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WUSTL Neuroscience Publications Archive - November 2012

Scopus Weekly Report:

November 21, 2012

November 14, 2012

November 7, 2012

November 21, 2012

Gutekunst, D.J.a , Smith, K.E.b , Commean, P.K.b , Bohnert, K.L.a , Prior, F.W.b , Sinacore, D.R.a
Impact of Charcot neuroarthropathy on metatarsal bone mineral density and geometric strength indices
(2012) Bone, 52 (1), pp. 407-413. Article in Press. 

a Applied Kinesiology Laboratory, Program in Physical Therapy, Washington University School of Medicine, 4444 Forest Park Blvd., Campus Box 8502, St. Louis, MO 63108, USA
b Electronic Radiology Laboratory, Mallinckrodt Institute of Radiology, Washington University School of Medicine, 4525 Scott Avenue, Campus Box 8131, St. Louis, MO 63110, USA

Abstract
Charcot neuroarthropathy (CN), an inflammatory condition characterized by rapid and progressive destruction of pedal bones and joints, often leads to deformity and ulceration in individuals with diabetes mellitus (DM) and peripheral neuropathy (PN). Repetitive, unperceived joint trauma may trigger initial CN damage, causing a proinflammatory cascade that can result in osteolysis and contribute to subsequent neuropathic fracture. We aimed to characterize osteolytic changes related to development and progression of CN by measuring bone mineral density (BMD) and geometric strength indices using volumetric quantitative computed tomography. Twenty individuals with DM. +. PN were compared to twenty age-, sex-, and race-matched individuals with DM. +. PN and acute CN. We hypothesized that individuals with acute CN would have decreased BMD and decreased total area, cortical area, minimum section modulus, and cortical thickness in the diaphysis of the second and fifth metatarsals. Results showed BMD was lower in both involved and uninvolved feet of CN participants compared to DM. +. PN participants, with greater reductions in involved CN feet compared to uninvolved CN feet. There was a non-significant increase in total area and cortical area in the CN metatarsals, which helps explain the finding of similar minimum section modulus in DM. +. PN and CN subjects despite the CN group's significantly lower BMD. Larger cortical area and section modulus are typically considered signs of greater bone strength due to higher resistance to compressive and bending loads, respectively. In CN metatarsals, however, these findings may reflect periosteal woven bone apposition, i.e., a hypertrophic response to injury rather than increased fracture resistance. Future research using these techniques will aid further understanding of the inflammation-mediated bony changes associated with development and progression of CN and other diseases. © 2012 Elsevier Inc.

Author Keywords
Bone mineral density;  Charcot neuroarthropathy;  Computed tomography;  Diabetes mellitus;  Peripheral neuropathy

Document Type: Article in Press
Source: Scopus

 

Reidy, N.a b , Morgan, A.a b , Thompson, D.K.a b , Inder, T.E.a c , Doyle, L.W.a b d , Anderson, P.J.a b c
Impaired Language Abilities and White Matter Abnormalities in Children Born Very Preterm and/or Very Low Birth Weight
(2012) Journal of Pediatrics, . Article in Press. 

a Murdoch Children's Research Institute, Victoria, Australia
b The University of Melbourne, Victoria, Australia
c School of Medicine, Washington University of St. Louis, St. Louis, MO
d The Royal Women's Hospital, Victoria, Australia

Abstract
Objectives: To investigate language abilities in children born very preterm (VPT; <32 weeks' gestational age) or very low birth weight (VLBW; <1500 g) at 7 years of age and compare their performances with children born at term, and to determine whether group differences could be explained by cerebral white matter abnormality on neonatal magnetic resonance imaging. Study design: A cohort of 198 children born <30 weeks' gestational age and/or <1250 g, and 70 term controls were examined. White matter abnormalities were rated quantitatively on brain magnetic resonance imaging at term-equivalent age. Language was assessed at age 7 years using standardized language tests. Differences between groups were tested in the 5 language subdomains of phonological awareness, semantics, grammar, discourse, and pragmatics. A mediation effect was tested between birth group, white matter abnormality, and language subdomains. Results: The VPT/VLBW group performed significantly worse than controls on all language subdomains (all P < .001). White matter abnormality mediated the effect of group differences on phonological awareness, and partly mediated this effect for semantics, grammar, and discourse. White matter abnormality was not significantly associated with pragmatics (P = .13). Conclusions: Language is an important area of concern in children born VPT/VLBW. Neonatal white matter abnormality is an important predictor of outcome; however, different language abilities are differentially associated with neonatal white matter abnormality. © 2012 Mosby, Inc. All rights reserved.

Document Type: Article in Press
Source: Scopus

 

Vaughn McCall, W.a , Reboussin, D.b , Prudic, J.c d , Haskett, R.F.e , Isenberg, K.f , Olfson, M.g , Rosenquist, P.B.a , Sackeim, H.A.c d h
Poor health-related quality of life prior to ECT in depressed patients normalizes with sustained remission after ECT
(2012) Journal of Affective Disorders, . Article in Press. 

a Department of Psychiatry and Health Behavior, Georgia Health Sciences University, USA
b Department of Biostatistics, Wake Forest University School of Medicine, USA
c Department of Biological Psychiatry, New York State Psychiatric Institute, USA
d Department of Psychiatry, College of Physicians and Surgeons, Columbia University, USA
e Western Psychiatric Institute and Clinic and Department of Psychiatry, University of Pittsburgh School of Medicine, USA
f Department of Psychiatry, Washington University School of Medicine, USA
g Department of Clinical and Genetic Epidemiology, New York State Psychiatric Institute, USA
h Department of Radiology, College of Physicians and Surgeons, Columbia University, USA

Abstract
Background: Health-related quality of life (HRQOL) is diminished in depressed adult outpatients and especially impaired among depressed patients referred for ECT. We compare pretreatment HRQOL in ECT and non-ECT depressed patients from two large samples, and examined whether sustained remission in depressive symptoms after ECT is associated with normalization of HRQOL. Methods: HRQOL was measured with the Medical Outcomes Study Short Form 36 (SF36) before ECT and 6 months after ECT in an effectiveness (n=286) and an efficacy (n=243) clinical trial. Results: ECT patients had very low baseline SF36 scores. With one exception, SF36 subscale scores in both trials were significantly lower than those of depressed outpatients. A minority of patients in both trials entered and sustained remission over the 24 week timeframe. Among sustained remitters, average SF36 scores were no different from normative scores of the general adult population, except that in the effectiveness study ECT patients reported less Bodily Pain (p<0.05) and better Mental Health (p<0.05), while in the efficacy study ECT patients reported more difficulty with Role-Emotional (p<0.01). Limitations: Only a modest number of patients were observed in sustained remission. Conclusions: HRQOL is very poor in patients referred for ECT. Depressed patients who experience sustained remission after ECT, however, can expect improvement in their quality of life that leaves many in a position indistinguishable from the general adult population. © 2012.

Author Keywords
Depression;  Electroconvulsive therapy;  Quality of life

Document Type: Article in Press
Source: Scopus

 

Li, H.a , Morrow-Howell, N.b , Proctor, E.b , Rubin, E.c
Social Support Resources and Post-Acute Recovery for Older Adults with Major Depression
(2012) Community Mental Health Journal, pp. 1-8. Article in Press. 

a School of Social Work, University of Illinois at Urbana-Champaign, 1010 W Nevada Street, Urbana, 61801, United States
b George Warren Brown School of Social Work, Washington University in St. Louis, One Brookings Drive, St. Louis, 63130, United States
c Department of Psychiatry, School of Medicine, Washington University in St. Louis, 660 S. Euclid Ave, St. Louis, 63110, United States

Abstract
This study assessed the relationships between older patients' social support resources and depressive symptoms and psychosocial functioning at 6 months following a psychiatric hospital discharge. The data used in this study were extracted from a prospective study titled "Service Use of Depressed Elders after Acute Care" (National Institute of Mental Health-56208). This sample included 148 older patients who participated in the initial and the 6-month follow-up assessment. Ordinary Least Squares regression (OLS) was used to examine important social support resources in relation to older patients' depressive symptoms and psychosocial functioning. A vast majority of patients were embedded in a social support network that consisted of acquaintances and confidants. Patients' depressive symptoms were related to availability of a confidant and the extent to which they spent time with others. However, patients' psychosocial functioning was not related to social support resources assessed in this study. © 2012 Springer Science+Business Media New York.

Author Keywords
Major depression;  Older adults;  Social support resources

Document Type: Article in Press
Source: Scopus

 

Nelson, K.B.a b , Bingham, P.c , Edwards, E.M.c d , Horbar, J.D.c e , Kenny, M.J.e f , Inder, T.g , Pfister, R.H.c e , Raju, T.h , Soll, R.F.c e
Antecedents of neonatal encephalopathy in the Vermont Oxford Network Encephalopathy Registry
(2012) Pediatrics, 130 (5), pp. 878-886. 

a Children's Hospital National Medical Center, Washington, DC, United States
b National Institute of Neurologic Disorders and Stroke, Bethesda, MD, United States
c Department of Pediatrics, University of Vermont, Burlington, VT, United States
d Department of Mathematics and Statistics, University of Vermont, Burlington, VT, United States
e Vermont Oxford Network, Burlington, VT, United States
f Department of Medical Biostatistics, University of Vermont, Burlington, VT, United States
g Department of Pediatrics, Washington University, St Louis, MO, United States
h National Institute of Child Health and Human Development, Bethesda, MD, United States

Abstract
BACKGROUND: Neonatal encephalopathy (NE) is a major predictor of death and long-term neurologic disability, but there are few studies of antecedents of NE. OBJECTIVES: To identify antecedents in a large registry of infants who had NE. METHODS: This was a maternal and infant record review of 4165 singleton neonates, gestational age of ≥36 weeks, meeting criteria for inclusion in the Vermont Oxford Network Neonatal Encephalopathy Registry. RESULTS: Clinically recognized seizures were the most prevalent condition (60%); 49% had a 5-minute Apgar score of ≤3 and 18% had a reduced level of consciousness. An abnormal maternal or fetal condition predated labor in 46%; maternal hypertension (16%) or small for gestational age (16%) were the most frequent risk factors. In 8%, birth defects were identified. The most prevalent birth complication was elevated maternal temperature in labor of ≥37.5°C in 27% of mothers with documented temperatures compared with 2% to 3.2% in controls in population-based studies. Clinical chorioamnionitis, prolonged membrane rupture, and maternal hypothyroidism exceeded rates in published controls. Acute asphyxial indicators were reported in 15% (in 35% if fetal bradycardia included) and inflammatory indicators in 24%. Almost one-half had neither asphyxial nor inflammatory indicators. Although most infants with NE were observably ill since the first minutes of life, only 54% of placentas were submitted for examination. CONCLUSIONS: Clinically recognized asphyxial birth events, indicators of intrauterine exposure to inflammation, fetal growth restriction, and birth defects were each observed in term infants with NE, but much of NE in this large registry remained unexplained. Copyright © 2012 by the American Academy of Pediatrics.

Author Keywords
Asphyxia;  Encephalopathy;  Newborn;  Perinatal factors;  Registries

Document Type: Article
Source: Scopus

 

Yellajoshyula, D.a b , Lim, J.-W.a c , Thompson Jr., D.M.a d , Witt, J.S.a , Patterson, E.S.a , Kroll, K.L.a
Geminin regulates the transcriptional and epigenetic status of neuronal fate-promoting genes during mammalian neurogenesis

(2012) Molecular and Cellular Biology, 32 (22), pp. 4549-4560. 

a Department of Developmental Biology, Washington University School of Medicine, St. Louis, MI, United States
b Department of Neurology, University of Michigan, Ann Arbor, MI, United States
c Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States
d Division of Endocrine and Oncologic Surgery, Department of Surgery, Washington University, School of Medicine and Siteman Cancer Center, St. Louis, MI, United States

Abstract
Regulating the transition from lineage-restricted progenitors to terminally differentiated cells is a central aspect of nervous system development. Here, we investigated the role of the nucleoprotein geminin in regulating neurogenesis at a mechanistic level during both Xenopus primary neurogenesis and mammalian neuronal differentiation in vitro. The latter work utilized neural cells derived from embryonic stem and embryonal carcinoma cells in vitro and neural stem cells from mouse forebrain. In all of these contexts, geminin antagonized the ability of neural basic helix-loop-helix (bHLH) transcription factors to activate transcriptional programs promoting neurogenesis. Furthermore, geminin promoted a bivalent chromatin state, characterized by the presence of both activating and repressive histone modifications, at genes encoding transcription factors that promote neurogenesis. This epigenetic state restrains the expression of genes that regulate commitment of undifferentiated stem and neuronal precursor cells to neuronal lineages. However, maintaining geminin at high levels was not sufficient to prevent terminal neuronal differentiation. Therefore, these data support a model whereby geminin promotes the neuronal precursor cell state by modulating both the epigenetic status and expression of genes encoding neurogenesis-promoting factors. Additional developmental signals acting in these cells can then control their transition toward terminal neuronal or glial differentiation during mammalian neurogenesis. © 2012, American Society for Microbiology.

Document Type: Article
Source: Scopus

 

Turan, T.N.a , Lynn, M.J.b , Nizam, A.b , Lane, B.b , Egan, B.M.a , Le, N.-A.b c , Lopes-Virella, M.F.a , Hermayer, K.L.a , Benavente, O.d , White, C.L.e , Virgil Brown, W.b c , Caskey, M.F.a , Steiner, M.R.a , Vilardo, N.f , Stuffebean, A.a , Derdeyn, C.P.g , Fiorella, D.h , Janis, S.i , Chimowitz, M.I.a
Rationale, design, and implementation of aggressive risk factor management in the stenting and aggressive medical management for prevention of recurrent stroke in intracranial stenosis (SAMMPRIS) trial
(2012) Circulation: Cardiovascular Quality and Outcomes, 5 (5), pp. e51-e60. 

a Medical University of South Carolina, Stroke Program, Harborview Office Tower, 19 Hagood Avenue, Charleston, SC 29425, United States
b Emory University, Atlanta, GA, United States
c Atlanta VAMC, Decatur, GA, United States
d University of British Columbia, Vancouver, Canada
e University of Texas, Health Science Center, San Antonio, United States
f Dartmouth Medical School, Hanover, NH, United States
g Washington University, St. Louis, MI, United States
h State University of New York, Stony Brook, United States
i National Institute of Neurological Disorders and Stroke, Bethesda, MD, United States

Author Keywords
Atherosclerosis;  Cerebrovascular circulation;  Lifestyle;  Risk factors;  Stroke

Document Type: Article
Source: Scopus

 

Wang, Y., Erpelding, T.N., Jankovic, L., Guo, Z., Robert, J.L., David, G., Wang, L.V.
In vivo three-dimensional photoacoustic imaging based on a clinical matrix array ultrasound probe.
(2012) Journal of biomedical optics, 17 (6), p. 061208. 

Washington University in St. Louis, Department of Biomedical Engineering, Optical Imaging Laboratory, 1 Brookings Drive, St. Louis, Missouri 63130, USA.

Abstract
We present an integrated photoacoustic and ultrasonic three-dimensional (3-D) volumetric imaging system based on a two-dimensional (2-D) matrix array ultrasound probe. A wavelength-tunable dye laser pumped by a Q-switched Nd:YAG laser serves as the light source and a modified commercial ultrasound imaging system (iU22, Philips Healthcare) with a 2-D array transducer (X7-2, Philips Healthcare) detects both the pulse-echo ultrasound and photoacoustic signals. A multichannel data acquisition system acquires the RF channel data. The imaging system enables rendering of co-registered 3-D ultrasound and photoacoustic images without mechanical scanning. The resolution along the azimuth, elevation, and axial direction are measured to be 0.69, 0.90 and 0.84 mm for photoacoustic imaging. In vivo 3-D photoacoustic mapping of the sentinel lymph node was demonstrated in a rat model using methylene blue dye. These results highlight the clinical potential of 3-D PA imaging for identification of sentinel lymph nodes for cancer staging in humans.

Document Type: Article
Source: Scopus

 

Guo, Z., Favazza, C., Garcia-Uribe, A., Wang, L.V.
Quantitative photoacoustic microscopy of optical absorption coefficients from acoustic spectra in the optical diffusive regime.
(2012) Journal of biomedical optics, 17 (6), p. 066011. 

Washington University, Department of Biomedical Engineering, Optical Imaging Laboratory, 1 Brookings Drive, Saint Louis, Missouri 63130, USA.

Abstract
Photoacoustic (PA) microscopy (PAM) can image optical absorption contrast with ultrasonic spatial resolution in the optical diffusive regime. Conventionally, accurate quantification in PAM requires knowledge of the optical fluence attenuation, acoustic pressure attenuation, and detection bandwidth. We circumvent this requirement by quantifying the optical absorption coefficients from the acoustic spectra of PA signals acquired at multiple optical wavelengths. With the acoustic spectral method, the absorption coefficients of an oxygenated bovine blood phantom at 560, 565, 570, and 575 nm were quantified with errors of <3%. We also quantified the total hemoglobin concentration and hemoglobin oxygen saturation in a live mouse. Compared with the conventional amplitude method, the acoustic spectral method provides greater quantification accuracy in the optical diffusive regime. The limitations of the acoustic spectral method was also discussed.

Document Type: Article
Source: Scopus

 

Wang, Y., Maslov, K., Wang, L.V.
Spectrally encoded photoacoustic microscopy using a digital mirror device.
(2012) Journal of biomedical optics, 17 (6), p. 066020. 

Washington University in St. Louis, Optical Imaging Laboratory, Department of Biomedical Engineering, 1 Brookings Drive, St. Louis, Missouri 63130, USA.

Abstract
We have developed spectrally encoded photoacoustic microscopy using a digital mirror device for multi-wavelength tomography, which enables fast spectral imaging of optical absorption. The optical illumination wavelengths are multiplexed at a laser pulse repetition rate of ≈ 2 kHz. Liquid samples, whole blood, and blood vessels in mouse ears were imaged. Compared with internal wavelength tuning of a narrow-band laser, external wavelength tuning based on a digital mirror device improves the data acquisition speed of spectral photoacoustic microscopy. Compared with external wavelength scanning of a wide-band laser with the same pulse energy, spectral encoding improves the signal-to-noise ratio.

Document Type: Article
Source: Scopus

November 14, 2012

Daniels, B.P.a , Cruz-Orengo, L.b , Pasieka, T.J.b , Couraud, P.-O.f , Romero, I.A.g , Weksler, B.h , Cooper, J.A.c , Doering, T.L.d , Klein, R.S.a b e
Immortalized human cerebral microvascular endothelial cells maintain the properties of primary cells in an in vitro model of immune migration across the blood brain barrier
(2012) Journal of Neuroscience Methods, 212 (1), pp. 173-179. Article in Press. 

a Department of Anatomy and Neurobiology, Washington University School of Medicine, Saint Louis, MO 63110, USA
b Department of Internal Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA
c Department of Cell Biology and Physiology, Washington University School of Medicine, Saint Louis, MO 63110, USA
d Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO 63110, USA
e Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA
f Institut Cochin, Centre National de la Recherche Scientifique UMR 8104, Institut National de la Santé et de la Recherche Médicale (INSERM) U567, Université René Descartes, Paris, France
g Department of Biological Sciences, The Open University, Milton Keynes MK7 6AA, UK
h Department of Medicine, Weill Medical College, New York 10065, USA

Abstract
The immortalized human cerebral microvascular endothelial cell line HCMEC/D3 presents a less expensive and more logistically feasible alternative to primary human brain microvascular endothelial cells (HBMEC's) for use in constructing in vitro models of the blood brain barrier (BBB). However, the fidelity of the HCMEC/D3 cell line to primary HBMEC's in studies of immune transmigration has yet to be established. Flow cytometric analysis of primary human leukocyte migration across in vitro BBB's generated with either HCMEC/D3 or primary HBMEC's revealed that HCMEC/D3 maintains the immune barrier properties of primary HBMEC's. Leukocyte migration responses and inflammatory cytokine production were statistically indistinguishable between both endothelial cell types, and both cell types responded similarly to astrocyte coculture, stimulation of leukocytes with phorbol myristate acetate (PMA) and ionomycin, and inflammatory cytokine treatment. This report is the first to validate the HCMEC/D3 cell line in a neuroimmunological experimental system via direct comparison to primary HBMEC's, demonstrating remarkable fidelity in terms of barrier resistance, immune migration profiles, and responsiveness to inflammatory cytokines. Moreover, we report novel findings demonstrating that interaction effects between immune cells and resident CNS cells are preserved in HCMEC/D3, suggesting that important characteristics of neuroimmune interactions during CNS inflammation are preserved in systems utilizing this cell line. Together, these findings demonstrate that HCMEC/D3 is a valid and powerful tool for less expensive and higher throughput in vitro investigations of immune migration at the BBB. © 2012 Elsevier B.V.

