords
Batten disease;  Lysosomal storage disease;  Neurodegeneration;  Neuroinflammation;  Neuronal ceroid lipofuscinosis

Document Type: Article
Source: Scopus

Dasanayake, I.S.a , Li, J.-S.b
Design of charge-balanced time-optimal stimuli for spiking neuron oscillators
(2014) Neural Computation, 26 (10), pp. 2223-2246. 

a University of CaliforniaSanta Barbara, CA, United States
b Washington UniversitySt. Louis, MO, United States

In this letter, we investigate the fundamental limits on how the interspike time of a neuron oscillator can be perturbed by the application of a bounded external control input (a current stimulus) with zero net electric charge accumulation.We use phase models to study the dynamics of neurons and derive charge-balanced controls that achieve the minimum and maximum interspike times for a given bound on the control amplitude. Our derivation is valid for any arbitrary shape of the phase response curve and for any value of the given control amplitude bound. In addition, we characterize the change in the structures of the charge-balanced time-optimal controls with the allowable control amplitude. We demonstrate the applicability of the derived optimal control laws by applying them to mathematically ideal and experimentally observed neuron phase models, including thewidely studied Hodgkin-Huxley phase model, and by verifying them with the corresponding original full state-space models. This work addresses a fundamental problem in the field of neural control and provides a theoretical investigation to the optimal control of oscillatory systems.

Document Type: Letter
Source: Scopus

Potts, L.G.a , Kolb, K.A.b
Effect of different signal-processing options on speech-in-noise recognition for Cochlear implant recipients with the Cochlear CP810 speech processor
(2014) Journal of the American Academy of Audiology, 25 (4), pp. 367-379. 

a Department of Otolaryngology, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8115, St Louis, MO 63110, United States
b HearUSA, Hoffman Estates, IL, United States

Background: Difficulty understanding speech in the presence of background noise is a common report among cochlear implant (CI) recipients. Several speech-processing options designed to improve speech recognition, especially in noise, are currently available in the Cochlear Nucleus CP810 speech processor. These include adaptive dynamic range optimization (ADRO), autosensitivity control (ASC), Beam, and Zoom. Purpose: The purpose of this study was to evaluate CI recipients' speech-in-noise recognition to determine which currently available processing option or options resulted in best performance in a simulated restaurant environment. Research Design: Experimental study with one study group. The independent variable was speech-processing option, and the dependent variable was the reception threshold for sentences score. Study Sample: Thirty-two adult CI recipients. Intervention: Eight processing options were tested: Beam, Beam + ASC, Beam + ADRO, Beam + ASC1 + ADRO, Zoom, Zoom + ASC, Zoom + ADRO, and Zoom + ASC + ADRO. Data Collection and Analysis: Participants repeated Hearing in Noise Test sentences presented at a 0° azimuth, with R-Space restaurant noise presented from a 360° eight-loudspeaker array at 70 dB sound pressure level. A one-way repeated-measures analysis of variance was used to analyze differences in Beam options, Zoom options, and Beam versus Zoom options. Results: Among the Beam options, Beam + ADRO was significantly poorer than Beam only, Beam + ASC, and Beam + ASC + ADRO. A 1.6-dB difference was observed between the best (Beam only) and poorest (Beam + ADRO) options. Among the Zoom options, Zoom only and Zoom + ADRO were significantly poorer than Zoom + ASC. A 2.2-dB difference was observed between the best (Zoom 1 ASC) and poorest (Zoom only) options. The comparison between Beam and Zoom options showed one significant difference, with Zoom only significantly poorer than Beam only. No significant difference was found between the other Beam and Zoom options (Beam + ASC vs Zoom + ASC, Beam + ADRO vs Zoom + ADRO, and Beam + ASC + ADRO vs Zoom + ASC + ADRO). The best processing option varied across subjects, with an almost equal number of participants performing best with a Beam option (n = 15) compared with a Zoom option (n = 17). There were no significant demographic or audiological moderating variables for any option. Conclusions: The results showed no significant differences between adaptive directionality (Beam) and fixed directionality (Zoom) when ASC was active in the R-Space environment. This finding suggests that noise-reduction processing is extremely valuable in loud semidiffuse environments in which the effectiveness of directional filtering might be diminished. However, there was no significant difference between the Beam-only and Beam + ASC options, which is most likely related to the additional noise cancellation performed by the Beam option (i.e., two-stage directional filtering and noise cancellation). In addition, the processing options with ADRO resulted in the poorest performances. This could be related to how the CI recipients were programmed or the loud noise level used in this study. The best processing option varied across subjects, but the majority performed best with directional filtering (Beam or Zoom) in combination with ASC. Therefore in a loud semidiffuse environment, the use of either Beam + ASC or Zoom + ASC is recommended.

