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Neuroscience Publications Archive - November 2016

 November 4, 2016



Finley, J.R., Sungkhasettee, V.W., Roediger, H.L., III, Balota, D.A.
Relative contributions of semantic and phonological associates to over-additive false recall in hybrid DRM lists
(2017) Journal of Memory and Language, 93, pp. 154-168. 

DOI: 10.1016/j.jml.2016.07.006

Department of Psychological and Brain Sciences, Washington University in St. Louis, United States

Two experiments explored false recall of unstudied critical items (e.g., chair) following the presentation of 16 semantic associates to the critical word (e.g., sit, desk), 16 phonological associates to the critical word (e.g., cheer, hair), and every composition of hybrid list in between (e.g., 14 semantic and 2 phonological associates). Results replicated the over-additive pattern of critical false recall from hybrid lists relative to pure lists found by Watson, Balota, and Roediger (2003) and clarified the form of the false recall function across varying degrees of hybridization. Both experiments showed that including just one or two of the other type of associate in an otherwise pure list led to a considerable increase in false recall. A within-subjects design (Experiment 1) suggested that after this initial rapid increase, false recall continued to increase gradually to an apex at the balanced hybrid list composition, whereas a between-subjects design (Experiment 2) showed that false recall plateaued after the initial rapid increase and that the overall shape of the function is a ziggurat. Furthermore, the function is roughly symmetrical; semantic and phonological associates appear to make equivalent contributions to over-additive false recall from hybrid lists. The results provide constraints on theoretical accounts of DRM false memories, and can be accommodated by a modified activation/monitoring framework. © 2016 Elsevier Inc.

Author Keywords
DRM paradigm;  False memory;  Hybrid list;  Phonological processing;  Semantic processing

Document Type: Article
Source: Scopus


Opladen, T.a , Cortès-Saladelafont, E.b , Mastrangelo, M.c , Horvath, G.d , Pons, R.e , Lopez-Laso, E.f , Fernández-Ramos, J.A.f , Honzik, T.g , Pearson, T.h , Friedman, J.i , Scholl-Bürgi, S.j , Wassenberg, T.k , Jung-Klawitter, S.a , Kuseyri, O.a , Jeltsch, K.a , Kurian, M.A.l , Garcia-Cazorla, À.b
The International Working Group on Neurotransmitter related Disorders (iNTD): A worldwide research project focused on primary and secondary neurotransmitter disorders
(2016) Molecular Genetics and Metabolism Reports, 9, pp. 61-66. 

DOI: 10.1016/j.ymgmr.2016.09.006

a Division of Child Neurology and Metabolic Diseases, University Children‘s Hospital Heidelberg, Germany
b Department of Child Neurology, Neurometabolic Unit, CIBERER-ISCIII, Hospital Sant Joan de Déu Barcelona, Spain
c Department of Pediatrics and Child Neuropsychiatry, Sapienza Università di Roma, Rome, Italy
d Division of Biochemical Diseases, Childrens Hospital, Vancouver, BC, Canada
e First Department of Pediatrics, Pediatric Neurology Unit, Agia Sofia Hospital, National and Kapodistrian University of Athens, Athens, Greece
f Department of Pediatric Neurology, Reina Sofia University Hospital, Maimonides Biomedical Research Institute of Cordoba (IMIBIC), University of Cordoba, CIBERER-ISCIII, Cordoba, Spain
g Dep. of Pediatrics, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic
h Department of Neurology, Washington University School of Medicine, St. Louis, United States
i Department of Neurosciences, University of California San Diego, Division of Neurology Rady Children's Hospital, Rady Children's Institute Genomic Medicine, San Diego, United States
j Department of Pediatrics I, Inherited Metabolic Disorders, Medical University of Innsbruck, Anichstrasse 35, Innsbruck, Austria
k Department of Neurology and Child Neurology, Radboudumc Nijmegen, Donders Institute of Brain Cognition and Behaviour, Netherlands
l Developmental Neurosciences, UCL- Institute of Child Health and Department of Neurology, Great Ormond Street Hospital for Children NHS Foundations Trust, London, United Kingdom

Introduction Neurotransmitters are chemical messengers that enable communication between the neurons in the synaptic cleft. Inborn errors of neurotransmitter biosynthesis, breakdown and transport are a group of very rare neurometabolic diseases resulting in neurological impairment at any age from newborn to adulthood. Methods and results The International Working Group on Neurotransmitter related Disorders (iNTD) is the first international network focusing on the study of primary and secondary neurotransmitter disorders. It was founded with the aim to foster exchange and improve knowledge in the field of these rare diseases. The newly established iNTD patient registry for neurotransmitter related diseases collects longitudinal data on the natural disease course, approach to diagnosis, therapeutic strategies, and quality of life of affected patients. The registry forms the evidence base for the development of consensus guidelines for patients with neurotransmitter related disorders. Conclusion The iNTD network and registry will improve knowledge and strengthen research capacities in the field of inborn neurotransmitter disorders. The evidence-based guidelines will facilitate standardized diagnostic procedures and treatment approaches. © 2016 The Authors

Author Keywords
Database;  Dopamine;  GABA;  Glycine;  Guideline;  Network;  Neurotransmitter;  Patient registry;  Serine;  Serotonin

Document Type: Article
Source: Scopus


Mogha, A.a , D'Rozario, M.a , Monk, K.R.a b
G Protein-Coupled Receptors in Myelinating Glia
(2016) Trends in Pharmacological Sciences, 37 (11), pp. 977-987. 

DOI: 10.1016/

a Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States
b Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States

The G protein-coupled receptor (GPCR) superfamily represents the largest class of functionally selective drug targets for disease modulation and therapy. GPCRs have been studied in great detail in central nervous system (CNS) neurons, but these important molecules have been relatively understudied in glia. In recent years, however, exciting new roles for GPCRs in glial cell biology have emerged. We focus here on the key roles of GPCRs in a specialized subset of glia, myelinating glia. We highlight recent work firmly establishing GPCRs as regulators of myelinating glial cell development and myelin repair. These advances expand our understanding of myelinating glial cell biology and underscore the utility of targeting GPCRs to promote myelin repair in human disease. © 2016 Elsevier Ltd

Author Keywords
G protein-coupled receptor (GPCR);  myelination;  oligodendrocyte;  remyelination;  Schwann cell

Document Type: Review
Source: Scopus


Dorsett, M.a , Liang, S.Y.a b
Diagnosis and Treatment of Central Nervous System Infections in the Emergency Department
(2016) Emergency Medicine Clinics of North America, 34 (4), pp. 917-942. 

DOI: 10.1016/j.emc.2016.06.013

a Division of Emergency Medicine, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8072, St Louis, MO, United States
b Division of Infectious Diseases, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8051, St Louis, MO, United States

Central nervous system (CNS) infections, including meningitis, encephalitis, and brain abscess, are rare but time-sensitive emergency department (ED) diagnoses. Patients with CNS infection can present to the ED with nonspecific signs and symptoms, including headache, fever, altered mental status, and behavioral changes. Neuroimaging and CSF fluid analysis can appear benign early in the course of disease. Delaying therapy negatively impacts outcomes, particularly with bacterial meningitis and herpes simplex virus encephalitis. Therefore, diagnosis of CNS infection requires vigilance and a high index of suspicion based on the history and physical examination, which must be confirmed with appropriate imaging and laboratory evaluation. © 2016 Elsevier Inc.

Author Keywords
Brain abscess;  Diagnosis;  Emergency department;  Encephalitis;  Meningitis;  Treatment

Document Type: Review
Source: Scopus


Babulal, G.M.a , Ghoshal, N.a , Head, D.b c d , Vernon, E.K.a , Holtzman, D.M.a b c , Benzinger, T.L.S.a e g , Fagan, A.M.a b c , Morris, J.C.a b f h i , Roe, C.M.a b
Mood Changes in Cognitively Normal Older Adults are Linked to Alzheimer Disease Biomarker Levels
(2016) American Journal of Geriatric Psychiatry, 24 (11), pp. 1095-1104. 

