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WUSTL Neuroscience Publications Archive - January 2015

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January 29, 2015

Guilliams, K.P.a b d , Fields, M.E.c , Hulbert, M.L.c
Higher-than-expected prevalence of silent cerebral infarcts in children with hemoglobin SC disease
(2015) Blood, 125 (2), pp. 416-417. 


a Division of Pediatric and Developmental Neurology, Department of Neurology, United States
b Division of Critical Care, Department of Pediatrics, Washington University School of MedicineSt. Louis, MO, United States
c Division of Hematology and Oncology, Department of Pediatrics, Washington University School of MedicineSt. Louis, MO, United States
d Department of Neurology, Department of Pediatrics, Washington University in St. Louis School of Medicine, 660 South Euclid Ave, Box 8111St. Louis, MO, United States


Document Type: Article
Source: Scopus




Kass, A.E.a , Wang, A.Z.b , Kolko, R.P.a , Holland, J.C.b , Altman, M.a , Trockel, M.c , Barr Taylor, C.c , Wilfley, D.E.a b
Identification as overweight by medical professionals: Relation to eating disorder diagnosis and risk
(2015) Eating Behaviors, 17, pp. 62-68. 


a Department of Psychology, Washington University in St. Louis, 660 South Euclid Avenue Campus Box 8134St. Louis, MO, United States
b Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue Campus Box 8134St. Louis, MO, United States
c Department of Psychiatry, Stanford University School of Medicine, 401 Quarry RoadStanford, CA, United States


Abstract
Purpose: Discussions about weight between medical professionals and young adults may increase risk of eating disorders (EDs). Clarifying the relation between screening for overweight and ED risk is needed. Methods: 548 college-age women were classified as at-risk (n= 441) or with an ED (n= 107), and were assessed for disordered eating attitudes, behaviors, and relevant history, including, "Has a doctor, nurse, or other medical professional ever told you that you were overweight?" Regression analyses were used to evaluate the relations between being identified as overweight and current disordered eating behaviors, attitudes, and ED diagnosis, without and with covariates (history of weight-related teasing, history of an ED, family history of being identified as overweight, and current body mass index). Results: 146 (26.6%) women reported being previously identified as overweight by a medical professional. There was no relation between being previously identified as overweight and having an ED. Those identified as overweight were more likely to have weight/shape concerns above a high-risk cutoff, but showed no difference in dietary restraint, binge eating, purging behaviors, or excessive exercise compared to those not identified. Conclusions: Being previously identified as overweight by a medical professional was associated with increased weight/shape concerns but not with current disordered eating behaviors or ED status. Minimizing the potential negative effects of overweight screening on weight and shape concerns by providing patients with strategies to increase healthy lifestyle behaviors and long-term support for healthy weight loss goals may have a positive impact on reducing the public health problem of overweight and obesity.


Author Keywords
Eating disorder risk;  Intervention;  Obesity;  Overweight;  Screening


Document Type: Article
Source: Scopus




Mooshagian, E.a b d , Keisler, A.a b , Zimmermann, T.a b , Schweickert, J.M.c , Wassermann, E.M.a
Modulation of corticospinal excitability by reward depends on task framing
(2015) Neuropsychologia, 68, pp. 31-37. 


a Behavioral Neurology Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 10 CENTER DR, MSC 1440Bethesda, MD, United States
b Center for Neuroscience and Regenerative Medicine, Uniformed Services University of Health Sciences, Henry M. Jackson FoundationRockville, MD, United States
c The Wake Kendall Group, PLLC, 5247 Wisconsin Avenue NW, Suite 4Washington, DC, United States
d Department of Anatomy and Neurobiology, Washington University School of MedicineSaint Louis, MO, United States


Abstract
Findings from previous transcranial magnetic stimulation (TMS) experiments suggest that the primary motor cortex (M1) is sensitive to reward conditions in the environment. However, the nature of this influence on M1 activity is poorly understood. The dopamine neuron response to conditioned stimuli encodes reward probability and outcome uncertainty, or the extent to which the outcome of a situation is known. Reward uncertainty and probability are related: uncertainty is maximal when probability is 0.5 and minimal when probability is 0 or 1 (i.e., certain outcome). Previous TMS-reward studies did not examine these factors independently. Here, we used single-pulse TMS to measure corticospinal excitability in 40 individuals while they performed a simple computer task, making guesses to find or avoid a hidden target. The task stimuli implied three levels of reward probability and two levels of uncertainty. We found that reward probability level interacted with the trial search condition. That is, motor evoked potential (MEP) amplitude, a measure of corticospinal neuron excitability, increased with increasing reward probability when participants were instructed to "find" a target, but not when they were instructed to "avoid" a target. There was no effect of uncertainty on MEPs. Response times varied with the number of choices. A subset of participants also received paired-pulse stimulation to evaluate changes in short-intracortical inhibition (SICI). No effects of SICI were observed. Taken together, the results suggest that the reward-contingent modulation of M1 activity reflects reward probability or a related aspect of utility, not outcome uncertainty, and that this effect is sensitive to the conceptual framing of the task.


Author Keywords
Corticospinal excitability;  Expectation;  Reward probability;  Transcranial magnetic stimulation;  Uncertainty


Document Type: Article
Source: Scopus




Springer, S.J.a c , Burkett, B.J.a , Schrader, L.A.a b
Modulation of BK channels contributes to activity-dependent increase of excitability through MTORC1 activity in CA1 pyramidal cells of mouse hippocampus
(2015) Frontiers in Cellular Neuroscience, 8 (JAN), art. no. 451, 12 p. 


a Tulane UniversityNew Orleans, LA, United States
b Department of Cell and Molecular Biology, Tulane UniversityNew Orleans, LA, United States
c McDonnell Sciences, Washington UniversitySt. Louis, MO, United States


Abstract
Memory acquisition and synaptic plasticity are accompanied by changes in the intrinsic excitability of CA1 pyramidal neurons. These activity-dependent changes in excitability are mediated by modulation of intrinsic currents which alters the responsiveness of the cell to synaptic inputs. The afterhyperpolarization (AHP), a major contributor to the regulation of neuronal excitability, is reduced in animals that have acquired several types of hippocampus-dependent memory tasks and also following synaptic potentiation by high frequency stimulation. BK channels underlie the fast AHP and contribute to spike repolarization, and this AHP is reduced in animals that successfully acquired trace-eyeblink conditioning. This suggests that BK channel function is activity-dependent, but the mechanisms are unknown. In this study, we found that blockade of BK channels with paxilline (10 μM) decreased IAHP amplitude and increased spike half-width and instantaneous frequency in response to a +100 pA depolarization. In addition, induction of long term potentiation (LTP) by theta burst stimulation (TBS) in CA1 pyramidal neurons reduced BK channel’s contribution to IAHP, spike repolarization, and instantaneous frequency. This result indicates that BK channel activity is decreased following synaptic potentiation. Interestingly, blockade of mammalian target of rapamycin (MTORC1) with rapamycin (400 nM) following synaptic potentiation restored BK channel function, suggesting a role for protein translation in signaling events which decreased postsynaptic BK channel activity following synaptic potentiation.


Author Keywords
Afterhyperpolarization;  Instantaneous frequency;  Rapamycin;  Theta burst stimulation;  Whole cell patch clamp


Document Type: Article
Source: Scopus




Cusack, R.a , Vicente-Grabovetsky, A.b , Mitchell, D.J.c , Wild, C.J.a , Auer, T.c , Linke, A.C.a , Peelle, J.E.d
Automatic analysis (aa): Efficient neuroimaging workflows and parallel processing using Matlab and XML
(2015) Frontiers in Neuroinformatics, 8 (JAN), 13 p. 


a Brain and Mind Institute, Western UniversityLondon, ON, Canada
b Donders Institute for Brain, Cognition and BehaviourNijmegen, Netherlands
c MRC Cognition and Brain Sciences UnitCambridge, United Kingdom
d Department of Otolaryngology, Washington University in St. LouisSt. Louis, MO, United States


Abstract
Recent years have seen neuroimaging data sets becoming richer, with larger cohorts of participants, a greater variety of acquisition techniques, and increasingly complex analyses. These advances have made data analysis pipelines complicated to set up and run (increasing the risk of human error) and time consuming to execute (restricting what analyses are attempted). Here we present an open-source framework, automatic analysis (aa), to address these concerns. Human efficiency is increased by making code modular and reusable, and managing its execution with a processing engine that tracks what has been completed and what needs to be (re)done. Analysis is accelerated by optional parallel processing of independent tasks on cluster or cloud computing resources. A pipeline comprises a series of modules that each perform a specific task. The processing engine keeps track of the data, calculating a map of upstream and downstream dependencies for each module. Existing modules are available for many analysis tasks, such as SPM-based fMRI preprocessing, individual and group level statistics, voxel-based morphometry, tractography, and multi-voxel pattern analyses (MVPA). However, aa also allows for full customization, and encourages efficient management of code: new modules may be written with only a small code overhead. aa has been used by more than 50 researchers in hundreds of neuroimaging studies comprising thousands of subjects. It has been found to be robust, fast, and efficient, for simple-single subject studies up to multimodal pipelines on hundreds of subjects. It is attractive to both novice and experienced users. aa can reduce the amount of time neuroimaging laboratories spend performing analyses and reduce errors, expanding the range of scientific questions it is practical to address.


Author Keywords
Diffusion tensor imaging (DTI);  Diffusion weighted imaging (DWI);  Functional magnetic resonance imaging (fMRI);  Multi-voxel pattern analysis (MVPA);  Neuroimaging;  Pipeline;  Software


Document Type: Article
Source: Scopus




Greenberg, J.K., Yarbrough, C.K., Radmanesh, A., Godzik, J., Yu, M., Jeffe, D.B., Smyth, M.D., Park, T.S., Piccirillo, J.F., Limbrick, D.D.
The Chiari Severity Index: A Preoperative Grading System for Chiari Malformation Type 1
(2015) Neurosurgery, . Article in Press. 


Departments of *Neurological Surgery, ‡Otolaryngology, and §Medicine, ¶Mallincrodt Institute of Radiology, Washington University School of Medicine in St. Louis, St. Louis, Missouri.


Abstract
BACKGROUND:: To develop evidence-based treatment guidelines for Chiari malformation type 1 (CM-1), preoperative prognostic indices capable of stratifying patients for comparative trials are needed.

OBJECTIVE:: To develop a preoperative Chiari Severity Index (CSI) integrating the clinical and neuroimaging features most predictive of long-term patient-defined improvement in quality of life (QOL) after CM-1 surgery.

METHODS:: We recorded preoperative clinical (eg, headaches, myelopathic symptoms) and neuroimaging (eg, syrinx size, tonsillar descent) characteristics. Brief follow-up surveys were administered to assess overall patient-defined improvement in QOL. We used sequential sequestration to develop clinical and neuroimaging grading systems and conjunctive consolidation to integrate these indices to form the CSI. We evaluated statistical significance using the Cochran-Armitage test and discrimination using the C statistic.

RESULTS:: Our sample included 158 patients. Sequential sequestration identified headache characteristics and myelopathic symptoms as the most impactful clinical parameters, producing a clinical grading system with improvement rates ranging from 81% (grade 1) to 58% (grade 3) (P = .01). Based on sequential sequestration, the neuroimaging grading system included only the presence (55% improvement) or absence (74% improvement) of a syrinx ≥6 mm (P = .049). Integrating the clinical and neuroimaging indices, improvement rates for the CSI ranged from 83% (grade 1) to 45% (grade 3) (P = .002). The combined CSI had moderately better discrimination (c = 0.66) than the clinical (c = 0.62) or neuroimaging (c = 0.58) systems alone.

CONCLUSION:: Integrating clinical and neuroimaging characteristics, the CSI is a novel tool that predicts patient-defined improvement after CM-1 surgery. The CSI may aid preoperative counseling and stratify patients in comparative effectiveness trials.

ABBREVIATIONS:: CM-1, Chiari malformation type 1CSI, Chiari Severity IndexQOL, quality of life


Document Type: Article in Press
Source: Scopus




Woehrer, A.a v , Lau, C.C.b , Prayer, D.c , Bauchet, L.d , Rosenfeld, M.e , Capper, D.f , Fisher, P.G.g , Kool, M.f , Müller, M.h , Kros, J.M.i , Kruchko, C.j , Wiemels, J.k , Wrensch, M.l , Danysh, H.E.b , Zouaoui, S.d , Heck, J.E.m , Johnson, K.J.n , Qi, X.o , O'Neill, B.P.p , Afzal, S.q , Scheurer, M.E.b , Bainbridge, M.N.r , Nousome, D.s , Bahassi, E.M.t , Hainfellner, J.A.a , Barnholtz-Sloan, J.S.u
Brain tumor epidemiology - A hub within multidisciplinary neuro-oncology. report on the 15th brain tumor epidemiology consortium (BTEC) annual meeting, Vienna, 2014
(2015) Clinical Neuropathology, 34 (1), pp. 40-46. 


a Institute of Neurology, Medical University of ViennaVienna, Austria
b Department of Pediatrics, Section of Hematology-Oncology, Baylor College of MedicineHouston, TX, United States
c Department of Biomedical Imaging and Image-guided Therapy, Medical University of ViennaVienna, Austria
d Department of Neurosurgery, CHU Montpellier, France
e Service of Neurology, Hospital Clínic, University of Barcelona, Spain
f German Cancer Research Center DKFZHeidelberg, Germany
g Division of Child Neurology, Department of Neurology, Stanford UniversityCA, United States
h SwissCoreBrussels, Belgium
i Erasmus MCRotterdam, Netherlands
j Central Brain Tumor Registry of the USHinsdale, IL, United States
k Department of Epidemiology and Biostatistics, University of CaliforniaSan Francisco, United States
l Department of Neurological Surgery, University of CaliforniaSan Francisco, United States
m Department of Epidemiology, University of CaliforniaLos Angeles, CA, United States
n Brown School Master of Public Health Program, Washington UniversitySt. Louis, MO, United States
o Division of Hematology-Oncology, The Vontz Center for Molecular Studies, University of CincinnatiOH, United States
p Department of Neurology, The Mayo ClinicRochester, MN, United States
q Division of Pediatric Hematology/Oncology, Dalhouse University, Canada
r Human Genome Sequencing Center, Baylor College of MedicineHouston, TX, United States
s Preventive Medicine, University of Southern CaliforniaLos Angeles, CA, United States
t Brain Tumor Center, University of CincinnatiOH, United States
u Case Comprehensive Cancer Center, Case Western Reserve University, School of MedicineCleveland, OH, United States


Abstract
The Brain Tumor Epidemiology Consortium (BTEC) is an open scientific forum, which fosters the development of multi-center, international and inter-disciplinary collaborations. BTEC aims to develop a better understanding of the etiology, outcomes, and prevention of brain tumors (http://epi.grants.cancer.gov/btec/). The 15th annual Brain Tumor Epidemiology Consortium Meeting, hosted by the Austrian Societies of Neuropathology and Neuro-oncology, was held on September 9 - 11, 2014 in Vienna, Austria. The meeting focused on the central role of brain tumor epidemiology within multidisciplinary neuro-oncology. Knowledge of disease incidence, outcomes, as well as risk factors is fundamental to all fields involved in research and treatment of patients with brain tumors; thus, epidemiology constitutes an important link between disciplines, indeed the very hub. This was reflected by the scientific program, which included various sessions linking brain tumor epidemiology with clinical neuro-oncology, tissue-based research, and cancer registration. Renowned experts from Europe and the United States contributed their personal perspectives stimulating further group discussions. Several concrete action plans evolved for the group to move forward until next year's meeting, which will be held at the Mayo Clinic at Rochester, MN, USA.