Author Keywords
Beam;  Cochlear implants;  R-Space;  Speech perception;  Zoom

Document Type: Article
Source: Scopus

Al-Zubeidi, D.a , Thangarajh, M.b , Pathak, S.c , Cai, C.d , Schlaggar, B.L.c , Storch, G.A.e , Grange, D.K.f , Watson Jr., M.E.g
Fatal human herpesvirus 6-associated encephalitis in two boys with underlying POLG mitochondrial disorders
(2014) Pediatric Neurology, 51 (3), pp. 448-452. 

a Division of Pediatric Infectious Diseases, Department of Pediatrics, Children's Mercy Hospital, Kansas City, MO, United States
b Division of Epilepsy, Neurophysiology, and Critical Care Neurology, Department of Neurology, Children's National Medical Center, Washington, DC, United States
c Department of Neurology, Washington University, St. Louis, MO, United States
d Department of Pathology and Immunology, Washington University, St. Louis, MO, United States
e Division of Pediatric Infectious Diseases, Department of Pediatrics, Washington University, St. Louis, MO, United States
f Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University, St. Louis, MO, United States
g Division of Pediatric Infectious Diseases, Department of Pediatrics, University of Michigan, Ann Arbor, MI, United States

Background Human herpesvirus 6 is a significant cause of the febrile illness roseola infantum in young children. Infection with human herpesvirus 6 typically causes a self-limited febrile illness but occasionally is associated with central nervous system manifestations, including febrile seizures and encephalitis. Host factors associated with severe manifestations of human herpesvirus 6-associated neurological disease remain poorly characterized. Case Reports We report two previously healthy young boys with human herpesvirus 6-associated encephalitis who developed a progressive, and ultimately fatal, encephalopathy with refractory movement disorder concurrent with acquisition of acute human herpesvirus 6 infection. Both children were treated with the antiviral ganciclovir without improvement of their neurological symptoms, although quantitative human herpesvirus 6 polymerase chain reaction of cerebrospinal fluid and/or blood confirmed a decline in viral load with treatment. The clinical course in both cases was most consistent with Alpers-Huttenlocher syndrome, given the intractable seizures, developmental regression, and, ultimately, death due to liver and renal failure. In support of this, postmortem analysis identified both children to be compound heterozygous for mutations in the mitochondrial polymerase γ gene, POLG. Conclusions POLG mutations are associated with Alpers-Huttenlocher syndrome; however, no prior studies have examined the role of acute human herpesvirus 6 infection in these patients presenting with severe neurological disease. It is possible the POLG mutation phenotype was unmasked and/or exacerbated by human herpesvirus 6 infection in these two patients, potentially contributing to a more rapid clinical deterioration. This report provides new insight into a previously unrecognized association between POLG mutations and poor neurological outcome after human herpesvirus 6 infection. © 2014 Elsevier Inc. All rights reserved.

Author Keywords
child;  encephalitis;  human herpesvirus 6 (HHV-6);  POLG

Document Type: Article
Source: Scopus

Izumi, Y.a b , Zorumski, C.F.a b
Metaplastic effects of subanesthetic ketamine on CA1 hippocampal function
(2014) Neuropharmacology, 86, pp. 273-281. 

a Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, United States
b Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, United States