DOI: 10.1016/j.jagp.2016.04.004

a Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
b Departments of Neurology, Washington University School of Medicine, St. Louis, MO, United States
c Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
d Hope Center for Psychology, Washington University School of Medicine, St. Louis, MO, United States
e Hope Center for Radiology, Washington University School of Medicine, St. Louis, MO, United States
f Hope Center for Physical Therapy, Washington University School of Medicine, St. Louis, MO, United States
g Hope Center for Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
h Hope Center for Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
i Hope Center for Occupational Therapy, Washington University School of Medicine, St. Louis, MO, United States

Objectives To evaluate whether cerebrospinal fluid (CSF) and PET Pittsburgh Compound B (PiB) biomarkers of underlying Alzheimer disease (AD) pathology (β-amyloid42 [Aβ42], tau, phosphorylated tau181 [ptau181], tau/Aβ42, ptau181/Aβ42 and mean cortical binding potential [MCBP] for PET-PiB) predict changes in mood in cognitively normal older adults. Setting Knight Alzheimer's Disease Research Center (ADRC) at Washington University (WU). Participants Participants, 65 years of age or older, were enrolled from longitudinal studies at the WU Knight ADRC. Measurements CSF, PET-PiB biomarkers, Clinical Dementia Rating (CDR), Mini-Mental State Examination (MMSE), Profile of Mood States-Short Form (POMS-SF), the Geriatric Depression Scale (GDS), and Neuropsychiatric Inventory Questionnaire (NPI-Q). Results Data from 118 participants at baseline and 66 participants at one-year follow-up were analyzed. CSF and PET biomarkers were not associated cross-sectionally with any mood disturbances at baseline (p > 0.05). Changes in mood as indicated by the total mood disturbance score on the POMS-SF, selected POMS-SF subscales, GDS, and NPI-Q scores from baseline to one-year follow-up were associated with (p < 0.05) CSF and PET-PiB biomarkers. There was no statistically significant decline in cognitive functioning. Conclusions Generally, higher values of CSF and PET-PiB biomarkers are associated with more changes in mood in cognitively normal older adults. Further work is needed to understand the temporal development of mood changes over several years during the phase of preclinical AD. Evaluating mood as a noncognitive outcome may provide further insight into the development of preclinical AD in cognitively normal older adults. © 2016 American Association for Geriatric Psychiatry

Author Keywords
Alzheimer disease;  biomarkers;  depression;  mood;  older adults

Document Type: Article
Source: Scopus


Werner, K.B.a , Sartor, C.E.b c , McCutcheon, V.V.b , Grant, J.D.b , Nelson, E.C.b , Heath, A.C.b , Bucholz, K.K.b
Association of Specific Traumatic Experiences With Alcohol Initiation and Transitions to Problem Use in European American and African American Women
(2016) Alcoholism: Clinical and Experimental Research, 40 (11), pp. 2401-2408. 

DOI: 10.1111/acer.13220

a George Warren Brown School of Social Work, Washington University, St. Louis, MO, United States
b Alcohol Research Center, Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
c Department of Psychiatry, Yale School of Medicine, New Haven, CT, United States

Background: The aims of this study were to (i) characterize racial differences in alcohol involvement and (ii) examine the risk conferred by specific trauma exposures and posttraumatic stress disorder (PTSD) for different stages of alcohol involvement in European American (EA) and African American (AA) women. Methods: Data are from the Missouri Adolescent Female Twins Study (N = 3,787, 14.6% AA; mean age at most recent interview = 24.5 [SD 2.8]). Trauma exposures (e.g., sexual abuse [SA], physical abuse [PA], witnessing another person being killed or injured, experiencing an accident, and experiencing a disaster) were modeled as time-varying predictors of alcohol initiation, transition to first alcohol use disorder (AUD) symptom, and transition to AUD diagnosis using Cox proportional hazards regression while taking into account other substance involvement, parental characteristics, and commonly co-occurring psychiatric disorders. Results: In EA women only, SA was associated with alcohol initiation prior to the age of 14, PA predicted transition from initiation to first AUD symptom, and PA, witnessing injury or death, and SA predicted transition to AUD diagnosis. No association was discovered between trauma exposures or PTSD for any stage of alcohol involvement in AA women. Conclusions: Results reveal trauma experiences as important contributors to all stages of alcohol involvement in EA women only, with different trauma types conferring risk for each stage of alcohol involvement. PTSD was not revealed as a significant predictor of AUD in EA or AA women, suggesting trauma, independent of PTSD, directly contributes to alcohol involvement. Findings highlight the importance of considering racial differences when developing etiologic models of the association of traumatic experiences with alcohol involvement. Copyright © 2016 by the Research Society on Alcoholism

Author Keywords
Alcohol;  Alcohol Use Disorder;  Racial Differences;  Traumatic Stress

Document Type: Article
Source: Scopus


Jusué-Torres, I.a , Jeon, L.H.a , Sankey, E.W.a , Lu, J.a , Vivas-Buitrago, T.a , Crawford, J.A.b , Pletnikov, M.V.b , Xu, J.c , Blitz, A.d , Herzka, D.A.e , Crain, B.f , Hulbert, A.g , Guerrero-Cazares, H.a , Gonzalez-Perez, O.h , McAllister, J.P.i , Quiñones-Hinojosa, A.f g , Rigamonti, D.a
A Novel Experimental Animal Model of Adult Chronic Hydrocephalus
(2016) Neurosurgery, 79 (5), pp. 746-756. 

DOI: 10.1227/NEU.0000000000001405

a Department of Neurosurgery, School of Medicine, Johns Hopkins University, Baltimore, MD, United States
b Department of Psychiatry and Behavioral Sciences, School of Medicine, Johns Hopkins University, Baltimore, MD, United States
c F. M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, School of Medicine, Johns Hopkins University, Baltimore, MD, United States
d Department of Radiology and Radiological Science, School of Medicine, Johns Hopkins University, Baltimore, MD, United States
e Department of Biomedical Engeniering, Johns Hopkins University, Baltimore, MD, United States
f Department of Pathology, Division of Neurophatology, School of Medicine, Johns Hopkins University, Baltimore, MD, United States
g Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, MD, United States
h Laboratory of Neuroscience, Facultad de Psicologia, University of Colima, Colima, Mexico
i Department of Neurosurgery, School of Medicine in St. Louis, Washington University, St. Louis, MO, United States

BACKGROUND: The pathogenesis of adult chronic hydrocephalus is not fully understood, and the temporal relationship between development of the radiological changes and neurological deterioration is unknown. OBJECTIVE: To clarify the progression of radiological-histological changes and subsequent clinical manifestations of adult chronic hydrocephalus. METHODS: Kaolin was injected bilaterally into the subarachnoid space overlying the cranial convexities in 20 adult rats. Magnetic resonance imaging (MRI) was obtained by using an 11.7 T scanner at 14, 60, 90, and 120 days after kaolin injection. Locomotor, gait, and cognitive evaluations were performed independently. Kaolin distribution and the associated inflammatory and fibrotic responses were histologically analyzed. RESULTS: Evans index of ventriculomegaly showed significant progressive growth in ventricular size over all time points examined. The greatest enlargement occurred within the first 2 months. Evans index also correlated with the extent of kaolin distribution by MRI and by pathological examination at all time points. First gait changes occurred at 69 days, anxiety at 80, cognitive impairment at 81, and locomotor difficulties after 120 days. Only locomotor deterioration was associated with Evans index or the radiological evaluation of kaolin extension. Inflammatory/fibrotic response was histologically confirmed over the cranial convexities in all rats, and its extension was associated with ventricular size and with the rate of ventricular enlargement. CONCLUSION: Kaolin injected into the subarachnoid space over the cerebral hemispheres of adult rats produces an inflammatory/fibrotic response leading in a slow-onset communicating hydrocephalus that is initially asymptomatic. Increased ventricular size eventually leads to gait, memory, and locomotor impairment closely resembling the course of human adult chronic hydrocephalus. ABBREVIATION: NPH, normal pressure hydrocephalus. Copyright © 2016 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Congress of Neurological Surgeons.

Author Keywords
Animal model;  Diagnosis;  Kaolin;  Normal pressure hydrocephalus;  Pathophysiology

Document Type: Article
Source: Scopus


Simon, N.G.a b , Noto, Y.-I.c d , Zaidman, C.M.e
Skeletal muscle imaging in neuromuscular disease
(2016) Journal of Clinical Neuroscience, 33, pp. 1-10. 