Author Keywords
Brain tumor;  Clinical research;  Epidemiology;  Risk factor research;  Tissue-based research


Document Type: Article
Source: Scopus




Capotosto, P.a , Spadone, S.a , Tosoni, A.a , Sestieri, C.a , Romani, G.L.a , Penna, S.D.a , Corbetta, M.a b
Dynamics of EEG rhythms support distinct visual selection mechanisms in parietal cortex: A simultaneous transcranial magnetic stimulation and EEG study
(2015) Journal of Neuroscience, 35 (2), pp. 721-730. 


a Department of Neuroscience, Imaging and Clinical Sciences, and Institute of Advanced Biomedical Technologies, University G. D’AnnunzioChieti, Italy
b Departments of Neurology, Radiology, and Anatomy and Neurobiology, Washington University School of MedicineSt. Louis, MO, United States


Abstract
Using repetitive transcranial magnetic stimulation (rTMS),wehave recently shown a functional anatomical distinction inhumanparietal cortex between regions involved in maintaining attention to a location [ventral intraparietal sulcus (vIPS)] and a region involved in shifting attention between locations [medial superior parietal lobule (mSPL)]. In particular, while rTMS interference over vIPS impaired target discrimination at contralateral attended locations, interference over mSPL affected performance following shifts of attention regardless of the visual field (Capotosto et al., 2013). Here, using rTMS interference in conjunction with EEG recordings of brain rhythms during the presentation of cues that indicate to either shift or maintain spatial attention, we tested whether this functional anatomical segregation involves different mechanisms of rhythm synchronization. The transient inactivation of vIPS reduced the amplitude of the expected parieto-occipital low-α (8-10 Hz) desynchronization contralateral to the cued location. Conversely, the transient inactivation of mSPL, compared with vIPS, reduced the high-α (10-12 Hz) desynchronization induced by shifting attention into both visual fields. Furthermore, rTMS induced a frequency-specific delay of task-related modulation of brain rhythms. Specifically, rTMS over vIPS or mSPL during maintenance (stay cues) or shifting (shift cues) of spatial attention, respectively, caused a delay of α parieto-occipital desynchronization. Moreover, rTMS over vIPS during stay cues caused a delay of δ (2-4 Hz) frontocentral synchronization. These findings further support the anatomo-functional subdivision of the dorsal attention network in subsystems devoted to shifting or maintaining covert visuospatial attention and indicate that these mechanisms operate in different frequency channels linking frontal to parieto-occipital visual regions.


Author Keywords
Attention;  EEG rhythms;  Parietal cortex;  TMS


Document Type: Article
Source: Scopus




Eling, P.a , Finger, S.b , Whitaker, H.c
Franz Joseph Gall and music: The faculty and the bump
(2015) Progress in Brain Research, . Article in Press. 


a Department of Psychology, Radboud University Nijmegen, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands
b Department of Psychology, Washington University, St. Louis, MO, USA
c Department of Psychology, Northern Michigan University, Marquette, MI, USA


Abstract
The traditional story maintains that Franz Joseph Gall's (1758-1828) scientific program began with his observations of schoolmates with bulging eyes and good verbal memories. But his search to understand human nature, in particular individual differences in capacities, passions, and tendencies, can also be traced to other important observations, one being of a young girl with an exceptional talent for music. Rejecting contemporary notions of cognition, Gall concluded that behavior results from the interaction of a limited set of basic faculties, each with its own processes for perception and memory, each with its own territory in both cerebral or cerebellar cortices. Gall identified 27 faculties, one being the sense of tone relations or music. The description of the latter is identical in both his Anatomie et Physiologie and Sur les Fonctions du Cerveau et sur Celles de Chacune de ses Parties, where he provided positive and negative evidences and discussed findings from humans and lower animals, for the faculty. The localization of the cortical faculty for talented musicians, he explained, is demonstrated by a "bump" on each side of the skull just above the angle of the eye; hence, the lower forehead of musicians is broader or squarer than in other individuals. Additionally, differences between singing and nonsinging birds also correlate with cranial features. Gall even brought age, racial, and national differences into the picture. What he wrote about music reveals much about his science and creative thinking.


Author Keywords
Amusia;  Cortical localization of function;  Craniology;  Gall (Franz Joseph);  Music faculty;  Musicians;  Organology;  Phrenology;  Physiognomy;  Spurzheim (Johann)


Document Type: Article in Press
Source: Scopus




Emnett, C.M.a b , Eisenman, L.N.c , Mohan, J.b , Taylor, A.A.b , Doherty, J.J.f , Paul, S.M.f g , Zorumski, C.F.b d e , Mennerick, S.b d e
Interaction between positive allosteric modulators and trapping blockers of the NMDA receptor channel
(2015) British Journal of Pharmacology, . Article in Press. 


a Graduate Program in Neuroscience Washington University St Louis, MO USA
b Department of Psychiatry Washington University School of Medicine St. Louis, MO USA
c Department of Neurology Washington University School of Medicine St. Louis, MO USA
d Department of Anatomy and Neurobiology Washington University School of Medicine St. Louis, MO USA
e Taylor Family Institute for Innovative Psychiatric Research Washington University School of Medicine St. Louis, MO USA
f Sage Therapeutics Cambridge, MA USA
g Appel Alzheimer's Disease Research Institute Brain and Mind Research Institute Departments of Psychiatry and Pharmacology Weill Cornell Medical College New York, NY USA


Abstract
Background and Purpose: Memantine and ketamine are clinically used, open-channel blockers of NMDA receptors exhibiting remarkable pharmacodynamic similarities despite strikingly different clinical profiles. Although NMDA channel gating constitutes an important difference between memantine and ketamine, it is unclear how positive allosteric modulators (PAMs) might affect the pharmacodynamics of these NMDA blockers. Experimental Approach: We used two different PAMs: SGE-201, an analogue of an endogenous oxysterol, 24S-hydroxycholesterol, along with pregnenolone sulphate (PS), to test on memantine and ketamine responses in single cells (oocytes and cultured neurons) and networks (hippocampal slices), using standard electrophysiological techniques. Key Results: SGE-201 and PS had no effect on steady-state block or voltage dependence of a channel blocker. However, both PAMs increased the actions of memantine and ketamine on phasic excitatory post-synaptic currents, but neither revealed underlying pharmacodynamic differences. SGE-201 accelerated the re-equilibration of blockers during voltage jumps. SGE-201 also unmasked differences among the blockers in neuronal networks - measured either by suppression of activity in multi-electrode arrays or by neuroprotection against a mild excitotoxic insult. Either potentiating NMDA receptors while maintaining the basal activity level or increasing activity/depolarization without potentiating NMDA receptor function is sufficient to expose pharmacodynamic blocker differences in suppressing network function and in neuroprotection. Conclusions and Implications: Positive modulation revealed no pharmacodynamic differences between NMDA receptor blockers at a constant voltage, but did expose differences during spontaneous network activity. Endogenous modulator tone of NMDA receptors in different brain regions may underlie differences in the effects of NMDA receptor blockers on behaviour.


Document Type: Article in Press
Source: Scopus




Weisman, J.S.a , Rodebaugh, T.L.a , Brown, P.J.b , Mulligan, E.A.c
Positive Affect and Social Anxiety Across the Lifespan: An Investigation of Age as a Moderator
(2015) Clinical Gerontologist, 38 (1), pp. 1-18. 


a Washington University in St. LouisSt. Louis, MO, United States
b Columbia University College of Physicians and Surgeons and New York State Psychiatric InstituteNew York, NY, United States
c VA Boston Healthcare SystemBrockton, MA, United States


Abstract
Recent literature has supported a moderate, inverse relationship between social anxiety and positive affect. It has been proposed, but not clearly established, that the inverse relationship between the constructs may be stronger in younger adults than in adults who are older. We tested this hypothesis in two archival data sets of community participants. The expected age-related interaction was not found in Study 1, which used a measure capturing a conflation of valence and arousal known as activated positive affect. Conversely, the interaction was present in Study 2, in which the positive affect measure was primarily based on valence. We found only partial support for the hypothesis, and results highlight the need for a more comprehensive measure of positive affect.


Author Keywords
aging;  anxiety disorders;  positive affect;  social anxiety;  social phobia


Document Type: Article
Source: Scopus




Shklyar, I.a , Geisbush, T.R.a , Mijialovic, A.S.a , Pasternak, A.b , Darras, B.T.b , Wu, J.S.c , Rutkove, S.B.a , Zaidman, C.M.d
Quantitative muscle ultrasound in Duchenne muscular dystrophy: A comparison of techniques
(2015) Muscle and Nerve, 51 (2), pp. 207-213. 


a The Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Beth Israel Deaconess Medical CenterBoston, MA, United States
b Boston Children's Hospital, Harvard Medical School, Beth Israel Deaconess Medical CenterBoston, MA, United States
c The Department of Radiology, Harvard Medical Schoo, Beth Israel Deaconess Medical CenterBoston, MA, United States
d Department of Neurology and Pediatrics, Washington University, St. Louis School of Medicine, Box 8111, 660 S. Euclid AvenueSt. Louis, MO, United States


Abstract
Introduction: Muscle pathology in Duchenne muscular dystrophy (DMD) can be quantified using ultrasound by measuring either the amplitudes of sound-waves scattered back from the tissue [quantitative backscatter analysis (QBA)] or by measuring these backscattered amplitudes after compression into grayscale levels (GSL) obtained from the images. Methods: We measured and compared QBA and GSL from 6 muscles of 25 boys with DMD and 25 healthy subjects, aged 2-14 years, with age and, in DMD, with function (North Star Ambulatory Assessment). Results: Both QBA and GSL were measured reliably (intraclass correlation≥0.87) and were higher in DMD than controls (P<0.0001). In DMD, average QBA and GSL measured from superficial regions of muscle increased (rho≥0.47, P<0.05) with both higher age and worse function; in contrast, GSL measured from whole regions of muscle did not. Conclusions: QBA and GSL measured from superficial regions of muscle can similarly quantify muscle pathology in DMD.


Author Keywords
Biomarker;  Duchenne muscular dystrophy;  Muscle;  Myopathy;  Ultrasound


Document Type: Article
Source: Scopus




Engelhardt, E.a , Inder, T.E.b , Alexopoulos, D.c , Dierker, D.L.d , Hill, J.e , Van Essen, D.d , Neil, J.J.f
Regional impairments of cortical folding in premature infants
(2015) Annals of Neurology, 77 (1), pp. 154-162. 


a School of Medicine, University of MissouriColumbia, MO, United States
b Department of Pediatric Newborn Medicine, Brigham and Women's HospitalBoston, MA, United States
c Department of Neurology, St Louis Children's Hospital, Washington University School of MedicineSt Louis, MO, United States
d Department of Anatomy and Neurobiology, Washington University School of MedicineSt Louis, MO, United States
e Department of Emergency Medicine, New York-Presbyterian HospitalNew York, NY, United States
f Department of Neurology, Boston Children's Hospital, 333 Longwood AveBoston, MA, United States


Abstract
Objective: This study was undertaken to evaluate the influence of preterm birth and other factors on cerebral cortical maturation. Methods: We have evaluated the effects of preterm birth on cortical folding by applying cortical cartography methods to a cohort of 52 preterm infants (&lt;31 weeks gestation, mild or no injury on conventional magnetic resonance imaging) and 12 term-born control infants. All infants were evaluated at term-equivalent postmenstrual age. Results: Preterm infants had lower values for the global measures of gyrification index (GI; 2.06 ± 0.07 vs 1.80±0.12, p &lt; 0.001; control vs preterm) and cortical surface area (CSA; 316 ± 24 cm2 vs 257 ± 40 cm2, p &lt; 0.001). Regional analysis of sulcal depth and cortical shape showed the greatest impact of preterm birth on the insula, superior temporal sulcus, and ventral portions of the pre- and postcentral sulci in both hemispheres. Although CSA and GI are related, CSA was more sensitive to antenatal and postnatal factors than GI. Both measures were lower in preterm infants of lower birth weight standard deviation scores and smaller occipitofrontal circumference at time of scan, whereas CSA alone was lower in association with smaller occipitofrontal circumference at birth. CSA was also lower in infants with higher critical illness in the first 24 hours of life, exposure to postnatal steroids, and prolonged endotracheal intubation. Interpretation: Preterm birth disrupts cortical development in a regionally specific fashion with abnormalities evident by term-equivalent postmenstrual age. This disruption is influenced by both antenatal growth and postnatal course.


Document Type: Article
Source: Scopus




Radmanesh, A.a , Fitzgerald, R.T.b
Social media and the neuroradiologist: A brief introduction
(2015) American Journal of Neuroradiology, 36 (1), pp. 30-31. 


a Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 S Kingshighway Blvd, Campus Box 8131St Louis, MO, United States
b Department of Radiology, University of Arkansas for Medical SciencesLittle Rock, AR, United States


Document Type: Review
Source: Scopus




Brey, J.K.a , Wolf, T.J.a b
Socioeconomic disparities in work performance following mild stroke
(2015) Disability and Rehabilitation, 37 (2), pp. 106-112. 


a Program in Occupational Therapy, United States
b Department of Neurology, Washington University, School of Medicine, 4444 Forest Park AvenueSt. Louis, MO, United States


Abstract
The purpose of this study was to investigate the relationships among the factors that influence return to work for young individuals with mild stroke from different socioeconomic backgrounds. Methods: Prospective cohort study of working adults with mild stroke (N=21). Participants completed an assessment battery of cognitive, work environment and work performance measures at approximately 3 weeks and 7 months post mild stroke. Individuals were placed in "skilled" and "unskilled" worker categories based on the Hollingshead Index. Results: Unskilled workers had significantly poorer scores on the majority of the cognitive assessments. Unskilled workers also perceived less social support (p=0.017) and autonomy (p=0.049) in work responsibilities than individuals in the skilled worker group and also reported significantly poorer work productivity due to stroke than those in the skilled group (p=0.015). Conclusions: Individuals from low socioeconomic backgrounds have more difficulty returning to work following mild stroke than individuals from higher socioeconomic backgrounds. Future work is needed to identify factors that can increase long-term work success and quality of work performance following a mild stroke that specifically targets the needs of individuals who have a lower socioeconomic status.Implications for RehabilitationMany persons, especially those of low socioeconomic status (SES), have decreased work productivity following mild stroke despite having no physical impairments and receiving little to no post-acute rehabilitation services.Acute care rehabilitation measures are not detecting mild cognitive deficits and work environment factors that could impact successful reintegration into work and the community.Follow-up services for individuals with mild stroke could improve readiness for work, work productivity and work sustainability, especially among individuals of low SES.


