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WashU weekly Neuroscience publications

“Changes in Dosing and Dose Timing of D-Cycloserine Explain Its Apparent Declining Efficacy for Augmenting Exposure Therapy for Anxiety-related Disorders: An Individual Participant-data Meta-analysis” (2019) Journal of Anxiety Disorders

Changes in Dosing and Dose Timing of D-Cycloserine Explain Its Apparent Declining Efficacy for Augmenting Exposure Therapy for Anxiety-related Disorders: An Individual Participant-data Meta-analysis
(2019) Journal of Anxiety Disorders, 68, art. no. 102149, . 

Rosenfield, D.a , Smits, J.A.J.b , Hofmann, S.G.c , Mataix-Cols, D.d e , de la Cruz, L.F.d e , Andersson, E.d , Rück, C.d e , Monzani, B.f , Pérez-Vigil, A.d , Frumento, P.g , Davis, M.h , de Kleine, R.A.i , Difede, J.j , Dunlop, B.W.h , Farrell, L.J.k l , Geller, D.m n , Gerardi, M.h , Guastella, A.J.o , Hendriks, G.-J.p w , Kushner, M.G.q , Lee, F.S.j , Lenze, E.J.r , Levinson, C.A.r , McConnell, H.l s , Plag, J.t , Pollack, M.H.u , Ressler, K.J.n v , Rodebaugh, T.L.h , Rothbaum, B.O.h , Storch, E.A.x , Ströhle, A.t , Tart, C.D.y , Tolin, D.F.z aa , van Minnen, A.p , Waters, A.M.k , Weems, C.F.ac , Wilhelm, S.m n , Wyka, K.j ad , Altemus, M.aa , Anderson, P.ae , Cukor, J.j , Finck, C.ab , Geffken, G.R.ai , Golfels, F.al , Goodman, W.K.am , Gutner, C.A.ag , Heyman, I.ah an , Jovanovic, T.h , Lewin, A.B.aj , McNamara, J.P.af , Murphy, T.K.aj , Norrholm, S.h , Thuras, P.q , Turner, C.ak , Otto, M.W.c

a Department of Psychology, Southern Methodist University, Dallas, United States
b Institute for Mental Health Research and Department of Psychology, The University of Texas, Austin, United States
c Department of Psychological and Brain Sciences, Boston University, Boston, United States
d Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
e Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden
f Department of Psychology, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London, United Kingdom
g Unit of Biostatistics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
h Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, United States
i Institute of Psychology, Leiden University, Netherlands
j Department of Psychiatry, Weill Cornell Medical CollegeNY, United States
k School of Applied Psychology, Griffith University, Brisbane, Australia
l Menzies Health Institute of Queensland, Brisbane, Australia
m Department of Psychiatry, Massachusetts General Hospital, Boston, United States
n Harvard Medical School, Boston, United States
o Brain and Mind Research Institute, Central Clinical School, University of Sydney, Sydney, Australia
p Behavioral Science Institute, Radboud University Nijmegen, Netherlands
q Department of Psychiatry, University of Minnesota-Twin Cities, Minneapolis, United States
r Department of Psychiatry, Washington University School of Medicine, St Louis, United States
s School of Medicine, Griffith University, Brisbane, Australia
t Department of Psychiatry and Psychotherapy, Charité – University Medicine Berlin, Campus Charité Mitte, Germany
u Department of Psychiatry, Rush University Medical Center, Chicago, United States
v McLean Hospital, Belmont, United States
w Overwaal Center of Expertise for Anxiety Disorders OCD and PTSD, Institution for Integrated Mental Health Care Pro Persona, Nijmegen, Netherlands
x Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, United States
y New Mexico VA Health Care System, Albuquerque, United States
z The Institute of Living, Hartford, United States
aa Yale University School of Medicine, New Haven, United States
ab DRK Kliniken Berlin Wiegmann Klinik, Berlin, Germany
ac Department of Human Development and Family Studies, Iowa State University, Ames, United States
ad City University of New York Graduate School of Public Health and Health Policy, New York, United States
ae Department of Psychology, Georgia State University, Atlanta, United States
af Department of Psychiatry, University of Florida, Gainesville, United States
ag Department of Psychiatry, Boston University School of Medicine, Boston, United States
ah Great Ormond Street Hospital for Children, London, United Kingdom
ai Geffken Group, PLLC, Gainesville, FL, United States
aj Department of Pediatrics, University of South Florida, Tampa, United States
ak Primary Care Clinical Unit, Faculty of Medicine, The University of Queensland, Brisbane, Australia
al Woltersdorf Hospital, Woltersdorf, Germany
am Department of Psychiatry, Baylor College of Medicine, United States
an University College, London, United Kingdom

Abstract
The apparent efficacy of d-cycloserine (DCS) for enhancing exposure treatment for anxiety disorders appears to have declined over the past 14 years. We examined whether variations in how DCS has been administered can account for this “declining effect”. We also investigated the association between DCS administration characteristics and treatment outcome to find optimal dosing parameters. We conducted a secondary analysis of individual participant data obtained from 1047 participants in 21 studies testing the efficacy of DCS-augmented exposure treatments. Different outcome measures in different studies were harmonized to a 0-100 scale. Intent-to-treat analyses showed that, in participants randomized to DCS augmentation (n = 523), fewer DCS doses, later timing of DCS dose, and lower baseline severity appear to account for this decline effect. More DCS doses were related to better outcomes, but this advantage leveled-off at nine doses. Administering DCS more than 60 minutes before exposures was also related to better outcomes. These predictors were not significant in the placebo arm (n = 521). Results suggested that optimal DCS administration could increase pre-to-follow-up DCS effect size by 50%. In conclusion, the apparent declining effectiveness of DCS over time may be accounted for by how it has been administered. Optimal DCS administration may substantially improve outcomes. Registration: The analysis plan for this manuscript was registered on Open Science Framework (https://osf.io/c39p8/). © 2019 Elsevier Ltd

Author Keywords
augmentation;  d-cycloserine;  decline effect;  dosing;  exposure

Document Type: Article
Publication Stage: Final
Source: Scopus

“Pain Inhibits GRPR Neurons via GABAergic Signaling in the Spinal Cord” (2019) Scientific Reports

Pain Inhibits GRPR Neurons via GABAergic Signaling in the Spinal Cord
(2019) Scientific Reports, 9 (1), art. no. 15804, . 

Bardoni, R.e , Shen, K.-F.a b g , Li, H.a f , Jeffry, J.a b , Barry, D.M.a b , Comitato, A.h , Li, Y.-Q.f , Chen, Z.-F.a b c d

a Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, United States
b Departments of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, United States
c Departments of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
d Departments of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, United States
e Departments of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, 41125, Italy
f Department of Anatomy & K. K. Leung Brain Research Centre, The Fourth Military Medical University, Xi’an, 710032, China
g Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China
h Departments of Life Sciences, University of Modena and Reggio Emilia, Modena, 41125, Italy

Abstract
It has been known that algogens and cooling could inhibit itch sensation; however, the underlying molecular and neural mechanisms remain poorly understood. Here, we show that the spinal neurons expressing gastrin releasing peptide receptor (GRPR) primarily comprise excitatory interneurons that receive direct and indirect inputs from C and Aδ fibers and form contacts with projection neurons expressing the neurokinin 1 receptor (NK1R). Importantly, we show that noxious or cooling agents inhibit the activity of GRPR neurons via GABAergic signaling. By contrast, capsaicin, which evokes a mix of itch and pain sensations, enhances both excitatory and inhibitory spontaneous synaptic transmission onto GRPR neurons. These data strengthen the role of GRPR neurons as a key circuit for itch transmission and illustrate a spinal mechanism whereby pain inhibits itch by suppressing the function of GRPR neurons. © 2019, The Author(s).

Document Type: Article
Publication Stage: Final
Source: Scopus

“De Novo Mutations in FOXJ1 Result in a Motile Ciliopathy with Hydrocephalus and Randomization of Left/Right Body Asymmetry” (2019) American Journal of Human Genetics

De Novo Mutations in FOXJ1 Result in a Motile Ciliopathy with Hydrocephalus and Randomization of Left/Right Body Asymmetry
(2019) American Journal of Human Genetics, 105 (5), pp. 1030-1039. 

Wallmeier, J.a , Frank, D.a , Shoemark, A.b c , Nöthe-Menchen, T.a , Cindric, S.a , Olbrich, H.a , Loges, N.T.a , Aprea, I.a , Dougherty, G.W.a , Pennekamp, P.a , Kaiser, T.a , Mitchison, H.M.d , Hogg, C.c , Carr, S.B.c , Zariwala, M.A.e , Ferkol, T.f , Leigh, M.W.g , Davis, S.D.r , Atkinson, J.h , Dutcher, S.K.i , Knowles, M.R.j , Thiele, H.k , Altmüller, J.k , Krenz, H.l , Wöste, M.l , Brentrup, A.m , Ahrens, F.n , Vogelberg, C.o , Morris-Rosendahl, D.J.p q , Omran, H.a

a Department of General Pediatrics, University Children’s Hospital Muenster, Muenster, 48149, Germany
b Molecular & Clinical Medicine, University of Dundee, Dundee, DD1 4HN, United Kingdom
c Department of Paediatric Respiratory Medicine, Royal Brompton and Harefield NHS Trust, London, SW3 6NP, United Kingdom
d Genetics and Genomic Medicine, University College London (UCL) Great Ormond Street Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, United Kingdom
e Department of Pathology and Laboratory Medicine, Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States
f Department of Pediatrics, Washington University School of Medicine, St Louis, MO 63110, United States
g Department of Pediatrics, Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States
h Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, United States
i McDonnell Genome Institute, Department of Genetics, Washington University School of Medicine, St. Louis, MO 63108, United States
j Department of Medicine, Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States
k Cologne Center for Genomics, Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, 50931, Germany
l Institute of Medical Informatics, University of Muenster, Muenster, 48149, Germany
m Department of Neurosurgery, University Hospital Muenster, Muenster, 48149, Germany
n Children’s Hospital “Altona,”, Hamburg, 22763, Germany
o Paediatric Department, University Hospital Carl Gustav Carus Dresden, TU Dresden, Dresden 01307, Germany
p Clinical Genetics and Genomics, Royal Brompton and Harefield NHS Foundation Trust, London, SW3 6NP, United Kingdom
q National Heart and Lung Institute, Imperial College London, London, SW3 6LY, United Kingdom
r Department of Pediatrics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States