DOI: 10.1016/j.jocn.2016.01.041

a St Vincent's Clinical School, University of New South Wales, Level 5 deLacy Building, St Vincent's Hospital, Victoria Street, Darlinghurst, NSW, Australia
b Department of Neurology, St Vincent's Hospital, Darlinghurst, NSW, Australia
c Department of Neurology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
d Brain and Mind Centre, Sydney Medical School, The University of SydneyNSW, Australia
e Department of Neurology, Washington University in St. Louis, St Louis, MO, United States

Skeletal muscle imaging is increasingly used as a complement to clinical and electrophysiological examination in neuromuscular disease. Ultrasound and MRI have developed as the modalities of choice, each with strengths and limitations. Characteristic changes of muscle denervation and myopathy are seen on imaging which may delineate the nature of the disease process or help guide muscle biopsy. Identifying patterns of muscle involvement in hereditary myopathies may inform genetic testing. This review discusses skeletal muscle imaging in neuromuscular disease focusing on practical applications of current and emerging ultrasound and MRI techniques. © 2016 Elsevier Ltd

Author Keywords
Denervation;  MRI;  Muscle imaging;  Myopathy;  Neuromuscular disease;  Ultrasound

Document Type: Review
Source: Scopus


Carbone, M.A.a b c , Yamamoto, A.a b c , Huang, W.a b c d , Lyman, R.A.a e , Meadors, T.B.a , Yamamoto, R.a , Anholt, R.R.H.a b c d , Mackay, T.F.C.a b c d
Genetic architecture of natural variation in Visual Senescence in Drosophila
(2016) Proceedings of the National Academy of Sciences of the United States of America, 113 (43), pp. E6620-E6629. 

DOI: 10.1073/pnas.1613833113

a Department of Biological Sciences, North Carolina State University, Raleigh, NC, United States
b W. M. Keck Center for Behavioral Biology, North Carolina State University, Raleigh, NC, United States
c Program in Genetics, North Carolina State University, Raleigh, NC, United States
d Initiative in Biological Complexity, North Carolina State University, Raleigh, NC, United States
e Department of Biology, Washington University, St. Louis, MO, United States

Senescence, i.e., functional decline with age, is a major determinant of health span in a rapidly aging population, but the genetic basis of interindividual variation in senescence remains largely unknown. Visual decline and age-related eye disorders are common manifestations of senescence, but disentangling age-dependent visual decline in human populations is challenging due to inability to control genetic background and variation in histories of environmental exposures. We assessed the genetic basis of natural variation in visual senescence by measuring age-dependent decline in phototaxis using Drosophila melanogaster as a genetic model system. We quantified phototaxis at 1, 2, and 4 wk of age in the sequenced, inbred lines of the Drosophila melanogaster Genetic Reference Panel (DGRP) and found an average decline in phototaxis with age. We observed significant genetic variation for phototaxis at each age and significant genetic variation in senescence of phototaxis that is only partly correlated with phototaxis. Genome-wide association analyses in the DGRP and a DGRP-derived outbred, advanced intercross population identified candidate genes and genetic networks associated with eye and nervous system development and function, including seven genes with human orthologs previously associated with eye diseases. Ninety percent of candidate genes were functionally validated with targeted RNAi-mediated suppression of gene expression. Absence of candidate genes previously implicated with longevity indicates physiological systems may undergo senescence independent of organismal life span. Furthermore, we show that genes that shape early developmental processes also contribute to senescence, demonstrating that senescence is part of a genetic continuum that acts throughout the life span.

Author Keywords
Aging;  Behavioral genetics;  Dgrp gwa analysis;  Phototaxis;  XQTL mapping

Document Type: Conference Paper
Source: Scopus


Greene, D.J., Williams III, A.C., Koller, J.M., Schlaggar, B.L., Black, K.J.
Brain structure in pediatric Tourette syndrome
(2016) Molecular Psychiatry, . Article in Press. 

DOI: 10.1038/mp.2016.194

Washington University School of Medicine, St Louis, MO, USA

Previous studies of brain structure in Tourette syndrome (TS) have produced mixed results, and most had modest sample sizes. In the present multicenter study, we used structural magnetic resonance imaging (MRI) to compare 103 children and adolescents with TS to a well-matched group of 103 children without tics. We applied voxel-based morphometry methods to test gray matter (GM) and white matter (WM) volume differences between diagnostic groups, accounting for MRI scanner and sequence, age, sex and total GM+WM volume. The TS group demonstrated lower WM volume bilaterally in orbital and medial prefrontal cortex, and greater GM volume in posterior thalamus, hypothalamus and midbrain. These results demonstrate evidence for abnormal brain structure in children and youth with TS, consistent with and extending previous findings, and they point to new target regions and avenues of study in TS. For example, as orbital cortex is reciprocally connected with hypothalamus, structural abnormalities in these regions may relate to abnormal decision making, reinforcement learning or somatic processing in TS.Molecular Psychiatry advance online publication, 25 October 2016; doi:10.1038/mp.2016.194. © 2016 The Author(s)

Document Type: Article in Press
Source: Scopus


Armstrong, R.A.a , McKee, A.C.b c d , Alvarez, V.E.b c , Cairns, N.J.e
Clustering of tau-immunoreactive pathology in chronic traumatic encephalopathy
(2016) Journal of Neural Transmission, pp. 1-8. Article in Press. 

DOI: 10.1007/s00702-016-1635-1

a Vision Sciences, Aston University, Birmingham, United Kingdom
b VA Boston, Boston, MA, United States
c Veterans Affairs Medical Center, Bedford, MA, United States
d Department of Neurology and Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, United States
e Departments of Neurology and Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, United States

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder which may result from repetitive brain injury. A variety of tau-immunoreactive pathologies are present, including neurofibrillary tangles (NFT), neuropil threads (NT), dot-like grains (DLG), astrocytic tangles (AT), and occasional neuritic plaques (NP). In tauopathies, cellular inclusions in the cortex are clustered within specific laminae, the clusters being regularly distributed parallel to the pia mater. To determine whether a similar spatial pattern is present in CTE, clustering of the tau-immunoreactive pathology was studied in the cortex, hippocampus, and dentate gyrus in 11 cases of CTE and 7 cases of Alzheimer’s disease neuropathologic change (ADNC) without CTE. In CTE: (1) all aspects of tau-immunoreactive pathology were clustered and the clusters were frequently regularly distributed parallel to the tissue boundary, (2) clustering was similar in two CTE cases with minimal co-pathology compared with cases with associated ADNC or TDP-43 proteinopathy, (3) in a proportion of cortical gyri, estimated cluster size was similar to that of cell columns of the cortico-cortical pathways, and (4) clusters of the tau-immunoreactive pathology were infrequently spatially correlated with blood vessels. The NFT and NP in ADNC without CTE were less frequently randomly or uniformly distributed and more frequently in defined clusters than in CTE. Hence, the spatial pattern of the tau-immunoreactive pathology observed in CTE is typical of the tauopathies but with some distinct differences compared to ADNC alone. The spread of pathogenic tau along anatomical pathways could be a factor in the pathogenesis of the disease. © 2016 Springer-Verlag Wien

Author Keywords
Alzheimer’s disease neuropathologic change (ADNC);  Chronic traumatic encephalopathy (CTE);  Neurofibrillary tangle;  Spatial correlation;  Spatial pattern;  Tauopathy

Document Type: Article in Press
Source: Scopus


Skjåkødegård, H.F.a i , Danielsen, Y.S.b , Morken, M.a , Linde, S.-R.F.a , Kolko, R.P.c , Balantekin, K.N.d e f g , Wilfley, D.E.d e f g , Júlíusson, P.B.a h
Study Protocol: A randomized controlled trial evaluating the effect of family-based behavioral treatment of childhood and adolescent obesity-The FABO-study
(2016) BMC Public Health, 16 (1), art. no. 1106, . 