Author Keywords
Blood brain barrier;  HCMEC/D3;  Immune trafficking;  In vitro model

Document Type: Article in Press
Source: Scopus

 

Spees, W.M.a b , Lin, T.-H.a , Song, S.-K.a b
White-matter diffusion fMRI of mouse optic nerve
(2012) NeuroImage, 65, pp. 209-215. Article in Press. 

a Biomedical MR Laboratory, Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA
b Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA

Abstract
Non-invasive assessment of white-matter functionality in the nervous system would be a valuable basic neuroscience and clinical diagnostic tool. Using standard MRI techniques, a visual-stimulus-induced 27% decrease in the apparent diffusion coefficient of water perpendicular to the axonal fibers (ADC
) is demonstrated for C57BL/6 mouse optic nerve in vivo. No change in ADC || (diffusion parallel to the optic nerve fibers) was observed during visual stimulation. The stimulus-induced changes are completely reversible. A possible vascular contribution was sought by carrying out the ADC measurements in hypercapnic mice with and without visual stimulus. Similar effects were seen in room-air-breathing and hypercapnic animals. The in vivo stimulus-induced ADC decreases are roughly similar to literature reports for ex vivo rat optic nerve preparations under conditions of osmotic swelling. The experimental results strongly suggest that osmotic after-effects of nerve impulses through the axonal fibers are responsible for the observed ADC decrease. © 2012 Elsevier Inc.

Author Keywords
Diffusion;  FMRI;  Mouse;  Optic nerve;  White matter

Document Type: Article in Press
Source: Scopus

 

Capotosto, P.a , Corbetta, M.a b , Romani, G.L.a , Babiloni, C.c d
Electrophysiological correlates of stimulus-driven reorienting deficits after interference with right parietal cortex during a spatial attention task: A TMS-EEG study
(2012) Journal of Cognitive Neuroscience, 24 (12), pp. 2363-2371. 

a Dip. Neuroscienze e Imaging, Università G. D'Annunzio, Istituto di Tecnologie Avanzate Biomediche, Via dei Vestini 33, Chieti, 66100, Italy
b Washington University School of Medicine, St. Louis, MO, United States
c Univ. di Foggia, Foggia, Italy
d San Raffaele Cassino, Italy

Abstract
TMS interference over right intraparietal sulcus (IPS) causally disrupts behaviorally and EEG rhythmic correlates of endogenous spatial orienting before visual target presentation [Capotosto, P., Babiloni, C., Romani, G. L., & Corbetta, M. Differential contribution of right and left parietal cortex to the control of spatial attention: A simultaneous EEG-rTMS study. Cerebral Cortex, 22, 446-454, 2012; Capotosto, P., Babiloni, C., Romani, G. L., & Corbetta, M. Fronto-parietal cortex controls spatial attention through modulation of anticipatory alpha rhythms. Journal of Neuroscience, 29, 5863-5872, 2009]. Here we combine data from our previous studies to examine whether right parietal TMS during spatial orienting also impairs stimulus-driven reorienting or the ability to efficiently process unattended stimuli, that is, stimuli outside the current focus of attention. Healthy volunteers (n = 24) performed a Posner spatial cueing task while their EEG activity was being monitored. Repetitive TMS (rTMS) was applied for 150 msec simultaneously to the presentation of a central arrow directing spatial attention to the location of an upcoming visual target. Right IPS-rTMS impaired target detection, especially for stimuli presented at unattended locations; it also caused a modulation of the amplitude of parieto-occipital positive ERPs peaking at about 480 msec (P3) post-target. The P3 significantly decreased for unattended targets and significantly increased for attended targets after right IPS-rTMS as compared with sham stimulation. Similar effects were obtained for left IPS stimulation albeit in a smaller group of volunteers. We conclude that disruption of anticipatory processes in right IPS has prolonged effects that persist during target processing. The P3 decrement may reflect interference with postdecision processes that are part of stimulus-driven reorienting. Right IPS is a node of functional interaction between endogenous spatial orienting and stimulusdriven reorienting processes in human vision. © 2012 Massachusetts Institute of Technology.

Document Type: Article
Source: Scopus

 

Jacobson, K.C.a , Hoffman, C.L.a , Vasilopoulos, T.a , Kremen, W.S.b c , Panizzon, M.S.b , Grant, M.D.d , Lyons, M.J.d , Xian, H.e , Franz, C.E.b
Genetic and environmental influences on individual differences in frequency of play with pets among middle-aged men: A behavioral genetic analysis
(2012) Anthrozoos, 25 (4), pp. 441-456. 

a Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, MC3077, CNPRU L-466D, 5841 South Maryland Ave, Chicago, IL 60637, United States
b Department of Psychiatry, University of California, San Diego, United States
c VA San Diego Healthcare System, La Jolla, CA, United States
d Department of Psychology, Boston University, United States
e Department of Psychiatry, Washington University School of Medicine, United States

Abstract
There is growing evidence that pet ownership and human- animal interaction (HAI) have benefits for human physical and psychological well-being. However, there may be pre-existing characteristics related to patterns of pet ownership and interactions with pets that could potentially bias results of research on HAI. The present study uses a behavioral genetic design to estimate the degree to which genetic and environmental factors contribute to individual differences in frequency of play with pets among adult men. Participants were from the ongoing longitudinal Vietnam Era Twin Study of Aging (VETSA), a population-based sample of 1,237 monozygotic (MZ) and dizygotic (DZ) twins aged 51-60 years. Results demonstrate that MZ twins have higher correlations than DZ twins on frequency of pet play, suggesting that genetic factors play a role in individual differences in interactions with pets. Structural equation modeling revealed that, according to the best model, genetic factors accounted for as much as 37% of the variance in pet play, although the majority of variance (63-71%) was due to environmental factors that are unique to each twin. Shared environmental factors, which would include childhood exposure to pets, overall accounted for <10% of the variance in adult frequency of pet play, and were not statistically significant. These results suggest that the effects of childhood exposure to pets on pet ownership and interaction patterns in adulthood may be mediated primarily by genetically-influenced characteristics. © ISAZ 2012 Printed in the UK.

Author Keywords
Genetics;  Pets;  Twins

Document Type: Article
Source: Scopus

 

Spaulding, S.
Mirror neurons are not evidence for the Simulation Theory
(2012) Synthese, 189 (3), pp. 515-534. 

Philosophy-Neuroscience-Psychology Program, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Recently, there as been a resurgence of interest in theories of mindreading. New discoveries in neuroscience have revitalized the languishing debate. The discovery of so-called mirror neurons has revived interest particularly in the Simulation Theory (ST) of mindreading. Both ST proponents and theorists studying mirror neurons have argued that mirror neurons are strong evidence in favor of ST over Theory Theory (TT). In this paper I argue against the prevailing view that mirror neurons are evidence for the ST of mindreading. My view is that on an appropriate construal of their function, mirror neurons do not operate like simulation theorists claim. In fact, mirror neurons are more appropriately understood as one element in an information-rich mindreading process. As such, mirror neurons fit in better with some sort of TT account of mindreading. I offer a positive account, the Model TT, which better explains the role of mirror neurons in social cognition. © 2012 Springer Science+Business Media B.V.

Author Keywords
Folk psychology;  Mindreading;  Mirror neurons;  Simulation Theory;  Theory Theory

Document Type: Article
Source: Scopus

 

Whitfield, J.B.a , Heath, A.C.b , Madden, P.A.F.b , Pergadia, M.L.b , Montgomery, G.W.a , Martin, N.G.a
Metabolic and Biochemical Effects of Low-to-Moderate Alcohol Consumption
(2012) Alcoholism: Clinical and Experimental Research, . Article in Press. 

a Queensland Institute of Medical Research Brisbane, Queensland Australia
b Department of Psychiatry Washington University School of Medicine St. Louis, Missouri

Abstract
Background: Alcohol consumption has multiple biochemical consequences. Only a few of these are useful as diagnostic markers, but many reflect potentially harmful or beneficial effects of alcohol. Average consumption of 2 to 4 drinks per day is associated with lower overall or cardiovascular mortality risk than either lower or higher intake. We have analyzed the dose-response relationships between reported alcohol consumption and 17 biomarkers, with emphasis on intake of up to 3 drinks per day. Methods: Biochemical tests were performed on serum from 8,396 study participants (3,750 men and 4,646 women, aged 51 ± 13 years, range 18 to 93) who had provided information on alcohol consumption in the week preceding blood collection. Results: Gamma glutamyl transferase, alanine aminotransferase, aspartate aminotransferase, carbohydrate-deficient transferrin, urate, ferritin, and bilirubin showed little or no change with alcohol consumption below 2 to 3 drinks per day, but increased with higher intake. High-density lipoprotein cholesterol and albumin showed increasing results, and insulin showed decreasing results, across the entire range of alcohol use. Biphasic responses, where subjects reporting 1 to 2 drinks per day had lower results than those reporting either more or less alcohol use, occurred for triglycerides, glucose, C-reactive protein, alkaline phosphatase, and butyrylcholinesterase. Increasing alcohol use was associated with decreasing low-density lipoprotein cholesterol (LDL-C) in younger women, but higher LDL-C in older men. Conclusions: Some markers show threshold relationships with alcohol, others show continuous ones, and a third group show biphasic or U-shaped relationships. Overall, the biochemical sequelae of low-to-moderate alcohol use are consistent with the epidemiological evidence on morbidity and mortality. © 2012 by the Research Society on Alcoholism.

Author Keywords
Alcohol;  Biomarkers;  Dose-Response Curve;  Population Study

Document Type: Article in Press
Source: Scopus

 

Anticevic, A.a b c , Cole, M.W.d , Murray, J.D.e f , Corlett, P.R.a c , Wang, X.-J.e f i , Krystal, J.H.a b c g h
The Role of Default Network Deactivation in Cognition and Disease
(2012) Trends in Cognitive Sciences, . Article in Press. 

a Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06510, USA
b National Institute on Alcohol Abuse and Alcoholism (NIAAA) Center for the Translational Neuroscience of Alcoholism (CTNA), Yale University, New Haven, CT 06519, USA
c Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, Department of Psychiatry, Yale University, New Haven, CT 06519, USA
d Department of Psychology, Washington University in St. Louis, St. Louis, MO, 63130, USA
e Department of Physics, Yale University, New Haven, CT 06520, USA
f Department of Neurobiology and Kavli Institute of Neuroscience, Yale University School of Medicine, New Haven, CT 06510, USA
g Psychiatry Services, Department of Psychiatry, Yale-New Haven Hospital, New Haven, CT 06510, USA
h Clinical Neuroscience Division, Veterans Affairs (VA) National Center for Post-Traumatic Stress Disorder (PTSD), VA Connecticut Healthcare System, West Haven, CT 06516, USA
i Center for Neural Science, New York University, 4 Washington Place, New York, NY 10003, USA

Abstract
A considerable body of evidence has accumulated over recent years on the functions of the default-mode network (DMN) - a set of brain regions whose activity is high when the mind is not engaged in specific behavioral tasks and low during focused attention on the external environment. In this review, we focus on DMN suppression and its functional role in health and disease, summarizing evidence that spans several disciplines, including cognitive neuroscience, pharmacological neuroimaging, clinical neuroscience, and theoretical neuroscience. Collectively, this research highlights the functional relevance of DMN suppression for goal-directed cognition, possibly by reducing goal-irrelevant functions supported by the DMN (e.g., mind-wandering), and illustrates the functional significance of DMN suppression deficits in severe mental illness. © 2012 Elsevier Ltd. All rights reserved.

Author Keywords
cognition;  computational modeling;  default-mode network;  schizophrenia;  suppression

Document Type: Article in Press
Source: Scopus

 

George, J.W.a , Skaggs, C.D.b , Thompson, P.A.f , Nelson, D.M.c , Gavard, J.A.d , Gross, G.A.e
A randomized controlled trial comparing a multimodal intervention and standard obstetrics care for low back and pelvic pain in pregnancy

(2012) American Journal of Obstetrics and Gynecology, . Article in Press. 

a Chiropractic Science Division, College of Chiropractic, Logan University, Chesterfield, MO
b Central Institute for Human Performance, Washington University School of Medicine, St. Louis, MO
c Division of Maternal Fetal Medicine and Ultrasound, Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO
d Division of Research, Department of Obstetrics, Gynecology, and Women's Health, St. Louis University School of Medicine, St. Louis, MO
e Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology, and Women's Health, St. Louis University School of Medicine, St. Louis, MO
f Department of Pediatrics, Sanford Research, Sanford Health, University of South Dakota, Sioux Falls, SD

Abstract
Objective: Women commonly experience low back pain during pregnancy. We examined whether a multimodal approach of musculoskeletal and obstetric management (MOM) was superior-to-standard obstetric care to reduce pain, impairment, and disability in the antepartum period. Study Design: A prospective, randomized trial of 169 women was conducted. Baseline evaluation occurred at 24-28 weeks gestation, with follow-up at 33 weeks gestation. Primary outcomes were the Numerical Rating Scale (NRS) for pain and the Quebec Disability Questionnaire (QDQ). Both groups received routine obstetric care. Chiropractic specialists provided manual therapy, stabilization exercises, and patient education to MOM participants. Results: The MOM group demonstrated significant mean reductions in Numerical Rating Scale scores (5.8 ± 2.2 vs 2.9 ± 2.5; P < .001) and Quebec Disability Questionnaire scores (4.9 ± 2.2 vs 3.9 ± 2.4; P < .001) from baseline to follow-up evaluation. The group that received superior-to-standard obstetric care demonstrated no significant improvements. Conclusion: A multimodal approach to low back and pelvic pain in mid pregnancy benefits patients more than standard obstetric care. © 2012 Mosby, Inc. All rights reserved.

Author Keywords
back pain;  exercise;  manipulation;  pregnancy

Document Type: Article in Press
Source: Scopus

 

Sacco, P.a , Kuerbis, A.b c , Goge, N.a , Bucholz, K.K.d
Help seeking for drug and alcohol problems among adults age 50 and older: A comparison of the NLAES and NESARC surveys
(2012) Drug and Alcohol Dependence, . Article in Press. 

a School of Social Work, University of Maryland-Baltimore, United States
b Department of Mental Health Services Policy and Research, Research Foundation for Mental Hygiene, Inc., 1052 Riverside Drive, New York, NY 10032, United States
c Department of Psychiatry, Columbia University College of Physicians and Surgeons, 3 Columbus Circle, Ste. 1404, New York, NY 10019, United States
d Midwest Alcoholism Research Center, Department of Psychiatry, Washington University School of Medicine, Campus Box 8134, St. Louis, MO 63108, United States

Abstract
Background: Due to population aging and generational changes in alcohol and drug use, substance use disorders and treatment need are projected to increase among adults over 50. We analyzed data from two national surveys conducted 10 years apart [(NLAES (1991-1992) and NESARC (2001-2002)] to explore changes in help-seeking for alcohol and drug problems among adults over age 50. Methods: Data were pooled on help seeking for substance related problems, sociodemographic and clinical variables, and services type (i.e., formal and informal). Differences between the surveys were assessed, and help seeking among those under age 50 was compared to younger individuals; changes in the sociodemographic and clinical correlates of help seeking among those over age 50 were examined. Results: Among those 50 and older, rates of lifetime help seeking for any substance problem were higher in NESARC than NLAES, and percentages of those considering but not getting help were also higher in NESARC. Among those 50+, rates of past-year help seeking for drug use were higher in NESARC, but among those with lifetime substance use disorders, help seeking rates for alcohol and any substance were lower in the NESARC. Older help seekers in the NESARC were less likely to be White, more likely to be low income, and more likely to be current or former drug users than NLAES help seekers. Conclusions: This study documents increased rates of help seeking for substance related problems among those 50 and older and identifies cohort differences in profile of past-year help seekers. © 2012.

Author Keywords
Age;  Epidemiology;  Services;  Treatment;  Trends

Document Type: Article in Press
Source: Scopus

 

Granados-Fuentes, D., Herzog, E.D.
The clock shop: Coupled circadian oscillators
(2012) Experimental Neurology, . Article in Press. 