Abstract
Hydrocephalus is one of the most prevalent form of developmental central nervous system (CNS) malformations. Cerebrospinal fluid (CSF) flow depends on both heartbeat and body movement. Furthermore, it has been shown that CSF flow within and across brain ventricles depends on cilia motility of the ependymal cells lining the brain ventricles, which play a crucial role to maintain patency of the narrow sites of CSF passage during brain formation in mice. Using whole-exome and whole-genome sequencing, we identified an autosomal-dominant cause of a distinct motile ciliopathy related to defective ciliogenesis of the ependymal cilia in six individuals. Heterozygous de novo mutations in FOXJ1, which encodes a well-known member of the forkhead transcription factors important for ciliogenesis of motile cilia, cause a motile ciliopathy that is characterized by hydrocephalus internus, chronic destructive airway disease, and randomization of left/right body asymmetry. Mutant respiratory epithelial cells are unable to generate a fluid flow and exhibit a reduced number of cilia per cell, as documented by high-speed video microscopy (HVMA), transmission electron microscopy (TEM), and immunofluorescence analysis (IF). TEM and IF demonstrate mislocalized basal bodies. In line with this finding, the focal adhesion protein PTK2 displays aberrant localization in the cytoplasm of the mutant respiratory epithelial cells. © 2019 American Society of Human Genetics

Author Keywords
cilia;  ciliogenesis;  ependyma;  FOXJ1;  hydrocephalus;  lung disease

Document Type: Article
Publication Stage: Final
Source: Scopus

“Microglia/Brain Macrophages as Central Drivers of Brain Tumor Pathobiology” (2019) Neuron

Microglia/Brain Macrophages as Central Drivers of Brain Tumor Pathobiology
(2019) Neuron, 104 (3), pp. 442-449. 

Gutmann, D.H.a , Kettenmann, H.b

a Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
b Cellular Neurosciences, Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, 13125, Germany

Abstract
One of the most common brain tumors in children and adults is glioma or astrocytoma. There are few effective therapies for these cancers, and patients with malignant glioma fare poorly, even after aggressive surgery, chemotherapy, and radiation. Over the past decade, it is now appreciated that these tumors are composed of numerous distinct neoplastic and non-neoplastic cell populations, which could each influence overall tumor biology and response to therapy. Among these noncancerous cell types, monocytes (microglia and macrophages) predominate. In this Review, we discuss the complex interactions involving microglia and macrophages relevant to glioma formation, progression, and response to therapy. Like other cancers, brain tumors (gliomas) are composed of many different cell types, including non-neoplastic monocytic cells (macrophages and microglia). In this Review, Gutmann and Kettenmann discuss the importance of these cells to glioma development, maintenance, and treatment response. © 2019 Elsevier Inc.

Author Keywords
glioblastoma;  glioma;  immune;  macrophages;  microglia;  monocyte

Document Type: Review
Publication Stage: Final
Source: Scopus

“Spatial Clustering of Inhibition in Mouse Primary Visual Cortex” (2019) Neuron

Spatial Clustering of Inhibition in Mouse Primary Visual Cortex
(2019) Neuron, 104 (3), pp. 588-600.e5. 

D’Souza, R.D., Bista, P., Meier, A.M., Ji, W., Burkhalter, A.

Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Whether mouse visual cortex contains orderly feature maps is debated. The overlapping pattern of geniculocortical inputs with M2 muscarinic acetylcholine receptor-rich patches in layer 1 (L1) suggests a non-random architecture. Here, we found that L1 inputs from the lateral posterior thalamus (LP) avoid patches and target interpatches. Channelrhodopsin-2-assisted mapping of excitatory postsynaptic currents (EPSCs) in L2/3 shows that the relative excitation of parvalbumin-expressing interneurons (PVs) and pyramidal neurons (PNs) by dLGN, LP, and cortical feedback is distinct and depends on whether the neurons reside in clusters aligned with patches or interpatches. Paired recordings from PVs and PNs show that unitary inhibitory postsynaptic currents (uIPSCs) are larger in interpatches than in patches. The spatial clustering of inhibition is matched by dense clustering of PV terminals in interpatches. The results show that the excitation/inhibition balance across V1 is organized into patch and interpatch subnetworks, which receive distinct long-range inputs and are specialized for the processing of distinct spatiotemporal features. © 2019 Elsevier Inc.

D’Souza, Bista, et al. show that parvalbumin interneuron-mediated inhibition in mouse primary visual cortex is spatially clustered and that these modules receive differential inputs to layer 1 from the first- and second-order thalamus and extrastriate visual cortex. © 2019 Elsevier Inc.

Author Keywords
inhibition;  intracortical feedback;  parvalbumin interneurons;  thalamocortical connections;  visual cortex

Document Type: Article
Publication Stage: Final
Source: Scopus

“AMIGO2 Scales Dendrite Arbors in the Retina” (2019) Cell Reports

AMIGO2 Scales Dendrite Arbors in the Retina
(2019) Cell Reports, 29 (6), pp. 1568-1578.e4. 

Soto, F.a , Tien, N.-W.a b , Goel, A.a , Zhao, L.a , Ruzycki, P.A.a , Kerschensteiner, D.a c d e

a John F. Hardesty, MD Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, Saint Louis, MO 63110, United States
b Graduate Program in Neuroscience, Washington University School of Medicine, Saint Louis, MO 63110, United States
c Department of Neuroscience, Washington University School of Medicine, Saint Louis, MO 63110, United States
d Department of Biomedical Engineering, Washington University School of Medicine, Saint Louis, MO 63110, United States
e Hope Center for Neurological Disorders, Washington University School of Medicine, Saint Louis, MO 63110, United States

Abstract
The size of dendrite arbors shapes their function and differs vastly between neuron types. The signals that control dendritic arbor size remain obscure. Here, we find that in the retina, starburst amacrine cells (SACs) and rod bipolar cells (RBCs) express the homophilic cell-surface protein AMIGO2. In Amigo2 knockout (KO) mice, SAC and RBC dendrites expand while arbors of other retinal neurons remain stable. SAC dendrites are divided into a central input region and a peripheral output region that provides asymmetric inhibition to direction-selective ganglion cells (DSGCs). Input and output compartments scale precisely with increased arbor size in Amigo2 KO mice, and SAC dendrites maintain asymmetric connectivity with DSGCs. Increased coverage of SAC dendrites is accompanied by increased direction selectivity of DSGCs without changes to other ganglion cells. Our results identify AMIGO2 as a cell-type-specific dendritic scaling factor and link dendrite size and coverage to visual feature detection. © 2019 The Author(s)

Soto et al. find that two retinal interneurons express the cell-surface protein AMIGO2. Deletion of Amigo2 causes dendrites of these neurons, but not others, to expand, preserving branching patterns and connectivity. Increased interneuron dendrite coverage is accompanied by enhanced response selectivity of retinal output neurons. © 2019 The Author(s)

Author Keywords
dendrites;  development;  direction selectivity;  leucine-rich repeat protein;  LRR;  retina;  rod bipolar cell;  starburst amacrine cell

Document Type: Article
Publication Stage: Final
Source: Scopus

“Erratum to: Genome-wide association study identifies loci associated with liability to alcohol and drug dependence that is associated with variability in reward-related ventral striatum activity in African- and European-Americans (Genes, Brain and Behavior, (e12580), 10.1111/gbb.12580)” (2019) Genes, Brain and Behavior

Erratum to: Genome-wide association study identifies loci associated with liability to alcohol and drug dependence that is associated with variability in reward-related ventral striatum activity in African- and European-Americans (Genes, Brain and Behavior, (e12580), 10.1111/gbb.12580)
(2019) Genes, Brain and Behavior, 18 (8), art. no. e12608, . 

Wetherill, L.a , Lai, D.a , Johnson, E.C.b , Anokhin, A.b , Bauer, L.c , Bucholz, K.K.b , Dick, D.M.d , Hariri, A.R.e , Hesselbrock, V.c , Kamarajan, C.f , Kramer, J.g , Kuperman, S.g , Meyers, J.L.f , Nurnberger, J.I., Jr.h , Schuckit, M.i , Scott, D.M.j , Taylor, R.E.k , Tischfield, J.l , Porjesz, B.f , Goate, A.M.m , Edenberg, H.J.a n , Foroud, T.a , Bogdan, R.o , Agrawal, A.b

a Indiana University. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
b Department of Psychiatry, Washington University. Washington University School of Medicine, Saint Louis, MO, United States
c Department of Psychiatry, University of Connecticut. University of Connecticut School of Medicine, Farmington, CT, United States
d Department of Psychology & College Behavioral and Emotional Health Institute, Virginia Commonwealth University, Virginia Commonwealth University, Richmond, VA, United States
e Duke Institute for Brain Sciences, Dept. of Psychology, Duke University, Durham, NC, United States
f SUNY. Henri Begleiter Neurodynamics Laboratory, Department of Psychiatry and Behavioral Sciences, SUNY Downstate Medical Center, Brooklyn, NY, United States
g Department of Psychiatry, University of Iowa. University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, IA, United States
h Indiana University. Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, United States
i Department of Psychiatry, University of California San Diego. University of California San Diego, San Diego, CA, United States
j Departments of Pediatrics and Human Genetics, Howard University, Washington, DC, United States
k Department of Pharmacology, Howard University, Washington, DC, United States
l Dept. of Genetics, Rutgers University, Piscataway, NJ, United States
m Department of Neuroscience, Icahn School of Medicine at Mt. Sinai, New York, NY, United States
n Indiana University. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States
o Department of Psychological and Brain Sciences, Washington University in Saint Louis, Saint Louis, MO, United States