DOI: 10.1186/s12889-016-3755-9

a Department of Medicine, Obesity Outpatient Clinic, Haukeland University Hospital, Bergen, Norway
b Department of Clinical Psychology, University of Bergen, Bergen, Norway
c Department of Psychiatry, University of Pittsburgh, School of Medicine, Pittsburgh, PA, United States
d Department of Psychiatry, Washington University, School of Medicine, St. Louis, MO, United States
e Department of Medicine, Washington University, School of Medicine, St. Louis, MO, United States
f Department of Pediatrics, Washington University, School of Medicine, St. Louis, MO, United States
g Department of Psychology, Washington University, School of Medicine, St. Louis, MO, United States
h Department of Clinical Science, University of Bergen, Bergen, Norway
i Department of Physiotherapy, Haukeland University Hospital, Bergen, Norway

Background: The purpose of the FABO-study is to evaluate the effect of family-based behavioral social facilitation treatment (FBSFT), designed to target children's family and social support networks to enhance weight loss outcomes, compared to the standard treatment (treatment as usual, TAU) given to children and adolescents with obesity in a routine clinical practice. Methods: Randomized controlled trial (RCT), in which families (n = 120) are recruited from the children and adolescents (ages 6-18 years) referred to the Obesity Outpatient Clinic (OOC), Haukeland University Hospital, Norway. Criteria for admission to the OOC are BMI above the International Obesity Task Force (IOTF) cut-off ≥ 35, or IOTF ≥ 30 with obesity related co-morbidity. Families are randomized to receive FBSFT immediately or following one year of TAU. All participants receive a multidisciplinary assessment. For TAU this assessment results in a plan and a contract for chancing specific lifestyle behaviors. Thereafter each family participates in monthly counselling sessions with their primary health care nurse to work on implementing these goals, including measuring their weight change, and also meet every third month for sessions at the OOC. In FBSFT, following assessment, families participate in 17 weekly sessions at the OOC, in which each family works on changing lifestyle behaviors using a structured cognitive-behavioral, socio-ecological approach targeting both parents and children with strategies for behavioral maintenance and sustainable weight change. Outcome variables include body mass index (BMI; kg/m2), BMI standard deviation score (SDS) and percentage above the IOTF definition of overweight, waist-circumference, body composition (bioelectric impedance (BIA) and dual-X-ray-absorptiometry (DXA)), blood tests, blood pressure, activity/inactivity and sleep pattern (measured by accelerometer), as well as questionnaires measuring depression, general psychological symptomatology, self-esteem, disturbed eating and eating disorder symptoms. Finally, barriers to treatment and parenting styles are measured via questionnaires. Discussion: This is the first systematic application of FBSFT in the treatment of obesity among youth in Norway. The study gives an opportunity to evaluate the effect of FBSFT implemented in routine clinical practice across a range of youth with severe obesity. Trial registration: NCT02687516. Registered 16th of February, 2016 © 2016 The Author(s).

Author Keywords
Childhood obesity;  Family-based behavioral treatment;  Randomized controlled trial

Document Type: Article
Source: Scopus


Rao, L.K., Flaker, A.M., Friedel, C.C., Kharasch, E.D.
Role of Cytochrome P4502B6 Polymorphisms in Ketamine Metabolism and Clearance
(2016) Anesthesiology, . Article in Press. 

DOI: 10.1097/ALN.0000000000001392

From the Division of Clinical and Translational Research, Department of Anesthesiology (L.K.R., A.M.F., C.C.F., E.D.K.), and Department of Biochemistry and Biophysics (E.D.K.), Washington University in St. Louis, St. Louis, Missouri; and the Center for Clinical Pharmacology, St. Louis College of Pharmacy and Washington University in St. Louis School of Medicine, St. Louis, Missouri (E.D.K.).

BACKGROUND:: At therapeutic concentrations, cytochrome P4502B6 (CYP2B6) is the major P450 isoform catalyzing hepatic ketamine N-demethylation to norketamine in vitro. The CYP2B6 gene is highly polymorphic. The most common variant allele, CYP2B6*6, is associated with diminished hepatic CYP2B6 expression and catalytic activity compared with wild-type CYP2B6*1/*1. CYP2B6.6, the protein encoded by the CYP2B6*6 allele, and liver microsomes from CYP2B6*6 carriers had diminished ketamine metabolism in vitro. This investigation tested whether humans with the CYP2B6*6 allele would have decreased clinical ketamine metabolism and clearance. METHODS:: Thirty volunteers with CYP2B6*1/*1, *1/*6, or *6/*6 genotypes (n = 10 each) received a subsedating dose of oral ketamine. Plasma and urine concentrations of ketamine and the major CYP2B6-dependent metabolites were determined by mass spectrometry. Subjects’ self-assessment of ketamine effects were also recorded. The primary outcome was ketamine N-demethylation, measured as the plasma norketamine/ketamine area under the curve ratio. Secondary outcomes included plasma ketamine enantiomer and metabolite area under the plasma concentration–time curve, maximum concentrations, apparent oral clearance, and metabolite formation clearances. RESULTS:: There was no significant difference between CYP2B6 genotypes in ketamine metabolism or any of the secondary outcome measures. Subjective self-assessment did reveal some differences in energy and level of awareness among subjects. CONCLUSIONS:: These results show that while the CYP2B6*6 polymorphism results in diminished ketamine metabolism in vitro, this allelic variant did not affect single, low-dose ketamine metabolism, clearance, and pharmacokinetics in vivo. While in vitro drug metabolism studies may be informative, clinical investigations in general are needed to validate in vitro observations. Copyright © by 2016, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. All Rights Reserved.

Document Type: Article in Press
Source: Scopus


Seo, D.-O.a , Funderburk, S.C.a d , Bhatti, D.L.a , Motard, L.E.a , Newbold, D.a , Girven, K.S.e , McCall, J.G.a , Krashes, M.d , Sparta, D.R.e , Bruchas, M.R.a b c
A GABAergic projection from the centromedial nuclei of the amygdala to ventromedial prefrontal cortex modulates reward behavior
(2016) Journal of Neuroscience, 36 (42), pp. 10831-10842. 

DOI: 10.1523/JNEUROSCI.1164-16.2016

a Department of Anesthesiology, Division of Basic Research, Washington University School of Medicine, St. Louis, MO, United States
b Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
c Pain Center, Washington University School of Medicine, St. Louis, MO, United States
d Diabetes, Endocrinology and Obesity Branch, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
e Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, United States

The neural circuitry underlying mammalian reward behaviors involves several distinct nuclei throughout the brain. It is widely accepted that the midbrain dopamine (DA) neurons are critical for the reward-related behaviors. Recent studies have shown that the centromedial nucleus of the amygdala (CeMA) has a distinct role in regulating reward-related behaviors. However, the CeMA and ventromedial PFC (vmPFC) interaction in reward regulation remains poorly understood. Here, we identify and dissect a GABAergic projection that originates in the CeMA and terminates in the vmPFC (VGat-CreCeMA-vmPFC) using viral-vector-mediated, cell-type-specific optogenetic techniques in mice. Pathway-specific optogenetic activation of the VGat-CreCeMA-vmPFC circuit in awake, behaving animals produced a positive, reward-like phenotype in real-time place preference and increased locomotor activity in open-field testing. In sucrose operant conditioning, the photoactivation of these terminals increased nose-poking effort with no effect on licking behavior and robustly facilitated the extinction of operant behavior. However, photoactivation of these terminals did not induce self-stimulation in the absence of an external reward. The results described here suggest that the VGat-CreCeMA-vmPFC projection acts to modulate existing reward-related behaviors. © 2016 the authors.

Author Keywords
Amygdala;  CEA;  MEA;  Reward;  VGat;  VmPFC

Document Type: Article
Source: Scopus


Ibrahim, A.a , Hor, S.b , Bahar, O.S.c , Dwomoh, D.a , McKay, M.M.c e , Esena, R.K.a , Agyepong, I.A.a d
Erratum to: Pathways to psychiatric care for mental disorders: A retrospective study of patients seeking mental health services at a public psychiatric facility in Ghana [Int J Ment Health Syst 10, (2016) (63)], DOI 10.1186/s13033-016-0095-1
(2016) International Journal of Mental Health Systems, 10 (1), art. no. 70, . 

DOI: 10.1186/s13033-016-0103-5

a University of Ghana, School of Public Health, P.O. Box LG13, Accra, Ghana
b Catholic Relief Services, RT 70 Gumani Residential Area, Tamale, Ghana
c New York University, Silver School of Social Work, New York, NY, United States
d Ghana Health Service, Private Mail Bag, Ministries, Accra, Ghana
e Washington University in St. Louis, The Brown School, St. Louis, MO, United States

Erratum to: Int J Ment Health Syst (2016) 10:63 DOI 10.1186/s13033-016-0095-1 In the original publication of this article [1], one of the co-authors' name was written incorrectly. 'Irene A. Agyeponge' should have been listed as 'Irene A. Agyepong'. This change has been reflected in the original publication as well. © The Author(s) 2016.

Document Type: Erratum
Source: Scopus


Bland, M.D.a b c , Birkenmeier, R.L.d , Barco, P.c , Lenard, E.e , Lang, C.E.a b c , Lenze, E.J.e
Enhanced medical rehabilitation: Effectiveness of a clinical training model
(2016) NeuroRehabilitation, 39 (4), pp. 481-498. 

