Arts & Sciences Brown School McKelvey School Medicine Weekly Publications

WashU weekly Neuroscience publications

“Pain And Opioid Systems, Implications In The Opioid Epidemic” (2019) Current Opinion in Behavioral Sciences

Pain And Opioid Systems, Implications In The Opioid Epidemic
(2019) Current Opinion in Behavioral Sciences, 26, pp. 69-74. 

Massaly, N.a b c , Morón, J.A.a b c d

a Department of Anesthesiology, Washington University in St. Louis, St. Louis, MO 63110, United States
b Washington University Pain Center, St. Louis, MO 63110, United States
c Washington University in St Louis, School of Medicine, St. Louis, MO 63110, United States
d Department of Neuroscience, Washington University in St. Louis, St. Louis, MO 63110, United States

Abstract
Pain has a useful protective role; through avoidance learning, it helps to decrease the probability of engaging in tissue-damaging, or otherwise dangerous experiences. In our modern society, the experience of acute post-surgical pain and the development of chronic pain states represent an unnecessary negative outcome. This has become an important health issue as more than 30% of the US population reports experiencing “unnecessary” pain at any given time. Opioid therapies are often efficacious treatments for severe and acute pain; however, in addition to their powerful analgesic properties, opioids produce potent reinforcing properties and their inappropriate use has led to the current opioid overdose epidemic in North America. Dissecting the allostatic changes occurring in nociceptors and neuronal pathways in response to pain are the first and most important steps in understanding the physiologic changes underlying the opioid epidemic. Full characterization of these adaptations will provide novel targets for the development of safer pharmacotherapies. In this review, we highlight the current efforts toward safer opioid treatments and describe our current knowledge of the interaction between pain and opioid systems. © 2018 Elsevier Ltd

Document Type: Review
Source: Scopus

“The Lifespan Human Connectome Project in Aging: An overview” (2019) NeuroImage

The Lifespan Human Connectome Project in Aging: An overview
(2019) NeuroImage, 185, pp. 335-348. 

Bookheimer, S.Y.a , Salat, D.H.b , Terpstra, M.c , Ances, B.M.d , Barch, D.M.d e h , Buckner, R.L.b f g , Burgess, G.C.e , Curtiss, S.W.i , Diaz-Santos, M.a , Elam, J.S.i , Fischl, B.b j , Greve, D.N.b , Hagy, H.A.c , Harms, M.P.e , Hatch, O.M.b , Hedden, T.b , Hodge, C.e , Japardi, K.C.a , Kuhn, T.P.a , Ly, T.K.a , Smith, S.M.k , Somerville, L.H.f , Uğurbil, K.c , van der Kouwe, A.b , Van Essen, D.i , Woods, R.P.l , Yacoub, E.c

a Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA, United States
b Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
c Center for Magnetic Resonance Research Imaging, Department of Radiology, University of Minnesota, Minneapolis, MN, United States
d Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
e Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
f Harvard University Department of Psychology and Center for Brain Science, Cambridge, MA, United States
g Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
h Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
i Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
j MIT Division of Health Sciences and Technology Computer Science and Artificial Intelligence Laboratory, United States
k Wellcome Centre for Integrative Neuroimaging – Oxford Centre for Functional Magnetic Resonance Imaging of the Brain (FMRIB), Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
l Departments of Neurology and Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA, United States

Abstract
The original Human Connectome Project yielded a rich data set on structural and functional connectivity in a large sample of healthy young adults using improved methods of data acquisition, analysis, and sharing. More recent efforts are extending this approach to include infants, children, older adults, and brain disorders. This paper introduces and describes the Human Connectome Project in Aging (HCP-A), which is currently recruiting 1200 + healthy adults aged 36 to 100+, with a subset of 600 + participants returning for longitudinal assessment. Four acquisition sites using matched Siemens Prisma 3T MRI scanners with centralized quality control and data analysis are enrolling participants. Data are acquired across multimodal imaging and behavioral domains with a focus on factors known to be altered in advanced aging. MRI acquisitions include structural (whole brain and high resolution hippocampal) plus multiband resting state functional (rfMRI), task fMRI (tfMRI), diffusion MRI (dMRI), and arterial spin labeling (ASL). Behavioral characterization includes cognitive (such as processing speed and episodic memory), psychiatric, metabolic, and socioeconomic measures as well as assessment of systemic health (with a focus on menopause via hormonal assays). This dataset will provide a unique resource for examining how brain organization and connectivity changes across typical aging, and how these differences relate to key characteristics of aging including alterations in hormonal status and declining memory and general cognition. A primary goal of the HCP-A is to make these data freely available to the scientific community, supported by the Connectome Coordination Facility (CCF) platform for data quality assurance, preprocessing and basic analysis, and shared via the NIMH Data Archive (NDA). Here we provide the rationale for our study design and sufficient details of the resource for scientists to plan future analyses of these data. A companion paper describes the related Human Connectome Project in Development (HCP-D, Somerville et al., 2018), and the image acquisition protocol common to both studies (Harms et al., 2018). © 2018

Author Keywords
Brain;  Connectivity;  Connectomics;  Diffusion imaging;  fMRI;  Functional connectivity;  Morphometry;  MRI;  Neuroimaging

Document Type: Article
Source: Scopus

“Archetypes of human cognition defined by time preference for reward and their brain correlates: An evolutionary trade-off approach” (2019) NeuroImage

Archetypes of human cognition defined by time preference for reward and their brain correlates: An evolutionary trade-off approach
(2019) NeuroImage, 185, pp. 322-334. 