Abstract
In the original manuscript Wetherill et al., 2019 (Genes, Brain and Behavior, 18[6], July 2019, e12580), allele labels for rs1890881 were swapped during the writing, but not analyses, of the neuroimaging section. This resulted in errors which are described and corrected below. Bolded yellow highlighted sections represent errors and corrections. 1. In Table on Page 11, the effect allele for rs1890881 should be labeled C not T. The beta value, including its direction of association, remains the same. The corrected table is: 5 Associations between response of the ventral striatum to positive > negative feedback and genotype in the Duke Neurogenetics Sample (Table presented.) SNP = single nucleotide polymorphism; chr5:141988181 was not available. 2.: In Results section 3.7 on Page 10, the allele label of T is incorrect in the following sentence ORIGINAL INCORRECT SENTENCE: “Carriers of the minor (T) allele of rs1890881 (chr 1), which was associated with decreased likelihood of ANYDEP in the trans-ancestral meta-analysis (effect driven by alcohol dependence), were characterized by blunted reactivity of the left VS among AA (beta =−0.134,P=.001).” The corrected sentence reads as follows: CORRECTED SENTENCE: “Carriers of the minor (C) allele of rs1890881 (chr 1), which was associated with decreased likelihood of ANYDEP in the trans-ancestral meta-analysis (effect driven by alcohol dependence), were characterized by blunted reactivity of the left VS among AA (beta = −0.134,P =.001). 3. In the Discussion section on page 12, the last paragraph on the left hand side begins with the following section describing the incorrect C allele for rs1890881 ORIGINAL INCORRECT SENTENCE: “In direct contrast to the results for rs75168521, rs1890881 (chromosome 1) major C allele homozygotes, who were at increased risk for ANYDEP (driven by the association with alcohol dependence) in the COGA GWAS, had elevated reward-related VS response (identical to Lai et al).” The corrected sentences reads as follows: CORRECTED SENTENCE: “In direct contrast to the results for rs75168521, rs1890881 (chromosome 1) major T allele homozygotes, who were at increased risk for ANYDEP (driven by the association with alcohol dependence) in the COGA GWAS, had elevated reward-related VS response (identical to Lai et al).” Reported statistics, conclusions, and interpretations of these data remain the same. Upon re-running analyses, no other errors were identified. We apologize for any inconvenience caused to readers. Note: The PubMed Central (PMC) version of the manuscript has been edited to incorporate these corrections. © 2019 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society

Document Type: Erratum
Publication Stage: Final
Source: Scopus

“V2a interneuron differentiation from mouse and human pluripotent stem cells” (2019) Nature Protocols

V2a interneuron differentiation from mouse and human pluripotent stem cells
(2019) Nature Protocols, 14 (11), pp. 3033-3058. 

Butts, J.C.a b , Iyer, N.c , White, N.d , Thompson, R.e , Sakiyama-Elbert, S.d , McDevitt, T.C.a f

a Gladstone Institutes, San Francisco, CA, United States
b Graduate Program in Bioengineering, University of California, San Francisco and University of California, Berkeley, CA, United States
c Department of Biomedical Engineering, University of Wisconsin–Madison, Madison, WI, United States
d Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, United States
e Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
f Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, United States

Abstract
V2a interneurons are located in the hindbrain and spinal cord, where they provide rhythmic input to major motor control centers. Many of the phenotypic properties and functions of excitatory V2a interneurons have yet to be fully defined. Definition of these properties could lead to novel regenerative therapies for traumatic injuries and drug targets for chronic degenerative diseases. Here we describe how to produce V2a interneurons from mouse and human pluripotent stem cells (PSCs), as well as strategies to characterize and mature the cells for further analysis. The described protocols are based on a sequence of small-molecule treatments that induce differentiation of PSCs into V2a interneurons. We also include a detailed description of how to phenotypically characterize, mature, and freeze the cells. The mouse and human protocols are similar in regard to the sequence of small molecules used but differ slightly in the concentrations and durations necessary for induction. With the protocols described, scientists can expect to obtain V2a interneurons with purities of ~75% (mouse) in 7 d and ~50% (human) in 20 d. © 2019, The Author(s), under exclusive licence to Springer Nature Limited.

Document Type: Article
Publication Stage: Final
Source: Scopus

“An atlas of cortical circular RNA expression in Alzheimer disease brains demonstrates clinical and pathological associations” (2019) Nature Neuroscience

An atlas of cortical circular RNA expression in Alzheimer disease brains demonstrates clinical and pathological associations
(2019) Nature Neuroscience, 22 (11), pp. 1903-1912. 

Dube, U.a b c , Del-Aguila, J.L.b , Li, Z.b , Budde, J.P.b , Jiang, S.b , Hsu, S.b , Ibanez, L.b , Fernandez, M.V.b , Farias, F.b , Norton, J.b , Gentsch, J.b , Wang, F.b , Allegri, R.k , Amtashar, F.l , Benzinger, T.l , Berman, S.m , Bodge, C.n , Brandon, S.l , Brooks, W.o , Buck, J.p , Buckles, V.l , Chea, S.q , Chrem, P.k , Chui, H.r , Cinco, J.s , Clifford, J.q , D’Mello, M.o , Donahue, T.l , Douglas, J.s , Edigo, N.k , Erekin-Taner, N.q , Fagan, A.l , Farlow, M.p , Farrar, A.l , Feldman, H.t , Flynn, G.l , Fox, N.s , Franklin, E.l , Fujii, H.u , Gant, C.l , Gardener, S.v , Ghetti, B.p , Goate, A.w , Goldman, J.x , Gordon, B.l , Gray, J.l , Gurney, J.l , Hassenstab, J.l , Hirohara, M.y , Holtzman, D.l , Hornbeck, R.l , DiBari, S.H.z , Ikeuchi, T.aa , Ikonomovic, S.m , Jerome, G.l , Jucker, M.ab , Kasuga, K.aa , Kawarabayashi, T.y , Klunk, W.m , Koeppe, R.ac , Kuder-Buletta, E.ab , Laske, C.ab , Levin, J.z , Marcus, D.l , Martins, R.v , Mason, N.S.ad , Maue-Dreyfus, D.l , McDade, E.l , Montoya, L.r , Mori, H.u , Nagamatsu, A.ae , Neimeyer, K.x , Noble, J.x , Norton, J.l , Perrin, R.l , Raichle, M.l , Ringman, J.r , Roh, J.H.af , Schofield, P.o , Shimada, H.u , Shiroto, T.y , Shoji, M.y , Sigurdson, W.l , Sohrabi, H.v , Sparks, P.ag , Suzuki, K.ae , Swisher, L.l , Taddei, K.v , Wang, J.w , Wang, P.l , Weiner, M.ah , Wolfsberger, M.l , Xiong, C.l , Xu, X.l , Salloway, S.d , Masters, C.L.e , Lee, J.-H.f , Graff-Radford, N.R.g , Chhatwal, J.P.h , Bateman, R.J.c , Morris, J.C.c , Karch, C.M.b i , Harari, O.b , Cruchaga, C.b c i j , the Dominantly Inherited Alzheimer Network (DIAN)ai

a Medical Scientist Training Program, Washington University School of Medicine, St. Louis, MO, United States
b Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave. CB8134, St. Louis, MO, United States
c Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
d Alpert Medical School of Brown University, 345 Blackstone Boulevard, Providence, RI, United States
e The Florey Institute, the University of Melbourne. Level 1, Howard Florey Laboratories, Royal Parade, Parkville, VIC, Australia
f Department of Neurology, University of Ulsan College of Medicine, Seoul, South Korea
g Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
h Massachusetts General Hospital, Department of Neurology, Harvard Medical School, Boston, MA, United States
i Hope Center for Neurological Disorders. Washington University School of Medicine, St. Louis, MO, United States
j NeuroGenomics and Informatics, Washington University School of Medicine, St. Louis, MO, United States
k FLENI Institute of Neurological Research (Fundacion para la Lucha contra las Enfermedades Neurologicas de la Infancia), Buenos Aires, Argentina
l Washington University in St. Louis School of Medicine, St. Louis, MO, United States
m University of Pittsburgh, Pittsburgh, PA, United States
n Brown University-Butler Hospital, Providence, RI, United States
o Neuroscience Research Australia, Sydney, Australia
p Indiana University, Bloomington, IN, United States
q Mayo Clinic Jacksonville, Jacksonville, FL, United States
r University of Southern California, Los Angeles, CA, United States
s University College London, London, United Kingdom
t University of California San Diego, San Diego, CA, United States
u Osaka City University, Osaka, Japan
v Edith Cowan University, Perth, Australia
w Icahn School of Medicine at Mount Sinai, New York, NY, United States
x Columbia University, New York, NY, United States
y Hirosaki University, Hirosaki, Japan
z German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany
aa Niigata University, Niigata, Japan
ab German Center for Neurodegnerative Diseases (DZNE) Tubingen, Tubingen, Germany
ac University of Michigan, Ann Arbor, MI, United States
ad University of Pittsburgh Medical Center, Pittsburgh, PA, United States
ae Tokyo University, Bunkyo, Japan
af Asan Medical Center, Seoul, South Korea
ag Brigham and Women’s Hospital, Boston, MA, United States
ah University of California San Francisco, San Francisco, CA, United States

Abstract
Parietal cortex RNA-sequencing (RNA-seq) data were generated from individuals with and without Alzheimer disease (AD; ncontrol = 13; nAD = 83) from the Knight Alzheimer Disease Research Center (Knight ADRC). Using this and an independent (Mount Sinai Brain Bank (MSBB)) AD RNA-seq dataset, cortical circular RNA (circRNA) expression was quantified in the context of AD. Significant associations were identified between circRNA expression and AD diagnosis, clinical dementia severity and neuropathological severity. It was demonstrated that most circRNA–AD associations are independent of changes in cognate linear messenger RNA expression or estimated brain cell-type proportions. Evidence was provided for circRNA expression changes occurring early in presymptomatic AD and in autosomal dominant AD. It was also observed that AD-associated circRNAs co-expressed with known AD genes. Finally, potential microRNA-binding sites were identified in AD-associated circRNAs for miRNAs predicted to target AD genes. Together, these results highlight the importance of analyzing non-linear RNAs and support future studies exploring the potential roles of circRNAs in AD pathogenesis. © 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.

Document Type: Article
Publication Stage: Final
Source: Scopus

“Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma” (2019) Nature

Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma
(2019) Nature, 574 (7780), pp. 707-711. Cited 1 time.