DOI: 10.3233/NRE-161380

a Program in Physical Therapy, Washington University, 4444 Forest Park, Saint Louis, MO, United States
b Department of Neurology, Washington University, Saint Louis, MO, United States
c Program in Occupational Therapy, Washington University, Saint Louis, MO, United States
d Program in Occupational Therapy, Maryville University, Saint Louis, MO, United States
e Department of Psychiatry, Healthy Mind Laboratory, Washington University, Saint Louis, MO, United States

BACKGROUND: Patient engagement in medical rehabilitation can be greatly influenced by their provider during therapy sessions. We developed Enhanced Medical Rehabilitation (EMR), a set of provider skills grounded in theories of behavior change. EMR utilizes 18 motivational techniques focused on providing frequent feedback to patients on their effort and progress and linking these to patient goals. OBJECTIVE: To examine the effectiveness of a clinical training protocol for clinicians to do EMR, as measured by clinician adherence. METHODS: A physical therapist, physical therapist assistant, occupational therapist, and certified occupational therapist assistant were trained in EMR. Training consisted of five formal training sessions and individual and group coaching. Adherence to EMR techniques was measured during two phases: Pre-Training and Maintenance, with an a priori target of 90 adherence by clinicians to each EMR technique. RESULTS: With training and coaching, clinician adherence per therapeutic activity significantly improved in 13 out of 18 items (p<0.05). The target of 90 adherence was not achieved for many items. CONCLUSIONS: Our training and coaching program successfully trained clinicians to promote patient engagement during therapeutic service delivery, although not typically to 90 or greater adherence. Ongoing coaching efforts were necessary to increase adherence.

Author Keywords
Therapeutic engagement, skilled nursing facility, rehabilitation

Document Type: Article
Source: Scopus


Klepin, H.D.a , Tooze, J.A.b , Pardee, T.S.a , Ellis, L.R.a , Berenzon, D.a , Mihalko, S.L.c , Danhauer, S.C.b , Rao, A.V.d , Wildes, T.M.e , Williamson, J.D.f , Powell, B.L.a , Kritchevsky, S.B.f
Effect of Intensive Chemotherapy on Physical, Cognitive, and Emotional Health of Older Adults with Acute Myeloid Leukemia
(2016) Journal of the American Geriatrics Society, 64 (10), pp. 1988-1995. 

DOI: 10.1111/jgs.14301

a Wake Forest Baptist Comprehensive Cancer Center, Wake Forest University, Winston-Salem, NC, United States
b Division of Public Health Sciences, Wake Forest School of Medicine, Wake Forest University, Winston-Salem, NC, United States
c Wake Forest University Department of Health and Exercise Science, Wake Forest University, Winston-Salem, NC, United States
d Duke University School of Medicine, Durham, NC, United States
e Washington University School of Medicine, St. Louis, MO, United States
f Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States

Objectives: To measure short-term changes in physical and cognitive function and emotional well-being of older adults receiving intensive chemotherapy for acute myeloid leukemia (AML). Design: Prospective observational study. Setting: Single academic institution. Participants: Individuals aged 60 and older with newly diagnosed AML who received induction chemotherapy (N = 49, mean age 70 ± 6.2, 56% male). Measurements: Geriatric assessment (GA) was performed during inpatient examination for AML and within 8 weeks after hospital discharge after induction chemotherapy. Measures were the Pepper Assessment Tool for Disability (activity of daily living, instrumental activity of daily living (IADL), mobility questions), Short Physical Performance Battery (SPPB), grip strength, Modified Mini-Mental State examination, Center for Epidemiologic Studies Depression Scale, and the Distress Thermometer. Changes in GA measures were assessed using paired t-tests. Analysis of variance models were used to evaluate relationships between GA variables and change in function over time. Results: After chemotherapy, IADL dependence worsened (mean 1.4 baseline vs 2.1 follow-up, P <.001), as did mean SPPB scores (7.5 vs 5.9, P =.02 for total). Grip strength also declined (38.9 ± 7.7 vs 34.2 ± 10.3 kg, P <.001 for men; 24.5 ± 4.8 vs 21.8 ± 4.7 kg, P =.007 for women). No significant changes in cognitive function (mean 84.7 vs 85.1, P =.72) or depressive symptoms (14.0 vs. 11.3, P =.11) were detected, but symptoms of distress declined (5.0 vs 3.2, P <.001). Participants with depressive symptoms at baseline and follow-up had greater declines in SPPB scores those without at both time points. Conclusions: Short-term survivors of intensive chemotherapy for AML had clinically meaningful declines in physical function. These data support the importance of interventions to maintain physical function during and after chemotherapy. Depressive symptoms before and during chemotherapy may be linked to potentially modifiable physical function declines. © 2016, Copyright the Authors Journal compilation © 2016, The American Geriatrics Society

Author Keywords
cognition;  depression;  elderly;  function;  leukemia

Document Type: Article
Source: Scopus


Davis, A.A.a , Racette, B.a b
Parkinson disease and cognitive impairment: Five new things
(2016) Neurology: Clinical Practice, 6 (5), pp. 452-458. 

DOI: 10.1212/CPJ.0000000000000285

a Department of Neurology, Washington University, School of Medicine, St. Louis, MO, United States
b School of Public Health, University of the Witwatersrand, Johannesburg, South Africa

Purpose of review: While the distinctive motor symptoms of Parkinson disease (PD) have been described for centuries, cognitive impairment has only recently been recognized as a central feature. Studies have yielded clues to the etiology and natural history of cognitive impairment in PD, but much remains unclear and effective therapies are needed. Recent findings: Longitudinal cohort studies demonstrate that almost all patients with PD will develop dementia if they live long enough. New CSF biomarker and genetic studies suggest that it may soon be possible to forecast and track the progression of dementia in PD. Sleep and sleep disturbance appear to be intrinsically linked with PD, although the implications for individual outcomes and opportunities for intervention are unclear. Multidisciplinary treatment approaches incorporating cognitive training may help to improve outcomes. Summary: We review several recent advances in understanding the pathophysiology, genetics, and management of cognitive impairment in PD. © 2016 American Academy of Neurology.

Document Type: Review
Source: Scopus


Yan, Z.a , Hu, B.a , Huang, Z.a , Zhong, L.b , Guo, X.a , Weng, A.a , Xiao, F.c , Zeng, W.a , Zhang, Y.a , Ding, J.a , Hou, P.a b
Single channel recordings reveal differential β2 subunit modulations between mammalian and drosophila BKca(β2) channels
(2016) PLoS ONE, 11 (10), art. no. e0163308, . 

DOI: 10.1371/journal.pone.0163308

a Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China
b Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Diseases, Washington University in St Louis, St Louis, United States
c Key Laboratory of Image Processing and Intelligent Control, Huazhong University of Science and Technology, Ministry of Education, Department of Biomedical Engineering, College of Life Science and Technology, Wuhan, Hubei, China

Large-conductance Ca2+- and voltage-activated potassium (BK) channels are widely expressed in tissues. As a voltage and calcium sensor, BK channels play significant roles in regulating the action potential frequency, neurotransmitter release, and smooth muscle contraction. After associating with the auxiliary β2 subunit, mammalian BK(β2) channels (mouse or human Slo1/β2) exhibit enhanced activation and complete inactivation. However, how the β2 subunit modulates the Drosophila Slo1 channel remains elusive. In this study, by comparing the different functional effects on heterogeneous BK(β2) channel, we found that Drosophila Slo1/β2 channel exhibits "paralyzed"-like and incomplete inactivation as well as slow activation. Further, we determined three different modulations between mammalian and Drosophila BK(β2) channels: 1) dSlo1/β2 doesn't have complete inactivation. 2) β2(K33,R34,K35) delays the dSlo1/Δ3-β2 channel activation. 3) dSlo1/β2 channel has enhanced pre-inactivation than mSlo1/β2 channel. The results in our study provide insights into the different modulations of β2 subunit between mammalian and Drosophila Slo1/β2 channels and structural basis underlie the activation and pre-inactivation of other BK(β) complexes. © 2016 Yan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Document Type: Article
Source: Scopus


Salter, A.a , Tyry, T.b , Wang, G.a , Fox, R.J.c , Cutter, G.d , Marrie, R.A.e
Examining the joint effect of disability, health behaviors, and comorbidity on mortality in MS
(2016) Neurology: Clinical Practice, 6 (5), pp. 397-408. 