Department of Biology, Washington University, St. Louis, MO 63130, USA

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

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

Document Type: Article in Press
Source: Scopus

 

Reiman, E.M.a b f g s , Quiroz, Y.T.h s j s , Fleisher, A.S.a s g l s , Chen, K.c s g i s , Velez-Pardo, C.j s s , Jimenez-Del-Rio, M.j s s , Fagan, A.M.k s s , Shah, A.R.k s s , Alvarez, S.m s s , Arbelaez, A.m s s , Giraldo, M.j s s , Acosta-Baena, N.j s s , Sperling, R.A.n o q , Dickerson, B.o , Stern, C.E.h p q , Tirado, V.j s s , Munoz, C.j s s , Reiman, R.A.f g , Huentelman, M.J.f s g s , Alexander, G.E.d e g , Langbaum, J.B.a s g s , Kosik, K.S.r s s , Tariot, P.N.a s b g s , Lopera, F.j s s
Brain imaging and fluid biomarker analysis in young adults at genetic risk for autosomal dominant Alzheimer's disease in the presenilin 1 E280A kindred: a case-control study
(2012) The Lancet Neurology, . Article in Press. 

a Banner Alzheimer's Institute, Phoenix, AZ, USA
b Department of Psychiatry, University of Arizona, Phoenix and Tucson, AZ, USA
c Department of Radiology, University of Arizona, Phoenix and Tucson, AZ, USA
d Department of Psychology, University of Arizona, Phoenix and Tucson, AZ, USA
e McKnight Brain Institute, University of Arizona, Phoenix and Tucson, AZ, USA
f Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA
g Arizona Alzheimer's Consortium, Phoenix, AZ, USA
h Center for Memory and Brain, Psychology Department, Boston University, Boston, MA, USA
i Department of Mathematics, Arizona State University, Tempe, AZ, USA
j University of Antioquia, Medellin, Colombia
k Department of Neurology, Washington University School of Medicine, St Louis, MO, USA
l Department of Neurology, University of California, San Diego, San Diego, CA, USA
m Hospital Pablo Tobón Uribe, Medellin, Colombia
n Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
o Department of Neurology, Massachusetts General Hospital, Boston, MA, USA
p Department of Radiology, Massachusetts General Hospital, Boston, MA, USA
q Athinoula A Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, MA, USA
r Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA, USA
s Alzheimer's Prevention Initiative

Abstract
Background: We have previously characterised functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's disease. To gain further knowledge on the preclinical phase of Alzheimer's disease, we sought to characterise structural and functional MRI, CSF, and plasma biomarkers in a cohort of young adults carrying a high-penetrance autosomal dominant mutation that causes early-onset Alzheimer's disease. Methods: Between January and August, 2010, 18-26-year-old presenilin 1 (PSEN1) E280A mutation carriers and non-carriers from the Colombian Alzheimer's Prevention Initiative Registry in Medellín Antioquia, Colombia, had structural MRI, functional MRI during associative memory encoding and novel viewing and control tasks, and cognitive assessments. Consenting participants also had lumbar punctures and venepunctures. Outcome measures were task-dependent hippocampal or parahippocampal activations and precuneus or posterior cingulate deactivations, regional grey matter reductions, CSF Aβ 1-42, total tau and phospho-tau 181 concentrations, and plasma Aβ 1-42 concentrations and Aβ 1-42:Aβ 1-40 ratios. Structural and functional MRI data were compared using automated brain mapping algorithms and search regions related to Alzheimer's disease. Cognitive and fluid biomarkers were compared using Mann-Whitney tests. Findings: 44 participants were included: 20 PSEN1 E280A mutation carriers and 24 non-carriers. The carrier and non-carrier groups did not differ significantly in their dementia ratings, neuropsychological test scores, or proportion of apolipoprotein E (APOE) e{open}4 carriers. Compared with non-carriers, carriers had greater right hippocampal and parahippocampal activation (p=0·001 and p&lt;0·014, respectively, after correction for multiple comparisons), less precuneus and posterior cingulate deactivation (all p&lt;0·010 after correction), and less grey matter in several parietal regions (all p&lt;0·002 uncorrected and corrected p=0·009 in the right parietal search region). In the 20 participants (ten PSEN1 E280A mutation carriers and ten non-carriers) who had lumbar punctures and venepunctures, mutation carriers had higher CSF Aβ 1-42 concentrations (p=0·008) and plasma Aβ 1-42 concentrations (p=0·01) than non-carriers. Interpretation: Young adults at genetic risk for autosomal dominant Alzheimer's disease have functional and structural MRI findings and CSF and plasma biomarker findings consistent with Aβ 1-42 overproduction. Although the extent to which the underlying brain changes are either neurodegenerative or developmental remain to be determined, this study shows the earliest known biomarker changes in cognitively normal people at genetic risk for autosomal dominant Alzheimer's disease. Funding: Banner Alzheimer's Foundation, Nomis Foundation, Anonymous Foundation, Forget Me Not Initiative, Boston University Department of Psychology, Colciencias, National Institute on Aging, National Institute of Neurological Disorders and Stroke, and the State of Arizona. © 2012 Elsevier Ltd. All rights reserved.

Document Type: Article in Press
Source: Scopus

 

Cavazos-Rehg, P.A.a , Krauss, M.J.a , Spitznage, E.L.b , Chaloupka, F.J.c , Luke, D.A.d , Waterman, B.e , Grucza, R.A.a , Bierut, L.J.a
Differential effects of cigarette price changes on adult smoking behaviours
(2012) Tobacco Control, . Article in Press. 

a Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA
b Department of Mathematics, Washington University in St. Louis, St. Louis, Missouri, USA
c Department of Economics, University of Illinois at Chicago, Chicago, Illinois, USA
d Center for Tobacco Policy Research, School of Social Work, Washington University in St. Louis, St. Louis, Missouri, USA
e Thomson Reuters Healthcare, Chicago, Illinois, USA

Abstract
Background: Raising cigarette prices through taxation is an important policy approach to reduce smoking. Yet, cigarette price increases may not be equally effective in all subpopulations of smokers. Purpose: To examine differing effects of state cigarette price changes with individual changes in smoking among smokers of different intensity levels. Methods: Data were derived from the National Epidemiologic Survey on Alcohol and Related Conditions, a nationally representative sample of US adults originally interviewed in 2001-2002 (Wave 1) and re-interviewed in 2004-2005 (Wave 2): 34 653 were re-interviewed in Wave 2, and 7068 smokers defined at Wave 1 were included in our study. Mixed effects linear regression models were used to assess whether the effects of changes in state cigarette prices on changes in daily smoking behaviour differed by level of daily smoking. Results: In the multivariable model, there was a significant interaction between change in price per pack of cigarettes from Wave 1 to Wave 2 and the number of cigarettes smoked per day (p=0.044). The more cigarettes smoked per day at baseline, the more responsive the smokers were to increases in price per pack of cigarettes (ie, number of cigarettes smoked per day was reduced in response to price increases). Conclusions: Our findings that heavier smokers successfully and substantially reduced their cigarette smoking behaviours in response to state cigarette price increases provide fresh insight to the evidence on the effectiveness of higher cigarette prices in reducing smoking. Copyright Article author (or their employer) 2012.

Document Type: Article in Press
Source: Scopus

 

Caputo, F.J.a , Wittenberg, A.M.a , Vemuri, C.a , Driskill, M.R.d , Earley, J.A.d , Rastogi, R.b , Emery, V.B.a , Thompson, R.W.a c
Supraclavicular decompression for neurogenic thoracic outlet syndrome in adolescent and adult populations
(2012) Journal of Vascular Surgery, . Article in Press. 

a Center for Thoracic Outlet Syndrome, Department of Surgery, Section of Vascular Surgery, Washington University School of Medicine, St. Louis, Mo
b Center for Thoracic Outlet Syndrome, Department of Anesthesiology, Pain Management, Washington University School of Medicine, St. Louis, Mo
c Center for Thoracic Outlet Syndrome, Department of Radiology, Washington University School of Medicine, St. Louis, Mo
d The Rehabilitation Institute of St. Louis, St. Louis, Mo

Abstract
Objective: This study was conducted to better define clinical results and understand factors determining responsiveness to surgical treatment for neurogenic thoracic outlet syndrome (NTOS) in adolescent and adult populations. Methods: A retrospective review was conducted for 189 patients with disabling NTOS who underwent primary supraclavicular decompression (scalenectomy, brachial plexus neurolysis and first rib resection, with or without pectoralis minor tenotomy) from April 2008 to December 2010. Clinical characteristics were compared between 35 adolescent patients (aged <21 years) and 154 adults (aged >21 years). Functional outcome measures were assessed before surgery and at 3- and 6-month follow-up using a composite NTOS Index combining the Disabilities of the Arm, Shoulder and Hand (DASH) survey, the Cervical-Brachial Symptom Questionnaire (CBSQ), and a 10-point visual analog scale (VAS) for pain. Results: Adolescent and adult patients were not significantly different with respect to sex (overall 72.5% female), side affected (58.7% right, 60.3% dominant limb), bony anomalies (23.3%), previous injury (55.6%), coexisting pain disorders (11.1%), and positive responses to scalene muscle anesthetic blocks (95.6%). Compared with adults, adolescent patients had a significantly (P < .05) lower incidence of depression (11.4% vs 41.6%), motor vehicle injury (5.7% vs 20.1%), previous operations (11.4% vs 29.9%), preoperative use of opiate medications (17.1% vs 44.8%), and symptom duration >2 years (24.2% vs 50.0%). Mean preoperative NTOS Index (scale 0-100) was significantly lower in adolescent vs adult patients (46.5 ± 3.6 vs 58.5 ± 1.7; P = .009), and hospital length of stay was 4.4 ± 0.2 vs 4.9 ± 0.1 days (P = .03), but the rate of postoperative complications was no different (overall, 4.2%). Although both groups exhibited significant improvement in functional outcome measures at 3 and 6 months, adolescent patients had significantly lower NTOS Index (10.4 ± 3.1 vs 39.3 ± 3.3; P < .001) and use of opiate medications (11.4% vs 47.4%; P < .001) compared with adults. Conclusions: Adolescents undergoing supraclavicular decompression for NTOS had more favorable preoperative characteristics and enhanced 3-month and 6-month functional outcomes than adults. Further study is needed to delineate the age-dependent and independent factors that promote optimal surgical outcomes for NTOS. © 2012 Society for Vascular Surgery.

Document Type: Article in Press
Source: Scopus

 

Aaronson, S.T.a , Carpenter, L.L.b , Conway, C.R.c d , Reimherr, F.W.e , Lisanby, S.H.f , Schwartz, T.L.g , Moreno, F.A.h , Dunner, D.L.i , Lesem, M.D.j , Thompson, P.M.k , Husain, M.l , Vine, C.J.m , Banov, M.D.n , Bernstein, L.P.o , Lehman, R.B.p , Brannon, G.E.q , Keepers, G.A.r , O'Reardon, J.P.s , Rudolph, R.L.t , Bunker, M.t
Vagus nerve stimulation therapy randomized to different amounts of electrical charge for treatment-resistant depression: Acute and chronic effects

(2012) Brain Stimulation, . Article in Press. 

a Sheppard Pratt Health System, Clinical Research Programs, 6501 N. Charles Street, Baltimore, MD 21285, USA
b Brown University/Butler Hospital, Providence, RI, USA
c Washington University School of Medicine, Saint Louis, MO, USA
d St. Louis University Health Science Center, Saint Louis, MO, USA
e Psychiatric and Behavioral Solutions, Salt Lake City, UT, USA
f Duke University School of Medicine, Durham, NC, USA
g SUNY Upstate Medical University, Syracuse, NY, USA
h The University of Arizona, Tucson, AZ, USA
i Center for Anxiety and Depression, Mercer Island, WA, USA
j Claghorn-Lesem Research Clinic, Ltd., Houston, TX, USA
k UT Health Science Center, San Antonio, TX, USA
l UT Southwestern Medical Center, Dallas, TX, USA
m Psych Recovery, Inc., Saint Paul, MN, USA
n Northwest Behavioral Research Center, Marietta, GA, USA
o North Shore University Health System, Evanston, IL, USA
p PharmaSite Research, Inc., Pikesville, MD, USA
q Brentwood Research Institute, Shreveport, LA, USA
r Oregon Health and Science University, Portland, OR, USA
s University of Medicine and Dentistry of New Jersey, Cherry Hill, NJ, USA
t Cyberonics, Inc., Houston, TX, USA

Abstract
Background: Major depressive disorder is a prevalent, disabling, and often chronic or recurrent psychiatric condition. About 35% of patients fail to respond to conventional treatment approaches and are considered to have treatment-resistant depression (TRD). Objective: We compared the safety and effectiveness of different stimulation levels of adjunctive vagus nerve stimulation (VNS) therapy for the treatment of TRD. Methods: In a multicenter, double blind study, 331 patients with TRD were randomized to one of three dose groups: LOW (0.25 mA current, 130 μs pulse width), MEDIUM (0.5-1.0 mA, 250 μs), or HIGH (1.25-1.5 mA, 250 μs). A highly treatment-resistant population (>97% had failed to respond to ≥6 previous treatments) was enrolled. Response and adverse effects were assessed for 22 weeks (end of acute phase), after which output current could be increased, if clinically warranted. Assessments then continued until Week 50 (end of long-term phase). Results: VNS therapy was well tolerated. During the acute phase, all groups showed statistically significant improvement on the primary efficacy endpoint (change in Inventory of Depressive Symptomatology-Clinician Administered Version [IDS-C]), but not for any between-treatment group comparisons. In the long-term phase, mean change in IDS-C scores showed continued improvement. Post-hoc analyses demonstrated a statistically significant correlation between total charge delivered per day and decreasing depressive symptoms; and analysis of acute phase responders demonstrated significantly greater durability of response at MEDIUM and HIGH doses than at the LOW dose. Conclusions: TRD patients who received adjunctive VNS showed significant improvement at study endpoint compared with baseline, and the effect was durable over 1 year. Higher electrical dose parameters were associated with response durability. © 2012 Elsevier Inc. All rights reserved.

Author Keywords
Dose response;  Treatment durability;  Treatment-resistant depression;  Vagus nerve stimulation;  VNS efficacy

Document Type: Article in Press
Source: Scopus

 

Lee, A.R.a , Lamb, R.R.a , Chang, J.H.a , Erdmann-Gilmore, P.b , Lichti, C.F.b f , Rohrs, H.W.c , Malone, J.P.b , Wairkar, Y.P.g , Diantonio, A.d , Townsend, R.R.b e , Culican, S.M.a
Identification of potential mediators of retinotopic mapping: A comparative proteomic analysis of optic nerve from WT and Phr1 retinal knockout mice
(2012) Journal of Proteome Research, 11 (11), pp. 5515-5526. 

a Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Chemistry, Washington University School of Medicine, St. Louis, MO 63110, United States
d Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, United States
e Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, United States
f Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, United States
g Department of Neurology, University of Texas Medical Branch, Galveston, TX 77555, United States

Abstract
Retinal ganglion cells (RGCs) transmit visual information topographically from the eye to the brain, creating a map of visual space in retino-recipient nuclei (retinotopy). This process is affected by retinal activity and by activity-independent molecular cues. Phr1, which encodes a presumed E3 ubiquitin ligase (PHR1), is required presynaptically for proper placement of RGC axons in the lateral geniculate nucleus and the superior colliculus, suggesting that increased levels of PHR1 target proteins may be instructive for retinotopic mapping of retinofugal projections. To identify potential target proteins, we conducted a proteomic analysis of optic nerve to identify differentially abundant proteins in the presence or absence of Phr1 in RGCs. 1D gel electrophoresis identified a specific band in controls that was absent in mutants. Targeted proteomic analysis of this band demonstrated the presence of PHR1. Additionally, we conducted an unbiased proteomic analysis that identified 30 proteins as being significantly different between the two genotypes. One of these, heterogeneous nuclear ribonucleoprotein M (hnRNP-M), regulates antero-posterior patterning in invertebrates and can function as a cell surface adhesion receptor in vertebrates. Thus, we have demonstrated that network analysis of quantitative proteomic data is a useful approach for hypothesis generation and for identifying biologically relevant targets in genetically altered biological models. © 2012 American Chemical Society.

Author Keywords
hnRNP-M;  label-free quantitative proteomics;  LC-MS;  Mycbp2;  network analysis;  Phr1;  proteomics;  retinal ganglion cell;  retinotopy;  ubiquitin ligase

Document Type: Article
Source: Scopus

 

Sweet, L.H.a , Hassenstab, J.J.b , McCaffery, J.M.c , Raynor, H.A.d , Bond, D.S.c , Demos, K.E.c , Haley, A.P.e , Cohen, R.A.c , Parigi, A.D.f , Wing, R.R.c
Brain response to food stimulation in obese, normal weight, and successful weight loss maintainers
(2012) Obesity, 20 (11), pp. 2220-2225. 

a Butler Hospital and Alpert Medical School, Brown University, Providence, RI, United States
b Washington University School of Medicine, St. Louis, MO, United States
c Miriam Hospital and Alpert Medical School, Brown University, Providence, RI, United States
d University of Tennessee at Knoxville, Knoxville, TN, United States
e University of Texas at Austin, Austin, TX, United States
f AstraZeneca, Wilmington, DE, United States

Abstract
As many people struggle with maintenance of weight loss, the study of successful weight loss maintainers (SWLM) can yield important insights into factors contributing to weight loss maintenance. However, little research has examined how SWLM differ from people who are obese or normal weight (NW) in brain response to orosensory stimulation. The goal of this study was to determine if SWLM exhibit different brain responses to orosensory stimulation. Brain response to 1-min orosensory stimulation with a lemon lollipop was assessed using functional magnetic resonance imaging among 49 participants, including SWLM (n = 17), NW (n = 18), and obese (n = 14) controls. Significant brain responses were observed in nine brain regions, including the bilateral insula, left inferior frontal gyrus, left putamen, and other sensory regions. All regions also exhibited significant attenuation of this response over 1 min. The SWLM exhibited greater response compared with the other groups in all brain regions. Findings suggest that the response to orosensory stimulation peaks within 40 s and attenuates significantly between 40 and 60 s in regions associated with sensation, reward, and inhibitory control. Greater reactivity among the SWLM suggests that greater sensory reactivity to orosensory stimulation, increased anticipated reward, and subsequently greater inhibitory processing are associated with weight loss maintenance.

Document Type: Article
Source: Scopus

 

Manousakis, G.a , Han, D.Y.b , Backonja, M.c
Cognitive outcome of cerebral fat embolism
(2012) Journal of Stroke and Cerebrovascular Diseases, 21 (8), pp. 906.e1-906.e3. 

a Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
b Department of Neurology, University of Kentucky Medical Center, Lexington, KY, United States
c Department of Neurology, University of Wisconsin, Madison, WI, United States

Abstract
Cerebral fat embolism is an uncommon but serious complication of long-bone fracture. We report a young adult patient who sustained fat embolism after a femoral fracture. He developed stupor and coma within 24 hours from his injury. His acute recovery was characterized by marked frontal dysfunction. A comprehensive neuropsychological evaluation 4 months later revealed overall normal cognitive function, except for mild residual frontal dysfunction and weakness of verbal memory. © 2012 by National Stroke Association.

Author Keywords
cognitive;  Fat embolism

Document Type: Article
Source: Scopus

 

McAvoy, M.a , Larson-Prior, L.a , Ludwikow, M.f , Zhang, D.a , Snyder, A.Z.a b , Gusnard, D.L.a c , Raichle, M.E.a b d e , d'Avossa, G.f
Dissociated mean and functional connectivity BOLD signals in visual cortex during eyes closed and fixation
(2012) Journal of Neurophysiology, 108 (9), pp. 2363-2372. 

a Department of Radiology, Washington University School of Medicine, 4525 Scott Ave., Campus Box 8225, Saint Louis, MO 63110, United States
b Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States
c Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, United States
d Department of Anatomy and Neurobiology, Washington University School of Medicine, Saint Louis, MO, United States
e Department of Biomedical Engineering, Washington University School of Engineering, Saint Louis, MO, United States
f School of Psychology, Bangor University, Bangor, United Kingdom

Abstract
We investigated the effects of resting state type on blood oxygen level-dependent (BOLD) signal and functional connectivity in two paradigms: participants either alternated between fixation and eyes closed or maintained fixation or eyes closed throughout each scan. The BOLD signal and functional connectivity of lower and higher tiers of the visual cortical hierarchy were found to be differentially modulated during eyes closed versus fixation. Fixation was associated with greater mean BOLD signals in primary visual cortex and lower mean BOLD signals in extrastriate visual areas than periods of eyes closed. In addition, analysis of thalamocortical functional connectivity during scans in which participants maintained fixation showed synchronized BOLD fluctuations between those thalamic nuclei whose mean BOLD signal was systematically modulated during alternating epochs of eyes closed and fixation, primary visual cortex and the attention network, while during eyes closed negatively correlated fluctuations were seen between the same thalamic nuclei and extrastriate visual areas. Finally, in all visual areas the amplitude of spontaneous BOLD fluctuations was greater during eyes closed than during fixation. The dissociation between early and late tiers of visual cortex, which characterizes both mean and functionally connected components of the BOLD signal, may depend on the reorganization of thalamocortical networks. Since dissociated changes in local blood flow also characterize transitions between different stages of sleep and wakefulness (Braun AR, Balkin TJ, Wesenten NJ, Gwadry F, Carson RE, Varga M, Baldwin P, Belenky G, Herscovitch P. Science 279: 91-95, 1998), our results suggest that dissociated endogenous neural activity in primary and extrastriate cortex may represent a general aspect of brain function. © 2012 the American Physiological Society.