Suzuki, H.a b , Kumar, S.A.a b c , Shuai, S.d e , Diaz-Navarro, A.f g , Gutierrez-Fernandez, A.f g , De Antonellis, P.a b , Cavalli, F.M.G.a b , Juraschka, K.a b c , Farooq, H.a b c , Shibahara, I.a b , Vladoiu, M.C.a b c , Zhang, J.a b , Abeysundara, N.a b , Przelicki, D.a b c , Skowron, P.a b c , Gauer, N.a b , Luu, B.a b , Daniels, C.a b , Wu, X.a b , Forget, A.h i , Momin, A.a b e , Wang, J.j , Dong, W.a b e , Kim, S.-K.k , Grajkowska, W.A.l , Jouvet, A.m , Fèvre-Montange, M.n , Garrè, M.L.o , Nageswara Rao, A.A.p , Giannini, C.q , Kros, J.M.r , French, P.J.s , Jabado, N.t , Ng, H.-K.u , Poon, W.S.v , Eberhart, C.G.w x y , Pollack, I.F.z , Olson, J.M.aa , Weiss, W.A.ab ac ad , Kumabe, T.ae , López-Aguilar, E.af , Lach, B.ag ah , Massimino, M.ai , Van Meir, E.G.aj ak al , Rubin, J.B.am an , Vibhakar, R.ao , Chambless, L.B.ap , Kijima, N.aq , Klekner, A.ar , Bognár, L.ar , Chan, J.A.as , Faria, C.C.at au , Ragoussis, J.av aw , Pfister, S.M.ax ay az , Goldenberg, A.ba bb , Wechsler-Reya, R.J.j bc , Bailey, S.D.bd be , Garzia, L.be bf , Morrissy, A.S.as bg , Marra, M.A.bh bi , Huang, X.a b , Malkin, D.bj , Ayrault, O.h i , Ramaswamy, V.b bj , Puente, X.S.f g , Calarco, J.A.bk , Stein, L.d , Taylor, M.D.a b c bl

a The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada
b Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada
c Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
d Informatics and Biocomputing, Ontario Institute for Cancer Research, Toronto, ON, Canada
e Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
f Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo, Spain
g Centro de Investigación Biomédica en Red de Cáncer, Madrid, Spain
h CNRS UMR, INSERM, Institut Curie, PSL Research University, Orsay, France
i CNRS UMR 3347, INSERM U1021, Université Paris Sud, Université Paris-Saclay, Orsay, France
j Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United States
k Department of Neurosurgery, Division of Pediatric Neurosurgery, Seoul National University Children’s Hospital, Seoul, South Korea
l Department of Pathology, The Children’s Memorial Health Institute, Warsaw, Poland
m Centre de Pathologie EST, Groupement Hospitalier EST, Université de Lyon, Bron, France
n CNRS UMR5292, INSERM U1028, Centre de Recherche en Neurosciences, Université de Lyon, Lyon, France
o Neuro-Oncology Unit, Istituto Giannina Gaslini, Genova, Italy
p Division of Pediatric Hematology/Oncology, Mayo Clinic, Rochester, MN, United States
q Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
r Department of Pathology, Erasmus University Medical Center, Rotterdam, Netherlands
s Department of Neurology, Erasmus University Medical Center, Rotterdam, Netherlands
t Division of Experimental Medicine, McGill University, Montreal, QC, Canada
u Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong
v Department of Surgery, The Chinese University of Hong Kong, Hong Kong
w Department of Pathology, John Hopkins University School of Medicine, Baltimore, MD, United States
x Department of Opthalmology, John Hopkins University School of Medicine, Baltimore, MD, United States
y Department of Oncology, John Hopkins University School of Medicine, Baltimore, MD, United States
z Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
aa Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States
ab Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, United States
ac Department of Pediatrics, University of California San Francisco, San Francisco, CA, United States
ad Department of Neurology, University of California San Francisco, San Francisco, CA, United States
ae Department of Neurosurgery, Kitasato University School of Medicine, Sagamihara, Japan
af Division of Pediatric Hematology/Oncology, Hospital Pediatría Centro Médico Nacional Century XXI, Mexico City, Mexico
ag Department of Pathology and Molecular Medicine, Division of Anatomical Pathology, McMaster University, Hamilton, ON, Canada
ah Department of Pathology and Laboratory Medicine, Hamilton General Hospital, Hamilton, ON, Canada
ai Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
aj Winship Cancer Institute, Emory University, Atlanta, GA, United States
ak Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery, School of Medicine, Emory University, Atlanta, GA, United States
al Department of Hematology and Medical Oncology, School of Medicine, Emory University, Atlanta, GA, United States
am Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
an Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
ao Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
ap Department of Neurological Surgery, Vanderbilt Medical Center, Nashville, TN, United States
aq Department of Neurosurgery, Osaka National Hospital, Osaka, Japan
ar Department of Neurosurgery, Medical and Health Science Centre, University of Debrecen, Debrecen, Hungary
as Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada
at Division of Neurosurgery, Centro Hospitalar Lisboa Norte, Hospital de Santa Maria, Lisbon, Portugal
au Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
av McGill University and Genome Quebec Innovation Centre, Department of Human Genetics, McGill University, Montreal, Canada
aw Department of Bioengineering, McGill University, Montreal, Canada
ax Hopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
ay Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
az Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany
ba Department of Computer Science, University of Toronto, Toronto, ON, Canada
bb Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada
bc Department of Pediatrics, University of California San Diego, San Diego, CA, United States
bd Department of Surgery, Division of Thoracic and Upper Gastrointestinal Surgery, Faculty of Medicine, McGill University, Montreal, QC, Canada
be Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada
bf Department of Surgery, Division of Orthopedic Surgery, Faculty of Medicine, McGill University, Montreal, QC, Canada
bg Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
bh Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada
bi Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
bj Division of Haematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada
bk Department of Cell and Systems Biology, University of Toronto, Toronto, Canada
bl Division of Neurosurgery, The Hospital for Sick Children, Toronto, ON, Canada

Abstract
In cancer, recurrent somatic single-nucleotide variants—which are rare in most paediatric cancers—are confined largely to protein-coding genes1–3. Here we report highly recurrent hotspot mutations (r.3A>G) of U1 spliceosomal small nuclear RNAs (snRNAs) in about 50% of Sonic hedgehog (SHH) medulloblastomas. These mutations were not present across other subgroups of medulloblastoma, and we identified these hotspot mutations in U1 snRNA in only <0.1% of 2,442 cancers, across 36 other tumour types. The mutations occur in 97% of adults (subtype SHHδ) and 25% of adolescents (subtype SHHα) with SHH medulloblastoma, but are largely absent from SHH medulloblastoma in infants. The U1 snRNA mutations occur in the 5′ splice-site binding region, and snRNA-mutant tumours have significantly disrupted RNA splicing and an excess of 5′ cryptic splicing events. Alternative splicing mediated by mutant U1 snRNA inactivates tumour-suppressor genes (PTCH1) and activates oncogenes (GLI2 and CCND2), and represents a target for therapy. These U1 snRNA mutations provide an example of highly recurrent and tissue-specific mutations of a non-protein-coding gene in cancer. © 2019, The Author(s), under exclusive licence to Springer Nature Limited.

Document Type: Article
Publication Stage: Final
Source: Scopus

“Dietary salt promotes cognitive impairment through tau phosphorylation” (2019) Nature

Dietary salt promotes cognitive impairment through tau phosphorylation
(2019) Nature, 574 (7780), pp. 686-690. 

Faraco, G.a , Hochrainer, K.a , Segarra, S.G.a , Schaeffer, S.a , Santisteban, M.M.a , Menon, A.a , Jiang, H.b , Holtzman, D.M.b , Anrather, J.a , Iadecola, C.a

a Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, United States
b Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University, St. Louis, MO, United States

Abstract
Dietary habits and vascular risk factors promote both Alzheimer’s disease and cognitive impairment caused by vascular factors1–3. Furthermore, accumulation of hyperphosphorylated tau, a microtubule-associated protein and a hallmark of Alzheimer’s pathology4, is also linked to vascular cognitive impairment5,6. In mice, a salt-rich diet leads to cognitive dysfunction associated with a nitric oxide deficit in cerebral endothelial cells and cerebral hypoperfusion7. Here we report that dietary salt induces hyperphosphorylation of tau followed by cognitive dysfunction in mice, and that these effects are prevented by restoring endothelial nitric oxide production. The nitric oxide deficiency reduces neuronal calpain nitrosylation and results in enzyme activation, which, in turn, leads to tau phosphorylation by activating cyclin-dependent kinase 5. Salt-induced cognitive impairment is not observed in tau-null mice or in mice treated with anti-tau antibodies, despite persistent cerebral hypoperfusion and neurovascular dysfunction. These findings identify a causal link between dietary salt, endothelial dysfunction and tau pathology, independent of haemodynamic insufficiency. Avoidance of excessive salt intake and maintenance of vascular health may help to stave off the vascular and neurodegenerative pathologies that underlie dementia in the elderly. © 2019, The Author(s), under exclusive licence to Springer Nature Limited.

Document Type: Article
Publication Stage: Final
Source: Scopus

“Low Back Pain–Related Disability in Parkinson Disease: Impact on Functional Mobility, Physical Activity, and Quality of Life” (2019) Physical Therapy

Low Back Pain–Related Disability in Parkinson Disease: Impact on Functional Mobility, Physical Activity, and Quality of Life
(2019) Physical Therapy, 99 (10), pp. 1346-1353. 

Duncan, R.P.a b , Van Dillen, L.R.c , Garbutt, J.M.d , Earhart, G.M.e , Perlmutter, J.S.f

a Program in Physical Therapy, Washington University School of Medicine in Saint Louis, 4444 Forest Park Blvd, Campus Box 8502, St Louis, MO 63108 (USA)
b Department of Neurology, Washington University School of Medicine in Saint Louis
c Program in Physical Therapy, Department of Orthopaedic Surgery, Washington University School of Medicine in Saint Louis
d Department of Medicine, Department of Pediatrics, Washington University School of Medicine in Saint Louis
e Program in Physical Therapy, Department of Neurology, Department of Neuroscience, Washington University School of Medicine in Saint Louis
f Department of Neurology, Program in Physical Therapy, Department of Neuroscience, Department of Radiology, Program in Occupational Therapy, Washington University School of Medicine in Saint Louis

Abstract
BACKGROUND: People with Parkinson disease (PD) frequently experience low back pain (LBP), yet the impact of LBP on functional mobility, physical activity, and quality of life (QOL) has not been described in PD. OBJECTIVE: The objectives of this study were to describe body positions and functional activities associated with LBP and to determine the relationships between LBP-related disability and PD motor sign severity, physical activity level, and QOL. DESIGN: The study was a cross-sectional study. METHODS: Thirty participants with idiopathic PD (mean age = 64.6 years [SD = 10.3]; 15 women) completed the Revised Oswestry Disability Questionnaire (RODQ), a measure of LBP-related disability. PD motor symptom severity was measured using the Movement Disorder Society-Unified Parkinson Disease Rating Scale Part III (MDS-UPRDS III). The Physical Activity Scale for the Elderly (PASE) was used to measure self-reported physical activity. The Parkinson Disease Questionnaire-39 (PDQ-39) was used to measure QOL. Descriptive statistics were used to characterize LBP intensity and LBP-related disability. Spearman correlations were used to determine relationships between the RODQ and the MDS-UPDRS III, PASE, and PDQ-39. RESULTS: LBP was reported to be of at least moderate intensity by 63.3% of participants. LBP most frequently impaired standing, sleeping, lifting, and walking. The RODQ was significantly related to the MDS-UPDRS III (r = 0.38), PASE (r = -0.37), PDQ-39 summary index (r = 0.55), PDQ-39 mobility subdomain (r = 0.54), and PDQ-39 bodily pain subdomain (r = 0.44). LIMITATIONS: Limitations included a small sample of people with mild to moderate PD severity, the fact that RODQ is a less frequently used measure of LBP-related disability, and the lack of a non-PD control group. CONCLUSIONS: LBP affected walking, sleeping, standing, and lifting in this small sample of people with mild to moderate PD. Greater LBP-related disability was associated with greater motor sign severity, lower physical activity level, and lower QOL in people with PD. © 2019 American Physical Therapy Association.