Author Keywords
Employment outcomes;  Return to work;  Socioeconomic disparities;  Stroke


Document Type: Article
Source: Scopus




Dart, R.C.a , Surratt, H.L.b , Cicero, T.J.c , Parrino, M.W.d , Severtson, S.G.a , Bucher-Bartelson, B.a , Green, J.L.a
Trends in opioid analgesic abuse and mortality in the United States
(2015) New England Journal of Medicine, 372 (3), pp. 241-248. 


a Rocky Mountain Poison and Drug Center, Denver Health and Hospital Authority, Mailcode 0180, 777 Bannock St.Denver, CO, United States
b Center for Applied Research on Substance Use and Health Disparities, Nova Southeastern UniversityFt. Lauderdale, FL, United States
c Department of Psychiatry, Washington University, School of MedicineSt. Louis, United States
d American Association for the Treatment of Opioid DependenceNew York, NY, United States


Abstract
Background The use of prescription opioid medications has increased greatly in the United States during the past two decades; in 2010, there were 16,651 opioid-related deaths. In response, hundreds of federal, state, and local interventions have been implemented. We describe trends in the diversion and abuse of prescription opioid analgesics using data through 2013. Methods We used five programs from the Researched Abuse, Diversion, and Addiction- Related Surveillance (RADARS) System to describe trends between 2002 and 2013 in the diversion and abuse of all products and formulations of six prescription opioid analgesics: oxycodone, hydrocodone, hydromorphone, fentanyl, morphine, and tramadol. The programs gather data from drug-diversion investigators, poison centers, substance-abuse treatment centers, and college students. Results Prescriptions for opioid analgesics increased substantially from 2002 through 2010 in the United States but then decreased slightly from 2011 through 2013. In general, RADARS System programs reported large increases in the rates of opioid diversion and abuse from 2002 to 2010, but then the rates flattened or decreased from 2011 through 2013. The rate of opioid-related deaths rose and fell in a similar pattern. Reported nonmedical use did not change significantly among college students. Conclusions Postmarketing surveillance indicates that the diversion and abuse of prescription opioid medications increased between 2002 and 2010 and plateaued or decreased between 2011 and 2013. These findings suggest that the United States may be making progress in controlling the abuse of opioid analgesics. Copyright + 2015 Massachusetts Medical Society.


Document Type: Article
Source: Scopus




Racette, B.A.a b
Manganism in the 21st century: The Hanninen lecture
(2014) NeuroToxicology, 45, pp. 201-207. 


a Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, Box 8111St. Louis, MO, United States
b University of the Witwatersrand, School of Public Health, Faculty of Health SciencesJohannesburg, South Africa


Abstract
Since the original description of the health effects of inhaled occupational manganese (Mn) by Couper in 1837, an extensive literature details the clinical syndrome and pathophysiology of what was thought to be a rare condition. In the last decade, conventional wisdom regarding the clinicopathological effects of Mn has been challenged. Past exposures to Mn were an order of magnitude higher than modern exposures in developed countries; therefore, the clinical syndrome seen in the time of Couper is no longer typical of modern Mn exposed workers. Parkinsonism (rigidity, bradykinesia, rest tremor, and postural instability) is present in 15% of Mn-exposed workers in welding industries, and these parkinsonian signs are associated with reduced health status and quality of life. These parkinsonian signs also overlap considerably with the clinical findings seen in early stages of Parkinson's disease (PD); although, molecular imaging suggests that Mn-exposed workers have dopaminergic dysfunction in a pattern unique from PD. Furthermore, geographic information system studies demonstrate that regions of the US with high industrial Mn emissions have an increased incidence of PD and increased PD associated mortality. This review will contrast historical, descriptive human studies in Mn-exposed subjects with more recent data and will suggest a research agenda for the 21st century.


Author Keywords
Dopamine;  Manganese;  Neurotoxicity;  Parkinson disease;  Parkinsonism;  PET


Document Type: Review
Source: Scopus




Van Essen, D.C.a b
In vivo architectonics: a cortico-centric perspective
(2014) NeuroImage, 93, pp. 157-164. 


a Department of Anatomy & Neurobiology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA. Electronic address: vanessen@wustl.edu
b Department of Anatomy & Neurobiology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA


Abstract
Recent advances in noninvasive structural imaging have opened up new approaches to cortical parcellation, many of which are described in this special issue on In Vivo Brodmann Mapping. In this introductory article, we focus on the emergence of cortical myelin maps as a valuable way to assess cortical organization in humans and nonhuman primates. We demonstrate how myelin maps are useful in three general domains: (i) as a way to identify cortical areas and functionally specialized regions in individuals and group averages; (ii) as a substrate for improved intersubject registration; and (iii) as a basis for interspecies comparisons. We also discuss how myelin-based cortical parcellation is complementary in important ways to connectivity-based parcellation using functional MRI or diffusion imaging and tractography. These observations and perspectives provide a useful background and context for other articles in this special issue.


Author Keywords
Cortical areas;  Myelin;  Networks;  Parcellation;  Registration


Document Type: Review
Source: Scopus




Glasser, M.F.a b c d e
Trends and properties of human cerebral cortex: correlations with cortical myelin content
(2014) NeuroImage, 93, pp. 165-175. 


a Department of Anatomy and Neurobiology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA. Electronic address: glasserm@wusm.wustl.edu
b Department of Radiology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA. Electronic address: goyalm@mir.wustl.edu
c Division of Neuropharmacology and Neurologic Diseases, Emory University, Atlanta, GA 30329, USA; Center for Translational and Social Neuroscience, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA; Department of Pathology, Emory University School of Medicine, Atlanta, GA 30329, USA. Electronic address: tpreuss@emory.edu
d Department of Anatomy and Neurobiology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA; Department of Radiology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA; Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA; Department of Biomedical Engineering, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA. Electronic address: marc@npg.wustl.edu
e Department of Anatomy and Neurobiology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA. Electronic address: vanessen@wustl.edu


Abstract
"In vivo Brodmann mapping" or non-invasive cortical parcellation using MRI, especially by measuring cortical myelination, has recently become a popular research topic, though myeloarchitectonic cortical parcellation in humans previously languished in favor of cytoarchitecture. We review recent in vivo myelin mapping studies and discuss some of the different methods for estimating myelin content. We discuss some ways in which myelin maps may improve surface registration and be useful for cross-modal and cross-species comparisons, including some preliminary cross-species results. Next, we consider neurobiological aspects of why some parts of cortex are more myelinated than others. Myelin content is inversely correlated with intracortical circuit complexity - in general, more myelin content means simpler and perhaps less dynamic intracortical circuits. Using existing PET data and functional network parcellations, we examine metabolic differences in the differently myelinated cortical functional networks. Lightly myelinated cognitive association networks tend to have higher aerobic glycolysis than heavily myelinated early sensory-motor ones, perhaps reflecting greater ongoing dynamic anabolic cortical processes. This finding is consistent with the hypothesis that intracortical myelination may stabilize intracortical circuits and inhibit synaptic plasticity. Finally, we discuss the future of the in vivo myeloarchitectural field and cortical parcellation--"in vivo Brodmann mapping"--in general.


Author Keywords
Aerobic glycolysis;  Cerebral cortex;  Cortical area;  Cortical parcellation;  Myelin map;  PET


Document Type: Review
Source: Scopus




Hong, J.S., Tillman, R., Luby, J.L.
Disruptive Behavior in Preschool Children: Distinguishing NormalMisbehavior from Markers of Current and Later ChildhoodConductDisorder
(2015) Journal of Pediatrics, . Article in Press. 


Department of Psychiatry, Washington University School of Medicine, St. Louis, MO


Abstract
Objectives: To investigate which disruptive behaviors in preschool were normative and transient vs markers of conduct disorder, as well as which disruptive behaviors predicted the persistence of conduct disorder into school age. Study design: Data from a longitudinal study of preschool children were used to investigate disruptive behaviors. Caregivers of preschoolers ages 3.0-5.11years (n=273) were interviewed using the Preschool Age Psychiatric Assessment to derive the following diagnostic groups: conduct disorder, externalizing disorder without conduct disorder, internalizing disorder without externalizing disorder, and healthy. At school age, participants were again assessed via an age-appropriate diagnostic interview. Logistic and linear regression with pairwise group comparisons was used to investigate clinical markers of preschool conduct disorder and predictors of school age conduct disorder. Results: Losing one's temper, low-intensity destruction of property, and low-intensity deceitfulness/stealing in the preschool period were found in both healthy and disordered groups. In contrast, high-intensity argument/defiant behavior, both low- and high-intensity aggression to people/animals, high-intensity destruction of property, high-intensity deceitfulness/stealing, and high-intensity peer problems were markers of preschool conduct disorder and predictors of school age conduct disorder. Inappropriate sexual behavior was not a marker for preschool conduct disorder but was a predictor of school age conduct disorder. Conclusion: These findings provide a guide for primary care clinicians to help identify preschoolers with clinical conduct disorder and those who are at risk for persistent conduct disorder in childhood. Preschoolers displaying these symptoms should be targeted for mental health assessment.

 


Document Type: Article in Press
Source: Scopus

 

January 22, 2015

Santello, M.a , Lang, C.E.b
Are movement disorders and sensorimotor injuries pathologic synergies? When normal multi-joint movement synergies become pathologic
(2015) Frontiers in Human Neuroscience, 8 (JAN), art. no. 1050, 13 p. 


a Neural Control of Movement Laboratory, School of Biological and Health Systems Engineering, Arizona State UniversityTempe, AZ, United States
b Department of Neurology, Washington University School of Medicine in St. LouisSt. Louis, MT, United States


Abstract
The intact nervous system has an exquisite ability to modulate the activity of multiple muscles acting at one or more joints to produce an enormous range of actions. Seemingly simple tasks, such as reaching for an object or walking, in fact rely on very complex spatial and temporal patterns of muscle activations. Neurological disorders such as stroke and focal dystonia affect the ability to coordinate multi-joint movements. This article reviews the state of the art of research of muscle synergies in the intact and damaged nervous system, their implications for recovery and rehabilitation, and proposes avenues for research aimed at restoring the nervous system’s ability to control movement.


Author Keywords
Carpal tunnel syndrome;  Coordination;  Degrees of freedom;  Dystonia;  Stroke


Document Type: Article
Source: Scopus

Storm, B.C.a , Angello, G.b , Buchli, D.R.c , Koppel, R.H.d , Little, J.L.e , Nestojko, J.F.e
A Review of Retrieval-Induced Forgetting in the Contexts of Learning, Eyewitness Memory, Social Cognition, Autobiographical Memory, and Creative Cognition
(2015) Psychology of Learning and Motivation - Advances in Research and Theory, . Article in Press. 


a Department of Psychology, University of California, Santa Cruz, CA, USA
b Department of Psychology, Texas A and M University, College Station, TX, USA
c Department of Psychology, University of California, Los Angeles, CA, USA
d Department of Psychology, University of Illinois at Chicago, Chicago, IL, USA
e Department of Psychology, Washington University in St. Louis, St. Louis, MO, USA


Abstract
Retrieving information from memory can cause the forgetting of other information in memory, a phenomenon referred to as retrieval-induced forgetting. Over the past 20years, retrieval-induced forgetting has been observed in a variety of experimental contexts and has been argued to impact a number of cognitive and psychological processes. Not simply a laboratory phenomenon, retrieval-induced forgetting appears to have important implications for furthering our basic understanding of memory and behavior. In the present chapter, we provide a selective review of retrieval-induced forgetting in five contexts-learning and education, eyewitness memory, social cognition, autobiographical memory, and creative cognition-and discuss the importance of studying retrieval-induced forgetting in situations beyond the typical retrieval-practice paradigm.


Author Keywords
Autobiographical memory;  Creative cognition;  Eyewitness memory;  Memory;  Retrieval-induced forgetting;  Social cognition;  Testing effects


Document Type: Article in Press
Source: Scopus

Karch, C.M., Goate, A.M.
Alzheimer's disease risk genes and mechanisms of disease pathogenesis
(2015) Biological Psychiatry, 77 (1), pp. 43-51. Cited 1 time.


Department of Psychiatry, Hope Center for Neurological Disorders, Washington University School of MedicineSt. Louis, MO, United States


Abstract
We review the genetic risk factors for late-onset Alzheimer's disease (AD) and their role in AD pathogenesis. More recent advances in understanding of the human genome - technologic advances in methods to analyze millions of polymorphisms in thousands of subjects - have revealed new genes associated with AD risk, including ABCA7, BIN1, CASS4, CD33, CD2AP, CELF1, CLU, CR1, DSG2, EPHA1, FERMT2, HLA-DRB5-DBR1, INPP5D, MS4A, MEF2C, NME8, PICALM, PTK2B, SLC24H4-RIN3, SORL1, and ZCWPW1. Emerging technologies to analyze the entire genome in large data sets have also revealed coding variants that increase AD risk: PLD3 and TREM2. We review the relationship between these AD risk genes and the cellular and neuropathologic features of AD. Understanding the mechanisms underlying the association of these genes with risk for disease will provide the most meaningful targets for therapeutic development to date.


Author Keywords
Alzheimers Disease;  Amyloid Precursor Protein;  Cholesterol Metabolism;  Endocytosis;  Genome-Wide Association Studies;  Immune Response


Document Type: Review
Source: Scopus

Gray, K.E.a , Cradock, M.M.b c , Kapp-Simon, K.A.d , Collett, B.R.e f , Pullmann, L.D.f , Speltz, M.L.e f f
Longitudinal analysis of parenting stress in mothers and fathers of infants with and without single-suture craniosynostosis
(2015) Cleft Palate-Craniofacial Journal, 52 (1), pp. 3-11. 


a Department of Health Services, University of WashingtonSeattle, WA, United States
b Department of Psychology, St. Louis Children's HospitalSt. Louis, MO, United States
c Department of Pediatrics, Washington University School of MedicineSt. Louis, MO, United States
d Department of Surgery, Northwestern University, Shriners Hospital for ChildrenChicago, IL, United States
e Psychiatry and Behavioral Medicine, Seattle Children's Hospital, Mailstop CL-08, 4800 Sand Point Way NESeattle, WA, United States
f Department of Psychiatry and Behavioral Sciences, University of WashingtonSeattle, WA, United States


Abstract
Objective: To examine longitudinal differences in reported stress between parents of children with and without single-suture craniosynostosis and to compare the stress reports of mothers and fathers. Design: Multi-site, nonrandomized prospective study. Setting/Participants: Children with single-suture craniosynostosis (cases) were identified via referral of the treating surgeon or physician at the time of diagnosis, and those without singlesuture craniosynostosis (controls) were recruited from pediatric practices, birthing centers, and announcements in print media. When children were aged 6, 18, and 36 months (on average), mothers and fathers of children with and without single-suture craniosynostosis completed the Parenting Stress Index. For cases, 247 mothers and 211 fathers completed the Parenting Stress Index at the first visit; corresponding numbers for controls were 254 and 220, respectively. Main Outcome Measures: The Parenting Stress Index Parent and Child Domains and subscales scores. Results: We found few differences between parents of infants with and without single-suture craniosynostosis, regardless of parent gender. Irrespective of case status, mothers consistently reported higher stress than fathers on the Parent Domain. Within the Parent Domain, mothers reported more stress than fathers on the Role Restriction and Spousal Support subscales. Conclusions: The parents of children with single-suture craniosynostosis reported levels of stress similar to those reported by parents of same-aged, unaffected children. Mothers reported greater stress than fathers, and these differences remained remarkably stable over time. This may reflect widely held perceptions of gender differences in parenting roles.