Author Keywords
FMRI;  Oscillatory signals;  Resting state;  Spontaneous activity;  Thalamocortical networks

Document Type: Article
Source: Scopus

 

Lusis, E.A.a , Scheithauer, B.W.b , Yachnis, A.T.c , Fischer, B.R.d , Chicoine, M.R.a , Paulus, W.e , Perry, A.f
Meningiomas in pregnancy: A clinicopathologic study of 17 cases
(2012) Neurosurgery, 71 (5), pp. 951-961. 

a Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
b Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
c Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL, United States
d Department of Neurosurgery, Muenster University Hospital, Muenster, Germany
e Institute of Neuropathology, Muenster University Hospital, Muenster, Germany
f Department of Pathology, Division of Neuropathology, University of California, San Francisco, 505 Parnassus Ave, San Francisco, CA 94143, United States

Abstract
BACKGROUND: Dramatic growth of meningiomas is occasionally encountered during pregnancy. While cell proliferation is often assumed, hemodynamic changes have also been touted as a cause. OBJECTIVE: We identified 17 meningiomas resected during pregnancy or within 3 weeks post-partum and characterized them to determine the cause of occasional rapid growth in pregnancy. METHODS: Seventeen tumors were identified from searches at 4 university centers. All available clinical records, radiology images, and tissue specimens were reviewed, with immunohistochemical studies performed as needed. RESULTS: Sixteen patients underwent tumor resection and 1 died of complications prior to surgery. Average patient age was 32 years. Nine experienced onset of symptoms in the third trimester or within 8 days post-partum. Principle physical findings included visual complaints (59%) and cranial nerve palsies (29%). Ten tumors (59%) were located in the skull base region. The Ki-67 labeling index was low (0.5-3.6%) in 11 of 13 benign (grade I) tumors and elevated (11-23.2%) in 3 of 4 atypical (grade II) meningiomas. Eight (50%) tumors featured hypervascularity with at least focal CD34-positive hemangioma-like microvasculature. Fourteen (82%) showed evidence of intra-and/or extracellular edema, 1 so extensive that its meningothelial nature was not apparent. Five tumors (29%) exhibited intratumoral hemorrhage and/or necrosis. CONCLUSION: Our series suggests that pregnancy-associated meningiomas located in the skull base are likely to require surgical intervention for visual complaints and cranial nerve palsies. The rapid tumor growth is more often due to potentially reversible hemodynamic changes rather than hormone-induced cellular proliferation. Copyright © 2012 by the Congress of Neurological Surgeons.

Author Keywords
Meningioma;  Pathology;  Pregnancy

Document Type: Article
Source: Scopus

 

Murphy, R.K.J.a , Ray, W.Z.a , Mackinnon, S.E.b
Repair of a median nerve transection injury using multiple nerve transfers, with long-term functional recovery
(2012) Journal of Neurosurgery, 117 (5), pp. 886-889. 

a Department of Neurological Surgery, Washington University, School of Medicine, St. Louis, MO, United States
b Division of Plastic and Reconstructive Surgery, Washington University, School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, United States

Abstract
Complete loss of median nerve motor function is a rare but devastating injury. Loss of median motor hand function and upper-extremity pronation can significantly impact a patient's ability to perform many activities of daily living independently. The authors report the long-term follow-up in a case of median nerve motor fiber transection that occurred during an arthroscopic elbow procedure, which was then treated with multiple nerve transfers. Motor reconstruction used the nerves to the supinator and extensor carpi radialis brevis to transfer to the anterior interosseous nerve and pronator. Sensory sensation was restored using the lateral antebrachial cutaneous (LABC) nerve to transfer to a portion of the sensory component of the median nerve, and a second cable of LABC nerve as a direct median nerve sensory graft. The patient ultimately recovered near normal motor function of the median nerve, but had persistent pain symptoms 4 years postinjury.

Author Keywords
Median nerve;  Nerve transection;  Nerve transfer;  Peripheral nerve

Document Type: Article
Source: Scopus

 

Depta, J.P.a , Kottke-Marchant, K.b , Bhatt, D.L.c
Response to letter regarding article clinical outcomes using a platelet function-guided approach for secondary prevention in patients with ischemic stroke or transient ischemic attack

(2012) Stroke, 43 (11), pp. e168. 

a Washington University School of Medicine, St Louis, MO, United States
b Cleveland Clinic, Cleveland, OH, United States
c VA Boston Healthcare System, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States

Document Type: Letter
Source: Scopus

 

Cross, A.H.a , Klein, R.S.b , Piccio, L.a
Rituximab combination therapy in relapsing multiple sclerosis
(2012) Therapeutic Advances in Neurological Disorders, 5 (6), pp. 311-319. 

a Department of Neurology, Washington University in St Louis, Campus Box 8111, 660 S Euclid, St Louis, MO 63110, United States
b Department of Internal Medicine, Washington University in St Louis, St Louis, MO, United States

Abstract
In multiple sclerosis (MS), the presence of B cells, plasma cells and excess immunoglobulins in central nervous system lesions and in the cerebrospinal fluid implicate the humoral immune system in disease pathogenesis. However, until the advent of specific B-cell-depleting therapies, the critical role of B cells and their products in MS was unproven. Rituximab, a monoclonal antibody that depletes B cells by targeting the CD20 molecule, has been shown to effectively reduce disease activity in patients with relapsing MS as a single agent. Our investigator-initiated phase II study is the only published clinical trial in which rituximab was used as an add-on therapy in patients with relapsing MS who had an inadequate response to standard injectable disease-modifying therapies (DMTs). The primary endpoint, magnetic resonance imaging (MRI) gadolinium-enhanced (GdE) lesion number before versus after rituximab, showed significant benefit of rituximab (74% of post-treatment MRI scans being free of GdE lesions compared with 26% free of GdE lesions at baseline; p < 0.0001). No differences were noted comparing patients on different DMTs. Several secondary clinical endpoints, safety and laboratory measurements (including B- and T-cell numbers in the blood and cerebrospinal fluid (CSF), serum and CSF chemokine levels, antibodies to myelin proteins) were assessed. Surprisingly, the decline in B-cell number was accompanied by a significant reduction in the number of T cells in both the peripheral blood and CSF. Rituximab therapy was associated with a significant decline of two lymphoid chemokines, CXCL13 and CCL19. No significant changes were observed in serum antibody levels against myelin proteins [myelin basic protein (MBP) and myelin/oligodendrocyte glycoprotein (MOG)] after treatment. These results suggest that B cells play a role in MS independent from antibody production and possibly related to their role in antigen presentation to T cells or to their chemokine/cytokine production. © 2012 The Author(s).

Author Keywords
B cells;  chemokines;  CXCL13;  gadolinium-enhanced magnetic resonance imaging;  multiple sclerosis;  rituximab;  T cells

Document Type: Review
Source: Scopus

 

Moreira, P.A.a , Oliveira, J.T.a , Cloninger, K.M.b , Azevedo, C.a , Sousa, A.a , Castro, J.a , Cloninger, C.R.c
The psychometrics and validity of the junior temperament and character inventory in Portuguese adolescents
(2012) Comprehensive Psychiatry, 53 (8), pp. 1227-1236. 

a Universidade Lusíada Do Porto, 4369-006 Porto, Portugal
b Anthropedia Foundation, Kerhonkson, NY 12446, United States
c School of Medicine, Washington University, St. Louis, MO 63110, United States

Abstract
Personality traits related to persistence and self-regulation of long-term goals can predict academic performance as well or better than measures of intelligence. The 5-factor model has been suggested to outperform some other personality tests in predicting academic performance, but it has not been compared to Cloninger's psychobiological model for this purpose. The aims of this study were, first, to evaluate the psychometric properties of the Junior Temperament and Character Inventory (JTCI) in adolescents in Portugal, and second, to evaluate the comparative validity of age-appropriate versions of Cloninger's 7-factor psychobiological model, Costa and McCrae's five-factor NEO-Personality Inventory-Revised, and Cattell's 16-personality-factor inventory in predicting academic achievement. All dimensions of the Portuguese JTCI had moderate to strong internal consistency. The Cattell's sixteen-personality- factor and NEO inventories provided strong construct validity for the JTCI in students younger than 17 years and for the revised adult version (TCI-Revised) in those 17 years and older. High TCI Persistence predicted school grades regardless of age as much or more than intelligence. High TCI Harm Avoidance, high Self-Transcendence, and low TCI Novelty Seeking were additional predictors in students older than 17. The psychobiological model, as measured by the JTCI and TCI-Revised, performed as well or better than other measures of personality or intelligence in predicting academic achievement. © 2012 Elsevier Inc. © 2012 Elsevier Inc. All rights reserved.

Document Type: Article
Source: Scopus

 

Schwartz, G.W.a , Okawa, H.a , Dunn, F.A.a , Morgan, J.L.b , Kerschensteiner, D.c d , Wong, R.O.a , Rieke, F.a e
The spatial structure of a nonlinear receptive field
(2012) Nature Neuroscience, 15 (11), pp. 1572-1580. 

a Department of Physiology and Biophysics, University of Washington, Seattle, Seattle, WA, United States
b Department of Molecular and Cell Biology, Harvard University, Cambridge, MA, United States
c Department of Ophthalmolgy and Visual Sciences, Washington University, St. Louis, MO, United States
d Department of Anatomy and Neurobiology, Washington University, St. Louis, MO, United States
e Howard Hughes Medical Institute, Seattle, WA, United States

Abstract
Understanding a sensory system implies the ability to predict responses to a variety of inputs from a common model. In the retina, this includes predicting how the integration of signals across visual space shapes the outputs of retinal ganglion cells. Existing models of this process generalize poorly to predict responses to new stimuli. This failure arises in part from properties of the ganglion cell response that are not well captured by standard receptive-field mapping techniques: nonlinear spatial integration and fine-scale heterogeneities in spatial sampling. Here we characterize a ganglion cell's spatial receptive field using a mechanistic model based on measurements of the physiological properties and connectivity of only the primary excitatory circuitry of the retina. The resulting simplified circuit model successfully predicts ganglion-cell responses to a variety of spatial patterns and thus provides a direct correspondence between circuit connectivity and retinal output.

Document Type: Article
Source: Scopus

 

Dobbins, I.G.a , Jaeger, A.a , Studer, B.b c , Simons, J.S.b c
Use of explicit memory cues following parietal lobe lesions
(2012) Neuropsychologia, 50 (13), pp. 2992-3003. 

a Department of Psychology, Washington University, St. Louis, MO, United States
b Department of Experimental Psychology, University of Cambridge, Cambridge, United Kingdom
c Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, United Kingdom

Abstract
The putative role of the lateral parietal lobe in episodic memory has recently become a topic of considerable debate, owing primarily to its consistent activation for studied materials during functional magnetic resonance imaging studies of recognition. Here we examined the performance of patients with parietal lobe lesions using an explicit memory cueing task in which probabilistic cues ("Likely Old" or "Likely New"; 75% validity) preceded the majority of verbal recognition memory probes. Without cues, patients and control participants did not differ in accuracy. However, group differences emerged during the "Likely New" cue condition with controls responding more accurately than parietal patients when these cues were valid (preceding new materials) and trending towards less accuracy when these cues were invalid (preceding old materials). Both effects suggest insufficient integration of external cues into memory judgments on the part of the parietal patients whose cued performance largely resembled performance in the complete absence of cues. Comparison of the parietal patients to a patient group with frontal lobe lesions suggested the pattern was specific to parietal and adjacent area lesions. Overall, the data indicate that parietal lobe patients fail to appropriately incorporate external cues of novelty into recognition attributions. This finding supports a role for the lateral parietal lobe in the adaptive biasing of memory judgments through the integration of external cues and internal memory evidence. We outline the importance of such adaptive biasing through consideration of basic signal detection predictions regarding maximum possible accuracy with and without informative environmental cues. © 2012 Elsevier Ltd.

Author Keywords
Decision biasing;  Episodic memory;  Parietal cortex;  Prefrontal cortex;  Signal detection

Document Type: Article
Source: Scopus

 

Patel, A., Sayuk, G.S., Kushnir, V.M., Gyawali, C.P.
Sensory neuromodulators in functional nausea and vomiting: Predictors of response
(2012) Postgraduate Medical Journal, . Article in Press. 

Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri, USA

Abstract
Background: Tricyclic antidepressants (TCAs) are known to benefit subjects with functional nausea and vomiting (FNV), but it is not known if alternate neuromodulators are also beneficial. We retrospectively evaluated outcomes and clinical predictors of response in FNV subjects treated with any neuromodulator, including TCAs. Methods: We identified 94 subjects (43.8±1.4 year, 79 F) with FNV (Rome III criteria) over a 12 year period, treated with neuromodulators and followed up for 8.5±1.1 months. Clinical presentation, demographics and gastric emptying study (GES) findings (when available) were extracted. Likert scales determined symptom severity at baseline and symptom response or remission at follow-up. Outcomes and predictors of response were evaluated using univariate and multivariate analyses. Results: At least moderate symptom improvement was reported by 72.3%, and 22.3% had symptom remission. Proportions achieving moderate improvement and remission, and mean outcome Likert scores were similar regardless of neuromodulator agent used or GES status. On univariate and multivariate logistic regression analysis, baseline symptom severity affected symptom response, and pain negatively impacted symptom remission to treatment (p≤0.04 for each); GES status failed to predict treatment response or remission. Conclusions: Symptom improvement with neuromodulators may be seen in over two-thirds of subjects with FNV regardless of the specific agent administered. Response may be suboptimal in pain predominant presentations. Copyright Article author (or their employer) 2012.

Document Type: Article in Press
Source: Scopus

 

Brown, J.M.a , Barbe, M.F.b , Albo, M.E.c , Lai, H.H.d , Ruggieri, M.R.e f g
Anatomical feasibility of performing intercostal and ilioinguinal nerve to pelvic nerve transfer: A possible technique to restore lower urinary tract innervation: Laboratory investigation
(2012) Journal of Neurosurgery: Spine, 17 (4), pp. 357-362. 

a Division of Neurosurgery, University of California San Diego, School of Medicine, San Diego, CA, United States
b Division of Urology, University of California San Diego, Medical Center, San Diego, CA, United States
c Anatomy and Cell Biology, PA, United States
d Division of Urology, Washington University, School of Medicine, St. Louis, MO, United States
e Departments of Urology, PA, United States
f Departments of Pharmacology, Temple University, School of Medicine, 3400 North Broad Street, Philadelphia, PA 19140, United States
g Shriners Hospital of Philadelphia, PA, United States

Abstract
Object. Nerve transfers are effective for restoring control to paralyzed somatic muscle groups and, recently, even to denervated detrusor muscle in a canine model. A pilot project was performed in cadavers to examine the feasibility of transferring somatic nerves to vesical branches of the pelvic nerve as a method for potentially restoring innervation to control the detrusor muscle in humans. Methods. Eleven cadavers were dissected bilaterally to expose intercostal, ilioinguinal, and iliohypogastric nerves, along with vesical branches of the pelvic nerve. Ease of access and ability to transfer the former 3 nerves to the pelvic vesical nerves were assessed, as were nerve cross-sectional areas. Results. The pelvic vesical nerves were accessed at the base of the bladder, inferior to the ureter and accompanied by inferior vesical vessels. The T-11 and T-12 intercostal nerves were too short for transfer to the pelvic vesical nerves without grafting. Ilioinguinal and iliohypogastric nerves (L-1 origin) were identified retroperitoneally and, with full dissection, were easily transferred to the pelvic vesical nerves intraabdominally. The mean cross-sectional area of the dominant pelvic vesical branch was 2.60 ± 0.169 mm2; ilioinguinal and iliohypogastric branches at the suggested transection site were 2.38 ± 0.32 mm2 (the means are expressed ± SEM). Conclusions. Use of the ilioinguinal or iliohypogastric nerves for heterotopic transfer to pelvic vesical nerves is surgically feasible, based on anatomical location and cross-sectional areas.

Author Keywords
Anatomy;  Bladder;  Cadaver dissection;  Ilioinguinal nerve;  Intercostal nerve;  Pelvic nerve

Document Type: Article
Source: Scopus

 

Schaefer, S.Y.a , Lang, C.E.a b c
Using dual tasks to test immediate transfer of training between naturalistic movements: A proof-of-principle study
(2012) Journal of Motor Behavior, 44 (5), pp. 313-327. 

a Program in Physical Therapy, Washington University, School of Medicine, St. Louis, MO 63108, United States
b Program in Occupational Therapy, Washington University, School of Medicine, St. Louis, MO, United States
c Department of Neurology, Washington University, School of Medicine, St. Louis, MO, United States

Abstract
Theories of motor learning predict that training a movement reduces the amount of attention needed for its performance (i.e., more automatic). If training one movement transfers, then the amount of attention needed for performing a second movement should also be reduced, as measured under dual task conditions. The authors purpose was to test whether dual task paradigms are feasible for detecting transfer of training between two naturalistic movements. Immediately following motor training, subjects improved performance of a second untrained movement under single and dual task conditions. Subjects with no training did not. Improved performance in the untrained movement was likely due to transfer, and suggests that dual tasks may be feasible for detecting transfer between naturalistic actions. © 2012 Copyright Taylor and Francis Group, LLC.

Author Keywords
feasibility;  motor training;  naturalistic movement;  transfer

Document Type: Article
Source: Scopus

 

Bailey, H.
Computer-paced versus experimenter-paced working memory span tasks: Are they equally reliable and valid?
(2012) Learning and Individual Differences, 22 (6), pp. 875-881. 

Washington University, 439 Psychology Buld. One Brookings Drive, Campus Box 1125, Saint Louis, MO 63130, United States

Abstract
Working memory span tasks are popular measures, in part, because performance on these tasks predicts performance on other measures of cognitive ability. The traditional method of span-task administration is the experimenter-paced version, whose reliability and validity have been repeatedly demonstrated. However, computer-paced span tasks are becoming increasingly more popular. Despite their popularity, no study had systematically compared experimenter-paced and computer-paced versions of the reading span and operation span tasks. Such a comparison is important because research labs in many universities across many countries administer these span tasks with a variety of methods. The purpose of the present study was to evaluate the reliability and validity of computer-paced span tasks and to compare these estimates to those of experimenter-paced span tasks. Results indicated that experimenter-paced and computer-paced span tasks share some overlap, but also measure additional and distinct processes. Computer-paced span tasks were highly reliable measures as well as valid indicators of fluid intelligence (Gf). Thus, computer-paced span tasks may be the optimal type of administration given their methodological advantages over experimenter-paced span tasks. © 2012 Elsevier Inc.

Author Keywords
Administration;  Computer-paced;  Fluid intelligence;  Span tasks;  Working memory

Document Type: Article
Source: Scopus

 

Sharma, A.K.a , Pavlova, S.T.a , Kim, J.b , Finkelstein, D.a , Hawco, N.J.a , Rath, N.P.c , Kim, J.b , Mirica, L.M.a
Bifunctional compounds for controlling metal-mediated aggregation of the Aβ 42 peptide
(2012) Journal of the American Chemical Society, 134 (15), pp. 6625-6636. 

a Department of Chemistry, Washington University, One Brookings Drive, St. Louis, MO 63130-4899, United States
b Department of Neurology, Washington University, School of Medicine, St. Louis, MO 63108, United States
c Department of Chemistry and Biochemistry, University of Missouri St. Louis, One University Boulevard, St. Louis, MO 63121-4400, United States

Abstract
Abnormal interactions of Cu and Zn ions with the amyloid β (Aβ) peptide are proposed to play an important role in the pathogenesis of Alzheimers disease (AD). Disruption of these metal-peptide interactions using chemical agents holds considerable promise as a therapeutic strategy to combat this incurable disease. Reported herein are two bifunctional compounds (BFCs) L1 and L2 that contain both amyloid-binding and metal-chelating molecular motifs. Both L1 and L2 exhibit high stability constants for Cu 2+ and Zn 2+ and thus are good chelators for these metal ions. In addition, L1 and L2 show strong affinity toward Aβ species. Both compounds are efficient inhibitors of the metal-mediated aggregation of the Aβ 42 peptide and promote disaggregation of amyloid fibrils, as observed by ThT fluorescence, native gel electrophoresis/Western blotting, and transmission electron microscopy (TEM). Interestingly, the formation of soluble Aβ 42 oligomers in the presence of metal ions and BFCs leads to an increased cellular toxicity. These results suggest that for the Aβ 42 peptide-in contrast to the Aβ 40 peptide-the previously employed strategy of inhibiting Aβ aggregation and promoting amyloid fibril dissagregation may not be optimal for the development of potential AD therapeutics, due to formation of neurotoxic soluble Aβ 42 oligomers. © 2012 American Chemical Society.