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

“Association of polygenic liability for alcohol dependence and EEG connectivity in adolescence and young adulthood”(2019) Brain Sciences

Association of polygenic liability for alcohol dependence and EEG connectivity in adolescence and young adulthood
(2019) Brain Sciences, 9 (10), art. no. 280, . 

Meyers, J.L.a , Chorlian, D.B.a , Johnson, E.C.b , Pandey, A.K.a , Kamarajan, C.a , Salvatore, J.E.c d , Aliev, F.c , de Viteri, S.S.-S.a , Zhang, J.a , Chao, M.e , Kapoor, M.e , Hesselbrock, V.f , Kramer, J.g , Kuperman, S.g , Nurnberger, J.h , Tischfield, J.i , Goate, A.e j , Foroud, T.k , Dick, D.M.c , Edenberg, H.J.k l , Agrawal, A.b , Porjesz, B.a

a Department of Psychiatry, State University of New York Downstate Medical Center, Brooklyn, NY 11203, United States
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Psychology, Virginia Commonwealth University, Richmond, VA 23284, United States
d Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA 23284, United States
e Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
f Department of Psychiatry, University of Connecticut School of Medicine, Farmington, CT 06030, United States
g Department of Psychiatry, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA 52242, United States
h Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN 46202, United States
i Department of Genetics and the Human Genetics Institute of New Jersey, Rutgers University, Newark, NJ 08901, United States
j Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
k Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
l Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, United States

Abstract
Differences in the connectivity of large-scale functional brain networks among individuals with alcohol use disorders (AUD), as well as those at risk for AUD, point to dysfunctional neural communication and related cognitive impairments. In this study, we examined how polygenic risk scores (PRS), derived from a recent GWAS of DSM-IV Alcohol Dependence (AD) conducted by the Psychiatric Genomics Consortium, relate to longitudinal measures of interhemispheric and intrahemispheric EEG connectivity (alpha, theta, and beta frequencies) in adolescent and young adult offspring from the Collaborative Study on the Genetics of Alcoholism (COGA) assessed between ages 12 and 31. Our findings indicate that AD PRS (p-threshold < 0.001) was associated with increased fronto-central, tempo-parietal, centro-parietal, and parietal-occipital interhemispheric theta and alpha connectivity in males only from ages 18–31 (beta coefficients ranged from 0.02–0.06, p-values ranged from 10−6–10−12), but not in females. Individuals with higher AD PRS also demonstrated more performance deficits on neuropsychological tasks (Tower of London task, visual span test) as well as increased risk for lifetime DSM-5 alcohol and opioid use disorders. We conclude that measures of neural connectivity, together with neurocognitive performance and substance use behavior, can be used to further understanding of how genetic risk variants from large GWAS of AUD may influence brain function. In addition, these data indicate the importance of examining sex and developmental effects, which otherwise may be masked. Understanding of neural mechanisms linking genetic variants emerging from GWAS to risk for AUD throughout development may help to identify specific points when neurocognitive prevention and intervention efforts may be most effective. © 2019 by the authors. Licensee MDPI, Basel, Switzerland.

Author Keywords
AD;  AUD;  Developmental trajectories;  EEG coherence;  Neural connectivity;  PRS;  Sex differences

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

“Interhemispheric transfer of post-amputation cortical plasticity within the human somatosensory cortex” (2019) NeuroImage

Interhemispheric transfer of post-amputation cortical plasticity within the human somatosensory cortex
(2019) NeuroImage, art. no. 116291, . 

Valyear, K.F.a b , Philip, B.A.a c , Cirstea, C.M.e , Chen, P.-W.a c , Baune, N.A.a c , Marchal, N.a d , Frey, S.H.a e

a Department of Psychological Sciences, University of Missouri, Columbia, MO, United States
b School of Psychology, Bangor University, Bangor, United Kingdom
c Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO, United States
d College of Engineering, University of Missouri, Columbia, MO, United States
e Department of Physical Medicine and Rehabilitation, University of Missouri School of Medicine, Columbia, MO, United States

Abstract
Animal models reveal that deafferenting forelimb injuries precipitate reorganization in both contralateral and ipsilateral somatosensory cortices. The functional significance and duration of these effects are unknown, and it is unclear whether they also occur in injured humans. We delivered cutaneous stimulation during functional magnetic resonance imaging (fMRI) to map the sensory cortical representation of the intact hand and lower face in a group of chronic, unilateral, upper extremity amputees (N = 19) and healthy matched controls (N = 29). Amputees exhibited greater activity than controls within the deafferented former sensory hand territory (S1f) during stimulation of the intact hand, but not of the lower face. Despite this cortical reorganization, amputees did not differ from controls in tactile acuity on their intact hands. S1f responses during hand stimulation were unrelated to tactile acuity, pain, prosthesis usage, or time since amputation. These effects appeared specific to the deafferented somatosensory modality, as fMRI visual mapping paradigm failed to detect any differences between groups. We conclude that S1f becomes responsive to cutaneous stimulation of the intact hand of amputees, and that this modality-specific reorganizational change persists for many years, if not indefinitely. The functional relevance of these changes, if any, remains unknown. © 2019 Elsevier Inc.

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

“Laryngeal adductor function following potassium titanyl phosphate laser welding of the recurrent laryngeal nerve” (2019) Laryngoscope

Laryngeal adductor function following potassium titanyl phosphate laser welding of the recurrent laryngeal nerve
(2019) Laryngoscope, . 

Bhatt, N.K., Faddis, B.T., Paniello, R.C.

Department of Otolaryngology–Head and Neck Surgery, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Objectives/Hypothesis: Recurrent laryngeal nerve (RLN) transection injuries may occur during thyroidectomy and other surgical procedures. Laser nerve welding has been shown to cause less technique-related axonal damage than the traditional suture method. We compared functional adductor results using these two methods of RLN repair. Study Design: Animal model. Methods: Canine hemilarynges underwent pretreatment testing of laryngeal adductor function, followed by RLN transection and repair using potassium titanyl phosphate (KTP) laser welding (n = 8) or microneural suture (n = 16) techniques. Six months later, adductor function was measured again and expressed as a proportion of the pretreatment value. Results: The mean laryngeal adductor pressure ratios were 82.4% (95% confidence interval [CI]: 72.8%-92.0%) for the laser repair group and 55.5% (95% CI: 49.4%-61.6%) for the suture control group, with a difference of 26.9% (95% CI: 15.3%-38.5%). Both spontaneous and stimulated glottic closure was observed in the laser welding and microsuture repair groups. Conclusions: Laser nerve welding resulted in greater strength of adduction than suture repair of an acutely transected RLN. Suture anastomosis may traumatize more axons than the laser. Stronger vocal fold adduction is associated clinically with better protection from aspiration and improved voice outcomes. KTP laser welding should be considered for anastomosis of the RLN and other nerves. Level of Evidence: NA. Laryngoscope, 2019. © 2019 The American Laryngological, Rhinological and Otological Society, Inc.

Author Keywords
dysphonia;  Larynx;  neurolaryngology;  voice

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

“Location and Cell-Type-Specific Bias of Metabotropic Glutamate Receptor, mGlu5, Negative Allosteric Modulators” (2019) ACS Chemical Neuroscience

Location and Cell-Type-Specific Bias of Metabotropic Glutamate Receptor, mGlu5, Negative Allosteric Modulators
(2019) ACS Chemical Neuroscience, . 

Jong, Y.-J.I., Harmon, S.K., O’Malley, K.L.

Department of Neuroscience, Washington University School of Medicine, Saint Louis, MO 63110, United States

Abstract
Emerging data indicate that G-protein coupled receptor (GPCR) signaling is determined by not only the agonist and a given receptor but also a variety of cell-type-specific factors that can influence a receptor’s response. For example, the metabotropic glutamate receptor, mGlu5, which is implicated in a number of neuropsychiatric disorders such as depression, anxiety, and autism, also signals from inside the cell which leads to sustained Ca2+ mobilization versus rapid transient responses. Because mGlu5 is an important drug target, many negative allosteric modulators (NAMs) have been generated to modulate its activity. Here we show that NAMs such as AFQ056, AZD2066, and RG7090 elicit very different end points when tested in postnatal neuronal cultures expressing endogenous mGlu5 receptors. For example, AFQ056 fails to block intracellular mGlu5-mediated Ca2+ increases whereas RG7090 is very effective. These differences are not due to differential receptor levels, since about the same number of mGlu5 receptors are present on neurons from the cortex, hippocampus, and striatum based on pharmacological, biochemical, and molecular data. Moreover, biotinylation studies reveal that more than 90% of the receptor is intracellular in these neurons. Taken together, these data indicate that the tested NAMs exhibit both location-dependent and cell type specific bias for mGlu5-mediated Ca2+ mobilization which may affect clinical outcomes. © Copyright © 2019 American Chemical Society.

Author Keywords
calcium;  GPCR;  intracellular;  mGlu5;  NAM;  neuron

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

“Neurostructural Heterogeneity in Youths With Internalizing Symptoms” (2019) Biological Psychiatry

Neurostructural Heterogeneity in Youths With Internalizing Symptoms
(2019) Biological Psychiatry, . 