Ketamine is a non-competitive N-methyl-d-aspartate receptor (NMDAR) antagonist of interest in neuropsychiatry. In the present studies, we examined the effects of subanesthetic, low micromolar ketamine on excitatory postsynaptic potentials (EPSPs), population spikes (PSs) and synaptic plasticity in the CA1 region of rat hippocampal slices. Ketamine acutely inhibited NMDAR-mediated synaptic responses with half-maximal effects near 10 μM. When administered for 15-30 min at 1-10 μM, ketamine had no effect on baseline dendritic AMPA receptor-mediated EPSPs, but persistently enhanced somatic EPSPs in the pyramidal cell body layer and augmented PS firing. Acute low micromolar ketamine also had no effect on the induction of long-term potentiation (LTP) but blocked long-term depression (LTD). Following 30 min administration of 1-10 μM ketamine, however, a slowly developing and persistent form of LTP inhibition was observed that took two hours following ketamine washout to become manifest. This LTP inhibition did not result from prolonged or enhanced NMDAR inhibition during drug washout. Effects of low ketamine on somatic EPSPs and LTP were not mimicked by a high ketamine concentration that completely inhibited NMDARs, and both of these effects were blocked by co-administration of low ketamine with a low concentration of the competitive NMDAR antagonist, 2-amino-5- phosphonovalerate or inhibitors of nitric oxide synthase. These results indicate that concentrations of ketamine relevant to psychotropic and psychotomimetic effects have complex metaplastic effects on hippocampal function that involve activation of unblocked NMDARs during ketamine exposure. © 2014 Elsevier Ltd. All rights reserved.

Author Keywords
Memory;  Modulation;  Nitric oxide;  NMDA receptor;  Psychosis;  Synaptic plasticity

Document Type: Article
Source: Scopus

Park, D.a , Li, P.b , Dani, A.b , Taghert, P.H.a
Peptidergic cell-specific synaptotagmins in Drosophila: Localization to dense-core granules and regulation by the bHLH protein dimmed
(2014) Journal of Neuroscience, 34 (39), pp. 13195-13207. 

a Department of Anatomy and Neurobiology, Washington University School of MedicineSt. Louis, MO, United States
b Department of Pathology and Immunology, Washington University School of MedicineSt. Louis, MO, United States

Bioactive peptides are packaged in large dense-core secretory vesicles, which mediate regulated secretion by exocytosis. In a variety of tissues, the regulated release of neurotransmitters and hormones is dependent on calcium levels and controlled by vesicle-associated synaptotagmin (SYT) proteins. Drosophila express seven SYT isoforms, of which two (SYT-α and SYT-β) were previously found to be enriched in neuroendocrine cells. Here we show that SYT-α and SYT-β tissue expression patterns are similar, though not identical. Furthermore, both display significant overlap with the bHLH transcription factor DIMM, a known neuroendocrine (NE) regulator. RNAi-mediated knockdown indicates that both SYT-α and SYT-β functions are essential in identified NE cells as these manipulations phenocopy loss-of-function states for the indicated peptide hormones. In Drosophila cell culture, both SYT-α and neuropeptide cargo form DIMM-dependent fluorescent puncta that are coassociated by super-resolution microscopy. DIMM is required to maintain SYT-α and SYT-β protein levels in DIMM-expressing cells in vivo. In neurons normally lacking all three proteins (DIMM− /SYT-α−/SYT-β−), DIMM misexpression conferred accumulation of endogenous SYT-α and SYT-β proteins. Furthermore transgenic SYT-α does not appreciably accumulate in nonpeptidergic neurons in vivo but does so if DIMM is comisexpressed. Among Drosophila syt genes, only syt-α and syt-β RNA levels are upregulated by DIMM overexpression. Together, these data suggest that SYT-α and SYT-β are important for NE cell physiology, that one or both are integral membrane components of the large dense-core vesicles, and that they are closely regulated by DIMM at a post-transcriptional level.