Author Keywords
Craniofacial condition;  Fathers;  Mothers;  Parenting stress;  Single-suture craniosynostosis


Document Type: Article
Source: Scopus

Thomas, J.B.a , Brier, M.R.a , Ortega, M.a , Benzinger, T.L.b c d , Ances, B.M.a b c d e
Weighted brain networks in disease: Centrality and entropy in human immunodeficiency virus and aging
(2015) Neurobiology of Aging, 36 (1), pp. 401-412. 


a Department of Neurology, Washington University in St Louis, School of MedicineSt. Louis, MO, United States
b Department of Radiology, Washington University in St Louis, School of MedicineSt. Louis, MO, United States
c Hope Center for Neurologic Diseases, Washington University in St Louis, School of MedicineSt. Louis, MO, United States
d Knight Alzheimer's Disease Research Center, Washington University in St Louis, School of MedicineSt. Louis, MO, United States
e Department of Biomedical Engineering, Washington University in St LouisSt. Louis, MO, United States


Abstract
Graph theory models can produce simple, biologically informative metrics of the topology of resting-state functional connectivity (FC) networks. However, typical graph theory approaches model FC relationships between regions (nodes) as unweighted edges, complicating their interpretability in studies of disease or aging. We extended existing techniques and constructed fully connected weighted graphs for groups of age-matched human immunodeficiency virus (HIV) positive (n = 67) and HIV negative (n = 77) individuals. We compared test-retest reliability of weighted versus unweighted metrics in an independent study of healthy individuals (n = 22) and found weighted measures to be more stable. We quantified 2 measures of node centrality (closeness centrality and eigenvector centrality) to capture the relative importance of individual nodes. We also quantified 1 measure of graph entropy (diversity) to measure the variability in connection strength (edge weights) at each node. HIV was primarily associated with differences in measures of centrality, and age was primarily associated with differences in diversity. HIV and age were associated with divergent measures when evaluated at the whole graph level, within individual functional networks, and at the level of individual nodes. Graph models may allow us to distinguish previously indistinguishable effects related to HIV and age on FC.


Author Keywords
Aging fc-MRI;  Centrality;  Graph theory;  HIV;  Neurodegeneration


Document Type: Article
Source: Scopus

Winder-Rhodes, S.E.a b , Hampshire, A.c d , Rowe, J.B.a c e , Peelle, J.E.f , Robbins, T.W.e , Owen, A.M.c g , Barker, R.A.a e
Association between MAPT haplotype and memory function in patients with Parkinson's disease and healthy aging individuals
(2015) Neurobiology of Aging, . Article in Press. 


a Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
b Department of Child and Adolescent Psychiatry, Institute of Psychiatry, King's College London, UK
c MRC Cognition and Brain Sciences Unit, Cambridge, UK
d The Division of Brain Sciences, Department of Medicine, Imperial College, London, UK
e Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK
f Department of Otolaryngology, Washington University in St. Louis, St. Louis, MO, USA
g The Brain and Mind Institute, The University of Western Ontario, London Ontario, Canada


Abstract
Genetic variation is associated with differences in the function of the brain as well as its susceptibility to disease. The common H1 haplotypic variant of the microtubule-associated protein tau gene (MAPT) has been related to an increased risk for Parkinson's disease (PD). Furthermore, among PD patients, H1 homozygotes have an accelerated progression to dementia. We investigated the neurocognitive correlates of MAPT haplotypes using functional magnetic resonance imaging. Thirty-seven nondemented patients with PD (19 H1/H1, 18 H2 carriers) and 40 age-matched controls (21 H1/H1, 19 H2 carriers) were scanned during performance of a picture memory encoding task. Behaviorally, H1 homozygosity was associated with impaired picture recognition memory in PD patients and control subjects. These impairments in the H1 homozygotes were accompanied by an altered blood-oxygen level-dependent response in the medial temporal lobe during successful memory encoding. Additional age-related differences in blood-oxygen level-dependent response were observed in the medial temporal lobes of H1 homozygotes with PD. These results suggest that common variation in MAPT is not only associated with the dementia of PD but also differences in the neural circuitry underlying aspects of cognition in normal aging.


Author Keywords
Aging;  Cognitive impairment;  Dementia;  FMRI;  Genetics;  Hippocampus;  MAPT;  Memory;  Parkinson's disease;  Picture recognition;  Tau


Document Type: Article in Press
Source: Scopus

Roediger, H.L., IIIa , Meade, M.L.b , Gallo, D.A.c , Olson, K.R.d
Bartlett revisited: Direct comparison of repeated reproduction and serial reproduction techniques
(2014) Journal of Applied Research in Memory and Cognition, 3 (4), pp. 266-271. Cited 1 time.


a Washington University in St. Louis, United States
b Montana State University, United States
c University of Chicago, United States
d University of Washington, United States


Abstract
Bartlett developed the procedures of repeated reproduction (the same person repeatedly recalling information) and serial reproduction (people transmitting information from one person to another). Our experiment directly compared recall accuracy across these two techniques, which has not previously been reported, using DRM word lists. Recall of the initial study list words remained constant across repeated reproductions but declined markedly across serial reproductions. In contrast, recall of associated words that were not originally studied (i.e. critical words) was steady across both conditions. Because more of the original list words were forgotten across each link of the serial reproduction chain, the proportion of critical items recalled (relative to list words) increased significantly as the list passed between people. Using output bound scoring, serial reproduction resulted in lower accuracy than repeated reproduction by the final recall trial. Our results are broadly consistent with Bartlett's (1932) informal observations: Serial reproduction produces greater forgetting of the original material than does repeated reproduction and also leads to greater distortion relative to the proportion of correct material recalled.


Author Keywords
DRM paradigm;  Errors of memory;  F.C. Bartlett;  Input-bound scoring;  Output-bound scoring;  Repeated reproduction;  Serial reproduction


Document Type: Article
Source: Scopus

Hosseini, H.S.a b , Beebe, D.C.c , Taber, L.A.a
Mechanical effects of the surface ectoderm on optic vesicle morphogenesis in the chick embryo
(2014) Journal of Biomechanics, 47 (16), pp. 3837-3846. 


a Department of Biomedical Engineering, Washington University, Campus Box 1097St. Louis, MO, United States
b Department of Physics, Washington UniversitySt Louis, MO, United States
c Department of Ophthalmology and Visual Sciences, Washington University School of MedicineSt. Louis, MO, United States


Abstract
Precise shaping of the eye is crucial for proper vision. Here, we use experiments on chick embryos along with computational models to examine the mechanical factors involved in the formation of the optic vesicles (OVs), which grow outward from the forebrain of the early embryo. First, mechanical dissections were used to remove the surface ectoderm (SE), a membrane that contacts the outer surfaces of the OVs. Principal components analysis of OV shapes suggests that the SE exerts asymmetric loads that cause the OVs to flatten and shear caudally during the earliest stages of eye development and later to bend in the caudal and dorsal directions. These deformations cause the initially spherical OVs to become pear-shaped. Exposure to the myosin II inhibitor blebbistatin reduced these effects, suggesting that cytoskeletal contraction controls OV shape by regulating tension in the SE. To test the physical plausibility of these interpretations, we developed 2-D finite-element models for frontal and transverse cross-sections of the forebrain, including frictionless contact between the SE and OVs. With geometric data used to specify differential growth in the OVs, these models were used to simulate each experiment (control, SE removed, no contraction). For each case, the predicted shape of the OV agrees reasonably well with experiments. The results of this study indicate that differential growth in the OV and external pressure exerted by the SE are sufficient to cause the global changes in OV shape observed during the earliest stages of eye development.


Author Keywords
Eye development;  Finite-element model;  Growth


Document Type: Article
Source: Scopus

Bauernfeind, A.L.a b , Babbitt, C.C.c
The appropriation of glucose through primate neurodevelopment
(2014) Journal of Human Evolution, 77, pp. 132-140. 


a Department of Anthropology, The George Washington UniversityWashington, DC, United States
b Department of Anatomy and Neurobiology, Washington University School of MedicineSt. Louis, MO, United States
c Department of Biology, University of Massachusetts AmherstAmherst, MA, United States


Abstract
The human brain is considerably larger and more energetically costly than that of other primate species. As such, discovering how human ancestors were able to provide sufficient energy to their brains is a central theme in the study of hominin evolution. However, many discussions of metabolism frequently omit the different ways in which energy, primarily glucose, is used once made available to the brain. In this review, we discuss two glucose metabolic pathways, oxidative phosphorylation and aerobic glycolysis, and their respective contributions to the energetic and anabolic budgets of the brain. While oxidative phosphorylation is a more efficient producer of energy, aerobic glycolysis contributes essential molecules for the growth of the brain and maintaining the structure of its cells. Although both pathways occur in the brain throughout the lifetime, aerobic glycolysis is a critical pathway during development, and oxidative phosphorylation is highest during adulthood. We outline how elevated levels of aerobic glycolysis may support the protracted neurodevelopmental sequence of humans compared with other primates. Finally, we review the genetic evidence for differences in metabolic function in the brains of primates and explore genes that may provide insight into how glucose metabolism may differ across species.


Author Keywords
Aerobic glycolysis;  Brain energetics;  Comparative genetics;  Development;  Human evolution;  Oxidative phosphorylation


Document Type: Article
Source: Scopus

 

January 15, 2015

Accurso, E.C.a , Fitzsimmons-Craft, E.E.b , Ciao, A.C.c , Le Grange, D.d
From efficacy to effectiveness: Comparing outcomes for youth with anorexia nervosa treated in research trials versus clinical care
(2015) Behaviour Research and Therapy, 65, pp. 36-41. 


a Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, 5841 S. Maryland Ave., MC 3077Chicago, IL, United States
b Department of Psychiatry, Washington University School of Medicine, Campus Box 8134, 660 S. Euclid Ave.St. Louis, MO, United States
c Western Washington University, Department of Psychology, MS-9172, 434 Academic Instruction Center, 516 High StreetBellingham, WA, United States
d University of California, San Francisco, Department of Psychiatry and Department of Pediatrics, 3333 California Street, Box 0503, LH Suite, 245San Francisco, CA, United States


Abstract
This study examined outcomes for 84 youth with anorexia nervosa (AN) who received family-based treatment (FBT) in a research trial (randomized trial care [RTC]: n=32) compared to fee-for-service care (specialty clinical care [SCC]: n=52) at an outpatient eating disorder clinic. Weight was collected up to 12 months post-baseline. Survival curves were used to examine time to weight restoration as predicted by type of care, baseline demographic and clinical characteristics, and their interaction. There was not a significant main effect for type of care, but its interaction with initial %EBW was significant (p=005), indicating that weight restoration was achieved faster in RTC compared to SCC for youth with a lower initial %EBW (i.e., ≤81), while rates of weight restoration were comparable for those with a higher initial %EBW (i.e., >81). These data suggest that FBT is as effective as it is efficacious, except for youth with lower initial body weights. Therefore, clinicians may need to be particularly active in encouraging early weight gain for this subset of patients. Nevertheless, this study suggests that FBT is appropriate as a first-line treatment for youth with AN who present for clinical care.


Author Keywords
Adolescent anorexia nervosa;  Effectiveness;  Efficacy;  Empirically supported treatment;  Family-based treatment


Document Type: Article
Source: Scopus

Ning, M.S.a , Perkins, S.M.b , Dewees, T.b , Shinohara, E.T.a
Evidence of high mortality in long term survivors of childhood medulloblastoma
(2015) Journal of Neuro-Oncology, 7 p. Article in Press. 


a Department of Radiation Oncology, Vanderbilt University Medical Center, 2220 Pierce Ave B1003Nashville, TN, United States
b Department of Radiation Oncology, Washington University School of Medicine, 4921 Parkview Place, CAM LLSaint Louis, MO, United States


Abstract
The diagnosis of pediatric medulloblastoma now carries a much improved overall survival; however as outcomes advance, late mortality, from causes such as disease recurrence and subsequent malignancies, are of increasing concern for these patients. Using the Surveillance, Epidemiology, and End Results database, the causes of late mortality in long term survivors of medulloblastoma were evaluated. Patients diagnosed with a medulloblastoma between the ages of 0–19 years who survived at least 5 years after diagnosis were included. Using U.S. population data, standardized mortality ratios (SMRs) were calculated. Cumulative incidence estimates and standardized incidence ratios (SIRs) of subsequent malignancies were calculated. A total of 455 patients were included in the analysis. All patients received radiation as part of therapy. Median age at diagnosis was 7 years, and mean follow-up was 16 years. By the time of last follow-up, 20.4 % of patients had died, representing an SMR of 24.0 (95 % CI 19.3–29.4). Overall survival at 30 years was 65.5 %. Primary recurrence accounted for 59 % of late deaths, while subsequent malignancy accounted for 11.8 %. SIR for subsequent malignancy in these patients was 10.4 (95 % CI 6.9–15.1). The most common secondary tumor was another brain tumor (32 %), followed by thyroid cancer (21 %). These data demonstrate that late mortality remains a significant problem in these patients. The causes of death are largely attributable to disease recurrence and secondary malignancies. Efforts to improve risk stratification and tailor therapy will help in reducing late mortality in this population.