Kaczkurkin, A.N.a h , Sotiras, A.b c f , Baller, E.B.a , Barzilay, R.a , Calkins, M.E.a , Chand, G.B.b c , Cui, Z.a , Erus, G.b c , Fan, Y.b c , Gur, R.E.a b , Gur, R.C.a b e , Moore, T.M.a , Roalf, D.R.a , Rosen, A.F.G.a , Ruparel, K.a , Shinohara, R.T.c d , Varol, E.b c g , Wolf, D.H.a c , Davatzikos, C.b c , Satterthwaite, T.D.a c

a Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
b Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
c Center for Biomedical Image Computing and Analytics, University of Pennsylvania, Philadelphia, PA, United States
d Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, PA, United States
e Philadelphia Veterans Administration Medical Center, Philadelphia, PA, United States
f Department of Radiology, Washington University, St. Louis, MO, United States
g Grossman Center for the Statistics of Mind, Center for Theoretical Neuroscience, Department of Statistics, Columbia University, New York, New York, United States
h Department of Psychology, Vanderbilt University, Nashville, TN, United States

Abstract
Background: Internalizing disorders such as anxiety and depression are common psychiatric disorders that frequently begin in youth and exhibit marked heterogeneity in treatment response and clinical course. Given that symptom-based classification approaches do not align with underlying neurobiology, an alternative approach is to identify neurobiologically informed subtypes based on brain imaging data. Methods: We used a recently developed semisupervised machine learning method (HYDRA [heterogeneity through discriminative analysis]) to delineate patterns of neurobiological heterogeneity within youths with internalizing symptoms using structural data collected at 3T from a sample of 1141 youths. Results: Using volume and cortical thickness, cross-validation methods indicated 2 highly stable subtypes of internalizing youths (adjusted Rand index = 0.66; permutation-based false discovery rate p < .001). Subtype 1, defined by smaller brain volumes and reduced cortical thickness, was marked by impaired cognitive performance and higher levels of psychopathology than both subtype 2 and typically developing youths. Using resting-state functional magnetic resonance imaging and diffusion images not considered during clustering, we found that subtype 1 also showed reduced amplitudes of low-frequency fluctuations in frontolimbic regions at rest and reduced fractional anisotropy in several white matter tracts. In contrast, subtype 2 showed intact cognitive performance and greater volume, cortical thickness, and amplitudes during rest compared with subtype 1 and typically developing youths, despite still showing clinically significant levels of psychopathology. Conclusions: We identified 2 subtypes of internalizing youths differentiated by abnormalities in brain structure, function, and white matter integrity, with one of the subtypes showing poorer functioning across multiple domains. Identification of biologically grounded internalizing subtypes may assist in targeting early interventions and assessing longitudinal prognosis. © 2019 Society of Biological Psychiatry

Author Keywords
Cortical thickness;  Heterogeneity;  Internalizing;  Structure;  Volume;  Youth

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

“Effects of Immersive Virtual Reality Headset Viewing on Young Children: Visuomotor Function, Postural Stability, and Motion Sickness” (2019) American Journal of Ophthalmology

Effects of Immersive Virtual Reality Headset Viewing on Young Children: Visuomotor Function, Postural Stability, and Motion Sickness
(2019) American Journal of Ophthalmology, . 

Tychsen, L., Foeller, P.

St Louis Children’s Hospital at Washington University Medical Center, St Louis, MO, United States

Abstract
Purpose: To assess the safety of VR 3D headset (virtual reality 3-dimensional binocular-stereoscopic near-eye display) use in young children. Product safety warnings that accompany VR headsets ban their use in children under age 13 years. Design: Prospective, interventional, before-and-after study. Methods: Recordings were obtained in 50 children (29 boys) aged 4-10 years (mean 7.2 ± 1.8 years). Minimum binocular corrected distance visual acuity (CDVA) was 20/50 (logarithm of the minimum angle of resolution [logMAR] 0.4) and stereoacuity 800 seconds of an arc or better. A Sony PlayStation VR headset was worn for 2 sequential play sessions (of 30 minutes each) of a first-person 3D flying game (Eagle Flight) requiring head movement to control flight direction (pitch, yaw, and roll axes). Baseline testing preceded VR exposure, and each VR session was followed by post-VR testing of binocular CDVA, refractive error, binocular eye alignment (strabismus), stereoacuity, and postural stability (imbalance). Visually induced motion sickness was probed using the Simulator Sickness Questionnaire modified for pediatric use (Peds SSQ). Visual-vestibulo-ocular reflex (V-VOR) adaptation was also tested pre- vs post-trial in 5 of the children. Safety was gauged as a decline or change from baseline in any visuomotor measure. Results: Forty-six of 50 children (94%) completed both VR play sessions with no significant change from baseline in measures of binocular CDVA (P =.89), refractive error (P =.36), binocular eye alignment (P =.90), or stereoacuity (P =.45). Postural stability degraded an average 9% from baseline after 60 minutes of VR exposure (P =.06). Peds SSQ scores increased a mean 4.7%—comparing pretrial to post-trial—for each of 4 symptom categories: eye discomfort (P =.02), head/neck discomfort (P =.03), fatigue (P =.03), and motion sickness (P =.01). None of the children who finished both trial sessions (94%) asked to end the play, and the majority were disappointed when play was halted. V-VOR gain remained unaltered in the 5 children tested. Three children (6% of participants) discontinued the trial during the first 10 minutes of the first session of VR play, 2 girls (aged 5 and 6 years) and 1 boy (aged 7 years). The girls reported discomfort consistent with mild motion sickness; the boy said he was bored and the headset was uncomfortable. No child manifested aftereffects (“flashbacks”) in the days following the VR exposure. Conclusion: Young children tolerate fully immersive 3D virtual reality game play without noteworthy effects on visuomotor functions. VR play did not induce significant post-VR postural instability or maladaption of the vestibulo-ocular reflex. The prevalence of discomfort and aftereffects may be less than that reported for adults. © 2019 Elsevier Inc.

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

“MRI Volumetric Quantification in Persons with a History of Traumatic Brain Injury and Cognitive Impairment” (2019) Journal of Alzheimer’s Disease

MRI Volumetric Quantification in Persons with a History of Traumatic Brain Injury and Cognitive Impairment
(2019) Journal of Alzheimer’s Disease, 72 (1), pp. 293-300. 

Meysami, S.a , Raji, C.A.b , Merrill, D.A.c d , Porter, V.R.a d , Mendez, M.F.a c e

a Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
b Mallinckrodt Institute of Radiology, Division of Neuroradiology, Washington University, St. Louis, MO, United States
c Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
d John Wayne Cancer Institute and Pacific Neuroscience Institute, Providence and St. Johns Health Center, Santa Monica, CA, United States
e V.A. Greater Los Angeles Healthcare System, Los Angeles, CA, United States

Abstract
Background: While traumatic brain injury (TBI) is recognized as a risk factor for dementia, there is lack of clinical tools to identify brain changes that may confer such vulnerability. Brain MRI volumetric quantification can sensitively identify brain atrophy. Objective: To characterize regional brain volume loss in persons with TBI presenting with cognitive impairment. Methods: IRB approved review of medical records in patients with cognitive decline focused on those who had documented TBI histories and brain MRI scans after TBI (n = 40, 67.7±14.5 years) with volumetric quantification by applying an FDA cleared software program. TBI documentation included head trauma mechanism. Brain volumes were compared to a normative database to determine the extent of atrophy. Correlations between these regions and global tests of cognition (MMSE in n = 17, MoCA in n = 27, n = 14 in both) were performed. Results: Multiple regions demonstrated volume loss in TBI, particularly ventral diencephalon, putamen, and pallidum with smaller magnitude of atrophy in temporal lobes and brainstem. Lobar structures showed strongest correlations between atrophy and lower scores on MMSE and MoCA. The hippocampus, while correlated to tests of cognitive function, was the least atrophic region as a function of TBI history. Conclusion: Persons with TBI history exhibit show regional brain atrophy. Several of these areas, such as thalamus and temporal lobes, also correlate with cognitive function. Alzheimer’s disease atrophy was less likely given relative sparing of the hippocampi. Volumetric quantification of brain MRI in TBI warrants further investigation to further determine its clinical potential in TBI and differentiating causes of cognitive impairment. © 2019 – IOS Press and the authors. All rights reserved.

Author Keywords
Magnetic resonance imaging;  traumatic brain injury;  volumetric quantification

Document Type: Article
Publication Stage: Final
Source: Scopus

“Postoperative Opioid Use and Pain Management Following Otologic and Neurotologic Surgery” (2019) Annals of Otology, Rhinology and Laryngology

Postoperative Opioid Use and Pain Management Following Otologic and Neurotologic Surgery
(2019) Annals of Otology, Rhinology and Laryngology, . 

Boyd, C.a , Shew, M.b , Penn, J.a , Muelleman, T.c , Lin, J.a , Staecker, H.a , Wichova, H.a

a Department of Otolaryngology—Head and Neck Surgery, University of Kansas, School of Medicine, Kansas City, KS, United States
b Clinical Fellow, Department of Otolaryngology—Head and Neck Surgery, Washington University School of Medicine, Kansas City, KS, United States
c Clinical Fellow, House Clinic, Los Angeles, CA, United States

Abstract
Objectives: The topic of prescription opioid overuse remains a growing concern in the United States. Our objective is to provide insight into pain perception and opioid use based on a patient cohort undergoing common otologic and neurotologic surgeries. Study Design: Prospective observational study with patient questionnaire. Setting: Single academic medical center. Subjects and Methods: Adult patients undergoing otologic and neurotologic procedures by two fellowship trained neurotologists between June and November of 2018 were included in this study. During first postoperative follow-up, participants completed a questionnaire assessing perceived postoperative pain and its impact on quality of life, pain management techniques, and extent of prescription opioid use. Results: A total of 47 patients met inclusion and exclusion criteria. The median pain score was 3 out of 10 (Interquartile Range [IQR] = 2-6) with no significant gender differences (P =.92). Patients were prescribed a median of 15.0 (IQR = 10.0-15.0) tablets of opioid pain medication postoperatively, but only used a median of 4.0 (IQR = 1.0-11.5) tablets at the time of first follow-up. Measured quality of life areas included sleep, physical activity, work, and mood. Sleep was most commonly affected, with 69.4% of patients noting disturbances. Conclusions: This study suggests that practitioners may over-estimate the need for opioid pain medication following otologic and neurotologic surgery. It also demonstrates the need for ongoing patient education regarding opioid risks, alternatives, and measures to prevent diversion. © The Author(s) 2019.

Author Keywords
miscellaneous;  opioid epidemic;  opioids;  otolaryngology;  otology;  pain;  prescribing

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

“How different aspects of motor dysfunction influence day-to-day function in huntington’s disease” (2019) Movement Disorders

How different aspects of motor dysfunction influence day-to-day function in huntington’s disease
(2019) Movement Disorders, . 