Author Keywords
DIMM;  Drosophila;  LDCV;  Neuropeptide;  Super-resolution;  Synaptotagmin

Document Type: Article
Source: Scopus

Khan, M.a , Rao, P.K.b , Rao, R.C.a b c
Shimmering lights
(2014) JAMA Ophthalmology, 132 (8), pp. 1015-1016. 

a Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan, 1000Wall St., Ann Arbor,MI 48105, United States
b Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St Louis, MO, United States
c Department of Pathology, University of Michigan Medical School, Ann Arbor, United States

Document Type: Short Survey
Source: Scopus

Tanofsky-Kraff, M.a d , Shomaker, L.B.a d g , Wilfley, D.E.e , Young, J.F.f , Sbrocco, T.a , Stephens, M.a , Ranzenhofer, L.M.a d , Elliott, C.a d , Brady, S.d , Radin, R.M.a d , Vannucci, A.a d , Bryant, E.J.a , Osborn, R.a , Berger, S.S.a d , Olsen, C.a , Kozlosky, M.b , Reynolds, J.C.c , Yanovski, J.C.d
Targeted prevention of excess weight gain and eating disorders in high-risk adolescent girls: A randomized controlled trial
(2014) American Journal of Clinical Nutrition, 100 (4), pp. 1010-1018. 

a Department of Medical and Clinical Psychology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge RoadBethesda, MD, United States
b Nutrition Department, Hatfield Clinical Research Center, NIHBethesda, MD, United States
c Nuclear Medicine Department, Hatfield Clinical Research Center, NIHBethesda, MD, United States
d Section on Growth and Obesity, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIHBethesda, MD, United States
e Department of Psychiatry, Washington University School of MedicineSt Louis, MO, United States
f Applied and Professional Psychology, Rutgers UniversityPiscataway Township, NJ, United States
g Department of Human Development and Family Studies, Colorado State UniversityFort Collins, CO, United States

Conclusions: The intervention with adolescent girls with loss-ofcontrol eating is associated with lower age-adjusted BMI and percentage of adiposity as well as improved mood symptoms over 1 y. Interpersonal psychotherapy further reduced objective binge eating. Additional research is needed to elucidate the mechanisms by which physical and psychological improvements were observed.

Results: Participation in both conditions was associated with decreases in expected BMI gain, age-adjusted BMI metrics, the percentage of fat by using dual-energy X-ray absorptiometry, symptoms of depression and anxiety, and the frequency of lossof- control eating over 12 mo of follow-up (Ps < 0.001) with no group difference. In follow-up analyses, interpersonal psychotherapy was more efficacious than health education at reducing objective binge eating at the 12-mo follow-up (P < 0.05).

Background: The high prevalence and incidence of obesity and eating disorders in US adolescent girls are serious health problems. Because of the shared risk factors for obesity and eating disorders, a targeted prevention of both conditions is a priority.

Objective: We determined whether an adapted interpersonal psychotherapy prevention program is more efficacious for reducing excess weight gain and worsening disordered eating than health education in adolescent girls at high risk of obesity and eating disorders.

Design: A parallel-group, randomized controlled trial was conducted between September 2008 and January 2013 in a university-based laboratory and a federal research hospital. The study included 113 adolescent (12-17-y-old) girls deemed at high risk of adult obesity and eating disorders because of a body mass index (BMI) between the 75th and 97th percentiles and reports of episodes of a loss of control over their eating. Girls were randomly assigned to participate in an adapted interpersonal psychotherapy or a health-education group program for 12 weekly 90-min group sessions. Follow-up assessments occurred immediately after group programs and at 6 and 12 mo.

Document Type: Article
Source: Scopus

Rudokas, M.W.a , Varga, Z.a , Schubert, A.R.a , Asaro, A.B.a , Silva, J.R.b
The Xenopus oocyte cut-open vaseline gap voltage-clamp technique with fluorometry.
(2014) Journal of visualized experiments : JoVE, (85), . 

a Department of Biomedical Engineering, Washington University in St. Louis.
b Department of Biomedical Engineering, Washington University in St. Louis;