DOI: 10.1212/CPJ.0000000000000269

a Division of Biostatistics, Washington University, St. Louis, MO, United States
b Division of Neurology, Dignity Health, St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States
c Department of Neurology and Neurological Institute, Cleveland ClinicOH, United States
d Department of Biostatistics, University of Alabama at Birmingham, United States
e Departments of Internal Medicine and Community Health Sciences, University of Manitoba, Winnipeg, Canada

Background: In multiple sclerosis (MS), comorbidities have been associated with disability progression and an increased risk of mortality. We investigated the association between comorbidities and mortality in MS after accounting for disability and health behaviors. Methods: We followed North American Research Committee on Multiple Sclerosis (NARCOMS) Registry participants who completed the Fall 2006 survey on comorbidities until death (reported or matched in the National Death Index) or date of last follow-up in 2014. We used proportional hazards regression to investigate the association between comorbidities and mortality, controlling for demographic, clinical, health behavior, and disability factors. Results: Of 9,496 participants meeting the inclusion criteria, 502 (5.3%) were deceased. Most participants reported having ≤3 comorbid conditions (70.9% survivors, 76.9% decedents). In individual regression models, vascular, visual, and mental comorbidities were associated with increased mortality risk after adjustment for factors associated with survival. When combined into a single model, vascular (hazard ratio 1.269; 1.041-1.547), visual (1.490; 1.199-1.852), and mental comorbidities (excluding anxiety, 1.239; 1.024-1.499) remained independently associated with an increased risk of mortality. Conclusions: Presence of comorbidities was independently associated with an increased risk of mortality as compared to absence of comorbidities after adjusting for factors associated with survival. Specifically, vascular, visual, and mental comorbidities increased the risk of mortality. This highlights the need for clinicians to attend to these comorbidities, which can be modified by treatments or other interventions, and potentially reduce the risk of mortality in persons with MS who have these conditions. © 2016 American Academy of Neurology.

Document Type: Article
Source: Scopus


D’Souza, R.D.a , Meier, A.M.a , Bista, P.a , Wang, Q.b , Burkhalter, A.a
Recruitment of inhibition and excitation across mouse visual cortex depends on the hierarchy of interconnecting areas
(2016) eLife, 5 (September2016), art. no. e19332, . 

DOI: 10.7554/eLife.19332

a Department of Neuroscience, Washington University School of Medicine, St. Louis, United States
b Allen Institute for Brain Science, Seattle, United States

Diverse features of sensory stimuli are selectively processed in distinct brain areas. The relative recruitment of inhibitory and excitatory neurons within an area controls the gain of neurons for appropriate stimulus coding. We examined how such a balance of inhibition and excitation is differentially recruited across multiple levels of a cortical hierarchy by mapping the locations and strengths of synaptic inputs to pyramidal and parvalbumin (PV)-expressing neurons in feedforward and feedback pathways interconnecting primary (V1) and two higher visual areas. While interareal excitation was stronger in PV than in pyramidal neurons in all layer 2/3 pathways, we observed a gradual scaling down of the inhibition/excitation ratio from the most feedforward to the most feedback pathway. Our results indicate that interareal gain control depends on the hierarchical position of the source and the target, the direction of information flow through the network, and the laminar location of target neurons. © D’Souza et al.

Document Type: Article
Source: Scopus


Lohse, K.R.a , Schaefer, S.Y.b c , Raikes, A.C.c , Boyd, L.A.d , Lang, C.E.e f g
Asking new questions with old data: The centralized open-access rehabilitation database for stroke
(2016) Frontiers in Neurology, 7 (SEP), art. no. 153, . 

DOI: 10.3389/fneur.2016.00153

a School of Kinesiology, Auburn University, Auburn, AL, United States
b School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ, United States
c Department of Health, Physical Education and Recreation, Utah State University, Logan, UT, United States
d Department of Physical Therapy, University of British Columbia, Vancouver, BC, Canada
e Program in Physical Therapy, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
f Program in Occupational Therapy, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
g Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States

Background: This paper introduces a tool for streamlining data integration in rehabilitation science, the Centralized Open-Access Rehabilitation database for Stroke (SCOAR), which allows researchers to quickly visualize relationships among variables, efficiently share data, generate hypotheses, and enhance clinical trial design. Methods: Bibliographic databases were searched according to inclusion criteria leaving 2,892 titles that were further screened to 514 manuscripts to be screened by full text, leaving 215 randomized controlled trials (RCTs) in the database (489 independent groups representing 12,847 patients). Demographic, methodological, and statistical data were extracted by independent coders and entered into SCOAR. Results: Trial data came from 114 locations in 27 different countries and represented patients with a wide range of ages, 62 year [41; 85] [shown as median (range)] and at various stages of recovery following their stroke, 141 days [1; 3372]. There was considerable variation in the dose of therapy that patients received, 20 h [0; 221], over interventions of different durations, 28 days [10; 365]. There was also a lack of common data elements (CDEs) across trials, but this lack of CDEs was most pronounced for baseline assessments of patient impairment and severity of stroke. Conclusion: Data integration across hundreds of RCTs allows clinicians and researchers to quickly visualize data from the history of the field and lays the foundation for making SCOAR a living database to which researchers can upload new data as trial results are published. SCOAR is a useful tool for clinicians and researchers that will facilitate data visualization, data sharing, the finding of relevant past studies, and the design of clinical trials by enabling more accurate and comprehensive power analyses. Furthermore, these data speak to the need for CDEs specific to stroke rehabilitation in randomized controlled trials. © 2016 Lohse, Schaefer, Raikes, Boyd and Lang.

Author Keywords
Informatics;  Rehabilitation;  Stroke

Document Type: Article
Source: Scopus


Nandi, A.a , Kafashan, M.a , Ching, S.a b
Controlling point process generalized linear models of neural spiking
(2016) Proceedings of the American Control Conference, 2016-July, art. no. 7526575, pp. 5779-5784. 

DOI: 10.1109/ACC.2016.7526575

a Faculty of Electrical and Systems Engineering, Washington University in St. Louis, St. Louis, MO, United States
b Division of Biology and Biomedical Sciences, Washington University in St. Louis, St. Louis, MO, United States

In brain networks, neurons communicate through action potentials or spikes. These spikes can be thought of as discrete events that constitute, in essence, a binary, time-varying spatial pattern over the entire network. A general hypothesis in neuroscience is that these patterns encode information, thus enabling function. Consequently, an emerging research direction in experimental neuroscience involves the use of neurostimulation technologies to artificially induce such patterns in a spatiotemporally precise manner - the so-called neurocontrol problem. In this work, we discuss the neurocontrol problem by means of statistical models, which, in contrast to more traditional dynamical-systems models, describe only the probability of spiking as a function of time. Thus, such models aggregate nonlinearity and uncertainty into a more tractable mathematical description. While statistical models are frequently used to describe experimental data, their use as tools for input construction is not as well explored. Here, we formulate an optimal control problem for spiking patterns via a weighted maximum likelihood approach and develop its solution. We demonstrate the design approach for a model network consisting of coupled stochastic integrate-and-fire neurons. Finally, we suggest how this overall framework can be used to develop a class of control analyses for point process models. © 2016 American Automatic Control Council (AACC).

Document Type: Conference Paper
Source: Scopus


Kim, S.A.a , Ching, S.b
Quasilinearization-based controllability analysis of neuronal rate networks
(2016) Proceedings of the American Control Conference, 2016-July, art. no. 7526836, pp. 7371-7376. 

DOI: 10.1109/ACC.2016.7526836

a Department of Biomedical Engineering, Washington University in Saint Louis, Saint Louis, MO, United States
b Department of Electrical and Systems Engineering, Division of Biology and Biomedical Sciences, Washington University in Saint Louis, Saint Louis, MO, United States

Recent interest has developed around the problem of assaying the controllability of networks in the brain. The analysis of such networks is highly nontrivial, owing to their overwhelming complexity. Thus, any controllability analysis must tradeoff against model complexity/explanatory power, and analysis tractability. Here, we consider a class of neuronal network models with nearly linear dynamics, whose primary complication arises due to a sigmoidal nonlinearity in the neuronal coupling. Exploiting the equivalence between the controllability gramian and the steady state covariance matrix of a linear system under white noise, we develop an approximate controllability analysis based on the method of stochastic linearization (quasilinearization). We show that for this relatively simple system, the quasilinear approach generates a significantly better characterization of controllability as compared with a Jacobian linearization. Our results provide a new tool for assessing controllability of networks with sigmoidal interactions, and, moreover, highlight the potential inaccuracy of linear characterizations of networks with even relatively mild nonlinearities. © 2016 American Automatic Control Council (AACC).