Author Keywords
Locoregional;  Neoplasm recurrence;  Pediatrics;  Second Malignancy;  SEER program;  Side effect


Document Type: Article in Press
Source: Scopus

Pomara, N.a b , Lee, S.H.a , Bruno, D.a b c , Silber, T.a d , Greenblatt, D.J.e , Petkova, E.a b , Sidtis, J.J.a b
Adverse performance effects of acute lorazepam administration in elderly long-term users: Pharmacokinetic and clinical predictors
(2015) Progress in Neuro-Psychopharmacology and Biological Psychiatry, 56, pp. 129-135. 


a Nathan Kline InstituteOrangeburg, NY, United States
b New York University School of MedicineNew York, NY, United States
c Liverpool Hope UniversityLiverpool, United Kingdom
d Washington University in St. LouisSt. Louis, MO, United States
e Tufts University School of MedicineBoston, MA, United States


Abstract
Background: The benzodiazepine lorazepam is widely utilized in the treatment of elderly individuals with anxiety disorders and related conditions. Negative effects of acute lorazepam administration on cognitive performance, especially memory, have been reported in both previously untreated elderly and in individuals who have received short term (up to three weeks) treatment with therapeutic doses. However, it remains unclear if these adverse cognitive effects also persist after long-term use, which is frequently found in clinical practice. Methods: Cognitively intact elderly individuals (n = 37) on long-term (at least three months) daily treatment with lorazepam were studied using a double-blind placebo-controlled cross-over study design. Subjects were administered their highest daily unit dose of lorazepam (0.25-3.00. mg) or placebo on different days, approximately 1. week apart in a random order, and were assessed on memory, psychomotor speed, and subjective mood states. Results: Subjects had significantly poorer recall and slowed psychomotor performance following acute lorazepam administration. There were no significant effects on self-ratings of mood, sedation, or anxiety in the whole group, but secondary analyses suggested a differential response in subjects with Generalized Anxiety Disorder. Conclusions: The reduced recall and psychomotor slowing that we observed, along with an absence of significant therapeutic benefits, following acute lorazepam administration in elderly long-term users reinforces the importance of cognitive toxicity as a clinical factor in benzodiazepine use, especially in this population.


Author Keywords
Aging;  Benzodiazepines;  Cognitive toxicity;  Lorazepam;  Memory loss;  Psychomotor slowing


Document Type: Article
Source: Scopus

Wippold, F.J., IIa , Brown, D.C.b , Broderick, D.F.c , Burns, J.d , Corey, A.S.e , Deshmukh, T.K.f , Douglas, A.C.g , Holloway, K.h i j , Jagadeesan, B.D.k , Jurgens, J.S.l m , Kennedy, T.A.n , Patel, N.D.o , Perlmutter, J.S.p q , Rosenow, J.M.i j r , Slavin, K.i j s , Subramaniam, R.M.t
ACR appropriateness criteria dementia and movement disorders
(2015) Journal of the American College of Radiology, 12 (1), pp. 19-28. 


a Neuroradiology Section, Mallinckrodt Institute of Radiology, 510 S Kingshighway BlvdSaint Louis, MO, United States
b Hampton Roads Radiology AssociatesNorfolk, VA, United States
c Mayo Clinic JacksonvilleJacksonville, FL, United States
d Montefiore Medical CenterBronx, NY, United States
e Emory UniverstiyAtlanta, GA, United States
f Children's Hospital of WisconsinMilwaukee, WI, United States
g Indiana University School of MedicineIndianapolis, IN, United States
h MCVH-Virginia Commonwealth UniversityRichmond, VA, United States
i American Association of Neurological SurgeonsRolling Meadows, IL, United States
j Congress of Neurological SurgeonsSchaumburg, IL, United States
k University of MinnesotaMinneapolis, MN, United States
l Walter Reed National Military Medical CenterBethesda, MD, United States
m Society of Nuclear Medicine and Molecular ImagingReston, VA, United States
n University of Wisconsin Hospital and ClinicMadison, WI, United States
o Fairfax Radiology Consultants PCFairfax, VA, United States
p Washington University in St LouisSt Louis, MO, United States
q American Academy of NeurologyMinneapolis, MN, United States
r Northwestern University Feinberg School of MedicineChicago, IL, United States
s UIC Medical CenterChicago, IL, United States
t Johns Hopkins Medical InstitutionBaltimore, MD, United States


Abstract
Neurodegenerative disease, including dementia, extrapyramidal degeneration, and motor system degeneration, is a growing public health concern and is quickly becoming one of the top health care priorities of developed nations. The primary function of anatomic neuroimaging studies in evaluating patients with dementia or movement disorders is to rule out structural causes that may be reversible. Lack of sensitivity and specificity of many neuroimaging techniques applied to a variety of neurodegenerative disorders has limited the role of neuroimaging in differentiating types of neurodegenerative disorders encountered in everyday practice. Nevertheless, neuroimaging is a valuable research tool and has provided insight into the structure and function of the brain in patients with neurodegenerative disorders. Advanced imaging techniques, such as functional neuroimaging with MRI and MR spectroscopy, hold exciting investigative potential for better understanding of neurodegenerative disorders, but they are not considered routine clinical practice at this time. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.


Author Keywords
Alzheimer disease;  Appropriateness Criteria;  dementia;  neurodegenerative;  Parkinson disease


Document Type: Article
Source: Scopus

Buddhala, C.a b c , Campbell, M.C.a d , Perlmutter, J.S.a c d e f g , Kotzbauer, P.T.a b c
Correlation between decreased CSF α-synuclein and Aβ1-42 in Parkinson disease
(2015) Neurobiology of Aging, 36 (1), pp. 476-484. 


a Department of Neurology, Washington University School of MedicineSt Louis, MO, United States
b Department of Developmental Biology, Washington University School of MedicineSt Louis, MO, United States
c Hope Center for Neurological Disorders, Washington University School of MedicineSt Louis, MO, United States
d Department of Radiology, Washington University School of MedicineSt Louis, MO, United States
e Department of Anatomy and Neurobiology, Washington University School of MedicineSt Louis, MO, United States
f Washington University School of MedicineSt Louis, MO, United States
g Washington University School of MedicineSt Louis, MO, United States


Abstract
Accumulation of misfolded α-synuclein (α-syn) protein in Lewy bodies and neurites is the cardinal pathologic feature of Parkinson disease (PD), but abnormal deposition of other proteins may also play a role. Cerebrospinal fluid (CSF) levels of proteins known to accumulate in PD may provide insight into disease-associated changes in protein metabolism and their relationship to disease progression. We measured CSF α-syn, amyloid β1-42 (Aβ1-42), and tau from 77 nondemented PD and 30 control participants. CSF α-syn and Aβ1-42 were significantly lower in PD compared with controls. In contrast with increased CSF tau in Alzheimer disease, CSF tau did not significantly differ between PD and controls. CSF protein levels did not significantly correlate with ratings of motor function or performance on neuropsychological testing. As expected, CSF Aβ1-42 inversely correlated with [11C]-Pittsburgh compound B (PiB) mean cortical binding potential, with PiB+ PD participants having lower CSF Aβ1-42 compared with PiB- PD participants. Furthermore, CSF α-syn positively correlated with Aβ1-42 in PD participants but not in controls, suggesting a pathophysiologic connection between the metabolisms of these proteins in PD.


Author Keywords
Aβ1-42;  Cerebrospinal fluid;  Imaging;  Nondemented;  Parkinson's disease;  PiB;  Tau;  α-Synuclein


Document Type: Article
Source: Scopus

Satoh, A.a , Brace, C.S.a , Rensing, N.b , Imai, S.-I.a
Deficiency of Prdm13, a dorsomedial hypothalamus-enriched gene, mimics age-associated changes in sleep quality and adiposity
(2015) Aging Cell, . Article in Press. 


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


Abstract
The dorsomedial hypothalamus (DMH) controls a number of essential physiological responses. We have demonstrated that the DMH plays an important role in the regulation of mammalian aging and longevity. To further dissect the molecular basis of the DMH function, we conducted microarray-based gene expression profiling with total RNA from laser-microdissected hypothalamic nuclei and tried to find the genes highly and selectively expressed in the DMH. We found neuropeptide VF precursor (Npvf), PR domain containing 13 (Prdm13), and SK1 family transcriptional corepressor (Skor1) as DMH-enriched genes. Particularly, Prdm13, a member of the Prdm family of transcription regulators, was specifically expressed in the compact region of the DMH (DMC), where Nk2 homeobox 1 (Nkx2-1) is predominantly expressed. The expression of Prdm13 in the hypothalamus increased under diet restriction, whereas it decreased during aging. Prdm13 expression also showed diurnal oscillation and was significantly upregulated in the DMH of long-lived BRASTO mice. The transcriptional activity of the Prdm13 promoter was upregulated by Nkx2-1, and knockdown of Nkx2-1 suppressed Prdm13 expression in primary hypothalamic neurons. Interestingly, DMH-specific Prdm13-knockdown mice showed significantly reduced wake time during the dark period and decreased sleep quality, which was defined by the quantity of electroencephalogram delta activity during NREM sleep. DMH-specific Prdm13-knockdown mice also exhibited progressive increases in body weight and adiposity. Our findings indicate that Prdm13/Nkx2-1-mediated signaling in the DMC declines with advanced age, leading to decreased sleep quality and increased adiposity, which mimic age-associated pathophysiology, and provides a potential link to DMH-mediated aging and longevity control in mammals.


Author Keywords
Age-associated pathophysiology;  Aging;  DMH-enriched gene;  Dorsomedial hypothalamus;  Nkx2-1;  NREM delta power;  Prdm13


Document Type: Article in Press
Source: Scopus

Few, L.R.a , Grant, J.D.a , Trull, T.J.b , Statham, D.J.c , Martin, N.G.d , Lynskey, M.T.e , Agrawal, A.a
Genetic variation in personality traits explains genetic overlap between borderline personality features and substance use disorders
Addiction, 109 (12), pp. 2118-2127. 


a Department of Psychiatry, Washington University School of MedicineSt Louis, MO, United States
b Department of Psychological Sciences, University of MissouriColumbia, MO, United States
c School of Social SciencesMaroochydore DC, QLD, Australia
d QIMR Medical Research InstituteBrisbane, Australia
e Institute of Psychiatry, King's College LondonLondon, United Kingdom


Abstract
Aims: To examine the genetic overlap between borderline personality features (BPF) and substance use disorders (SUDs) and the extent to which variation in personality traits contributes to this covariance. Design: Genetic structural equation modelling was used to partition the variance in and covariance between personality traits, BPF and SUDs into additive genetic, shared and individual-specific environmental factors. Setting: All participants were registered with the Australian Twin Registry. Participants: A total of 3127 Australian adult twins participated in the study. Measurements: Diagnoses of DSM-IV alcohol and cannabis abuse/dependence (AAD; CAD) and nicotine dependence (ND) were derived via computer-assisted telephone interview. BPF and five-factor model personality traits were derived via self-report questionnaires. Findings: Personality traits, BPF and substance use disorders were partially influenced by genetic factors with heritability estimates ranging from 0.38 (neuroticism; 95% confidence interval: 0.30-0.45) to 0.78 (CAD; 95% confidence interval: 0.67-0.86). Genetic and individual-specific environmental correlations between BPF and SUDs ranged from 0.33 to 0.56 (95% CI=0.19-0.74) and 0.19-0.32 (95% CI=0.06-0.43), respectively. Overall, there was substantial support for genetic influences that were specific to AAD, ND and CAD (30.76-68.60%). Finally, genetic variation in personality traits was responsible for 11.46% (extraversion for CAD) to 59.30% (neuroticism for AAD) of the correlation between BPF and SUDs. Conclusions: Both genetic and individual-specific environmental factors contribute to comorbidity between borderline personality features and substance use disorders. A substantial proportion of this comorbidity can be attributed to variation in normal personality traits, particularly neuroticism.


Author Keywords
Alcohol use disorders;  Borderline personality disorder;  Cannabis use disorders;  Comorbidity;  Five-factor model;  Genetics;  Nicotine dependence;  Personality traits;  Substance use disorders


Document Type: Article
Source: Scopus

Huettner, J.E.
Glutamate receptor pores
Journal of Physiology, 593 (1), pp. 49-59. Cited 1 time.


Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid AvenueSt Louis, MO, United States


Abstract
Glutamate receptors are ligand-gated ion channels that mediate fast excitatory synaptic transmission throughout the central nervous system. Functional receptors are homo- or heteromeric tetramers with each subunit contributing a re-entrant pore loop that dips into the membrane from the cytoplasmic side. The pore loops form a narrow constriction near their apex with a wide vestibule toward the cytoplasm and an aqueous central cavity facing the extracellular solution. This article focuses on the pore region, reviewing how structural differences among glutamate receptor subtypes determine their distinct functional properties.


Document Type: Article
Source: Scopus

Prichep, L.S.a , Naunheim, R.b , Bazarian, J.c , Mould, W.A.d , Hanley, D.e
Identification of hematomas in mild traumatic brain injury using an index of quantitative brain electrical activity
(2015) Journal of Neurotrauma, 32 (1), pp. 17-22. 


a NYU School of Medicine, Brain Research Laboratories, Department of PsychiatryNew York, NY, United States
b Washington University, School of Medicine, Department of Emergency MedicineSt. Louis, MO, United States
c University of Rochester, School of Medicine and Dentistry, Department of Emergency MedicineRochester, NY, United States
d Department of Clinical Research, Johns Hopkins UniversityBaltimore, MD, United States
e Division of Brain Injury Outcomes, Johns Hopkins University, School of MedicineBaltimore, MD, United States


Abstract
Rapid identification of traumatic intracranial hematomas following closed head injury represents a significant health care need because of the potentially life-threatening risk they present. This study demonstrates the clinical utility of an index of brain electrical activity used to identify intracranial hematomas in traumatic brain injury (TBI) presenting to the emergency department (ED). Brain electrical activity was recorded from a limited montage located on the forehead of 394 closed head injured patients who were referred for CT scans as part of their standard ED assessment. A total of 116 of these patients were found to be CT positive (CT+), of which 46 patients with traumatic intracranial hematomas (CT+) were identified for study. A total of 278 patients were found to be CT negative (CT-) and were used as controls. CT scans were subjected to quanitative measurements of volume of blood and distance of bleed from recording electrodes by blinded independent experts, implementing a validated method for hematoma measurement. Using an algorithm based on brain electrical activity developed on a large independent cohort of TBI patients and controls (TBI-Index), patients were classified as either positive or negative for structural brain injury. Sensitivity to hematomas was found to be 95.7% (95% CI=85.2, 99.5), specificity was 43.9% (95% CI=38.0, 49.9). There was no significant relationship between the TBI-Index and distance of the bleed from recording sites (F=0.044, p=0.833), or volume of blood measured F=0.179, p=0.674). Results of this study are a validation and extension of previously published retrospective findings in an independent population, and provide evidence that a TBI-Index for structural brain injury is a highly sensitive measure for the detection of potentially life-threatening traumatic intracranial hematomas, and could contribute to the rapid, quantitative evaluation and treatment of such patients.