The cut-open oocyte Vaseline gap (COVG) voltage clamp technique allows for analysis of electrophysiological and kinetic properties of heterologous ion channels in oocytes. Recordings from the cut-open setup are particularly useful for resolving low magnitude gating currents, rapid ionic current activation, and deactivation. The main benefits over the two-electrode voltage clamp (TEVC) technique include increased clamp speed, improved signal-to-noise ratio, and the ability to modulate the intracellular and extracellular milieu. Here, we employ the human cardiac sodium channel (hNaV1.5), expressed in Xenopus oocytes, to demonstrate the cut-open setup and protocol as well as modifications that are required to add voltage clamp fluorometry capability. The properties of fast activating ion channels, such as hNaV1.5, cannot be fully resolved near room temperature using TEVC, in which the entirety of the oocyte membrane is clamped, making voltage control difficult. However, in the cut-open technique, isolation of only a small portion of the cell membrane allows for the rapid clamping required to accurately record fast kinetics while preventing channel run-down associated with patch clamp techniques. In conjunction with the COVG technique, ion channel kinetics and electrophysiological properties can be further assayed by using voltage clamp fluorometry, where protein motion is tracked via cysteine conjugation of extracellularly applied fluorophores, insertion of genetically encoded fluorescent proteins, or the incorporation of unnatural amino acids into the region of interest(1). This additional data yields kinetic information about voltage-dependent conformational rearrangements of the protein via changes in the microenvironment surrounding the fluorescent molecule.


Document Type: Article
Source: Scopus


October 1, 2014

Daniels, B.P.a b , Sestito, S.R.a , Rouse, S.T.a
An expanded task battery in the Morris water maze reveals effects of Toxoplasma gondii infection on learning and memory in rats
(2014) Parasitology International, 64 (1), pp. 5-12. 

a Division of Science, Southern Wesleyan UniversityCentral, SC, United States
b Department of Internal Medicine, Washington University School of MedicineSaint Louis, MO, United States

Infection with the neurotropic parasite Toxoplasma gondii is widespread among human populations; however, the impacts of latent central nervous system (CNS) T. gondii infection have only recently come to light. Epidemiological evidence in humans and experimental studies in rodents have revealed a number of neurological and behavioral sequelae following the establishment of latent CNS toxoplasmosis. Here, we report alterations in learning and memory task performance in latently infected rats using the Morris water maze. While simple spatial reference learning was intact, infected rodents exhibited poor performance compared to controls in probe trials requiring spatial memory recall and progressively poorer performance with increasing time intervals before memory testing, but, surprisingly, enhanced performance in reversal learning tasks. Despite obvious changes to memory task performance, no cysts were detected in the hippocampi of infected rats. Instead, cysts were stochastically distributed across the entire brain, suggesting that behavioral alterations in this study were due to accumulated changes in neurophysiology across multiple anatomical regions. Together, these data provide new evidence that latent toxoplasmosis contributes to neurocognitive symptoms in mammalian hosts, and does so on a broad anatomical scale within the CNS.

Author Keywords
Behavior;  Morris water maze;  Toxoplasma gondii;  Toxoplasmosis

Document Type: Article
Source: Scopus

Shyng, C.a , Sands, M.S.a b
Astrocytosis in infantile neuronal ceroid lipofuscinosis: Friend or foe?
(2014) Biochemical Society Transactions, 42, pp. 1282-1285. 

a Department of Medicine, Washington University School of Medicine, 660South Euclid AvenueSt. Louis, MO, United States
b Department of Genetics, Washington University School of Medicine, 660 South Euclid AvenueSt. Louis, MO, United States

Infantile neuronal ceroid lipofuscinosis (INCL; infantile Batten disease) is an inherited paediatric neurodegenerative disease. INCL is caused by a deficiency in the lysosomal enzyme palmitoyl-protein thioesterase-1 (PPT1) and is thus classified as a lysosomal storage disease. Pathological examination of both human and murine INCL brains reveals progressive, widespread neuroinflammation. In fact, astrocyte activation appears to be the first histological sign of disease. However, the role of astrocytosis in INCL was poorly understood. The hallmark of astrocyte activation is the up-regulation of intermediate filaments, such as glial fibrillary acidic protein (GFAP) and vimentin. The role of astrocytosis in INCL was studied in a murine model lacking PPT1 and the intermediate filaments GFAP and vimentin (triple-knockout). This murine model of INCL with attenuated astrocytosis had an exacerbated pathological and clinical phenotype. The triple-knockout mouse had a significantly shortened lifespan, and accelerated cellular and humoural neuroinflammatory response compared with the parental PPT1-/-mouse. The data obtained from the triple-knockout mouse strongly suggest that astrocyte activation plays a beneficial role in early INCL disease progression. A more thorough understanding of the glial responses to lysosomal enzyme deficiencies and the accumulation of undergraded substrates will be crucial to developing effective therapeutics.