Document Type: Article
Source: Scopus

November 7, 2012

Fleisher, A.S.a b c , Chen, K.a c d , Liu, X.a , Ayutyanont, N.a , Roontiva, A.a , Thiyyagura, P.a , Protas, H.a , Joshi, A.D.e , Sabbagh, M.f , Sadowsky, C.H.f , Sperling, R.A.g , Clark, C.M.e h , Mintun, M.A.e i , Pontecorvo, M.J.e , Coleman, R.E.j , Doraiswamy, P.M.j , Johnson, K.A.g k , Carpenter, A.P.e , Skovronsky, D.M.e h , Reiman, E.M.a c l m
Apolipoprotein E ε4 and age effects on florbetapir positron emission tomography in healthy aging and Alzheimer disease
(2013) Neurobiology of Aging, 34 (1), pp. 1-12. 

a Banner Alzheimer's Institute, Phoenix, AZ, United States
b Department of Neurosciences, University of California, San Diego, CA, United States
c Arizona Alzheimer's Consortium, AZ, United States
d Department of Mathematics, Arizona State University, Tempe, AZ, United States
e Avid Radiopharmaceuticals, Philadelphia, PA, United States
f Nova SE University, Fort Lauderdale, FL, United States
g Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
h University of Pennsylvania, School of Medicine, Philadelphia, PA, United States
i Washington University, School of Medicine, St. Louis, MO, United States
j Department of Radiology, Duke University Medical Center, Durham, NC, United States
k Departments of Neurology and Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
l Department of Psychiatry, University of Arizona, College of Medicine, Phoenix, AZ, United States
m Banner Sun Health Research Institute, Phoenix, AZ, United States

Abstract
Objectives: Investigate apolipoprotein E ε4 (APOE4) gene and aging effects on florbetapir F18 positron emission tomography (PET) in normal aging and Alzheimer's disease (AD). Methods: Florbetapir F18 PET images were analyzed from 245 participants, 18-92 years of age, from Avid Radiopharmaceutical's multicenter registered trials, including 86 younger healthy control volunteers (yHC), 61 older healthy control volunteers (oHC), 53 mild cognitive impairment (MCI) patients, and 45 AD dementia patients (DAT). Mean florbetapir standard uptake value ratios (SUVRs) were used to evaluate the effects of APOE4 carrier status, older age, and their interaction in each of these groups. Results: In comparison with non-carriers, the APOE4 carriers in each of the oHC, MCI, and DAT groups had higher mean cortical-to-cerebellar florbetapir SUVRs, patterns of florbetapir PET elevations characteristic of DAT, and a higher proportion meeting florbetapir PET positivity criteria. Only the oHC group had a significant association between mean cortical florbetapir SUVRs and age. In cognitively normal adults, without regards to APOE4 genotype, amyloid began to increase at age 58 (95% confidence interval [CI]: 52.3-63.7), with a predicted typical age of florbetapir positivity occurring around age 71 years. Presence of the APOE4 gene reduced the age of predicted florbetapir positivity in normal aging to around age 56 years, approximately 20 years younger than non-carriers. Interpretation: Cerebral amyloid deposition is associated with APOE4 carrier status in older healthy control subjects and symptomatic AD patients, and increases with age in older cognitively normal individuals. Amyloid imaging positivity appears to begin near age 56 years in cognitively intact APOE4 carriers and age 76 years in APOE4 non-carriers. © 2013 Elsevier Inc.

Author Keywords
Aging;  Alzheimer;  Alzheimer risk;  Amyloid PET;  Apolipoprotein;  Florbetapir;  PET

Document Type: Article
Source: Scopus

 

Stewart, R.S.a , Teng, H.b , Wilkinson, R.S.a
"Late" macroendosomes and acidic endosomes in vertebrate motor nerve terminals
(2012) Journal of Comparative Neurology, 520 (18), pp. 4275-4293. 

a Department of Cell Biology and Physiology, Washington University, School of Medicine, St. Louis, MO 63110, United States
b Molecular Biosensor and Imaging Center, Carnegie Mellon University, Pittsburgh, PA 15213, United States

Abstract
Activity at the vertebrate nerve-muscle synapse creates large macroendosomes (MEs) via bulk membrane infolding. Visualized with the endocytic probe FM1-43, most (94%) of the ~25 MEs/terminal created by brief (30-Hz, 18-second) stimulation dissipate rapidly (~1 minute) into vesicles. Others, however, remain for hours. Here we study these "late" MEs by using 4D live imaging over a period of ~1 hour after stimulation. We find that some (51/398 or 13%) disappear spontaneously via exocytosis, releasing their contents into the extracellular milieu. Others (at least 15/1,960 or 1%) fuse or closely associate with a second class of endosomes that take up acidophilic dyes (acidic endosomes [AEs]). AEs are plentiful (~47/terminal) and exist independent of stimulation. Unlike MEs, which exhibit Brownian motion, AEs exhibit directed motion (average, 83 nm/sec) on microtubules within and among terminal boutons. AEs populate the axon as well, where movement is predominantly retrograde. They share biochemical and immunohistochemical markers (e.g., lysosomal-associated membrane protein [LAMP-1]) with lysosomes. Fusion/association of MEs with AEs suggests a sorting/degradation pathway in nerve terminals wherein the role of AEs is similar to that of lysosomes. Based on our data, we propose that MEs serve as sorting endosomes. Thus their contents, which include plasma membrane proteins, vesicle proteins, and extracellular levels of Ca 2+, can be targeted either toward the reformation and budding of synaptic vesicles, toward secretion via exocytosis, or toward a degradation process that utilizes AEs either for lysis within the terminal or for transport toward the cell body. © 2012 Wiley Periodicals, Inc.

Author Keywords
Endocytosis;  Synapse;  Vesicle processing

Document Type: Article
Source: Scopus

 

Mullin, J.E.a , Cooper, B.P.b , Kirkham, F.J.c , Rosen, C.L.d , Strunk, R.C.e , DeBaun, M.R.f , Redline, S.g , Kemp, J.S.e
Stability of polysomnography for one year and longer in children with sickle cell disease
(2012) Journal of Clinical Sleep Medicine, 8 (5), pp. 535-539. 

a Case Western Reserve University School of Medicine, Cleveland, OH, United States
b St. Louis University School of Public Health, St. Louis, MO, United States
c UCL Institute of Child Health, London, United Kingdom
d Department of Pediatrics, Division of Pediatric Pulmonology, Case Western Reserve University School of Medicine, Cleveland, OH, United States
e Department of Pediatrics, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO, 63110, United States
f Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN, United States
g Department of Medicine, Harvard Medical School, Brigham and Women's Hospital and Beth Israel Deaconess Medical Center, Boston, MA, United States

Abstract
Study Objectives: Serious morbidity may be linked to sleep disordered breathing (SDB) among children with sickle cell disease (SCD). We investigated the stability of polysomnography (PSG) results among children not having acute complications of SCD. Methods: Two PSGs were performed on a subsample of 63 children 4 to 18 years of age from the Sleep and Asthma Cohort Study. All had Hb SS or HbSβ0 disease. Two PSGs were compared for 45 subjects. Excluded from comparison were 18 children who had begun transfusions or hydroxyurea, had an adenotonsillectomy between the PSGs, or had a pain crisis or the acute chest syndrome within 3 months of the second PSG. Sleep disordered breathing was identifi ed using 2 thresholds for the apnea hypopnea index (AHI): ≥ 2 or ≥ 5 respiratory events per hour. Results: Ages were 12.3 yrs ± 4.0, BMI, 18.2 ± 3.2. Interval between PSGs was 581 ± 119 days (19.1 ± 3.9 months). Ten of 45 changed from ≥ 2 events per hour to &lt; 2; 3 of 45 from &lt; 2 to ≥ 2; 7 of 45 had ≥ 2 on both nights. Six of 45 changed from ≥ 5 to &lt; 5, 2 of 45 from &lt; 5 to ≥ 5, and 1 had ≥ 5 on both nights (McNemar χ 2, p = 0.09, and p = 0.29). Conclusions: In the absence of acute SCD complications, overnight PSG usually remains stable or improves over a 12- to 30-month period. Only 6.7% subjects, or fewer, had AHI on a subsequent PSG that would re-classify the child as having SDB not identifi ed in the earlier PSG.

Author Keywords
Obstructive sleep apnea;  Polysomnography;  Sickle cell disease

Document Type: Article
Source: Scopus

 

Germain, N.D.a , Hartman, N.W.a c , Cai, C.a d , Becker, S.a , Naegele, J.R.a b , Grabel, L.B.a
Teratocarcinoma formation in embryonic stem cell-derived neural progenitor hippocampal transplants
(2012) Cell Transplantation, 21 (8), pp. 1603-1611. 

a Department of Biology, Wesleyan University, Middletown, CT, United States
b Wesleyan University, Middletown, CT, United States
c Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, United States
d Department of Pathology and Immunology, Washington University, School of Medicine, St. Louis, MO, United States

Abstract
Embryonic stem cells (ESCs) hold great therapeutic potential due to their ability to differentiate into cells of the three primary germ layers, which can be used to repopulate disease-damaged tissues. In fact, two cell therapies using ESC derivatives are currently in phase I clinical trials. A main concern in using ESCs and their derivatives for cell transplantation is the ability of undifferentiated ESCs to generate tumors in the host. Positive selection steps are often included in protocols designed to generate particular cell types from ESCs; however, the transition from ESC to progenitor cell or terminally differentiated cell is not synchronous, and residual undifferentiated cells often remain. In our transplants of ESC-derived neural progenitors (ESNPs) into the adult mouse hippocampus, we have observed the formation of teratocarcinomas. We set out to reduce teratocarcinoma formation by enrichment of ESNPs using fluorescence-activated cell sorting (FACS) and have found that, although enrichment prior to transplant reduces the overall rate of teratocarcinoma formation, the tumorigenicity of cell batches can vary widely, even after FACS enrichment to as much as 95% ESNPs. Our data suggest that this variability may be due to the percentage of residual ESCs remaining in the transplant cell population and to the presence of pluripotent epiblast-like cells, not previously identified in transplant batches. Our data emphasize the need for stringent characterization of transplant cell populations that will be used for cell replacement therapies in order to reduce the risk of tumor formation. © 2012 Cognizant Comm. Corp.

Author Keywords
Embryonic stem cells;  Hippocampus;  Neural progenitor;  Teratocarcinoma

Document Type: Article
Source: Scopus

 

Jin, S.C.a , Pastor, P.b c d , Cooper, B.a , Cervantes, S.b , Benitez, B.A.a , Razquin, C.b , Goate, A.a , Cruchaga, C.a
Pooled-DNA sequencing identifies novel causative variants in PSEN1, GRN and MAPT in a clinical early-onset and familial Alzheimer's disease Ibero-American cohort
(2012) Alzheimer's Research and Therapy, 4 (4), art. no. 34, . 

a Department of Psychiatry, Washington University, School of Medicine, 660 South Euclid Avenue B8134, St. Louis, MO 63110, United States
b Neurogenetics Laboratory, Campus Universitario, University of Navarra, 31080 Pamplona, Navarra, Spain
c Department of Neurology, Campus Universitario, University of Navarra School of Medicine, 31080 Pamplona, Navarra, Spain
d CIBERNED, Centro de Investigacián Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, C/Sinesio Delgado, 4, 28029, Madrid, Spain

Abstract
Introduction. Some familial Alzheimer's disease (AD) cases are caused by rare and highly-penetrant mutations in APP, PSEN1, and PSEN2. Mutations in GRN and MAPT, two genes associated with frontotemporal dementia (FTD), have been found in clinically diagnosed AD cases. Due to the dramatic developments in next-generation sequencing (NGS), high-throughput sequencing of targeted genomic regions of the human genome in many individuals in a single run is now cheap and feasible. Recent findings favor the rare variant-common disease hypothesis by which the combination effects of rare variants could explain a large proportion of the heritability. We utilized NGS to identify rare and pathogenic variants in APP, PSEN1, PSEN2, GRN, and MAPT in an Ibero-American cohort. Methods. We performed pooled-DNA sequencing of each exon and flanking sequences in APP, PSEN1, PSEN2, MAPT and GRN in 167 clinical and 5 autopsy-confirmed AD cases (15 familial early-onset, 136 sporadic early-onset and 16 familial late-onset) from Spain and Uruguay using NGS. Follow-up genotyping was used to validate variants. After genotyping additional controls, we performed segregation and functional analyses to determine the pathogenicity of validated variants. Results: We identified a novel G to T transition (g.38816G>T) in exon 6 of PSEN1 in a sporadic early-onset AD case, resulting in a previously described pathogenic p.L173F mutation. A pathogenic p.L392V mutation in exon 11 was found in one familial early-onset AD case. We also identified a novel CC insertion (g.10974-10975insCC) in exon 8 of GRN, which introduced a premature stop codon, resulting in nonsense-mediated mRNA decay. This GRN mutation was associated with lower GRN plasma levels, as previously reported for other GRN pathogenic mutations. We found two variants in MAPT (p.A152T, p.S318L) present only in three AD cases but not controls, suggesting that these variants could be risk factors for the disease. Conclusions: We found pathogenic mutations in PSEN1, GRN and MAPT in 2.33% of the screened cases. This study suggests that pathogenic mutations or risk variants in MAPT and in GRN are as frequent in clinical AD cases as mutations in APP, PSEN1 and PSEN2, highlighting that pleiotropy of MAPT or GRN mutations can influence both FTD and AD phenotypic traits. © 2012 Jin et al.; licensee BioMed Central Ltd.

Document Type: Article
Source: Scopus

 

Nimmakayalu, M.a , Noble, N.a , Horton, V.K.a , Willing, M.b , Copeland, S.c , Sheffield, V.a , Nagy, P.L.d , Wassink, T.a , Patil, S.a , Shchelochkov, O.A.a
2q24 deletions: Further characterization of clinical findings and their relation to the SCN cluster

(2012) American Journal of Medical Genetics, Part A, 158 A (11), pp. 2767-2774. 

a Division of Medical Genetics, Department of Pediatrics, University of Iowa Hospitals and Clinics, Iowa City, IA, United States
b Department of Pediatrics, Washington University, School of Medicine, St Louis, MO, United States
c Genetic Services Branch, Division of Services, Children with Special Health Needs Maternal and Child Health Bureau, Rockville, MD, United States
d Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, United States

Abstract
As the resolution of molecular cytogenetic methods continues to improve, it has become increasingly possible to refine genotype-phenotype correlations based upon gene involvement. We report three new patients with nonrecurrent deletions involving subbands of 2q24. These patients were referred for evaluation of developmental delay, but were found to have unique, nonoverlapping clinical features. Patient 1 presented with infantile seizures, microcephaly, and brain anomalies, along with facial dysmorphism, growth retardation, neuromuscular scoliosis, and later with developmental regression. Array comparative genomic hybridization (aCGH) detected an 8Mb interstitial deletion encompassing the neuronal sodium channel (SCN) gene cluster. Patient 2 presented with growth retardation, congenital heart defect, and hypotonia. Patient 3 presented with developmental delay and behavioral problems. Patients 2 and 3 had no history of seizures, microcephaly, or brain anomalies and were found to have deletions of 2q24, ~8Mb and <500kb respectively, centromeric to and outside the SCN cluster. It has been demonstrated that mutations and copy number variants (CNVs) affecting the SCN gene cluster result in severe, early-onset seizures. It is however, less clear whether haploinsufficiency of regions outside the SCN cluster may result in phenotypically recognizable and clinically significant features. We discuss additional dosage sensitive genes that may exist outside the SCN cluster. Our and published data indicate that 2q24 deletions not involving the SCN cluster are associated with fewer neurobehavioral problems, but may predispose to congenital malformations. © 2012 Wiley Periodicals, Inc.

Author Keywords
2q24;  2q31.1;  Array comparative genomic hybridization (aCGH);  Dravet syndrome;  FIGN;  Growth retardation;  Microcephaly;  SCN cluster;  SCN1A;  SCN2A;  SCN3A;  SCN7A;  SCN9A;  Seizures;  SLC4A10

Document Type: Article
Source: Scopus

 

Bodner, K.E.a , Aldridge, K.b , Moffitt, A.J.a , Peck, D.c , White, D.A.d , Christ, S.E.a
A volumetric study of basal ganglia structures in individuals with early-treated phenylketonuria
(2012) Molecular Genetics and Metabolism, 107 (3), pp. 302-307. 

a Department of Psychological Sciences, University of Missouri, Columbia, MO, United States
b Department of Pathology and Anatomical Sciences, University of Missouri, School of Medicine, Columbia, MO, United States
c Department of Child Health, University of Missouri, School of Medicine, Columbia, MO, United States
d Department of Psychology, Washington University, St. Louis, MO, United States

Abstract
Whereas the impact of early-treated phenylketonuria (ETPKU) on cortical white matter is well documented, relatively little is known regarding the potential impact of this metabolic disorder on deep gray matter structures such as the basal ganglia. The current study used high-resolution (1mm 3) magnetic resonance imaging to investigate bilateral basal ganglia structures (i.e., putamen, caudate nucleus, and nucleus accumbens) in a sample of 13 individuals with ETPKU and a demographically-matched sample of 13 neurologically intact individuals without PKU. Consistent with previous research, we found smaller whole brain volumes in the ETPKU group compared with the non-PKU group. Individuals with ETPKU also had significantly larger putamen volumes than non-PKU individuals. In addition, the degree of putamen enlargement was correlated with blood phenylalanine levels and full scale IQ in the ETPKU group. These findings are consistent with the hypothesis that ETPKU-related increases in phenylalanine lead to decreased central dopamine levels thus impacting dopamine-dependent brain regions such as the putamen that play an important role in cognition. © 2012 Elsevier Inc.