Author Keywords
classifier function;  mild TBI (mTBI);  neuroimaging;  quantitative EEG (QEEG);  traumatic hematomas


Document Type: Article
Source: Scopus

Meng, H.a , Laurens, J.b , Blázquez, P.M.b , Angelaki, D.E.a
In vivo properties of cerebellar interneurons in the macaque caudal vestibular vermis
Journal of Physiology, 593 (1), pp. 321-330. 


a Department of Neuroscience, Baylor College of MedicineHouston, TX, United States
b Department of Otolaryngology, Washington University School of MedicineSt Louis, MO, United States


Abstract
The cerebellar cortex is among the brain's most well-studied circuits and includes distinct classes of excitatory and inhibitory interneurons. Several studies have attempted to characterize the in vivo properties of cerebellar interneurons, yet little is currently known about their stimulus-driven properties. Here we quantify both spontaneous and stimulus-driven responses of interneurons in lobules X (nodulus) and IXc,d (ventral uvula) of the macaque caudal vermis during vestibular stimulation. Interneurons were identified as cells located >100 μm from the Purkinje cell layer that did not exhibit complex spikes. Based on baseline firing, three types of interneurons could be distinguished. First, there was a group of very regular firing interneurons with high mean discharge rates, which consistently encoded tilt, rather than translational head movements. Second, there was a group of low firing interneurons with a range of discharge regularity. This group had more diverse vestibular properties, where most were translation-selective and a few tilt- or gravitoinertial acceleration-selective. Third, we also encountered interneurons that were similar to Purkinje cells in terms of discharge regularity and mean firing rate. This group also encoded mixtures of tilt and translation signals. A few mossy fibres showed unprocessed, otolith afferent-like properties, encoding the gravitoinertial acceleration. We conclude that tilt- and translation-selective signals, which reflect neural computations transforming vestibular afferent information, are not only encountered in Purkinje cell responses. Instead, upstream interneurons within the cerebellar cortex are also characterized by similar properties, thus implying a widespread network computation.


Document Type: Article
Source: Scopus

Madubata, C.C.a , Olsen, M.A.b c , Stwalley, D.L.b , Gutmann, D.H.d , Johnson, K.J.e
Neurofibromatosis type 1 and chronic neurological conditions in the United States: An administrative claims analysis
(2015) Genetics in Medicine, 17 (1), pp. 36-42. 


a School of Medicine, Washington UniversitySt. Louis, MO, United States
b Department of Medicine, School of Medicine, Washington UniversitySt. Louis, MO, United States
c Department of Surgery, School of Medicine, Washington UniversitySt. Louis, MO, United States
d Department of Neurology, School of Medicine, Washington UniversitySt. Louis, MO, United States
e Brown School, Washington UniversitySt. Louis, MO, United States


Abstract
Purpose:Neurofibromatosis type 1 has been linked to several neurological conditions, including epilepsy, Parkinson disease, headache, multiple sclerosis, and sleep disturbances, predominantly through case reports and patient series that lack comparison groups. Our objective was to assess whether specific neurological conditions occur more frequently in individuals with neurofibromatosis type 1 versus those without neurofibromatosis type 1. Methods:We used the 2006-2010 MarketScan Commercial Claims and Encounters database to examine associations between neurological conditions and neurofibromatosis type 1. The neurofibromatosis type 1 group was identified through ≥2 International Classification of Diseases, Ninth Revision, Clinical Modification neurofibromatosis codes (237.70, 237.71) occurring ≥30 days apart or one inpatient neurofibromatosis code. A nonneurofibromatosis type 1 comparison group was frequency matched to the neurofibromatosis type 1 group on age and enrollment length at a 10:1 ratio. Unconditional logistic regression was employed to calculate adjusted odds ratios and 95% confidence intervals for associations between neurofibromatosis and neurological conditions. Results:Compared with the nonneurofibromatosis type 1 group (n = 85,790), the neurofibromatosis type 1 group (n = 8,579) had significantly higher odds of health insurance claims for epilepsy (odds ratio: 7.3; 95% confidence interval: 6.4-8.3), Parkinson disease (odds ratio: 3.1; 95% confidence interval: 1.3-7.5), headache (odds ratio: 2.9; 95% confidence interval: 2.6-3.1), multiple sclerosis (odds ratio: 1.9; 95% confidence interval: 1.2-2.9), and sleep disturbances/disorder (odds ratio: 1.4; 95% confidence interval: 1.2-3.6). Conclusion:This large study provides strong evidence for positive associations between several neurological conditions and neurofibromatosis type 1.


Author Keywords
diabetes;  MarketScan;  neurofibromatosis type 1;  neurological conditions


Document Type: Article
Source: Scopus

Hood, A.a , Antenor-Dorsey, J.A.V.b , Rutlin, J.b , Hershey, T.b c d , Shimony, J.S.c , McKinstry, R.C.c e , Grange, D.K.e , Christ, S.E.f , Steiner, R.g h i , White, D.A.a
Prolonged exposure to high and variable phenylalanine levels over the lifetime predicts brain white matter integrity in children with phenylketonuria
(2015) Molecular Genetics and Metabolism, 114 (1), pp. 19-24. 


a Department of Psychology, Washington University, Campus Box 1125St. Louis, MO, United States
b Department of Psychiatry, Washington University School of Medicine, Campus Box 8134St. Louis, MO, United States
c Mallinckrodt Institute of Radiology, Washington University School of Medicine, Campus Box 8131St. Louis, MO, United States
d Department of Neurology, Washington University School of Medicine, Campus Box 8111St. Louis, MO, United States
e Department of Pediatrics, Washington University School of Medicine, Campus Box 8116St. Louis, MO, United States
f Department of Psychological Sciences, University of Missouri, 210 McAlester HallColumbia, MO, United States
g Department of Pediatrics, Institute on Development and Disability, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd.Portland, OR, United States
h Department of Molecular and Medical Genetics, Institute on Development and Disability, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd.Portland, OR, United States
i Marshfield Clinic Research Foundation, 1000 N. Oak St.Marshfield, WI, United States


Abstract
In this study, we retrospectively examined the microstructural white matter integrity of children with early- and continuously-treated PKU (. N=. 36) in relation to multiple indices of phenylalanine (Phe) control over the lifetime. White matter integrity was assessed using mean diffusivity (MD) from diffusion tensor imaging (DTI). Eight lifetime indices of Phe control were computed to reflect average Phe (mean, index of dietary control), variability in Phe (standard deviation, standard error of estimate, % spikes), change in Phe with age (slope), and prolonged exposure to Phe (mean exposure, standard deviation exposure). Of these indices, mean Phe, mean exposure, and standard deviation exposure were the most powerful predictors of widespread microstructural white matter integrity compromise. Findings from the two previously unexamined exposure indices reflected the accumulative effects of elevations and variability in Phe. Given that prolonged exposure to elevated and variable Phe was particularly detrimental to white matter integrity, Phe should be carefully monitored and controlled throughout childhood, without liberalization of Phe control as children with PKU age.


Author Keywords
Brain;  Diffusion tensor imaging;  Exposure;  Phenylalanine;  Phenylketonuria;  White matter


Document Type: Article
Source: Scopus

Neta, M.a , Miezin, X.M.b c g , Nelson, S.M.i , Dubis, J.W.b , Dosenbach, N.U.b , Schlaggar, B.L.b c d e , Petersen, S.E.b c e f g h
Spatial and temporal characteristics of error-related activity in the human brain
(2015) Journal of Neuroscience, 35 (1), pp. 253-266. 


a Department of Psychology, University of Nebraska-LincolnLincoln, NE, United States
b Departments of Neurology, Washington UniversitySt Louis, MO, United States
c Departments of Radiology, Washington UniversitySt Louis, MO, United States
d Departments of Pediatrics, Washington UniversitySt Louis, MO, United States
e Departments of Anatomy and Neurobiology, Washington UniversitySt Louis, MO, United States
f Departments of Neurosurgery, Washington University School of MedicineSt Louis, MO, United States
g Departments of Psychology, Washington UniversitySt Louis, MO, United States
h Departments of Biomedical Engineering, Washington UniversitySt Louis, MO, United States
i VISN 17 Center of Excellence for Research on Returning War VeteransWaco, TX, United States


Abstract
A number of studies have focused on the role of specific brain regions, such as the dorsal anterior cingulate cortex during trials on which participants make errors, whereas others have implicated a host of more widely distributed regions in the human brain. Previous work has proposed that there are multiple cognitive control networks, raising the question of whether error-related activity can be found in each of these networks. Thus, to examine error-related activity broadly, we conducted a meta-analysis consisting of 12 tasks that included both error and correct trials. These tasks varied by stimulus input (visual, auditory), response output (button press, speech), stimulus category (words, pictures), and task type (e.g., recognition memory, mental rotation). We identified 41 brain regions that showed a differential fMRI BOLD response to error and correct trials across a majority of tasks. These regions displayed three unique response profiles: (1) fast, (2) prolonged, and (3) a delayed response to errors, as well as a more canonical response to correct trials. These regions were found mostly in several control networks, each network predominantly displaying one response profile. The one exception to this “one network, one response profile” observation is the frontoparietal network, which showed prolonged response profiles (all in the right hemisphere), and fast profiles (all but one in the left hemisphere). We suggest that, in the place of a single localized error mechanism, these findings point to a large-scale set of error-related regions across multiple systems that likely subserve different functions.


Author Keywords
Error;  Functional networks;  Meta-analysis;  Resting state;  Task control


Document Type: Article
Source: Scopus

Yu, W.a , McConathy, J.b , Olson, J.J.c , Goodman, M.M.a
System a amino acid transport-targeted brain and systemic tumor PET imaging agents 2-amino-3-[18F]fluoro-2-methylpropanoic acid and 3-[18F]fluoro-2-methyl-2-(methylamino)propanoic acid
(2015) Nuclear Medicine and Biology, 42 (1), pp. 8-18. 


a Department of Radiology and Imaging Sciences, School of Medicine, Emory UniversityAtlanta, GA, United States
b Mallinckrodt Institute of Radiology, Washington University School of MedicineSt. Louis, GA, United States
c Department of Neurosurgery, School of Medicine, Emory UniversityAtlanta, GA, United States


Abstract
Introduction: Amino acid based radiotracers target tumor cells through increased uptake by membrane-associated amino acid transport (AAT) systems. In the present study, four structurally related non-natural 18F-labeled amino acids, (R)- and (S)-[18F]FAMP 1 and (R)- and (S)-[18F]MeFAMP 2 have been prepared and evaluated in vitro and in vivo for their potential utility in brain and systemic tumor imaging based upon primarily system A transport with positron emission tomography (PET). Methods: The transport of enantiomers of [18F]FAMP 1 and [18F]MeFAMP 2 was measured through in vitro uptake assays in human derived cancer cells including A549 (lung), DU145 (prostate), SKOV3 (ovary), MDA MB468 (breast) and U87 (brain) in the presence and absence of amino acid transporter inhibitors. The in vivo biodistribution of these tracers was evaluated using tumor mice xenografts at 15, 30, 60 and 120min post injection. Results: All four tracers showed moderate to high levels of uptake (1-9%ID/5×105 cells) by the cancer cell lines tested in vitro. AAT cell inhibition assays demonstrated that (R)-[18F]1 and (S)-[18F]1 entered these tumor cells via mixed AATs, likely but not limited to system A and system L. In contrast, (R)-[18F]2 and (S)-[18F]2 showed high selectivity for system A AAT. Similar to the results of in vitro cell studies, the tumor uptake of all four tracers was good to high and persisted over the 2hours time course of in vivo studies. The accumulation of these tracers was higher in tumor than most normal tissues including blood, brain, muscle, bone, heart, and lung, and the tracers with the highest in vitro selectivity for system A AAT generally demonstrated the best tumor imaging properties. Higher uptake of these tracers was observed in the pancreas, kidney and spleen compared to tumors. Conclusions: These preclinical studies demonstrate good imaging properties in a wide range of tumors for all four amino acids evaluated with (R)-[18F]2 having the highest selectivity for system A AAT.


Author Keywords
Fluorine-18;  PET;  System A amino acid transport;  Tumor imaging;  [18F]FAMP;  [18F]MeFAMP


Document Type: Article
Source: Scopus

Warrington, N.M.a , Sun, T.a , Luo, J.b , McKinstry, R.C.a c , Parkin, P.C.d , Ganzhorn, S.a , Spoljaric, D.a , Albers, A.C.e , Merkelson, A.f , Stewart, D.R.g , Stevenson, D.A.h , Viskochil, D.i , Druley, T.E.a , Forys, J.T.a , Reilly, K.M.j , Fisher, M.J.k l , Tabori, U.d , Allen, J.C.f , Schiffman, J.D.h , Gutmann, D.H.e , Rubin, J.B.a m
The cyclic AMP pathway is a sex-specific modifier of glioma risk in type I neurofibromatosis patients
(2015) Cancer Research, 75 (1), pp. 16-21. 


a Division of Pediatric Hematology/Oncology, Department of Pediatrics, Washington University School of MedicineSaint Louis, MO, United States
b Division of Biostatistics, Washington University School of MedicineSaint Louis, MO, United States
c Mallinckrodt Institute of Radiology, Washington University School of MedicineSaint Louis, MO, United States
d Department of Pediatrics, Hospital for Sick Children, University of TorontoToronto, ON, Canada
e Department of Neurology, Washington University School of MedicineSaint Louis, MO, United States
f Department of Pediatrics, New York University Langone Medical CenterNew York, NY, United States
g Clinical Genetics Branch, National Cancer Institute, NIHRockville, MD, United States
h Division of Medical Genetics, University of UtahSalt Lake City, UT, United States
i Huntsman Cancer Institute, University of UtahSalt Lake City, UT, United States
j Rare Tumors Initiative, Center for Cancer Research, National Cancer Institute, NCIBethesda, MD, United States
k Division of Oncology, Children's Hospital of PhiladelphiaPA, United States
l Department of Pediatrics, Perelman School of Medicine, University of PennsylvaniaPhiladelphia, PA, United States
m Department of Anatomy and Neurobiology, Washington University School of MedicineSaint Louis, MO, United States


Abstract
Identifying modifiers of glioma risk in patients with type neurofibromatosis (NF1) could help support personalized tumor surveillance, advance understanding of gliomagenesis, and potentially identify novel therapeutic targets. Here, we report genetic polymorphisms in the human adenylate cyclase gene adenylate cyclase 8 (ADCY8) that correlate with glioma risk in NF1 in a sex-specific manner, elevating risk in females while reducing risk in males. This finding extends earlier evidence of a role for cAMP in gliomagenesis based on results in a genetically engineered mouse model (Nf1 GEM). Thus, sexually dimorphic cAMP signaling might render males and females differentially sensitive to variation in cAMP levels. Using male and female Nf1 GEM, we found significant sex differences exist in cAMP regulation and in the growth-promoting effects of cAMP suppression. Overall, our results establish a sex-specific role for cAMP regulation in human gliomagenesis, specifically identifying ADCY8 as a modifier of glioma risk in NF1.