Document Type: Conference Paper
Source: Scopus


Lai, H.H.a b , Shen, B.a , Rawal, A.a , Vetter, J.a
The relationship between depression and overactive bladder/urinary incontinence symptoms in the clinical OAB population
(2016) BMC Urology, 16 (1), pp. 1-8. 

DOI: 10.1186/s12894-016-0179-x

a Department of Surgery, Division of Urologic Surgery, Washington University, School of Medicine, 4960 Children's Place, Campus Box 8242, St Louis, MO, United States
b Department of Anesthesiology, Washington University, School of Medicine, 4960 Children's Place, Campus Box 8242, St Louis, MO, United States

Background: To investigate the relationship between depression and overactive bladder (OAB)/urinary incontinence symptoms among the clinical OAB population. Methods: Patients who were diagnosed with overactive bladder (OAB) and age-matched control subjects without OAB were enrolled. Depression symptoms were assessed using the Hospital Anxiety and Depression Scale (HADS-D). OAB/incontinence symptoms were assessed using the validated questionnaires: ICIQ-UI, ICIQ-OAB, UDI-6, IIQ-7, and OAB-q. Results: 27.5 % of OAB patients in our study had depression (HADS ≥8), and 12 % of OAB patients had moderate to severe depression (HADS-D ≥11). OAB patients reported significantly higher HADS-D depression scores compared to age-matched controls (5.3 ± 3.9 versus 2.8 ± 3.9, p = 0.004). OAB patients with depression reported more severe incontinence symptoms (ICIQ-UI), greater bother and more impact on quality of life (UDI-6, IIQ-7) compared to OAB patients without depression (p = 0.001, 0.01, <0.001, respectively). However there were no differences in ICIQ-OAB and OAB-q. Among OAB patients, there were positive correlations between the severity of depression symptoms and OAB/incontinence symptoms (p-values <0.001 to 0.035). Conclusions: 27.5 % of OAB patients have depression. OAB patients with depression reported more severe urinary incontinence symptoms, greater bother and more impact on quality of life compared to those without depression. Future studies are needed to further examine the mechanistic links between depression and OAB/urinary incontinence. © 2016 The Author(s).

Author Keywords
Depression;  Overactive bladder;  Psychosocial;  Urinary incontinence;  Urinary urgency

Document Type: Article
Source: Scopus


Dadey, D.Y.A.a b , Kamath, A.A.a , Leuthardt, E.C.a , Smyth, M.D.a
Laser interstitial thermal therapy for subependymal giant cell astrocytoma: Technical case report
(2016) Neurosurgical Focus, 41 (4), art. no. E9, . 

DOI: 10.3171/2016.7.FOCUS16231

a Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
b Medical Scientist Training Program, Washington University School of Medicine, St. Louis, MO, United States

Subependymal giant cell astrocytoma (SEGA) is a rare tumor occurring almost exclusively in patients with tuberous sclerosis complex. Although open resection remains the standard therapy, complication rates remain high. To minimize morbidity, less invasive approaches, such as endoscope-assisted resection, radiosurgery, and chemotherapy with mTOR pathway inhibitors, are also used to treat these lesions. Laser interstitial thermal therapy (LITT) is a relatively new modality that is increasingly used to treat a variety of intracranial lesions. In this report, the authors describe two pediatric cases of SEGA that were treated with LITT. In both patients the lesion responded well to this treatment modality, with tumor shrinkage observed on follow-up MRI. These cases highlight the potential of LITT to serve as a viable minimally invasive therapeutic approach to the management of SEGAs in the pediatric population. © AANS, 2016.

Author Keywords
Laser interstitial thermal therapy;  LITT;  SEGA;  Subependymal giant cell astrocytoma;  Ventriculostomy

Document Type: Article
Source: Scopus


Luking, K.R.a , Pagliaccio, D.b , Luby, J.L.c , Barch, D.M.c d e f
Reward Processing and Risk for Depression Across Development
(2016) Trends in Cognitive Sciences, . Article in Press. 

DOI: 10.1016/j.tics.2016.04.002

a Department of Psychology, Stony Brook University, Stony Brook, NY 11794, USA
b Emotion and Development Branch, National Institute of Mental Health (NIMH), Bethesda, MD 20892, USA
c Department of Psychiatry, Washington University in St. Louis, St. Louis, MO 63130, USA
d Department of Psychology, Washington University in St. Louis, St. Louis, MO 63130, USA
e Department of Radiology, Washington University in St. Louis, St. Louis, MO 63130, USA
f Neuroscience Program, Washington University in St. Louis, St. Louis, MO 63130, USA

Striatal response to reward has been of great interest in the typical development and psychopathology literatures. These parallel lines of inquiry demonstrate that although typically developing adolescents show robust striatal response to reward, adolescents with major depressive disorder (MDD) and those at high risk for MDD show a blunted response to reward. Understanding how these findings intersect is crucial for the development and application of early preventative interventions in at-risk children, ideally before the sharp increase in the rate of MDD onset that occurs in adolescence. Robust findings relating blunted striatal response to reward and MDD risk are reviewed and situated within a normative developmental context. We highlight the need for future studies investigating longitudinal development, specificity to MDD, and roles of potential moderators and mediators. Offspring of depressed mothers are at increased risk for developing depression and show blunted responses to reward, relative to low-risk peers, within the dorsal and ventral striatum.The strongest evidence for the relationship between depression risk and blunted striatal response to reward has been found during mid-adolescence, a time in development when healthy low-risk groups show maximal striatal response to reward.Blunted striatal response to reward is not simply a consequence of experiencing depression because both never-depressed high-risk adolescents and currently depressed adolescents show a similarly blunted striatal response to reward relative to low-risk controls.Blunted striatal response to reward may specifically relate to maternal depression, and not to maternal anxiety.Blunted striatal response to reward may co-occur with enhanced responses to loss of reward or punishment in high-risk groups. © 2016 Elsevier Ltd.

Author Keywords
Depression;  Development;  Reward

Document Type: Article in Press
Source: Scopus


Jones, J.R.a c , McMahon, D.G.a b
The core clock gene Per1 phases molecular and electrical circadian rhythms in SCN neurons
(2016) PeerJ, 2016 (9), art. no. e2297, . 

DOI: 10.7717/PEERJ.2297

a Neuroscience Graduate Program, Vanderbilt University, Nashville, TN, United States
b Department of Biological Sciences, Vanderbilt University, Nashville, TN, United States
c Department of Biology, Washington University in St. Louis, St. Louis, MO, United States

The brain's biological clock, the suprachiasmatic nucleus (SCN), exhibits endogenous 24-hour rhythms in gene expression and spontaneous firing rate; however, the functional relationship between these neuronal rhythms is not fully understood. Here, we used a Per1::GFP transgenic mouse line that allows for the simultaneous quantification of molecular clock state and firing rate in SCN neurons to examine the relationship between these key components of the circadian clock. We find that there is a stable, phased relationship between E-box-driven clock gene expression and spontaneous firing rate in SCN neurons and that these relationships are independent of light input onto the system or of GABAA receptor-mediated synaptic activity. Importantly, the concordant phasing of gene and neural rhythms is disrupted in the absence of the homologous clock gene Per1, but persists in the absence of the core clock gene Per2. These results suggest that Per1 plays a unique, non-redundant role in phasing gene expression and firing rate rhythms in SCN neurons to increase the robustness of cellular timekeeping. © 2016 Jones and McMahon.

Author Keywords
Circadian;  Firing rate;  Molecular clock;  Per1;  Suprachiasmatic

Document Type: Article
Source: Scopus


Samdani, A.F.a , Bennett, J.T.a , Ames, R.J.b , Asghar, J.K.c , Orlando, G.d , Pahys, J.M.a , Yaszay, B.e , Miyanji, F.f , Lonner, B.S.g , Lehman, R.A., Jr.h , Newton, P.O.e , Cahill, P.J.i , Betz, R.R.j
Reversible intraoperative neurophysiologic monitoring alerts in patients undergoing arthrodesis for adolescent idiopathic scoliosis: What Are the Outcomes of Surgery?
(2016) Journal of Bone and Joint Surgery - American Volume, 98 (17), pp. 1478-1483. 