Author Keywords
Basal ganglia;  Caudate;  Magnetic resonance imaging;  Phenylketonuria;  Putamen;  Striatum

Document Type: Article
Source: Scopus

 

Nishida, T.a b , Faughnan, M.E.b c d e , Krings, T.b f , Chakinala, M.b g , Gossage, J.R.b h , Young, W.L.b i j k , Kim, H.b i l m , Pourmohamad, T.i , Henderson, K.J.a b , Schrum, S.D.b g , James, M.b h , Quinnine, N.b i , Bharatha, A.n , terBrugge, K.G.b f , White, R.I.a b
Brain arteriovenous malformations associated with hereditary hemorrhagic telangiectasia: Gene-phenotype correlations
(2012) American Journal of Medical Genetics, Part A, 158 A (11), pp. 2829-2834. 

a Yale HHT Center, Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, CT, United States
b Brain Vascular Malformation Consortium, Rare Disease Clinical Research Network, United States
c Division of Respirology, Department of Medicine, University of Toronto, Toronto, ON, Canada
d Toronto HHT Program, Division of Respirology, Department of Medicine, St. Michael's Hospital, Toronto, ON, Canada
e Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, ON, Canada
f Division of Neuroradiology, Department of Medical Imaging, Toronto Western Hospital, University of Toronto, Toronto, ON, Canada
g Pulmonary Critical Care division, Department of Internal medicine, Washington University School of Medicine, St. Louis, MO, United States
h Georgia Health Sciences University, Augusta, GA, United States
i Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California-San Francisco, San Francisco, CA, United States
j Department of Neurological Surgery, University of California-San Francisco, San Francisco, CA, United States
k Department of Neurology, University of California-San Francisco, San Francisco, CA, United States
l Department of Epidemiology and Biostatistics, University of California-San Francisco, San Francisco, CA, United States
m Institute for Human Genetics, University of California-San Francisco, San Francisco, CA, United States
n Division of Neuroradiology, Department of Medical Imaging, St. Michael's Hospital, University of Toronto, Toronto, ON, Canada

Abstract
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disease with a wide spectrum of vascular malformations (VMs) involving multiple organs. Nine to 16% of patients with HHT harbor brain arteriovenous malformations (AVMs), which can cause intracranial hemorrhage (ICH). Our objective was to study clinical manifestations of brain AVMs in patients with HHT and correlate these with the specific gene mutated. We reviewed records of 171 patients with HHT and brain AVMs. A history of ICH was found in 27% (41/152) patients, with a mean age of 26±18 range, (0-68) years. All of patients with ICH were neurologically asymptomatic prior to ICH. Multiple brain AVMs were found in 23% (170/39) of patients on initial examination. Genetic test results were available in 109 (64%) patients. Mutations in ENG, ACVRL1, and SMAD4 were present in 75 (69%), 18 (17%), and 2 (2%), respectively. A history of ICH was reported in 24% of patients with an ENG mutation and 27% of patients with an ACVRL1 mutation, with a mean age of 26±16 (range, 2-50) and 18±21 (0-48) years, respectively. No statistically significant differences in age at first brain AVM diagnosis, prevalence of ICH history, age at ICH, or other manifestations of brain AVMs were observed among gene groups. In conclusion, no evidence for differences in brain AVM characteristics was observed among HHT gene groups, although we cannot exclude clinically important differences. Larger studies are needed to further guide brain AVM screening decisions in patients with HHT. © 2012 Wiley Periodicals, Inc.

Author Keywords
Brain arteriovenous malformation;  Genotype;  Hereditary hemorrhagic telangiectasia;  Intracranial hemorrhage

Document Type: Article
Source: Scopus

 

McNicholas, C.P., Madden, T., Zhao, Q., Secura, G., Allsworth, J.E., Peipert, J.F.
Cervical lidocaine for IUD insertional pain: A randomized controlled trial
(2012) American Journal of Obstetrics and Gynecology, 207 (5), pp. 384.e1-384.e6. 

Department of Obstetrics and Gynecology, Washington University, St. Louis School of Medicine, 4533 Clayton Ave., St. Louis, MO 63110, United States

Abstract
Objective: Anticipated pain with intrauterine device (IUD) insertion may be a barrier to widespread use. Our objective was to evaluate the efficacy of intracervical 2% lidocaine gel for pain relief with IUD insertion. Study Design: We performed a double-blind, randomized controlled trial of women undergoing IUD insertion. Participants were randomly assigned to 2% lidocaine or placebo gel. Study gel (3 mL) was placed 3 minutes prior to IUD insertion. Pain scores were measured at various time points using a 10-point visual analog scale. Results: Of the 200 participants randomized, 199 completed the study. Pain scores among lidocaine and placebo arms were similar at tenaculum placement (lidocaine and placebo: median, 4; range, 0-10; P =.15) and with insertion (lidocaine: median, 5; range, 1-10; placebo: median, 6; range, 0-10; P =.16). These results did not differ by parity. Conclusion: Topical or intracervical 2% lidocaine gel prior to IUD insertion does not decrease pain scores. © 2012 Mosby, Inc.

Author Keywords
intrauterine device;  lidocaine gel;  pain

Document Type: Article
Source: Scopus

 

Das, S.K., Wineland, A., Kallogjeri, D., Piccirillo, J.F.
Cognitive speed as an objective measure of tinnitus
(2012) Laryngoscope, 122 (11), pp. 2533-2538. 

Department of Otolaryngology-Head and Neck Surgery, Campus Box 8115, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, United States

Abstract
Objectives/Hypothesis: Subjective, chronic tinnitus is a common but poorly understood condition. The heterogeneity within tinnitus has hindered the development of functional severity measures and effective treatment. Tinnitus at least partially results from maladaptive cortical processes that are associated with cognitive deficits. This study examined whether cognitive processing speed might serve as a novel objective measure of tinnitus severity, and whether the psychiatric comorbidities of depression and somatization are predictive of self-reported tinnitus severity. Study Design: Cross-sectional study of 92 chronic tinnitus participants. Methods: The Tinnitus Handicap Inventory (THI) captured the self-reported severity of tinnitus. Cognitive processing speed was objectively measured by the Brain Speed Test (BST), a short computerized test from Posit Science. Somatization and depression were captured by the Whiteley-7 and Patient Health Questionnaire-9 scales. The results of these tests were combined into a Composite Psychiatric State (CPS) variable. The ability of BST z score and CPS level to predict THI was assessed. Results: There was a significant correlation (r = 0.54, P <.001) between BST z scores and THI in those with bothersome tinnitus (THI ≥ 30). Additionally, BST z score was correlated with the validated neurocognitive tests. Multivariate analysis identified BST z score and CPS level as independent predictors of THI. Conclusions: In severe tinnitus, BST provides an objective measure of the functional impact of tinnitus. Cognitive processing speed and psychiatric state are independent predictors of self-reported tinnitus severity. These measures help define clinical subgroups within tinnitus: one subgroup whose functional impact is primarily cognitive and another whose functional impact is primarily psychiatric. Laryngoscope, 2012 Copyright © 2012 The American Laryngological, Rhinological, and Otological Society, Inc.

Author Keywords
cognition;  depression;  Level of Evidence: 2c;  somatization;  Tinnitus

Document Type: Article
Source: Scopus

 

Luby, J.L.
Commentry
(2012) Evidence-Based Mental Health, 15 (4), p. 108. 

Washington University in St. Louis, 18 S. Kingshighway, L-101, St. Louis, MO 63108, United States

Document Type: Note
Source: Scopus

 

Schechter, E.
Intentions and Unified Agency: Insights from the Split-brain Phenomenon
(2012) Mind and Language, 27 (5), pp. 570-594. 

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

Abstract
Under experimental conditions, behavior suggesting dual agency is easily elicited from split-brain subjects who usually behave in an unremarkable fashion. This article presents a model of split-brain agency that accounts for this apparent tension. Right and left hemisphere are associated with distinct agents, R and L, each of whose unity is grounded in the special inferential and experiential relations that its mental states bear to each other. These same relations do not hold interhemispherically; rather, unified behavior is largely the result of a split-brain subject's having a single body, much of whose coordination in action is maintained by forces operating downstream of reasons and intentions and conscious experiences. The split-brain subject as a whole is still a unified agent as well, however, in virtue of R's and L's intentions bearing, with respect to one and the same body, those special causal powers that an individual's intentions (and hers alone) bear to her body (and to her body alone). © 2012 Blackwell Publishing Ltd.

Document Type: Article
Source: Scopus

 

Mercuri, E.a b , McDonald, C.c , Mayhew, A.d , Florence, J.e , Mazzone, E.a , Bianco, F.a , Decostre, V.f , Servais, L.f , Ricotti, V.b , Goemans, N.g , Vroom, E.h
International workshop on assessment of upper limb function in Duchenne Muscular Dystrophy. Rome, 15-16 February 2012
(2012) Neuromuscular Disorders, 22 (11), pp. 1025-1028. 

a Department of Paediatric Neurology, Catholic University, Rome, Italy
b Dubowitz Neuromuscular Centre, Institute of Child Health, London, United Kingdom
c Department of Physical Medicine and Rehabilitation, University of California, Davis, United States
d Institute of Genetic Medicine, Newcastle Upon Tyne, United Kingdom
e Department of Neurology, Washington University School of Medicine, St. Louis, United States
f Institut de Myologie, GH Pitié Salpêtrière, Paris, France
g Child Neurology, University Hospitals Leuven, Leuven, Belgium
h Duchenne Parent Project, Netherlands

Document Type: Article
Source: Scopus

 

Szatmari, P.a , Charman, T.b , Constantino, J.N.c
Into, and Out of, the "valley of death": Research in autism spectrum disorders

(2012) Journal of the American Academy of Child and Adolescent Psychiatry, 51 (11), pp. 1108-1112. 

a Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON L8S 4K1, Canada
b Institute of Education, University of London, United Kingdom
c Washington University in St. Louis, United States

Document Type: Editorial
Source: Scopus

 

Braganza, M.Z.a b , Kitahara, C.M.a , Berrington De González, A.a , Inskip, P.D.a , Johnson, K.J.b , Rajaraman, P.a
Ionizing radiation and the risk of brain and central nervous system tumors: A systematic review
(2012) Neuro-Oncology, 14 (11), pp. 1316-1324. 

a Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Blvd., Rockville, MD 20852, United States
b Washington University, St. Louis, MO, United States

Abstract
Although exposure to moderate-to-high doses of ionizing radiation is the only established environmental risk factor for brain and CNS tumors, it is not clear whether this relationship differs across tumor subtypes, by sex or age at exposure, or at the low-to-moderate range of exposure. This systematic review summarizes the epidemiologic evidence on the association between ionizing radiation exposure and risk of brain/CNS tumors. Articles included in this review estimated radiation exposure doses to the brain and reported excess relative risk (ERR) estimates for brain/CNS tumors. Eight cohorts were eligible for inclusion in the analysis. Average age at exposure ranged from 8 months to 26 years. Mean dose to the brain ranged from 0.07 to 10 Gy. Elevated risks for brain/CNS tumors were consistently observed in relation to ionizing radiation exposure, but the strength of this association varied across cohorts. Generally, ionizing radiation was more strongly associated with risk for meningioma compared with glioma. The positive association between ionizing radiation exposure and risk for glioma was stronger for younger vs older ages at exposure. We did not observe an effect modification on the risk for meningioma by sex, age at exposure, time since exposure, or attained age. The etiologic role of ionizing radiation in the development of brain/CNS tumors needs to be clarified further through additional studies that quantify the association between ionizing radiation and risk for brain/CNS tumors at low-to-moderate doses, examine risks across tumor subtypes, and account for potential effect modifiers. © 2012 The Author(s).

Author Keywords
brain cancer;  brain tumors;  glioma;  ionizing radiation;  meningioma

Document Type: Review
Source: Scopus

 

Kristjansson, S.D.a , Agrawal, A.a , Lynskey, M.T.a , Chassin, L.A.b
Marijuana expectancies and relationships with adolescent and adult marijuana use
(2012) Drug and Alcohol Dependence, 126 (1-2), pp. 102-110. 

a Washington University School of Medicine, Department of Psychiatry, United States
b Arizona State University, Psychology Department, United States

Abstract
Background: Outcome expectancy is a central construct in models of addiction and relapse. Much expectancy research has been conducted in the context of alcohol; however, less is known about the structure of expectancies for marijuana and their associations with marijuana use outcomes. Methods: The data are taken from waves 3 and 4 of a longitudinal high-risk study of parents and adolescent offspring. Of those families who were retained at wave 3, 225 were high-risk and 205 were matched controls (low-risk). In the present study, we examine the factorial structure of marijuana expectancies (wave 3) in the offspring (using an instrument adapted from the alcohol literature) and test whether expectancies mediate the associations of familial risk for substance use, lifetime marijuana use in adolescence (wave 3) and current use in young adulthood (wave 4; reported approximately 5. years later). Results: We quantified four marijuana expectancy factors similar to those identified in previous studies when the offspring were adolescents (Mn age = 15.2) and results of our mediation models suggest that negative marijuana expectancies (but not positive expectancies) together with lifetime adolescent marijuana use completely mediated the association between familial risk and current use of marijuana during young adulthood (Mn age = 20.2). Conclusion: Familial risk for current marijuana use in young adulthood appears to be transmitted through two orthogonal, prospective pathways. One pathway involves marijuana use during adolescence, and the second pathway involves reduced expectancies that using marijuana will result in cognitive and behavioral impairments. © 2012 Elsevier Ireland Ltd.

Author Keywords
Adolescent;  Adult;  Expectancy;  Familial risk;  Marijuana use;  Mediation

Document Type: Article
Source: Scopus

 

Ponce-Balbuena, D.a , Rodríguez-Menchaca, A.A.b , López-Izquierdo, A.a , Ferrer, T.a , Kurata, H.T.c , Nichols, C.G.d , Sánchez-Chapula, J.A.a
Molecular mechanisms of chloroquine inhibition of heterologously expressed Kir6.2/SUR2A channels
(2012) Molecular Pharmacology, 82 (5), pp. 803-813. 

a Unidad de Investigacion Carlos Mendez Del Centro Universitario de Investigaciones Biomedicas, Universidad de Colima, Av 25 de Julio 965 Col. Villas San Sebastián, Colima, Col. México, CP 28045, Mexico
b Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de San Luis Potosí, San Luis Potosí, Mexico
c Anesthesiology, Pharmacology, and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
d Cell Biology and Physiology, Center for the Investigation of Membrane Excitability Disorders, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Chloroquine and related compounds can inhibit inwardly rectifying potassium channels by multiple potential mechanisms, including pore block and allosteric effects on channel gating. Motivated by reports that chloroquine inhibition of cardiac ATP-sensitive inward rectifier K + current (I KATP) is antifibrillatory in rabbit ventricle, we investigated the mechanism of chloroquine inhibition of ATP-sensitive potassium (K ATP) channels (Kir6.2/SUR2A) expressed in human embryonic kidney 293 cells, using inside-out patch-clamp recordings. We found that chloroquine inhibits the Kir6.2/SUR2A channel by interacting with at least two different sites and by two mechanisms of action. A fast-onset effect is observed at depolarized membrane voltages and enhanced by the N160D mutation in the central cavity, probably reflecting direct channel block resulting from the drug entering the channel pore from the cytoplasmic side. Conversely, a slow-onset, voltage-independent inhibition of I KATP is regulated by chloroquine interaction with a different site and probably involves disruption of interactions between Kir6.2/SUR2A and phosphatidylinositol 4,5-bisphosphate. Our findings reveal multiple mechanisms of K ATP channel inhibition by chloroquine, highlighting the numerous convergent regulatory mechanisms of these ligand-dependent ion channels. Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics.

Document Type: Article
Source: Scopus

 

Wei, X.a , Yu, J.W.a , Shattuck, P.b , McCracken, M.a , Blackorby, J.a
Science, Technology, Engineering, and Mathematics (STEM) Participation Among College Students with an Autism Spectrum Disorder
(2012) Journal of Autism and Developmental Disorders, pp. 1-8. Article in Press. 

a Center for Education and Human Services, SRI International, 333 Ravenswood Avenue, BS169, Menlo Park, 94025-3493, United States
b Washington University, Campus Box 1196, 1 Brookings Dr, St Louis, 63130, United States

Abstract
Little research has examined the popular belief that individuals with an autism spectrum disorder (ASD) are more likely than the general population to gravitate toward science, technology, engineering, and mathematics (STEM) fields. This study analyzed data from the National Longitudinal Transition Study-2, a nationally representative sample of students with an ASD in special education. Findings suggest that students with an ASD had the highest STEM participation rates although their college enrollment rate was the third lowest among 11 disability categories and students in the general population. Disproportionate postsecondary enrollment and STEM participation by gender, family income, and mental functioning skills were found for young adults with an ASD. Educational policy implications are discussed. © 2012 Springer Science+Business Media New York.

Author Keywords
Autism spectrum disorder;  College major;  Postsecondary enrollment;  Science, Technology, Engineering and Mathematics (STEM);  Young adult

Document Type: Article in Press
Source: Scopus

 

Keller, M.F.a b s , Saad, M.c d x y , Bras, J.e u , Bettella, F.g , Nicolaou, N.h , Simón-Sánchez, J.h z , Mittag, F.c , Büchel, F.c , Sharma, M.i j v w , Gibbs, J.R.a e s u , Schulte, C.i j v , Moskvina, V.k l , Durr, A.m n o p , Holmans, P.k l , Kilarski, L.L.k l , Guerreiro, R.e u , Hernandez, D.G.a e s u , Brice, A.m n o p aa ab ac bd cl , Ylikotila, P.q , Stefánsson, H.g bh , Majamaa, K.r , Morris, H.R.k l bw , Williams, N.k l bw , Gasser, T.d e i j , Heutink, P.g h , Wood, N.W.e f t u dg , Hardy, J.e u , Martinez, M.c d f g , Singleton, A.B.a s , Nalls, M.A.a s , Plagnol, V.t , Sheerin, U.-M.u , Lesage, S.aa ab ac , Sveinbjörnsdóttir, S.ad ae af , Arepalli, S.s , Barker, R.ag , Ben-Shlomo, Y.ah , Berendse, H.W.ai , Berg, D.v , Bhatia, K.aj , de Bie, R.M.A.ak , Biffi, A.al am , Bloem, B.an , Bochdanovits, Z.z , Bonin, M.ao , Brockmann, K.v , Brooks, J.s , Burn, D.J.ap , Charlesworth, G.u , Chen, H.aq , Chinnery, P.F.ar , Chong, S.s , Clarke, C.E.as at , Cookson, M.R.s , Cooper, J.M.au , Corvol, J.C.aa ab ac av , Counsell, C.aw , Damier, P.ax , Dartigues, J.-F.ay , Deloukas, P.az , Deuschl, G.ba , Dexter, D.T.bb , van Dijk, K.D.ai , Dillman, A.s , Durif, F.bc , Dürr, A.aa ab ac bd , Edkins, S.az , Evans, J.R.be , Foltynie, T.bf , Gao, J.aq , Gardner, M.u , Goate, A.bg , Gray, E.az , Gústafsson, Ó.bh bi , Harris, C.aw , van Hilten, J.J.bj , Hofman, A.bk , Hollenbeck, A.bl , Holton, J.bm , Hu, M.bn , Huang, X.bo , Huber, H.d , Hudson, G.ar , Hunt, S.E.az , Huttenlocher, J.bh , Illig, T.bp , Jónsson, P.V.bq , Lambert, J.-C.br bs , Langford, C.az be , Lees, A.bm , Lichtner, P.bt , Limousin, P.bu , Lopez, G.bv , Lorenz, D.ba , McNeill, A.au , Moorby, C.as , Moore, M.s , Morrison, K.E.as bx , Mudanohwo, E.by , O'Sullivan, S.S.bm , Pearson, J.bw , Perlmutter, J.S.bz , Pétursson, H.ao bh , Pollak, P.ca , Post, B.an , Potter, S.C.az , Ravina, B.cb , Revesz, T.bm , Riess, O.ao , Rivadeneira, F.cc , Rizzu, P.z , Ryten, M.u , Sawcer, S.J.cd de , Schapira, A.au , Scheffer, H.ce , Shaw, K.bm , Shoulson, I.cf , Sidransky, E.bv , Smith, C.cg , Spencer, C.C.A.ch , Steinberg, S.bh , Stockton, J.D.as , Strange, A.ch , Talbot, K.ci , Tanner, C.M.cj , Tashakkori-Ghanbaria, A.az , Tison, F.ck , Trabzuni, D.u , Traynor, B.J.s , Uitterlinden, A.G.cb , Velseboer, D.ak , Vidailhet, M.aa ab cl , Walker, R.cf , van de Warrenburg, B.an , Wickremaratchi, M.cm , Williams-Gray, C.H.ag , Winder-Rhodes, S.cn , Stefánsson, K.bh , Donnelly, P.ch co , Barroso, I.az , Blackwell, J.M.cp cq , Bramon, E.cr , Brown, M.A.cs , Casas, J.P.ct cu , Corvin, A.cv , Duncanson, A.cw , Jankowski, J.cx cy cz , Markus, H.S.da , Mathew, C.G.db , Palmer, C.N.A.dc , Plomin, R.dd , Rautanen, A.ch , Trembath, R.C.da , Viswanathan, A.C.df , Band, G.ch , Bellenguez, C.ch , Freeman, C.ch , Hellenthal, G.ch , Giannoulatou, E.ch , Pirinen, M.ch , Pearson, R.ch , Su, Z.ch , Vukcevic, D.ch , Gwilliam, R.az , Blackburn, H.az , Bumpstead, S.J.az , Dronov, S.az , Gillman, M.az , Hammond, N.az , Jayakumar, A.az , McCann, O.T.az , Liddle, J.az , Ravindrarajah, R.az , Ricketts, M.az , Waller, M.az , Weston, P.az , Widaa, S.az , Whittaker, P.az , McCarthy, M.I.dh
Using genome-wide complex trait analysis to quantify 'missing heritability' in Parkinson's disease
(2012) Human Molecular Genetics, 21 (22), art. no. dds335, pp. 4996-5009. 

a Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, United States
b Department of Biological Anthropology, Temple University, Philadelphia, PA, United States
c Institut National de la Sante et de la Recherche Medicale, UMR 1043, Centre de Physiopathologie de Toulouse-Purpan, Toulouse, France
d Paul Sabatier University, Toulouse, France
e Department of Molecular Neuroscience, Institute of Neurology, London, United Kingdom
f UCL Genetics Institute, University College London, London, United Kingdom
g deCODE genetics, Scientific Services, Sturlugata 8, IS-101 Reykjavik, Iceland
h Department of Clinical Genetics, Section of Medical Genomics, VU University Medical Centre, Amsterdam, Netherlands
i Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tubingen, Tübingen, Germany
j Deutsches Zentrum fur Neurodegenerative Erkrangungen, German Center for Neurodegenerative Diseases, Tubingen, Germany
k Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Cardiff, United Kingdom
l Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, United Kingdom
m Université Pierre et Marie Curie-Paris, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière, UMR-S975, Paris, France
n Département de Géné tique, AP-HP, Hô pital de la Salpê triè re, Paris, France
o Institut National de la Sante et de la Recherche Medicale, UMR-S975, Paris, France
p Centre National de la Recherche Scientifique, UMR-7225, Paris, France
q Department of Neurology, Turku University Hospital, University of Turku, Finland
r Department of Clinical Medicine, Neurology, University of Oulu, Finland
s Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, United States
t UCL Genetics Institute, London, United Kingdom
u Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom
v Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
w DZNE, German Center for Neurodegenerative Diseases, Tübingen, Germany
x INSERM U563, CPTP, Toulouse, France
y Paul Sabatier University, Toulouse, France
z Department of Clinical Genetics, Section of Medical Genomics, VU University Medical Centre, Amsterdam, Netherlands
aa INSERM, UMR-S975, Paris, France
ab Université Pierre et Marie Curie-Paris, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, Paris, France
ac CNRS, Paris, France
ad Department of Neurology, Landspítali University Hospital, Reykjavík, Iceland
ae Department of Neurology, MEHT Broomfield Hospital, Chelmsford, Essex, United Kingdom
af Queen Mary College, University of London, London, United Kingdom
ag Department of Neurology, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom
ah School of Social and Community Medicine, University of Bristol, United Kingdom
ai Department of Neurology and Alzheimer Center, VU University Medical Center, Netherlands
aj Department of Motor Neuroscience, UCL Institute of Neurology, United Kingdom
ak Department of Neurology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
al Center for Human Genetic Research and Department of Neurology, Massachusetts General Hospital, Boston, MA, United States
am Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, United States
an Department of Neurology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
ao Department of Medical Genetics, Institute of Human Genetics, University of Tübingen, Tübingen, Germany
ap Newcastle University Clinical Ageing Research Unit, Campus for Ageing and Vitality, Newcastle upon Tyne, United Kingdom
aq Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, NC, United States
ar Neurology M4104, The Medical School, Framlington Place, Newcastle upon Tyne, United Kingdom
as School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, United Kingdom
at Department of Neurology, City Hospital, Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, United Kingdom
au Department of Clinical Neurosciences, UCL Institute of Neurology, United Kingdom
av INSERM CIC-9503, Hôpital Pitié-Salpêtrière, Paris, France
aw University of Aberdeen, Division of Applied Health Sciences, Population Health Section, Aberdeen, United Kingdom
ax CHU Nantes, CIC0004, Service de Neurologie, Nantes, France
ay INSERM U897, Université Victor Segalen, Bordeaux, France
az Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom
ba Klinik für Neurologie, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Christian-Albrechts-Universität Kiel, Kiel, Germany
bb Parkinson's Disease Research Group, Faculty of Medicine, Imperial College London, London, United Kingdom
bc Service de Neurologie, Hôpital Gabriel Montpied, Clermont-Ferrand, France
bd AP-HP, Pitié-Salpêtrière Hospital, France
be Cambridge Centre for Brain Repair, Cambridge, United Kingdom
bf UCL Institute of Neurology, United Kingdom
bg Department of Psychiatry, Department of Neurology, Washington University School of Medicine, MI, United States
bh deCODE genetics, Iceland
bi Department of Psychiatry, Oslo University Hospital, N-0407 Oslo, Norway
bj Department of Neurology, Leiden University Medical Center, Leiden, Netherlands
bk Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands
bl AARP, Washington, DC, United States
bm Queen Square Brain Bank for Neurological Disorders, UCL Institute of Neurology, United Kingdom
bn Department of Clinical Neurology, John Radcliffe Hospital, Oxford, United Kingdom
bo Departments of Neurology, Radiology, Neurosurgery, Pharmacology, Kinesiology, and Bioengineering, Pennsylvania State University-Milton S. Hershey Medical Center, Hershey, PA, United States
bp Institute of Epidemiology, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany
bq Department of Geriatrics, Landspítali University Hospital, Reykjavík, Iceland
br INSERM U744, Lille, France
bs Institut Pasteur de Lille, Université de Lille Nord, Lille, France
bt Institute of Human Genetics, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany
bu Institute of Neurology, Sobell Department, Unit of Functional Neurosurgery, London, United Kingdom
bv Section on Molecular Neurogenetics, Medical Genetics Branch, NHGRI, National Institutes of Health, United States
bw MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, United Kingdom
bx Neurosciences Department, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
by Neurogenetics Unit, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, United Kingdom
bz Department of Neurology, Radiology, and Neurobiology, Washington University, St Louis, MO, United States
ca Service de Neurologie, CHU de Grenoble, Grenoble, France
cb Translational Neurology, Biogen Idec, MA, United States
cc Departments of Epidemiology and Internal Medicine, Erasmus University Medical Center, Netherlands
cd University of Cambridge, Department of Clinical Neurosciences, Addenbrooke's Hospital, Cambridge, United Kingdom
ce Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
cf Department of Neurology, University of Rochester, Rochester, NY, United States
cg Department of Pathology, University of Edinburgh, Edinburgh, United Kingdom
ch Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7LJ, United Kingdom
ci University of Oxford, Department of Clinical Neurology, John Radcliffe Hospital, Oxford, United Kingdom
cj Clinical Research Department, The Parkinson's Institute and Clinical Center, Sunnyvale, CA, United States
ck Service de Neurologie, Hôpital Haut-Lévêque, Pessac, France
cl UMR-7225, France
cm Department of Neurology, Cardiff University, Cardiff, United Kingdom
cn Department of Psychiatry and Medical Research Council, Wellcome Trust Behavioural and Clinical Neurosciences Institute, University of Cambridge, United Kingdom
co Department of Statistics, University of Oxford, Oxford OX1 3TG, United Kingdom
cp Telethon Institute for Child Health Research, Centre for Child Health Research, University of Western Australia, 100 Roberts Road, Subiaco, WA 6008, Australia
cq Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Cambridge CB2 0XY, United Kingdom
cr Department of Psychosis Studies, NIHR Biomedical Research Centre for Mental Health at the Institute of Psychiatry, King's College London and The South London and Maudsley NHS Foundation Trust, Denmark Hill, London SE5 8AF, United Kingdom
cs Diamantina Institute of Cancer, Immunology and Metabolic Medicine, Princess Alexandra Hospital, University of Queensland, Brisbane, QLD, Australia
ct Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London WC1E 7HT, United Kingdom
cu Department of Epidemiology and Public Health, University College London, London WC1E 6BT, United Kingdom
cv Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine, Trinity College Dublin, Dublin 2, Ireland
cw Molecular and Physiological Sciences, The Wellcome Trust, London NW1 2BE, United Kingdom
cx Centre for Digestive Diseases, Queen Mary University of London, London E1 2AD, United Kingdom
cy Digestive Diseases Centre, Leicester Royal Infirmary, Leicester LE7 7HH, United Kingdom
cz Department of Clinical Pharmacology, University of Oxford, Old Road Campus, Oxford OX3 7DQ, United Kingdom
da Clinical Neurosciences, St George's University of London, London SW17 0RE, United Kingdom
db King's College London, Department of Medical and Molecular Genetics, School of Medicine, Guy's Hospital, London SE1 9RT, United Kingdom
dc Biomedical Research Centre, Ninewells Hospital and Medical School, Dundee DD1 9SY, United Kingdom
dd King's College London Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Denmark Hill, London SE5 8AF, United Kingdom
de University of Cambridge Department of Clinical Neurosciences, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom
df NIHR Biomedical Research Centre for Ophthalmology, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London EC1V 2PD, United Kingdom
dg Department Molecular Neuroscience, Institute of Neurology, Queen Square, London WC1N 3BG, United Kingdom
dh Oxford Centre for Diabetes, Endocrinology and Metabolism (ICDEM), Churchill Hospital, Oxford OX3 7LJ, United Kingdom

Abstract
Genome-wide association studies (GWASs) have been successful at identifying single-nucleotide polymorphisms (SNPs) highly associated with common traits; however, a great deal of the heritable variation associated with common traits remains unaccounted for within the genome. Genome-wide complex trait analysis (GCTA) is a statistical method that applies a linear mixed model to estimate phenotypic variance of complex traits explained by genome-wide SNPs, including those not associated with the trait in a GWAS. We applied GCTA to 8 cohorts containing 7096 case and 19 455 control individuals of European ancestry in order to examine the missing heritability present in Parkinson's disease (PD). We meta-analyzed our initial results to produce robust heritability estimates for PD types across cohorts. Our results identify 27% (95% CI 17-38, P = 8.08E - 08) phenotypic variance associated with all types of PD, 15% (95% CI -0.2 to 33, P = 0.09) phenotypic variance associated with early-onset PD and 31% (95% CI 17-44, P = 1.34E - 05) phenotypic variance associated with late-onset PD. This is a substantial increase from the genetic variance identified by top GWAS hits alone (between 3 and 5%) and indicates there are substantially more risk loci to be identified. Our results suggest that although GWASs are a useful tool in identifying the most common variants associated with complex disease, a great deal of common variants of small effect remain to be discovered. © Published by Oxford University Press 2012.

Document Type: Article
Source: Scopus

 

Earhart, G.M., McNeely, M.E.
Response to "Does STN-DBS Improve Balance in Parkinson Disease?"

(2012) 
Parkinsonism and Related Disorders, . Article in Press. 

Program in Physical Therapy, Washington University School of Medicine, St. Louis, MO 63108, USA

Document Type: Article in Press
Source: Scopus

 

Malinzak, M.D.a b , Kay, R.F.a , Hullar, T.E.c
Locomotor head movements and semicircular canal morphology in primates
(2012) Proceedings of the National Academy of Sciences of the United States of America, 109 (44), pp. 17914-17919. 

a Department of Evolutionary Anthropology, Duke University, Durham, NC 27708, United States
b Department of Radiology, Duke University Medical Center, Durham, NC 27710, United States
c Department of Otolaryngology, Washington University, School of Medicine, Saint Louis, MO 63110, United States

Abstract
Animal locomotion causes head rotations, which are detected by the semicircular canals of the inner ear. Morphologic features of the canals influence rotational sensitivity, and so it is hypothesized that locomotion and canal morphology are functionally related. Most prior research has compared subjective assessments of animal "agility" with a single determinant of rotational sensitivity: the mean canal radius of curvature (R). In fact, the paired variables of R and body mass are correlated with agility and have been used to infer locomotion in extinct species. To refine models of canal functional morphology and to improve locomotor inferences for extinct species, we compare 3D vector measurements of head rotation during locomotion with 3D vector measures of canal sensitivity. Contrary to the predictions of conventional models that are based upon R, we find that axes of rapid head rotation are not aligned with axes of either high or low sensitivity. Instead, animals with fast head rotations have similar sensitivities in all directions, which they achieve by orienting the three canals of each ear orthogonally (i.e., along planes at 90° angles to one another). The extent to which the canal configuration approaches orthogonality is correlated with rotational head speed independent of body mass and phylogeny, whereas R is not.

Author Keywords
Angular velocity;  Vestibular

Document Type: Article
Source: Scopus

 

Harms, M.B.a c , Neumann, D.b , Benitez, B.A.b , Cooper, B.b , Carrell, D.b , Racette, B.A.a c , Perlmutter, J.S.a c d , Goate, A.b c , Cruchaga, C.b c
Parkinson disease is not associated with C9ORF72 repeat expansions
(2012) Neurobiology of Aging, . Article in Press. 

a Department of Neurology, Washington University School of Medicine, Saint Louis, MO, USA
b Hope Center for Neurological Disorders, Department of Neurology, Washington University School of Medicine, Saint Louis, MO, USA
c Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, USA
d Mallinckrodt Institute of Radiology, Neurobiology, Physical Therapy and Occupational Therapy, Saint Louis, MO, USA

Abstract
Hexanucleotide expansions in the C9ORF72 gene are frequently found in patients with amyotrophic lateral sclerosis, frontotemporal dementia or both, some of whom exhibit concurrent extrapyramidal symptoms. To determine if repeat expansions are a cause of Parkinson's disease (PD), we used repeat-primed polymerase chain reaction to investigate the frequency of C9ORF72 repeat expansions in a cohort of 478 patients with PD and 662 control subjects. Three control subjects were found to be expansion carriers, and no expansions were found among patients, suggesting that C9ORF72 expansions are not a common cause of PD. © 2012 Elsevier Inc. All rights reserved.

Author Keywords
C9ORF72;  Genetics;  Hexanucleotide repeat;  Parkinson disease

Document Type: Article in Press
Source: Scopus

 

Kliese, N.a , Gobrecht, P.a , Pachow, D.a , Andrae, N.a , Wilisch-Neumann, A.a , Kirches, E.a , Riek-Burchardt, M.b , Angenstein, F.c , Reifenberger, G.d , Riemenschneider, M.e , Meese, E.f , Panayotova-Dimitrova, D.g , Gutmann, D.H.h , Mawrin, C.a
miRNA-145 is downregulated in atypical and anaplastic meningiomas and negatively regulates motility and proliferation of meningioma cells
(2012) Oncogene, . Article in Press. 

a Institute of Neuropathology, Otto-von-Guericke University, Magdeburg, Germany
b Project Group Neuropharmacology, Leibniz-Institute for Neurobiology, Magdeburg, Germany
c Laboratory for Non-Invasive Animal Imaging, Leibniz-Institute for Neurobiology, Magdeburg, Germany
d Department of Neuropathology, Heinrich Heine University, Düsseldorf, Germany
e Department of Neuropathology, University of Regensburg, Regensburg, Germany
f Department of Human Genetics, Saarland University, Homburg/Saar, Germany
g Department of Dermatology, University of Heidelberg, Heidelberg, Germany
h Department of Neurology, Washington University School of Medicine, St Louis, MO, USA

Abstract
Meningiomas are frequent, mostly benign intracranial or spinal tumors. A small subset of meningiomas is characterized by histological features of atypia or anaplasia that are associated with more aggressive biological behavior resulting in increased morbidity and mortality. Infiltration into the adjacent brain tissue is a major factor linked to higher recurrence rates. The molecular mechanisms of progression, including brain invasion are still poorly understood. We have studied the role of micro-RNA 145 (miR-145) in meningiomas and detected significantly reduced miR-145 expression in atypical and anaplastic tumors as compared with benign meningiomas. Overexpression of miR-145 in IOMM-Lee meningioma cells resulted in reduced proliferation, increased sensitivity to apoptosis, reduced anchorage-independent growth and reduction of orthotopic tumor growth in nude mice as compared with control cells. Moreover, meningioma cells with high miR-145 levels had impaired migratory and invasive potential in vitro and in vivo. PCR-array studies of miR145-overexpressing cells suggested that collagen type V alpha (COL5A1) expression is downregulated by miR-145 overexpression. Accordingly, COL5A1 expression was significantly upregulated in atypical and anaplastic meningiomas. Collectively, our data indicate an important anti-migratory and anti-proliferative function of miR-145 in meningiomas.Oncogene advance online publication, 29 October 2012; doi:10.1038/onc.2012.468.

Document Type: Article in Press
Source: Scopus

 

Wilson, J., Buchowski, J.M.
Post-traumatic deformity: Prevention and management
(2012) Handbook of Clinical Neurology, 109, pp. 369-384. 

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

Abstract
Traumatic spinal column injuries (SCI) can result in devastating deformities that often have long-term impact on the patient's quality of life. These deformities result in pain and occasionally neurological deficits. The deformities affecting adults often differ slightly from those in the pediatric population. In adults, injuries to the spinal column frequently result in a sagittal plane deformity, such as kyphosis or lordosis. However, in children, spinal cord injuries often cause coronal deformities, such as scoliosis. Patients with post-traumatic spinal column deformities may present acutely immediately after the injury, many years after the inciting event, or at any time in-between. Patients with post-traumatic spinal deformity initially complain of pain at the site of the deformity, but with time may complain of pain above or below the deformity as a result of degenerative changes. Any change or worsening of neurological status is a worrisome complaint, and often these patients require surgical intervention. Procedures such as fusions and spinal column osteotomies have shown promising results in treating patients with post-traumatic spinal deformities and have been shown to improve their quality of life. © 2012 Elsevier B.V.

Document Type: Article
Source: Scopus

 

Sakiyama-Elbert, S.a , Johnson, P.J.a , Hodgetts, S.I.b c , Plant, G.W.b c d , Harvey, A.R.b
Scaffolds to promote spinal cord regeneration
(2012) Handbook of Clinical Neurology, 109, pp. 575-594. 

a Department of Biomedical Engineering, Washington University, St. Louis, MO, United States
b School of Anatomy Physiology and Human Biology, University of Western Australia, Nedlands, Australia
c Spinal Cord Repair Laboratory, University of Western Australia, Nedlands, Australia
d Stanford Partnership for Spinal Cord Injury and Repair, Stanford Institute for Neuro-Innovation and Translational Neurosciences, Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, United States

Abstract
Substantial research effort in the spinal cord injury (SCI) field is directed towards reduction of secondary injury changes and enhancement of tissue sparing. However, pathway repair after complete transections, large lesions, or after chronic injury may require the implantation of some form of oriented bridging structure to restore tissue continuity across a trauma zone. These matrices or scaffolds should be biocompatible and create an environment that facilitates tissue growth and vascularization, and allow axons to regenerate through and beyond the implant in order to reconnect with " normal" tissue distal to the injury. The myelination of regrown axons is another important requirement. In this chapter, we describe recent advances in biomaterial technology designed to provide a terrain for regenerating axons to grow across the site of injury and/or create an environment for endogenous repair. Many different types of scaffold are under investigation; they can be biodegradable or nondegradable, natural or synthetic. Scaffolds can be designed to incorporate immobilized signaling molecules and/or used as devices for controlled release of therapeutic agents, including growth factors. These bridging structures can also be infiltrated with specific cell types deemed suitable for spinal cord repair. © 2012 Elsevier B.V.