Document Type: Article
Source: Scopus

Sharkey, E.K.a , Zoellner, N.L.a , Abadin, S.a , Gutmann, D.H.b , Johnson, K.J.a
Validity of participant-reported diagnoses in an online patient registry: A report from the NF1 Patient Registry Initiative
(2015) Contemporary Clinical Trials, 40, pp. 392-404. 


a Brown School, Washington UniversitySt. Louis, MO, United States
b Department of Neurology, Washington University School of MedicineSt. Louis, MO, United States


Abstract
Background: With increased internet accessibility worldwide, it is now possible to assemble individuals with rare diseases through web-based patient registries. However, the validity of participant-reported medical diagnoses is unknown. The objective of this study was to evaluate the accuracy of participant-reported Neurofibromatosis Type 1 (NF1) diagnoses among participants in the NF1 Patient Registry Initiative (NPRI). Methods: Subjects enrolled in the NPRI from 5/17/2011 to 7/7/2014 were included. Medical records (MRs) were obtained for participants who returned medical record release forms (MRRFs) during the study period. Participants were classified as having definite, probable, suspected, or no NF1 diagnosis based on MR information. To assess whether a returned MRRF served as a reliable marker of MR-documented NF1, we calculated the positive predictive value (PPV) as the proportion of individuals with MR-documented NF1 among those from whom MRs were obtained. We further examined whether a returned MRRF predicted the number of reported NF1 clinical signs in multivariable linear regression analyses. Results: A total of 1456 individuals were included in the analyses. Of 416 individuals who returned MRRFs, 205 MRs were reviewed within the study period. The PPV ranged from 72.0 to 98.5% when including definite or definite/probable/suspected cases, respectively. The mean number of reported NF1 clinical signs was similar between those who returned (mean. =. 3.3. ±. 1.2) and did not return (mean. =. 3.2. ±. 1.3) their MRRFs. MRRF return was not a significant predictor of the number of NF1 clinical signs after adjusting for covariates. Conclusion: These data strongly suggest that individuals enrolling in the NPRI accurately report their NF1 diagnosis.


Author Keywords
Brain tumor;  Medical records;  Neurofibromatosis Type 1 (NF1);  Rare disease;  Registry;  Validity


Document Type: Article
Source: Scopus

Malcolm, H.R.a , Heo, Y.-Y.b , Elmore, D.E.b , Maurer, J.A.a
Heteromultimerization of prokaryotic bacterial cyclic nucleotide-gated (bCNG) ion channels, members of the mechanosensitive channel of small conductance (MscS) superfamily
(2014) Biochemistry, 53 (51), pp. 8005-8007. 


a Department of Chemistry, Washington University in St. LouisSt. Louis, MO, United States
b Department of Chemistry, Wellesley CollegeWellesley, MA, United States


Abstract
Traditionally, prokaryotic channels are thought to exist as homomultimeric assemblies, while many eukaryotic ion channels form complex heteromultimers. Here we demonstrate that bacterial cyclic nucleotide-gated channels likely form heteromultimers in vivo. Heteromultimer formation is indicated through channel modeling, pull-down assays, and real-time polymerase chain reaction analysis. Our observations demonstrate that prokaryotic ion channels can display complex behavior and regulation akin to that of their eukaryotic counterparts.


Document Type: Article
Source: Scopus

Fürst, O.a , Nichols, C.G.b , Lamoureux, G.c , Davanzo, N.a
Identification of a cholesterol-binding pocket in inward rectifier K+ (Kir) channels
(2014) Biophysical Journal, 107 (12), pp. 2786-2796. 


a Département de Physiologie Moléculaire et Intégrative, Groupe d'Étude des Protéines Membranaires (GÉPROM), Université de MontréalMontreal, QC, Canada
b Department of Cell Biology and Physiology, Washington University, School of MedicineSt. Louis, MO, United States
c Department of Chemistry and Biochemistry, Centre for Research in Molecular Modeling (CERMM), Concordia UniversityMontreal, QC, Canada


Abstract
Cholesterol is the major sterol component of all mammalian plasma membranes. Recent studies have shown that cholesterol inhibits both bacterial (KirBac1.1 and KirBac3.1) and eukaryotic (Kir2.1) inward rectifier K+ (Kir) channels. Lipid-sterol interactions are not enantioselective, and the enantiomer of cholesterol (ent-cholesterol) does not inhibit Kir channel activity, suggesting that inhibition results from direct enantiospecific binding to the channel, and not indirect effects of changes to the bilayer. Furthermore, conservation of the effect of cholesterol among prokaryotic and eukaryotic Kir channels suggests an evolutionary conserved cholesterol-binding pocket, which we aimed to identify. Computational experiments were performed by docking cholesterol to the atomic structures of Kir2.2 (PDB: 3SPI) and KirBac1.1 (PDB: 2WLL) using Autodock 4.2. Poses were assessed to ensure biologically relevant orientation and then clustered according to location and orientation. The stability of cholesterol in each of these poses was then confirmed by molecular dynamics simulations. Finally, mutation of key residues (S95H and I171L) in this putative binding pocket found within the transmembrane domain of Kir2.1 channels were shown to lead to a loss of inhibition by cholesterol. Together, these data provide support for this location as a biologically relevant pocket.


Document Type: Article
Source: Scopus

Bittel, D.C.a , Bittel, A.J.a , Tuttle, L.J.b , Hastings, M.K.a , Commean, P.K.a , Mueller, M.J.a , Cade, W.T.a , Sinacore, D.R.a
Adipose tissue content, muscle performance and physical function in obese adults with type 2 diabetes mellitus and peripheral neuropathy
(2014) Journal of Diabetes and its Complications, . Article in Press. 


a Program in Physical Therapy, Washington University School of Medicine, 4444 Forest Park Ave, St Louis, MO, 63110
b Doctor of Physical Therapy Program, School of Exercise and Nutritional Sciences, San Diego State University, 5500 Campanile Dr, San Diego, CA, 92182


Abstract
Aims: To determine leg intermuscular (IMAT) and subcutaneous (SQAT) adipose tissue and their relationships with muscle performance and function in obese adults with and without type 2 diabetes and peripheral neuropathy (T2DMPN). Methods: Seventy-nine age-matched obese adults were studied, 13 T2DM, 54 T2DMPN, and 24 obese controls. Leg fat (%IMAT, %SQAT) volumes were quantified using MRI. Ankle plantar flexion (PF) torque and power were assessed with isokinetic dynamometry. Physical function was assessed with 9-item Physical Performance Test (PPT), 6-minute walk distance, single-limb balance, and time to ascend 10 stairs. One-way ANOVAs determined group differences, and multiple regression predicted PPT score from disease status, % IMAT, and PF power. Results: T2DMPN participants had 37% greater IMAT volumes and 15% lower SQAT volumes than controls (p = 01). T2DMPN and T2DM showed reduced PF torque and power compared to controls. T2DMPN participants had lower PPT score, 6-minute walk, single-limb balance, and stair climbing than controls (all p. &#60;. .05). %IMAT volume correlated inversely, and %SQAT correlated directly, with PPT. Leg %IMAT and disease status predicted 49% of PPT score. Conclusions: T2DMPN may represent a shift in adipose tissue accumulation from SQAT to IMAT depots, which is inversely associated with muscle performance and physical function.


Author Keywords
Adipose tissue;  Diabetes;  Muscle;  Neuropathy;  Physical function


Document Type: Article in Press
Source: Scopus

Levinson, C.A.a , Rapp, J.b , Riley, E.N.a
Addressing the fear of fat: extending imaginal exposure therapy for anxiety disorders to anorexia nervosa
(2014) Eating and Weight Disorders, 19 (4), pp. 521-524. 


a Washington University in St. Louis, 1 Brookings Drive, Campus Box 1125St. Louis, MO, United States
b McCallum Place Eating Disorder Treatment CenterSt. Louis, United States


Document Type: Article
Source: Scopus

Wolf, T.J.a , Chuh, A.a , Floyd, T.b , McInnis, K.a , Williams, E.a
Effectiveness of occupation-based interventions to improve areas of occupation and social participation after stroke: An evidence-based review
(2014) American Journal of Occupational Therapy, 69 (1), art. no. 2087151, . 


a Program in Occupational Therapy, School of Medicine, Washington UniversitySt. Louis, MO, United States
b U.S. Army, Warrior Transition BattalionFort Belvoir, VA, United States


Abstract
This evidence-based review examined the evidence supporting the use of occupation-based interventions to improve areas of occupation and social participation poststroke. A total of 39 studies met the inclusion criteria and were critically evaluated. Most of the literature targeted activity of daily living (ADL)-based interventions and collectively provided strong evidence for the use of occupation-based interventions to improve ADL performance. The evidence related to instrumental ADLs was much more disparate, with limited evidence to support the use of virtual reality interventions and emerging evidence to support driver education programs to improve occupational performance poststroke. Only 6 studies addressed leisure, social participation, or rest and sleep, with sufficient evidence to support only leisure-based interventions. The implications of this review for research, education, and practice in occupational therapy are also discussed.


Author Keywords
Activities of daily living;  Evaluation studies as topic;  Human activities;  Social participation;  Stroke


Document Type: Review
Source: Scopus

Herzog, E.D.a , Kiss, I.Z.b , Mazuski, C.a
Measuring Synchrony in the Mammalian Central Circadian Circuit
(2014) Methods in Enzymology, . Article in Press. 


a Department of Biology, Washington University, St. Louis, Missouri, USA
b Department of Chemistry, Saint Louis University, St. Louis, Missouri, USA


Abstract
Circadian clocks control daily rhythms in physiology and behavior across all phyla. These rhythms are intrinsic to individual cells that must synchronize to their environment and to each other to anticipate daily events. Recent advances in recording from large numbers of cells for many circadian cycles have enabled researchers to begin to evaluate the mechanisms and consequences of intercellular circadian synchrony. Consequently, methods have been adapted to estimate the period, phase, and amplitude of individual circadian cells and calculate synchrony between cells. Stable synchronization requires that the cells share a common period. As a result, synchronized cells maintain constant phase relationships to each (e.g., with cell 1 peaking an hour before cell 2 each cycle). This chapter reviews how circadian rhythms are recorded from single mammalian cells and details methods for measuring their period and phase synchrony. These methods have been useful, for example, in showing that specific neuropeptides are essential to maintain synchrony among circadian cells.


Author Keywords
Circadian;  Fourier transform;  Period gene;  Rayleigh plot;  Synchronization Index;  Vasoactive intestinal polypeptide


Document Type: Article in Press
Source: Scopus

Giglio, V.a b , Puddu, P.E.c , Holland, M.R.d , Camastra, G.e , Ansalone, G.e , Ricci, E.a f , Mela, J.g , Sciarra, F.a , Di Gennaro, M.b
Ultrasound Tissue Characterization Does Not Differentiate Genotype, But Indexes Ejection Fraction Deterioration in Becker Muscular Dystrophy
(2014) Ultrasound in Medicine and Biology, 40 (12), pp. 2777-2785. 


a Centre for Neuromuscular Diseases, Unione Italiana Lotta alla Distrofia Muscolare (UILDM)Rome, Italy
b Cardiology Division and ICU, Ospedale San Paolo, CivitavecchiaRome, Italy
c Laboratory of Biotechnologies Applied to Cardiovascular Medicine, Department of Cardiovascular, Respiratory, Nephrological and Geriatrical Sciences, La Sapienza, University of RomeRome, Italy
d Physics Department, Washington UniversitySt Louis, MO, United States
e Cardiology Division and ICU, Ospedale Madre Giuseppina VanniniRome, Italy
f Neurology Institute, Catholic UniversityRome, Italy
g Muscular Dystrophy Research Unit, UILDMRome, Italy


Abstract
The aims of the study were, first, to assess whether myocardial ultrasound tissue characterization (UTC) in Becker muscular dystrophy (BMD) can be used to differentiate between patients with deletions and those without deletions; and second, to determine whether UTC is helpful in diagnosing the evolution of left ventricular dysfunction, a precursor of dilated cardiomyopathy. Both cyclic variation of integrated backscatter and calibrated integrated backscatter (cIBS) were assessed in 87 patients with BMD and 70 controls. The average follow-up in BMD patients was 48 ± 12mo. UTC analysis was repeated only in a subgroup of 40 BMD patients randomly selected from the larger overall group (15 with and 25 without left ventricular dysfunction). Discrimination between BMD patients with and without dystrophin gene deletion was not possible on the basis of UTC data: average cvIBS was 5.2±1.2 and 5.5±1.4dB, and average cIBS was 29.9±4.7 and 29.6±5.8, respectively, significantly different (p<0.001) only from controls (8.6±0.5 and 24.6±1.2dB). In patients developing left ventricular dysfunction during follow-up, cIBS increased to 31.3±5.4dB, but not significantly (p=0.08). The highest cIBS values (34.6±5.3dB, p<0.09 vs. baseline, p<0.01 vs BMD patients without left ventricular dysfunction) were seen in the presence of severe left ventricular dysfunction. Multivariate statistics indicated that an absolute change of 6dB in cIBS is associated with a high probability of left ventricular dysfunction. UTC analysis does not differentiate BMD patients with or without dystrophin gene deletion, but may be useful in indexing left ventricular dysfunction during follow-up.


Author Keywords
Becker muscular dystrophy;  Cardiomyopathy;  Genetics;  Myocardial tissue characterization

 


Document Type: Article
Source: Scopus

 

January 8, 2015

Izumi, Y., Zorumski, C.F.
Sensitivity of N-Methyl-D-Aspartate receptor-mediated excitatory postsynaptic potentials and synaptic plasticity to TCN 201 and TCN 213 in rat hippocampal slices
(2015) Journal of Pharmacology and Experimental Therapeutics, 352 (2), art. no. A11, pp. 267-273. 


Department of Psychiatry, Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, 660 South Euclid AvenueSt. Louis, MO, United States


Abstract
Whereas ifenprodil has been used as a selective GluN1/GluN2B (NR1/NR2B, B-type) receptor antagonist to distinguish between GluN2B (NR2B) and GluN2A (NR2A)-containing N-methyl-Daspartate receptors (NMDARs), TCN 201 (3-chloro-4-fluoro-N-[4-[[2-(phenylcarbonyl)hydrazino]carbonyl]benzyl]benzenesulphonamide) and TCN 213 [N-(cyclohexylmethyl)-2-[{5-[(phenylmethyl)amino]-1,3,4-thiadiazol-2-yl}thio]acetamide] have been found to be selective GluN1/GluN2A (NR1/NR2A, A-type) antagonists. Based on the premise that A- and B-types are major synaptic NMDARs, we examined whether inhibition of NMDAR excitatory postsynaptic potentials (EPSPs) by the TCN compounds and ifenprodil are complementary. Contrary to this prediction, inhibition of NMDAR EPSPs by the TCN compounds and ifenprodil were largely overlapping in the CA1 region of hippocampal slices from 30-day-old rats. After partial inhibition by ifenprodil, TCN compounds produced little further suppression of NMDAR EPSPs. Similarly, after partial inhibition by TCN compounds ifenprodil failed to further suppress NMDAR EPSPs. However, low micromolar D-2-amino-5-phosphonovalerate, a competitive NMDAR antagonist,which alone only partially inhibitsNMDAR EPSPs, markedly suppresses residual NMDAR responses in the presence of ifenprodil or the TCNs, suggesting that low 2-amino-5-phosphonovalerate antagonizes both ifenprodil- and TCN-insensitive synaptic NMDARs. These observations can be most readily interpreted if ifenprodil and TCNs act on a similar population of synaptic NMDARs. Recent lines of evidence suggest that the majority of hippocampal synaptic NMDARs are triheteromers. If so, modulation of GluN2A, and not just GluN2B NMDARs, could dampen long-term depression (LTD). Indeed, both TCNs, like ifenprodil, blocked LTD, suggesting the involvement of ifenprodil- and TCN-sensitive NMDARs in LTD induction. However, the TCNs plus ifenprodil failed to inhibit long-term potentiation (LTP), suggesting that neither ifenprodil- nor TCN-sensitive NMDARs are essential for LTP induction.