Author Keywords
Astrocytosis;  Glial fibrillary acidic protein;  Infantile neuronal ceroid lipofuscinosis;  Intermediate filament;  Lysosomal storage disease;  Vimentin

Document Type: Article
Source: Scopus

Kniepmann, K.
Family caregiving for husbands with stroke: An occupational perspective on leisure in the stress process
(2014) OTJR Occupation, Participation and Health, 34 (3), pp. 131-140. 

Occupational Therapy and Neurology, Washington University School of Medicine, 4444 Forest Park Avenue, Box 8505St. Louis, MO, United States

This study adapted the Stress Process Model with occupational assessments to identify stress, leisure changes, burden levels, and health-related quality of life in 20 caregivers of workingage husbands with mild to moderate stroke in the past 2 years. Primary stress was based on participants' perceptions of their husbands' functional behavior skills. Secondary strain was indicated by reduction of leisure activities that the caregivers wished to still do or do more - a phenomena labeled Leisure Loss. Outcomes were burden and health-related quality of life. Wives whose husbands had more functional behavior difficulties experienced significantly more Leisure Loss. Wives with Leisure Loss had significantly higher burden scores than those who continued their leisure participation, but health-related quality of life scores were not different. These findings suggest that leisure participation is important as health promotion for family caregivers, with potential to enhance health of the relative with stroke and the entire family.

Author Keywords
Family caregiving;  Stress Process Model;  Stroke

Document Type: Article
Source: Scopus

Penckofer, S.a , Doyle, T.a , Byrn, M.b , Lustman, P.J.c
State of the Science: Depression and Type 2 Diabetes
(2014) Western Journal of Nursing Research, 36 (9), pp. 1158-1182. 

a Loyola University ChicagoMaywood, IL, United States
b Saint Mary’s CollegeNotre Dame, IN, United States
c Washington UniversitySt. Louis, MO, United States

Depression is a significant comorbid condition in diabetes. Individuals with type 2 diabetes (T2DM) are 2 times more likely to experience depression or elevated depressive symptoms compared to those without T2DM. The aims of this state of the science review were to summarize the putative links between diabetes and depression and review empirically supported treatments of depression in diabetes. Findings suggest that a bidirectional association between depression and T2DM exists and that several biological and psychosocial mediators underlie these conditions. Available data indicate that conventional treatments (antidepressant medication, cognitive behavioral therapy, and collaborative care) reduce depression and symptoms of depression; however more controlled studies and development of novel therapies are needed. Glycemic outcomes have most frequently been examined, but findings have been mixed. Self-care and adherence outcomes have been less well studied. Emerging evidence suggests that these outcomes may be important targets for future depression research in T2DM.

Author Keywords
antidepressants;  cognitive-behavioral therapy;  collaborative care;  depression;  diabetes

Document Type: Article
Source: Scopus

Meyer, H.a , Weihl, C.C.b
The VCP/p97 system at a glance: Connecting cellular function to disease pathogenesis
(2014) Journal of Cell Science, 127 (18), pp. 3877-3883. 

a Centre for Medical Biotechnology, Faculty of Biology, University of Duisburg-EssenEssen, Germany
b Department of Neurology and Hope Center for Neurological Disorders, Washington University School of MedicineSt Louis, MO, United States

The ATPase valosin-containing protein (VCP)/p97 has emerged as a central and important element of the ubiquitin system. Together with a network of cofactors, it regulates an ever-expanding range of processes that stretch into almost every aspect of cellular physiology. Its main role in proteostasis and key functions in signaling pathways are of relevance to degenerative diseases and genomic stability. In this Cell Science at a Glance and the accompanying poster, we give a brief overview of this complex system. In addition, we discuss the pathogenic basis for VCP/p97-associated diseases and then highlight in more detail new exciting links to the translational stress response and RNA biology that further underscore the significance of the VCP/p97 system.

Author Keywords
ALS;  Cdc48;  IBMPFD;  p97;  Ubiquitin;  VCP


Document Type: Article
Source: Scopus