DOI: 10.2106/JBJS.15.01379

a Shriners Hospitals for Children-Philadelphia, Philadelphia, PA, United States
b Temple University School of Medicine, Philadelphia, PA, United States
c Nicklaus Children's Hospital, Miami, FL, United States
d Department of Orthopaedics and Traumatology, University of Messina, Messina, Italy
e Rady Children's Hospital, San Diego, CA, United States
f BC Children's Hospital, Vancouver, BC, Canada
g Mount Sinai Beth Israel Medical Center, New York, NY, United States
h Washington University School of Medicine, St. Louis, MO, United States
i Children's Hospital of Philadelphia, Philadelphia, PA, United States
j Institute for Spine and Scoliosis, Lawrenceville, NJ, United States

Background: Confidence in intraoperative neurophysiologic monitoring (IONM) data can allow scoliosis surgeons to proceed with surgery even after a monitoring alert, assuming the recovery of signals. We sought to determine the outcomes of surgical treatment of adolescent idiopathic scoliosis (AIS) after a notable IONM alert. Methods: We identified 676 patients who underwent arthrodesis with use of IONM for the treatment of AIS. The patients were divided into 2 cohorts: those who experienced a lower-extremity IONM alert and those who did not. An alert was defined as a notable change in IONM data, specifically, a ≥50% drop in somatosensory evoked potentials (SSEPs) and/or in transcranial motor evoked potentials (tcMEPs). Results: Of the 676 patients, 36 (5.3%) experienced IONM alerts. Those patients had a larger preoperative major Cobb angle (mean of 61° ± 13° compared with 55° ± 12° for the no-alert group; p < 0.01), a greater number of levels fused (mean of 12 ± 2 compared with 11 ± 2; p < 0.01), a longer operative duration (mean of 357 ± 157 minutes compared with 298 ± 117 minutes; p < 0.01), a higher estimated blood loss (1,857 ± 1,323 mL compared with 999 ± 796 mL; p < 0.01), and a greater volume of autologous blood transfused (mean of 527 ± 525 mL compared with 268 ± 327 mL; p < 0.01). Among patients who experienced an alert and had a completed operation (34 of 36 patients), mean postoperative radiographic measurements were similar to those of the no-alert group in terms of the percentage of correction of the major Cobb angle (alert, 66% ± 13%; no alert, 64% ± 19%; p = 0.53) and of rib prominence (alert, 49% ± 36%; no alert, 47% ± 46%; p = 0.83) and measurement of thoracic kyphosis (alert, 23° ± 10°; no alert, 22° ± 2°; p = 0.58). The Scoliosis Research Society (SRS)-22 outcome scores were also similar between the 2 cohorts. Conclusions: Notable IONM changes occurred in 5.3% of the patients who underwent arthrodesis for AIS. Those patients had larger preoperative deformity, a longer operative duration, a greater number of levels fused, a higher estimated blood loss, and a greater volume of autologous blood transfused. Return of IONM data guided the surgeon to safely complete the procedure in 34 of 36 patients, with correction similar to that of patients who did not experience an alert. Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. Copyright © 2016 by The Journal of Bone and Joint Surgery, Incorporated.

Document Type: Review
Source: Scopus


Qian, M.a , Engler-Chiurazzi, E.B.b , Lewis, S.E.b , Rath, N.P.c , Simpkins, J.W.b , Covey, D.F.a d e
Structure-activity studies of non-steroid analogues structurally-related to neuroprotective estrogens
(2016) Organic and Biomolecular Chemistry, 14 (41), pp. 9790-9805. 

DOI: 10.1039/c6ob01726f

a Department of Developmental Biology, Campus Box 8103, Washington University in St. Louis, School of Medicine, 660 S. Euclid Ave., St. Louis, MO, United States
b Center for Basic and Translational Stroke Research, West Virginia University, Morgantown, WV, United States
c Department of Chemistry and Biochemistry, Center for Nanoscience, University of Missouri-St. Louis, St. Louis, MO, United States
d Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
e Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States

Estrone and 17β-estradiol are phenolic steroids that are known to be neuroprotective in multiple models of neuronal injury. Previous studies have identified the importance of their phenolic steroid A-ring for neuroprotection and have identified ortho substituents at the C-2 and C-4 positions on the phenol ring that enhance this activity. To investigate the importance of the steroid ring system for neuroprotective activity, phenolic compounds having the cyclopent[b]anthracene, cyclopenta[b]phenanthrene, benz[f]indene, benz[e]indene, indenes linked to a phenol, and a phenolic spiro ring system were prepared. New synthetic methods were developed to make some of the cyclopent[b]anthracene analogues as well as the spiro ring system. Compounds were evaluated for their ability to protect HT-22 hippocampal neurons from glutamate neurotoxicity and their activity relative to a potent neuroprotective analogue of 17β-estradiol was determined. An adamantyl substituent placed ortho to the phenolic hydroxyl group gave neuroprotective analogues in all ring systems studied. © The Royal Society of Chemistry 2016.

Document Type: Article
Source: Scopus


Bierut, L.a , Cesarini, D.b
How genetic and other biological factors interact with smoking decisions
(2015) Big Data, 3 (3), pp. 198-202. 

DOI: 10.1089/big.2015.0013

a Washington University in St. Louis, 660 South Euclid, St. Louis, MO, United States
b New York University, New York, NY, United States

Despite clear links between genes and smoking, effective public policy requires far richer measurement of the feedback between biological, behavioral, and environmental factors. The Kavli HUMAN Project (KHP) plans to exploit the plummeting costs of data gathering and to make creative use of new technologies to construct a longitudinal panel data set that would compare favorably to existing longitudinal surveys, both in terms of the richness of the behavioral measures and the cost-effectiveness of the data collection. By developing a more comprehensive approach to characterizing behavior than traditional methods, KHP will allow researchers to paint a much richer picture of an individual's life-cycle trajectory of smoking, alcohol, and drug use, and interactions with other choices and environmental factors. The longitudinal nature of KHP will be particularly valuable in light of the increasing evidence for how smoking behavior affects physiology and health. The KHP could have a transformative impact on the understanding of the biology of addictive behaviors such as smoking, and of a rich range of prevention and amelioration policies. © Mary Ann Liebert, Inc. 2015.

Author Keywords
deep phenotyping;  genetics;  smoking;  smoking cessation

Document Type: Article
Source: Scopus



Price, A.R.a , Bonner, M.F.b , Peelle, J.E.c , Grossman, M.d
Converging evidence for the neuroanatomic basis of combinatorial semantics in the angular gyrus
(2015) The Journal of neuroscience : the official journal of the Society for Neuroscience, 35 (7), pp. 3276-3284. 

DOI: 10.1523/JNEUROSCI.3446-14.2015

a Penn FTD Center and Department of Neurology and Neuroscience Graduate Group, University of Pennsylvania, Philadelphia, Pennsylvania 19104 and
b Penn FTD Center and Department of Neurology and
c Department of Otolaryngology, Washington University in St. Louis, St. Louis, Missouri 63130
d Penn FTD Center and Department of Neurology and

Human thought and language rely on the brain's ability to combine conceptual information. This fundamental process supports the construction of complex concepts from basic constituents. For example, both "jacket" and "plaid" can be represented as individual concepts, but they can also be integrated to form the more complex representation "plaid jacket." Although this process is central to the expression and comprehension of language, little is known about its neural basis. Here we present evidence for a neuroanatomic model of conceptual combination from three experiments. We predicted that the highly integrative region of heteromodal association cortex in the angular gyrus would be critical for conceptual combination, given its anatomic connectivity and its strong association with semantic memory in functional neuroimaging studies. Consistent with this hypothesis, we found that the process of combining concepts to form meaningful representations specifically modulates neural activity in the angular gyrus of healthy adults, independent of the modality of the semantic content integrated. We also found that individual differences in the structure of the angular gyrus in healthy adults are related to variability in behavioral performance on the conceptual combination task. Finally, in a group of patients with neurodegenerative disease, we found that the degree of atrophy in the angular gyrus is specifically related to impaired performance on combinatorial processing. These converging anatomic findings are consistent with a critical role for the angular gyrus in conceptual combination. Copyright © 2015 the authors 0270-6474/15/353276-09$15.00/0.

Author Keywords
angular gyrus;  combinatorial semantics;  compositionality;  conceptual combination;  semantic integration;  semantic memory

Document Type: Article
Source: Scopus