Document Type: Article
Source: Scopus

Sobaco, A.a , Treiman, R.b , Peereman, R.c , Borchardt, G.d , Pacton, S.a
The influence of graphotactic knowledge on adults’ learning of spelling
(2014) Memory and Cognition, 12 p. Article in Press. 


a Institut de Psychologie, Université Paris Descartes, INSERM U894, Centre de Psychiatrie et NeurosciencesParis, France
b Psychology Department, Washington University in St. LouisSt. Louis, MO, United States
c Psychology Department, Université Grenoble AlpesGrenoble, France
d Psychology Department, Université de NîmesMontpellier, France


Abstract
Three experiments investigated whether and how the learning of spelling by French university students is influenced by the graphotactic legitimacy of the spellings. Participants were exposed to three types of novel spellings: AB, which do not contain doublets (e.g., guprane); AAB, with a doublet before a single consonant, which is legitimate in French (e.g., gupprane); and ABB, with a doublet after a single consonant, which is illegitimate (e.g., guprrane). In Experiment 1, the nonwords were embedded within texts that participants read for meaning. In Experiment 2, participants read the nonwords in isolation, with or without instruction to memorize their spellings; they copied the nonwords in Experiment 3. In all of these conditions, AB and AAB spellings were learned more readily than ABB spellings. Although participants were highly knowledgeable about the illegitimacy of ABB spellings, the orthographic distinctiveness of these spellings did not make them easier to recall than legitimate spellings. When recalling ABB spellings, participants sometimes made transposition errors, doubling the wrong consonant of a cluster (e.g., spelling gupprane instead of guprrane). Participants almost never transposed the doubling for AAB items. Transposition errors, biased in the direction of replacing illegitimate with legitimate orthographic patterns, show that graphotactic knowledge influences memory for specific items. An analysis of the spellings produced in the copy phase and final recall test of Experiment 3 further suggests that transposition errors resulted not so much from reconstructive processes at the time of recall but from reconstructive processes or inefficient encoding at earlier points.


Author Keywords
Graphotactic regularities;  Implicit learning;  Reading;  Recall;  Spelling;  Statistical learning


Document Type: Article in Press
Source: Scopus

Green, R.C.a b , Christensen, K.D.a , Cupples, L.A.c , Relkin, N.R.d , Whitehouse, P.J.e , Royal, C.D.M.f , Obisesan, T.O.g , Cook-Deegan, R.h , Linnenbringer, E.i , Butson, M.B.e , Fasaye, G.-A.j , Levinson, E.k , Roberts, J.S.l
A randomized noninferiority trial of condensed protocols for genetic riskdisclosure of Alzheimer's disease
(2014) Alzheimer's and Dementia, . Article in Press. 


a Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
b Partners Personalized Medicine, Boston, MA, USA
c Departments of Biostatistics and Epidemiology, Boston University School of Public Health, Boston, MA, USA
d Department of Neurology, Weill Medical College of Cornell University, New York, NY, USA
e Department of Neurology, Case Western Reserve University, Cleveland, OH, USA
f Department of African and African American Studies, Duke University, Durham, NC, USA
g Department of Medicine, Howard University School of Medicine, Washington, DC, USA
h Sanford School of Public Policy, Duke University, Durham, NC, USA
i Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA
j Walter Reed National Military Medical Center, Bethesda, MD, USA
k Department of Surgery, Columbia University, New York, NY, USA
l Department of Health Behavior and Health Education, University of Michigan School of Public Health, Ann Arbor, MI, USA


Abstract
Background: Conventional multisession genetic counseling is currently recommended when disclosing APOE genotype for the risk of Alzheimer's disease (AD) in cognitively normal individuals. Objective: To evaluate the safety of brief disclosure protocols for disclosing APOE genotype for the risk of AD. Methods: A randomized, multicenter noninferiority trial was conducted at four sites. Participants were asymptomatic adults having a first-degree relative with AD. A standard disclosure protocol by genetic counselors (SP-GC) was compared with condensed protocols, with disclosures by genetic counselors (CP-GC) and by physicians (CP-MD). Preplanned co-primary outcomes were anxiety and depression scales 12months after disclosure. Results: Three hundred and forty-three adults (mean age 58.3, range 33-86years, 71% female, 23% African American) were randomly assigned to the SP-GC protocol (n=115), CP-GC protocol (n=116), or CP-MD protocol (n=112). Mean postdisclosure scores on all outcomes were well below cut-offs for clinical concern across protocols. Comparing CP-GC with SP-GC, the 97.5% upper confidence limits at 12months after disclosure on co-primary outcomes of anxiety and depression ranged from a difference of 1.2 to 2.0 in means (all P&#60;.001 on noninferiority tests), establishing noninferiority for condensed protocols. Results were similar between European Americans and African Americans. Conclusions: These data support the safety of condensed protocols for APOE disclosure for those free of severe anxiety or depression who are actively seeking such information.


Author Keywords
Alzheimer;  APOE;  Genetics;  Genomics;  Personalized medicine;  Risk assessment


Document Type: Article in Press
Source: Scopus

Zhou, D.a , Zhang, Z.b , He, L.-M.b , Du, J.a , Zhang, F.a , Sun, C.-K.a , Zhou, Y.a , Wang, X.-W.a , Lin, G.c , Song, K.-M.d , Wu, L.-G.b , Yang, Q.a
Conversion of Fibroblasts to Neural Cells by p53 Depletion
(2014) Cell Reports, 9 (6), pp. 2034-2042. 


a Cancer Biology Division, Washington University School of MedicineSaint Louis, MO, United States
b Synaptic Transmission Section, NINDS/NIHBethesda, MD, United States
c Institute of Reproductive and Stem Cell Engineering, Central South UniversityChangsha, China
d Research Biotechnology Business Unit, Sigma-Aldrich CorporationSt. Louis, MO, United States


Abstract
Conversion from fibroblasts to neurons has recently been successfully induced. However, the underlying mechanisms are poorly understood. Here, we find that depletion of p53 alone converts fibroblasts into all three major neural lineages. The induced neuronal cells express multiple neuron-specific proteins and generate action potentials and transmitter-receptor-mediated currents. Surprisingly, depletion does not affect the well-known tumorigenic p53 target, p21. Instead, knockdown of p53 upregulates neurogenic transcription factors, which in turn boosts fibroblast-neuron conversion. p53 binds the promoter of the neurogenic transcription factor Neurod2 and regulates its expression during fibroblast-neuron conversion. Furthermore, our method provides a high efficiency of conversion in late-passage fibroblasts. Genome-wide transcriptional analysis shows that the p53-deficiency-induced neurons exhibit an expression profile different from parental fibroblasts and similar to control-induced neurons. The results may help to understand and improve neural conversion mechanisms to develop robust neuron-replacement therapy strategies.


Document Type: Article
Source: Scopus

Bui, D.C., Maddox, G.B., Zou, F., Hale, S.S.
Examining the lag effect under incidental encoding: Contributions of semantic priming and reminding
(2014) Quarterly Journal of Experimental Psychology, 67 (11), pp. 2134-2148. 


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


Abstract
Memory is better when repeated learning events are spaced than when they are massed (spacing effect), as well as when material is processed semantically than when it is processed graphemically (levels-of-processing effect). Examination of the relationship between levels of processing and spacing for both deeply and shallowly encoded items has shown a spacing effect for items processed deeply, but not shallowly. A semantic priming account of spacing was proposed to explain the interaction between levels of processing and spacing on memory. The current study manipulated levels of processing and the amount of spacing (lag) that occurred between repetitions of items that were incidentally encoded. Results from Experiments 1A and 1B revealed lag effects in test performance when items were deeply and shallowly encoded. Although these findings are inconsistent with a semantic priming account, they can be interpreted within a reminding account, which is explored in Experiment 2. Results from the second experiment indicate that bringing reminding under conscious control benefited items that were presented at a long lag but not at a shorter lag. Together, this study provides evidence that is difficult to accommodate with a semantic priming account of spacing and instead provides additional support for a reminding account suggesting that automatic and controlled processes may both underlie the reminding process.


Author Keywords
Lag effect;  Levels of processing;  Reminding;  Semantic priming;  Spacing effect


Document Type: Article
Source: Scopus

Ma, Y.a , Smith, C.E.a , Lai, C.-Q.a , Irvin, M.R.b , Parnell, L.D.a , Lee, Y.-C.a , Pham, L.a , Aslibekyan, S.b , Claas, S.A.b , Tsai, M.Y.c , Borecki, I.B.d , Kabagambe, E.K.e , Berciano, S.f , Ordovás, J.M.a f g , Absher, D.M.h , Arnett, D.K.b
Genetic variants modify the effect of age on APOE methylation in the Genetics of Lipid Lowering Drugs and Diet Network study
(2014) Aging Cell, . Article in Press. 


a Nutrition and Genomics Laboratory Jean Mayer US Department of Agriculture Human Nutrition Research Center on Aging at Tufts University Boston, MA USA
b Department of Epidemiology University of Alabama at Birmingham Birmingham, AL USA
c Department of Laboratory Medicine and Pathology University of Minnesota Minneapolis, MN USA
d Department of Genetics Washington University School of Medicine St. Louis, MO USA
e Department of Medicine Vanderbilt University Nashville, TN USA
f Instituto Madrileño de Estudios Avanzados en Alimentacio´n (IMDEA-FOOD) Madrid Spain
g Department of Epidemiology Centro Nacional Investigaciones Cardiovasculares (CNIC) Madrid Spain
h Hudson Alpha Institute for Biotechnology Huntsville, AL USA


Abstract
Although apolipoprotein E (APOE) variants are associated with age-related diseases, the underlying mechanism is unknown and DNA methylation may be a potential one. With methylation data, measured by the Infinium Human Methylation 450 array, from 993 participants (age ranging from 18 to 87 years) in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study, and from Encyclopedia of DNA Elements (ENCODE) consortium, combined with published methylation datasets, we described the methylation pattern of 13 CpG sites within APOE locus, their correlations with gene expression across cell types, and their relationships with age, plasma lipids, and sequence variants. Based on methylation levels and the genetic regions, we categorized the 13 APOE CpG sites into three groups: Group 1 showed hypermethylation (> 50%) and were located in the promoter region, Group 2 exhibited hypomethylation (&#60; 50%) and were located in the first two exons and introns, and Group 3 showed hypermethylation (> 50%) and were located in the exon 4. APOE methylation was negatively correlated with gene expression (minimum r = -0.66, P = 0.004). APOE methylation was significantly associated with age (minimum P = 2.06E-08) and plasma total cholesterol (minimum P = 3.53E-03). Finally, APOE methylation patterns differed across APOE ε variants (minimum P = 3.51E-05) and the promoter variant rs405509 (minimum P = 0.01), which further showed a significant interaction with age (P = 0.03). These findings suggest that methylation may be a potential mechanistic explanation for APOE functions related to aging and call for further molecular mechanistic studies.


Author Keywords
Age;  Apolipoprotein E;  DNA methylation;  Epidemiology;  Interaction;  Variants


Document Type: Article in Press
Source: Scopus

Musiek, E.S.
Protein clearance ain't what it used to be
(2014) Science Translational Medicine, 6 (268), p. 268ec220. 


Department of Neurology, Washington University School of MedicineSt. Louis, MO, United States


Document Type: Editorial
Source: Scopus

Engelhardt, E.a , Inder, T.E.b , Alexopoulos, D.c , Dierker, D.L.d , Hill, J.e , Van Essen, D.d , Neil, J.J.f
Regional impairments of cortical folding in premature infants
(2014) Annals of Neurology, . Article in Press. 


a School of Medicine, University of MissouriColumbia, MO
b Department of Pediatric Newborn MedicineBrigham and Women's HospitalBoston, MA
c Department of NeurologySt Louis Children's Hospital, Washington University School of MedicineSt Louis, MO
d Department of Anatomy and NeurobiologyWashington University School of MedicineSt Louis, MO
e Department of Emergency MedicineNew York-Presbyterian HospitalNew York, NY
f Department of NeurologyBoston Children's HospitalBoston, MA


Abstract
Objective: This study was undertaken to evaluate the influence of preterm birth and other factors on cerebral cortical maturation. Methods: We have evaluated the effects of preterm birth on cortical folding by applying cortical cartography methods to a cohort of 52 preterm infants (&amp;#60;31 weeks gestation, mild or no injury on conventional magnetic resonance imaging) and 12 term-born control infants. All infants were evaluated at term-equivalent postmenstrual age. Results: Preterm infants had lower values for the global measures of gyrification index (GI; 2.06±0.07 vs 1.80±0.12, p&amp;#60;0.001; control vs preterm) and cortical surface area (CSA; 316±24 cm2 vs 257±40 cm2, p&amp;#60;0.001). Regional analysis of sulcal depth and cortical shape showed the greatest impact of preterm birth on the insula, superior temporal sulcus, and ventral portions of the pre- and postcentral sulci in both hemispheres. Although CSA and GI are related, CSA was more sensitive to antenatal and postnatal factors than GI. Both measures were lower in preterm infants of lower birth weight standard deviation scores and smaller occipitofrontal circumference at time of scan, whereas CSA alone was lower in association with smaller occipitofrontal circumference at birth. CSA was also lower in infants with higher critical illness in the first 24 hours of life, exposure to postnatal steroids, and prolonged endotracheal intubation. Interpretation: Preterm birth disrupts cortical development in a regionally specific fashion with abnormalities evident by term-equivalent postmenstrual age. This disruption is influenced by both antenatal growth and postnatal course.


Document Type: Article in Press
Source: Scopus

Sheline, Y.I.a , West, T.b , Yarasheski, K.c , Jasielec, M.S.d , Hettinger, J.C.e f g , Tripoli, D.L.e f g , Xiong, C.d f , Frederiksen, C.h , Grzelak, M.V.f , Bateman, R.J.e f g , Morris, J.C.e f , Lee, J.-M.e f g , Cirrito, J.R.e f g
Reply to comment on "an antidepressant decreases CSF Aβ production in healthy individuals and in transgenic AD mice"
(2014) Science Translational Medicine, 6 (268), . 


a Departments of Psychiatry, Radiology, and Neurology, University of PennsylvaniaPhiladelphia, PA, United States
b C2N Diagnostics LLCSt. Louis, MO, United States
c Department of Medicine, Washington UniversitySt. Louis, MO, United States
d Department of Biostatistics, Washington UniversitySt. Louis, MO, United States
e Department of Neurology, Washington UniversitySt. Louis, MO, United States
f Knight Alzheimer's Disease Research Center, Washington University Medical CenterSt. Louis, MO, United States
g Hope Center for Neurological Disorders, Washington UniversitySt. Louis, MO, United States
h Department of Surgery, Washington UniversitySt. Louis, MO, United States

 Document Type: Letter
Source: Scopus