Document Type: Article
Source: Scopus

 

Juknis, N.a , Cooper, J.M.b , Volshteyn, O.a
The changing landscape of spinal cord injury
(2012) Handbook of Clinical Neurology, 109, pp. 149-166. 

a Spinal Cord Injury Rehabilitation Section, Neurorehabilitation Division, Department of Neurology, Washington University, St. Louis, MO, United States
b Physical Medicine and Rehabilitation, NW Center for Integrative Medicine, Tacoma, WA, United States

Abstract
In the past quarter century, spinal cord injury medicine has welcomed the proliferation of new medications and technologies that improve the survival and quality of life for people with spinal cord injury, but also endured the failure of strategies we hoped would salvage the cord in the acute phase. Surgical decompression and spinal stabilization should be pursued whenever indicated and feasible; however, there is no compelling evidence that early decompression facilitates neurological improvement. Methylprednisolone, the subject of over two decades of trials, has proven to be of marginal benefit in improving functional outcome.Recent advances in the management of the respiratory, cardiovascular, autonomic, endocrine, skeletal and integumentary systems have not only changed morbidity and survival of spinal cord injury patients but also improved quality of life.Progress has been made in the early diagnosis and effective treatment of cardiac arrhythmias, neurogenic shock, autonomic dysreflexia and orthostatic hypotension. Aggressive respiratory care for high cervical level of injury patients should include an option for phrenic nerve pacing as it is a viable rehabilitative strategy for appropriately selected patients. Pressure ulcers remain a significant psychological, financial, and functional burden for many people with SCI and for healthcare providers. This area will continue to require further work on early prevention and education. Despite extensive scientific and clinical data on neurogenic osteoporosis, there is no consensus regarding the best pharmacotherapeutic agents, dosing regimens, or rehabilitative strategies for prevention and treatment of bone loss. This chapter will focus on the advances. © 2012 Elsevier B.V.

Document Type: Article
Source: Scopus

 

Jin, Y.N.a , Chen, P.-C.a e , Watson, J.A.a , Walters, B.J.a f , Phillips, S.E.a , Green, K.b , Schmidt, R.b , Wilson, J.A.a , Johnson, G.V.c , Roberson, E.D.d , Dobrunz, L.E.a , Wilson, S.M.a
Usp14 Deficiency Increases Tau Phosphorylation without Altering Tau Degradation or Causing Tau-Dependent Deficits
(2012) PLoS ONE, 7 (10), art. no. e47884, . 

a Department of Neurobiology, Civitan International Research Center, University of Alabama at Birmingham, Birmingham, AL, United States
b Division of Neuropathology, Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, United States
c Department of Anesthesiology, University of Rochester, Rochester, NY, United States
d Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, United States
e Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, United States
f Department of Developmental Biology, St. Jude Children's Research Hospital, Memphis, TN, United States

Abstract
Regulated protein degradation by the proteasome plays an essential role in the enhancement and suppression of signaling pathways in the nervous system. Proteasome-associated factors are pivotal in ensuring appropriate protein degradation, and we have previously demonstrated that alterations in one of these factors, the proteasomal deubiquitinating enzyme ubiquitin-specific protease 14 (Usp14), can lead to proteasome dysfunction and neurological disease. Recent studies in cell culture have shown that Usp14 can also stabilize the expression of over-expressed, disease-associated proteins such as tau and ataxin-3. Using Usp14-deficient ax J mice, we investigated if loss of Usp14 results in decreased levels of endogenous tau and ataxin-3 in the nervous system of mice. Although loss of Usp14 did not alter the overall neuronal levels of tau and ataxin-3, we found increased levels of phosphorylated tau that correlated with the onset of axonal varicosities in the Usp14-deficient mice. These changes in tau phosphorylation were accompanied by increased levels of activated phospho-Akt, phosphorylated MAPKs, and inactivated phospho-GSK3β. However, genetic ablation of tau did not alter any of the neurological deficits in the Usp14-deficient mice, demonstrating that increased levels of phosphorylated tau do not necessarily lead to neurological disease. Due to the widespread activation of intracellular signaling pathways induced by the loss of Usp14, a better understanding of the cellular pathways regulated by the proteasome is required before effective proteasomal-based therapies can be used to treat chronic neurological diseases. © 2012 Jin et al.

Document Type: Article
Source: Scopus

 

Kidokoro, H.a b c , Kubota, T.b , Hayakawa, M.c , Kato, Y.b , Okumura, A.d
Neonatal seizure identification on reduced channel EEG
(2012) Archives of Disease in Childhood: Fetal and Neonatal Edition, . Article in Press. 

a Department of Pediatrics, Washington University in St. Louis, St. Louis, Missouri, USA
b Department of Pediatrics, Anjo Kosei Hospital, Anjo, Japan
c Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
d Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan

Abstract
Using a standard digital EEG system, we conducted simulations to determine the optimal locations and numbers of electrodes for seizure detection in neonates with reduced-channel EEG monitoring. The results showed that C3-C4 should be selected for a one-channel recording, but two-channel seizure monitoring is recommended for increased accuracy. Copyright Article author (or their employer) 2012.

Document Type: Article in Press
Source: Scopus

 

Sato, C.a , Turkoz, M.a , Dearborn, J.T.b , Wozniak, D.F.b , Kopan, R.a , Hass, M.R.a
Loss of RBPj in Postnatal Excitatory Neurons Does Not Cause Neurodegeneration or Memory Impairments in Aged Mice
(2012) PLoS ONE, 7 (10), art. no. e48180, . 

a Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Previous studies suggest that loss of γ-secretase activity in postnatal mouse brains causes age-dependent memory impairment and neurodegeneration. Due to the diverse array of γ-secretase substrates, it remains to be demonstrated whether loss of cleavage of any specific substrate(s) is responsible for these defects. The bulk of the phenotypes observed in mammals deficient for γ-secretase or exposed to γ-secretase inhibitors are caused by the loss of Notch receptor proteolysis. Accordingly, inhibition of Notch signaling is the main cause for untoward effects for γ-secretase inhibitors as therapeutics for Alzheimer's disease. Therefore, we wished to determine if loss of canonical Notch signaling is responsible for the age-dependent neurodegeneration observed upon γ-secrectase deficiency in the mouse brain. We generated postnatal forebrain-specific RBPj conditional knockout (cKO) mice using the CamKII-Cre driver and examined behavior and brain pathology in 12-18 month old animals. Since all four mammalian Notch receptor homologues signal via this DNA binding protein, these mice lack canonical Notch signaling. We found that loss of RBPj in mature excitatory neurons was well tolerated, with no evidence for neurodegeneration or of learning and memory impairment in mice aged up to 18 months. The only phenotypic deficit we observed in the RBPj-deficient mice was a subtle abnormality in olfactory preferences, particularly in females. We conclude that the loss of canonical Notch signaling through the four receptors is not responsible for age-dependent neurodegeneration or learning and memory deficits seen in γ-secretase deficient mice. © 2012 Sato et al.

Document Type: Article
Source: Scopus

 

Hashimoto, T.a , Serrano-Pozo, A.a , Hori, Y.a , Adams, K.W.a , Takeda, S.a , Banerji, A.O.a , Mitani, A.a , Joyner, D.a , Thyssen, D.H.a , Bacskai, B.J.a , Frosch, M.P.a , Spires-Jones, T.L.a , Finn, M.B.b , Holtzman, D.M.a , Hyman, B.T.a
Apolipoprotein e, especially apolipoprotein E4, increases the oligomerization of amyloid β peptide

(2012) Journal of Neuroscience, 32 (43), pp. 15181-15192. 

a Department of Neurology, Alzheimer's Disease Research Unit, Massachusetts General Hospital, Charlestown, MA 02129, United States
b Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Alzheimer's disease (AD) is the most common progressive neurodegenerative disorder causing dementia. Massive deposition of amyloid β peptide (Aβ) as senile plaques in the brain is the pathological hallmark of AD, but oligomeric, soluble forms of Aβ have been implicated as the synaptotoxic component. The apolipoprotein E ε4 (apoE ε4) allele is known to be a genetic risk factor for developing AD. However, it is still unknown how apoE impacts the process of Aβ oligomerization. Here, we found that the level of Aβ oligomers in APOE ε4/ ε4AD patient brains is 2.7 times higher than those in APOE ε3/ε3 AD patient brains, matched for total plaque burden, suggesting that apoE4 impacts the metabolism of Aβ oligomers. To test this hypothesis, we examined the effect of apoE on Aβ oligomer formation. Using both synthetic Aβ and a split-luciferase method for monitoringAβ oligomers, we observed that apoE increased the level of Aβ oligomers in an isoform-dependent manner (E2<E3<E4). This effect appears to be dependent on the ApoE C-terminal domain. Moreover, these results were confirmed using endogenous apoE isolated from the TBS-soluble fraction of human brain, which increased the formation of Aβ oligomers. Together, these data show that lipidated apoE, especially apoE4, increases Aβ oligomers in the brain. Higher levels of Aβ oligomers in the brains of APOE ε4/ε4 carriers compared with APOE ε3/ε3 carriers may increase the loss of dendritic spines and accelerate memory impairments, leading to earlier cognitive decline in AD. © 2012 the authors.

Document Type: Article
Source: Scopus

 

Marre, O.a , Amodei, D.a , Deshmukh, N.a , Sadeghi, K.a c , Soo, F.a , Holy, T.E.d , Berry II, M.J.a b
Mapping a complete neural population in the retina
(2012) Journal of Neuroscience, 32 (43), pp. 14859-14873. 

a Department of Molecular Biology, Princeton, NJ 08544, United States
b Princeton Neuroscience Institute, Princeton, NJ 08544, United States
c Center for Theoretical Neuroscience, Columbia University, New York, NY 10027, United States
d Department of Anatomy and Neurobiology, Washington University in St. Louis, St. Louis, MO 63130, United States

Abstract
Recording simultaneously from essentially all of the relevant neurons in a local circuit is crucial to understand how they collectively represent information. Here we show that the combination of a large, dense multielectrode array and a novel, mostly automated spikesorting algorithm allowed us to record simultaneously from a highly overlapping population of >200 ganglion cells in the salamander retina. By combining these methods with labeling and imaging, we showed that up to 95% of the ganglion cells over the area of the array were recorded. By measuring the coverage of visual space by the receptive fields of the recorded cells, we concluded that our technique captured a neural population that forms an essentially complete representation of a region of visual space. This completeness allowed us to determine the spatial layout of different cell types as well as identify a novel group of ganglion cells that responded reliably to a set of naturalistic and artificial stimuli but had no measurable receptive field. Thus, our method allows unprecedented access to the complete neural representation of visual information, a crucial step for the understanding of population coding in sensory systems. © 2012 the authors.

Document Type: Article
Source: Scopus

 

Hart, S.J.a , Lucena, N.a b , Cleary, K.M.a , Belger, A.a , Donkers, F.C.L.a
Modulation of early and late 1 event-related potentials by emotion
(2012) Frontiers in Integrative Neuroscience, (OCTOBER 2012), pp. 1-26. 

a Department of Psychiatry, University of North Carolina, Chapel Hill School of Medicine, Chapel Hill, NC, United States
b Department of Psychology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Although emotionally salient stimuli influence higher order information processing, the relative vulnerability of specific stages of cognitive processing to modulation by emotional input remains elusive. To test the temporal dynamics of emotional interference during executive function, we recorded event-related potentials while participants performed an effortful anticipation task with aversive emotional and neutral distracters. Participants were presented with a modified delayed Stroop task that dissociated the anticipation of an easier or more difficult task (instructional cues to attend to word versus color) from the response to the Stroop stimulus, while aversive and neutral pictures were displayed during the delay period. Our results indicated a relative decrease in the amplitude of the contingent negative variation (CNV) during aversive trials that was greater during the early anticipatory phase than during the later response preparation phase, and greater during (the more difficult) color than word trials. During the initial stage of cue processing, there was also significant interaction between emotion and anticipatory difficulty on N1 amplitude, where emotional stimuli led to significantly enhanced negativity during color cues relative to word cues. These results suggest that earlier processes of orientation and effortful anticipation may reflect executive engagement that is influenced by emotional interference while later phases of response preparation may be modulated by emotional interference regardless of anticipatory difficulty. © 2012 Hart, Lucena, Cleary, Belger and Donkers.

Author Keywords
Anticipation;  Contingent negative variation;  Distraction;  Emotion

Document Type: Article
Source: Scopus

 

Wang, L.a , Roe, C.M.a b , Snyder, A.Z.a c , Brier, M.R.a , Thomas, J.B.a , Xiong, C.b d , Benzinger, T.L.b c , Morris, J.C.a b , Ances, B.M.a
Alzheimer disease family history impacts resting state functional connectivity
(2012) Annals of Neurology, 72 (4), pp. 571-577. 

a Department of Neurology, Washington University in Saint Louis, Box 8111, 660 South Euclid Ave, Saint Louis, MO 63110, United States
b Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University in Saint Louis, Saint Louis, MO, United States
c Department of Radiology, Washington University in Saint Louis, Saint Louis, MO, United States
d Division of Biostatistics, Washington University in Saint Louis, Saint Louis, MO, United States

Abstract
Objective: Offspring whose parents have Alzheimer disease (AD) are at increased risk for developing dementia. Patients with AD typically exhibit disruptions in the default mode network (DMN). The aim of this study was to investigate the effect of a family history of late onset AD on DMN integrity in cognitively normal individuals. In particular, we determined whether a family history effect is detectable in apolipoprotein E (APOE) ε4 allele noncarriers. Methods: We studied a cohort of 348 cognitively normal participants with or without family history of late onset AD. DMN integrity was assessed by resting state functional connectivity magnetic resonance imaging. Results: A family history of late onset AD was associated with reduced resting state functional connectivity between particular nodes of the DMN, namely the posterior cingulate and medial temporal cortex. The observed functional connectivity reduction was not attributable to medial temporal structural atrophy. Importantly, we detected a family history effect on DMN functional connectivity in APOE ε4 allele noncarriers. Interpretation: Unknown genetic factors, embodied in a family history of late onset AD, may affect DMN integrity prior to cognitive impairment. ANN NEUROL 2012;72:571-577 Copyright © 2012 American Neurological Association.

Document Type: Article
Source: Scopus

 

Ortinau, C.a , Inder, T.a b c , Lambeth, J.a , Wallendorf, M.d , Finucane, K.e , Beca, J.f
Congenital heart disease affects cerebral size but not brain growth
(2012) Pediatric Cardiology, 33 (7), pp. 1138-1146. 

a Department of Pediatrics, St. Louis Children's Hospital, Washington University in St Louis, St. Louis, MO 63110, United States
b Department of Neurology, Washington University in St Louis, St. Louis, MO 63110, United States
c Mallinkrodt Institute of Radiology, Washington University in St. Louis, St. Louis, MO 63110, United States
d Washington University in St. Louis, St. Louis, MO 63110, United States
e Department of Pediatric Cardiac Surgery, Starship Children's Hospital, Auckland, New Zealand
f Pediatric Intensive Care Unit, Starship Children's Hospital, Auckland, New Zealand

Abstract
Infants with congenital heart disease (CHD) have delayed brain maturation and alterations in brain volume. Brain metrics is a simple measurement technique that can be used to evaluate brain growth. This study used brain metrics to test the hypothesis that alterations in brain size persist at 3 months of age and that infants with CHD have slower rates of brain growth than control infants. Fifty-seven infants with CHD underwent serial brain magnetic resonance imaging (MRI). To evaluate brain growth across the first 3 months of life, brain metrics were undertaken using 19 tissue and fluid spaces shown on MRIs performed before surgery and again at 3 months of age. Before surgery, infants with CHD have smaller frontal, parietal, cerebellar, and brain stem measures (p<0.001). At 3 months of age, alterations persisted in all measures except the cerebellum. There was no difference between control and CHD infants in brain growth. However, the cerebellum trended toward greater growth in infants with CHD. Somatic growth was the primary factor that related to brain growth. Presence of focal white matter lesions before and after surgery did not relate to alterations in brain size or growth. Although infants with CHD have persistent alterations in brain size at 3 months of age, rates of brain growth are similar to that of healthy term infants. Somatic growth was the primary predictor of brain growth, emphasizing the importance of optimal weight gain in this population. © Springer Science+Business Media, LLC 2012.

Author Keywords
Brain;  Congenital heart disease;  Growth;  Magnetic resonance imaging

Document Type: Article
Source: Scopus

 

Jagadeesan, B.D.a , Cross III, D.T.a b , Delgado Almandoz, J.E.a , Derdeyn, C.P.a b c , Loy, D.N.a , McKinstry, R.C.a , Benzinger, T.L.S.a , Moran, C.J.a b
Susceptibility-weighted imaging: A new tool in the diagnosis and evaluation of abnormalities of the vein of galen in children
(2012) American Journal of Neuroradiology, 33 (9), pp. 1747-1751. 

a Section of Neuroradiology, Mallinckrodt Institute of Radiology, Washington University, Saint Louis, MO, United States
b Department of Neurological Surgery, Washington University, Saint Louis, MO, United States
c Department of Neurology, Washington University, Saint Louis, MO, United States

Abstract
We retrospectively identified 9 consecutive children, 3 males and 6 females (age 5.2 ± 6.3 years, range 1 day to 18 years), with known or suspected AVGs who underwent MR imaging, including SWI, at our institution between January 2007 and March 2011. On the SWI sequence, arterialized blood flow was considered to be present in the vein of Galen or its tributaries when these showed abnormal signal hyperintensity from arteriovenous shunting. SWI findings were correlated with findings from DSA studies or findings from time-of-flight or contrast-enhanced MR angiography sequences. SWI was found to accurately differentiate between high-flow and low-flow AVGs and was also useful in characterizing the arterial supply and venous drainage patterns associated with high-flow AVGs.

Document Type: Article
Source: Scopus

 

Cross, A.H., Cross, K.A., Piccio, L.
Update on multiple sclerosis, its diagnosis and treatments
(2012) Clinical Chemistry and Laboratory Medicine, 50 (7), pp. 1203-1210. 

Department of Neurology, Washington University, School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, United States

Abstract
Multiple sclerosis (MS) is a central nervous system disorder, characterized by mononuclear cell inflammation, demyelination and often with extensive axonal injury. It was first described neuropathologically in the late 1800s. MS has an interesting geographical epidemiology, with a higher rate at latitudes further from the equator in both directions. Women outnumber males by about 2:1; this ratio has been increasing in recent years. Genome wide association studies have thus far identified over 50 genetic susceptibility loci, and these are rapidly expanding. Several environmental risk factors have been identified, including low serum vitamin D levels, exposure to Epstein-Barr virus and cigarette smoking. MS displays a heterogeneous disease course; most patients with the disease begin with a relapsing-remitting course, but often eventually develop steady disability progression. A small percentage of MS patients have a progressive course without clinical relapses. Several treatments are now available to decrease relapse rate and slow the accumulation of disability in patients with relapsing MS, but there is currently no effective treatment to slow the progressive forms of MS. © 2012 by Walter de Gruyter • Berlin • Boston.

Author Keywords
Autoimmunity;  Cerebrospinal fluid;  Magnetic resonance imaging;  Multiple sclerosis;  Oligoclonal bands

Document Type: Review
Source: Scopus