Carlozzi, N.E.a , Schilling, S.G.a b , Boileau, N.R.a , Chou, K.L.c , Perlmutter, J.S.d , Frank, S.e , McCormack, M.K.f g , Stout, J.C.h , Paulsen, J.S.i , Lai, J.-S.j , Dayalu, P.c

a Department of Physical Medicine and Rehabilitation, University of Michigan, Ann Arbor, MI, United States
b Institute for Social Research, University of Michigan, Ann Arbor, MI, United States
c Department of Neurology, University of Michigan, Ann Arbor, MI, United States
d Department of Neurology, Radiology, Neuroscience, Physical Therapy and Occupational Therapy, Washington University in St. Louis, St. Louis, MO, United States
e Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, United States
f Department of Psychiatry, Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ, United States
g Department of Pathology, Rowan-SOM (School of Medicine), Stratford, NJ, United States
h School of Psychological Sciences, Monash University, Clayton, VIC, Australia
i Department of Psychiatry, Neurology, and Psychological and Brain Sciences, The University of Iowa, Iowa City, IA, United States
j Department of Medical Social Sciences, Northwestern University, Chicago, IL, United States

Abstract
Purpose: This study examined the relationships between different aspects of motor dysfunction (chorea, dystonia, rigidity, incoordination, oculomotor dysfunction, dysarthria, and gait difficulties) and functional status in persons with Huntington’s disease. Methods: A total of 527 persons with Huntington’s disease completed the Unified Huntington’s Disease Rating Scale motor, total functional capacity, and functional assessments. Results: Confirmatory factor analysis indicated that a 4-factor model provided a better model fit than the existing 5-factor model. Exploratory factor analysis identified the following 4 factors from the motor scale: dystonia, chorea, rigidity, and a general motor factor. Regression indicated that dystonia (β = −0.47 and −0.79) and rigidity (β = −0.28 and −0.59) had strong associations with function, whereas chorea had modest correlations (β = −0.16 and −0.15). Conclusions: Dystonia and rigidity have stronger relationships with functional status than chorea in persons with Huntington’s disease. The findings underscore the need for further research regarding the effects of dystonia and rigidity on functioning. © 2019 International Parkinson and Movement Disorder Society. © 2019 International Parkinson and Movement Disorder Society

Author Keywords
chorea;  dystonia;  HDQLIFE;  Health-related quality of life;  Huntington’s disease;  motor function

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

“Selection design phase II trial of high dosages of tamoxifen and creatine in amyotrophic lateral sclerosis” (2019) Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration

Selection design phase II trial of high dosages of tamoxifen and creatine in amyotrophic lateral sclerosis
(2019) Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, . 

Babu, S.a , Macklin, E.A.b , Jackson, K.E.c , Simpson, E.d , Mahoney, K.a , Yu, H.a , Walker, J.a , Simmons, Z.e , David, W.S.a , Barkhaus, P.E.f , Simionescu, L.g , Dimachkie, M.M.h , Pestronk, A.i , Salameh, J.S.j , Weiss, M.D.k , Brooks, B.R.l , Schoenfeld, D.b , Shefner, J.m , Aggarwal, S.a , Cudkowicz, M.E.a , Atassi, N.a

a Department of Neurology, Sean M Healey & AMG Center for ALS at Massachusetts General Hospital, Neurological Clinical Research Institute, Boston, MA, United States
b Biostatistics Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
c Office of the Prescription Drug Monitoring Program, Maryland Department of Health, Baltimore, MD, United States
d McCance Center for Brain Health at Massachusetts General Hospital, Boston, MA, United States
e Penn State Health Hershey Medical Center, Hershey, PA, United States
f Medical College of Wisconsin, Milwaukee, WI, United States
g SUNY Upstate Medical Center, Syracuse, NY, United States
h University of Kansas Medical Center, Kansas City, KS, United States
i Washington University School of Medicine, St. Louis, MO, United States
j American University of Beirut Medical Center, Beirut, Lebanon
k University of Washington Medical Center, Seattle, WA, United States
l Atrium Health Neurosciences Institute, Carolinas Medical Center, University of North Carolina School of Medicine, Charlotte, NC, United States
m Barrow Neurological Institute and University of Arizona College of Medicine, Phoenix, AZ, United States

Abstract
Objective: To conduct a phase-II trial using a ranking and selection paradigm where multiple treatments are compared with limited sample size and the best is chosen for a subsequent efficacy trial versus placebo. This strategy can find an effective treatment faster than traditional strategy of conducting larger trials against placebo. Methods: Sixty amyotrophic lateral sclerosis (ALS) participants were randomized 1:1:1 to creatine 30 g/day (CRE), tamoxifen 40 mg/day (T40), or tamoxifen 80 mg/day (T80), with matching placebo. The primary outcome was 38-week change in ALS Functional Rating Scale-Revised (ALSFRS-R), analyzed in a repeated-measures ANOVA. Secondary outcomes included slow vital capacity (SVC), quantitative muscle strength, early drug discontinuation (EDD), adverse events (AEs), and survival. Results: CRE participants experienced higher rates of drug-related AEs (82% vs. 43% T40, 47% T80) and EDD (50% vs. 24% T40, 29% T80). T80 participants experienced slower adjusted mean decline in ALSFRS-R in points/month (–0.80 vs. –0.84 T40, –0.85 CRE) and quantitative muscle strength but not in SVC and higher rates of mortality. Conclusion: Efficacy of T80 ranked numerically superior to CRE and T40 with respect to ALSFRS-R decline. Following the selection paradigm, T80 would be chosen to test against placebo. The approach was not designed to distinguish among treatments that are nearly equally effective or ineffective. If treatments are equivalent, then under the paradigm, it does not matter which treatment is selected. Newer approaches for increasing trial efficiency, including an adaptive platform trial design, may mitigate limitations of the selection design. © 2019, © 2019 World Federation of Neurology on behalf of the Research Group on Motor Neuron Diseases.

Author Keywords
Creatine;  selection design;  tamoxifen;  trial

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

“Correction: Whole exome sequencing study identifies novel rare and common Alzheimer’s-Associated variants involved in immune response and transcriptional regulation (Molecular Psychiatry, (2018), 10.1038/s41380-018-0112-7)” (2019) Molecular Psychiatry

Correction: Whole exome sequencing study identifies novel rare and common Alzheimer’s-Associated variants involved in immune response and transcriptional regulation (Molecular Psychiatry, (2018), 10.1038/s41380-018-0112-7)
(2019) Molecular Psychiatry, . 

Bis, J.C.a , Jian, X.b , Kunkle, B.W.c , Chen, Y.d , Hamilton-Nelson, K.L.c , Bush, W.S.e , Salerno, W.J.f , Lancour, D.g , Ma, Y.g , Renton, A.E.h , Marcora, E.h i , Farrell, J.J.g , Zhao, Y.j , Qu, L.j , Ahmad, S.k , Amin, N.l , Amouyel, P.l m n , Beecham, G.W.c , Below, J.E.o , Campion, D.p q , Cantwell, L.j , Charbonnier, C.p , Chung, J.g , Crane, P.K.a , Cruchaga, C.r , Cupples, L.A.d s , Dartigues, J.-F.t , Debette, S.t u , Deleuze, J.-F.v , Fulton, L.w , Gabriel, S.B.x , Genin, E.y , Gibbs, R.A.f , Goate, A.h i , Grenier-Boley, B.l , Gupta, N.x , Haines, J.L.e , Havulinna, A.S.z aa , Helisalmi, S.ab , Hiltunen, M.ac , Howrigan, D.P.ad ae , Ikram, M.A.k , Kaprio, J.z , Konrad, J.r , Kuzma, A.j , Lander, E.S.x , Lathrop, M.af , Lehtimäki, T.ag , Lin, H.ah , Mattila, K.ag , Mayeux, R.ai , Muzny, D.M.f , Nasser, W.f , Neale, B.ad ae , Nho, K.aj , Nicolas, G.p , Patel, D.g , Pericak-Vance, M.A.c , Perola, M.z aa ak , Psaty, B.M.a al am an , Quenez, O.p , Rajabli, F.c , Redon, R.ao , Reitz, C.ai , Remes, A.M.ab ap , Salomaa, V.aa , Sarnowski, C.d , Schmidt, H.aq , Schmidt, M.c , Schmidt, R.aq , Soininen, H.ab ar , Thornton, T.A.as , Tosto, G.ai , Tzourio, C.t , van der Lee, S.J.k , van Duijn, C.M.k , Valladares, O.j , Vardarajan, B.ai , Wang, L.-S.j , Wang, W.j , Wijsman, E.at au , Wilson, R.K.w , Witten, D.as au , Worley, K.C.f , Zhang, X.d g , Bellenguez, C.l , Lambert, J.-C.l , Kurki, M.I.z ad ae , Palotie, A.z ad ae , Daly, M.x z ae , Boerwinkle, E.f av , Lunetta, K.L.d , Destefano, A.L.d aw , Dupuis, J.d , Martin, E.R.c , Schellenberg, G.D.j , Seshadri, S.s aw ax , Naj, A.C.j , Fornage, M.b av , Farrer, L.A.d g aw ay az , Alzheimer’s Disease Sequencing Projectba

a Department of Medicine (General Internal Medicine), University of Washington, Seattle, WA, United States
b Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States
c John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, United States
d Departments of Biostatistics, Boston University School of Public Health, Boston, MA, United States
e Case Western Reserve University, Cleveland Heights, OH, United States
f Human Genome Sequencing Center and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
g Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, United States
h Department of Neuroscience and Ronald M Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States
i Department of Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
j University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
k Erasmus University Medical Center, Rotterdam, Netherlands
l Inserm, U1167, RID-AGE-Risk Factors and Molecular Determinants of Aging-Related Diseases, Lille, France
m Institut Pasteur de Lille, Lille, France
n University Lille, U1167-Excellence Laboratory LabEx DISTALZ, Lille, France
o Department of Medical Genetics, Vanderbilt University Medical Center, Nashville, TN, United States
p Department of Genetics and CNR-MAJ, Normandie Université, UNIROUEN, Inserm U1245 and Rouen University Hospital, F 76000, Normandy Centre for Genomic and Personalized Medicine, Rouen, France
q Department of Research, Centre Hospitalier du Rouvray, Sotteville-lès-, Rouen, France
r Department of Psychiatry, Washington University, St. Louis, MO, United States
s National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham, MA, United States
t University of Bordeaux, Inserm, Bordeaux Population Health Research Center, team VINTAGE, UMR 1219, Bordeaux, F-33000, France
u Department of Neurology and Institute for Neurodegenerative Diseases, Bordeaux University Hospital, Memory Clinic, Bordeaux, F-33000, France
v Centre National de Recherche en Génomique Humaine, Institut François Jacob, Direction de le Recherche Fondamentale, CEA, Evry, France
w McDonnell Genome Institute, Washington University, St. Louis, MO, United States
x Broad Institute of MIT and Harvard, Cambridge, MA, United States
y Inserm UMR-1078, CHRU Brest, Université Brest, Brest, France
z Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
aa National Institute for Health and Welfare, Helsinki, Finland
ab Institute of Clinical Medicine – Neurology and Department of Neurology, University of Eastern Finland, Kuopio, Finland
ac Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
ad Program in Medical and Population Genetics and Genetic Analysis Platform, Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, United States
ae Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, United States
af McGill University and Génome Québec Innovation Centre, Montréal, Canada
ag Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland
ah Department of Medicine (Computational Biomedicine), Boston University School of Medicine, Boston, MA, United States
ai Columbia University, New York, NY, United States
aj Indiana University School of Medicine, Indianapolis, IN, United States
ak University of Tartu, Estonian Genome Center, Tartu, Estonia
al Department of Epidemiology, University of Washington, Seattle, WA, United States
am Department of Health Services, University of Washington, Seattle, WA, United States
an Kaiser Permanente Washington Health Research Institute, Seattle, WA, United States
ao Inserm, CNRS, Univ. Nantes, CHU Nantes, l’institut du thorax, Nantes, France
ap Unit of Clinical Neuroscience, Neurology, University of Oulu and Medical Research Center, Oulu University Hospital, Oulu, Finland
aq Department of Neurology, Clinical Division of Neurogeriatrics, Medical University of Graz, Graz, Austria
ar Department of Neurology, Kuopio University Hospital, Kuopio, Finland
as Department of Statistics, University of Washington, Seattle, WA, United States
at Department of Medicine (Medical Genetics), University of Washington, Seattle, WA, United States
au Department of Biostatistics, University of Washington, Seattle, WA, United States
av School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, United States
aw Departments of Neurology, Boston University School of Medicine, Boston, MA, United States
ax Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio, TX, United States
ay Department of Epidemiology, Boston University School of Public Health, Boston, MA, United States
az Department of Ophthalmology, Boston University School of Medicine, Boston, MA, United States

Abstract
Following publication, the authors noticed that ‘Laura Cantwell’, ‘Otto Valladares’, and ‘Li-San Wang’ were inadvertently omitted from the author list. These authors have now been added to the author list in 21st, 77th, and 79th position, respectively. This has been corrected in both the PDF and HTML versions of the article. © 2019, The Author(s).

Document Type: Erratum
Publication Stage: Article in Press
Source: Scopus

“Left transradial access for cerebral angiography” (2019) Journal of NeuroInterventional Surgery

Left transradial access for cerebral angiography
(2019) Journal of NeuroInterventional Surgery, . 

Barros, G.a , Bass, D.I.a , Osbun, J.W.b c d , Chen, S.H.e , Brunet, M.-C.e , Peterson, E.C.e , Walker, M.a f , Kelly, C.M.a f , Levitt, M.R.a f g h

a Neurological Surgery, University of Washington, Seattle, WA 98104, United States
b Neurological Surgery, Washington University in St Louis, St Louis, MO, United States
c Radiology, Washington University in St Louis, St Louis, MO, United States
d Neurology, Washington University in St Louis, St Louis, MO, United States
e Neurological Surgery, University of Miami School of Medicine, Miami, FL, United States
f Stroke and Applied Neuroscience Center, University of Washington, Seattle, WA, United States
g Radiology, University of Washington, Seattle, WA, United States
h Mechanical Engineering, University of Washington, Seattle, WA, United States

Abstract
Introduction: Transradial access is increasingly used among neurointerventionalists as an alternative to the transfemoral route. Currently available data, building on the interventional cardiology experience, primarily focus on right radial access. However, there are clinical scenarios when left-sided access may be indicated. The purpose of this study was to evaluate the technical feasibility of left transradial access to cerebral angiography across three institutions. Methods: A retrospective chart review was performed for patients who underwent cerebral angiography accessed via the left radial artery at three institutions between January 2018 and July 2019. The outcome variables studied were successful catheterization, vascular complications, and fluoroscopic time. Results: Nineteen patients underwent a total of 25 cerebral angiograms via left transradial access for cerebral aneurysms (n=15), basilar occlusion (n=1), carotid stenosis (n=1), arteriovenous malformation (n=1), and cervical neurofibroma (n=1). There were 12 diagnostic angiograms and 13 interventional angiograms. The left transradial approach was chosen due to left vertebrobasilar pathology (n=22), right subclavian stenosis (n=2), and previous right arm amputation (n=1). There was one instance of radial artery spasm, which resolved after catheter removal, and one conversion to transfemoral access in an interventional case due to lack of distal catheter support. There were no procedural complications. Conclusions: Left transradial access in diagnostic and interventional cerebral angiography is a technically feasible, safe, and an effective alternative when indicated, and may be preferable for situations in which pathology locations or anatomic limitations preclude right-sided radial access. © Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.

Author Keywords
angiography;  artery;  technique

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

“Recognizing the True Cost of Medical Spending – An Assessment of Ranibizumab for Retinal Disorders” (2019) JAMA Ophthalmology

Recognizing the True Cost of Medical Spending – An Assessment of Ranibizumab for Retinal Disorders
(2019) JAMA Ophthalmology, . 

Kymes, S.M.a , Vollman, D.b c

a Lundbeck, Six Parkway North, Deerfield, IL 60015, United States
b Veterans Administration Health Services, St Louis, MI, United States
c Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St Louis, MI, United States

Document Type: Note
Publication Stage: Article in Press
Source: Scopus

“Phosphorylation of the HCN channel auxiliary subunit TRIP8b is altered in an animal model of temporal lobe epilepsy and modulates channel function” (2019) Journal of Biological Chemistry

Phosphorylation of the HCN channel auxiliary subunit TRIP8b is altered in an animal model of temporal lobe epilepsy and modulates channel function
(2019) Journal of Biological Chemistry, 294 (43), pp. 15743-15758. 

Foote, K.M.a b c , Lyman, K.A.a c d , Han, Y.a c , Michailidis, I.E.c , Heuermann, R.J.e , Mandikian, D.f , Trimmer, J.S.f g , Swanson, G.T.b h , Chetkovich, D.M.c

a Davee Department of Neurology and Clinical Neurosciences, Northwestern University, Chicago, IL 60611, United States
b Department of Pharmacology, Northwestern University, Chicago, IL 60611, United States
c Vanderbilt University Medical Center, Department of Neurology, Nashville, TN 37232, United States
d Department of Medicine, Stanford University, Palo Alto, CA 94305, United States
e Department of Neurology, Washington University, School of Medicine, St. Louis, MO 63110, United States
f Departments of Neurobiology, Physiology, and Behavior, University of California, Davis, CA 95616, United States
g Departments of Physiology and Membrane Biology, University of California, Davis, CA 95616, United States
h Department of Neurobiology, Northwestern University, Evanston, IL 60208, United States

Abstract
Temporal lobe epilepsy (TLE) is a prevalent neurological disorder with many patients experiencing poor seizure control with existing anti-epileptic drugs. Thus, novel insights into the mechanisms of epileptogenesis and identification of new drug targets can be transformative. Changes in ion channel function have been shown to play a role in generating the aberrant neuronal activity observed in TLE. Previous work demonstrates that hyperpolarization-activated cyclic nucleotide-gated (HCN) channels regulate neuronal excitability and are mislocalized within CA1 pyramidal cells in a rodent model of TLE. The subcellular distribution of HCN channels is regulated by an auxiliary subunit, tetratricopeptide repeat- containing Rab8b-interacting protein (TRIP8b), and disruption of this interaction correlates with channel mislocalization. However, the molecular mechanisms responsible for HCN channel dysregulation in TLE are unclear. Here we investigated whether changes in TRIP8b phosphorylation are sufficient to alter HCN channel function. We identified a phosphorylation site at residue Ser237 of TRIP8b that enhances binding to HCN channels and influences channel gating by altering the affinity of TRIP8b for the HCN cytoplasmic domain. Using a phosphospecific antibody, we demonstrate that TRIP8b phosphorylated at Ser237 is enriched in CA1 distal dendrites and that phosphorylation is reduced in the kainic acid model of TLE. Overall, our findings indicate that the TRIP8b-HCN interaction can be modulated by changes in phosphorylation and suggest that loss of TRIP8b phosphorylation may affect HCN channel properties during epileptogenesis. These results highlight the potential of drugs targetingposttranslationalmodificationstorestoreTRIP8bphosphorylation to reduce excitability in TLE. © 2019 Foote et al.

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

“Neurodevelopmental Outcomes in Neonates with Mild Hypoxic Ischemic Encephalopathy Treated with Therapeutic Hypothermia” (2019) American Journal of Perinatology

Neurodevelopmental Outcomes in Neonates with Mild Hypoxic Ischemic Encephalopathy Treated with Therapeutic Hypothermia
(2019) American Journal of Perinatology, 36 (13), pp. 1337-1343. 

Rao, R.a , Trivedi, S.b , Distler, A.a , Liao, S.a , Vesoulis, Z.a , Smyser, C.a , Mathur, A.M.a

a Division of Newborn Medicine, Department of Pediatrics, Washington University, School of Medicine, Campus Box 8116, 660 South Euclid, St Louis, MO 63110, United States
b Division of Newborn Medicine, Ann and Robert Laurie School of Medicine, Chicago, IL, United States

Abstract
Objective To review developmental outcomes of neonates with mild hypoxic-ischemic encephalopathy (HIE) treated with therapeutic hypothermia (TH). Study Design Neonates ≥35 weeks’ gestation with mild HIE/TH (TH group, n = 30) were matched with healthy term-born infants (control group, n = 30) and reviewed for the presence and severity of magnetic resonance imaging (MRI)-detected neurological injury. Neurodevelopmental outcomes were assessed using the Bayley Scales of Infant Development (BSID). Results MRI injury was present in 13/30 (43.3%) neonates (11 mild, 1 moderate, and 1 severe injuries) in the TH group. The mean (standard deviation [SD]) corrected age at BSID III was 29.3 (3.9) months in the controls compared with 14.7 (3.9) months in the TH group (p < 0.01). The mean (SD) cognitive, language, and motor composite scores in neonates in the TH group (n = 16, 53.3%) and control groups (n = 30, 100%) were 99.4 (17.1) versus 93.0 (12.3), (p = 0.15), 89.5 (15.5) versus 100.2 (18.4), (p = 0.054), and 93.1 (15.4) versus 100.8 (16.3) (p = 0.13), respectively. Conclusion Developmental outcomes of neonates with mild HIE/TH were similar to healthy, term-born neonates. © 2019 Thieme Medical Publishers, Inc.. All rights reserved.

Author Keywords
magnetic resonance imaging;  mild hypoxic-ischemic encephalopathy;  neurodevelopmental outcomes;  therapeutic hypothermia

Document Type: Article
Publication Stage: Final
Source: Scopus