Cona, G.a f , Koçillari, L.b f f , Palombit, A.c f f , Bertoldo, A.c f f , Maritan, A.b f f , Corbetta, M.d f e f

a Department of General Psychology, University of Padua, Italy
b Department of Physics, University of Padua, Italy
c Department of Information Engineering, University of Padua, Italy
d Department of Neuroscience, University of Padua, Italy
e Departments of Neurology, Radiology, Neuroscience, Washington University School of Medicine, Saint Louis, United States
f Padova Neuroscience Center (PNC), University of Padua, Italy

Abstract
Biological systems carry out multiple tasks in their lifetime, which, in the course of evolution, may lead to trade-offs. In fact phenotypes (different species, individuals within a species, circuits, bacteria, proteins, etc.) cannot be optimal at all tasks, and, according to Pareto optimality theory, lay into a well-defined geometrical distribution (polygons and/or polyhedrons) in the space of traits. The vertices of this distribution contain archetypes, namely phenotypes that are specialists at one of the tasks, whereas phenotypes toward the center of the geometrical distribution show average performance across tasks. We applied this theory to the variability of cognitive and behavioral scores measured in 1206 individuals from the Human Connectome Project. Among all possible combinations of pairs of traits, we found the best fit to Pareto optimality when individuals were plotted in the trait-space of time preferences for reward, evaluated with the Delay Discounting Task (DDT). The DDT measures subjects’ preference in choosing either immediate smaller rewards or delayed larger rewards. Time preference for reward was described by a triangular distribution in which each of the three vertices included individuals who used a particular strategy to discount reward. These archetypes accounted for variability on many cognitive, personality, and socioeconomic status variables, as well as differences in brain structure and functional connectivity, with only a weak influence of genetics. In summary, time preference for reward reflects a core variable that biases human phenotypes via natural and cultural selection. © 2018

Author Keywords
Brain;  Delay discounting task;  Evolutionary psychology;  Functional connectivity;  Human connectome project;  Multi-objective optimization;  Reward;  Self-control

Document Type: Article
Source: Scopus
Access Type: Open Access

“Investigating the Ca2+-dependent and Ca2+-independent mechanisms for mammalian cone light adaptation” (2018) Scientific Reports

Investigating the Ca2+-dependent and Ca2+-independent mechanisms for mammalian cone light adaptation
(2018) Scientific Reports, 8 (1), art. no. 15864, . 

Vinberg, F.a b , Kefalov, V.J.a

a Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, United States
b John A. Moran Eye Center, University of Utah, Salt Lake City, UT, United States

Abstract
Vision is mediated by two types of photoreceptors: rods, enabling vision in dim light; and cones, which function in bright light. Despite many similarities in the components of their respective phototransduction cascades, rods and cones have distinct sensitivity, response kinetics, and adaptation capacity. Cones are less sensitive and have faster responses than rods. In addition, cones can function over a wide range of light conditions whereas rods saturate in moderately bright light. Calcium plays an important role in regulating phototransduction and light adaptation of rods and cones. Notably, the two dominant Ca2+-feedbacks in rods and cones are driven by the identical calcium-binding proteins: guanylyl cyclase activating proteins 1 and 2 (GCAPs), which upregulate the production of cGMP; and recoverin, which regulates the inactivation of visual pigment. Thus, the mechanisms producing the difference in adaptation capacity between rods and cones have remained poorly understood. Using GCAPs/recoverin-deficient mice, we show that mammalian cones possess another Ca2+-dependent mechanism promoting light adaptation. Surprisingly, we also find that, unlike in mouse rods, a unique Ca2+-independent mechanism contributes to cone light adaptation. Our findings point to two novel adaptation mechanisms in mouse cones that likely contribute to the great adaptation capacity of cones over rods. © 2018, The Author(s).

Document Type: Article
Source: Scopus
Access Type: Open Access

“Homeostatic plasticity and emergence of functional networks in a whole-brain model at criticality” (2018) Scientific Reports

Homeostatic plasticity and emergence of functional networks in a whole-brain model at criticality
(2018) Scientific Reports, 8 (1), art. no. 15682, . 

Rocha, R.P.a b c , Koçillari, L.b c , Suweis, S.b c , Corbetta, M.c d e , Maritan, A.b c

a Department of Physics, School of Philosophy, Sciences and Letters of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil
b Dipartimento di Fisica e Astronomia, Università di Padova and INFN, via Marzolo 8, Padova, I-35131, Italy
c Padova Neuroscience Center, Università di Padova, Padova, Italy
d Dipartimento di Neuroscienze, Università di Padova, Padova, Italy
e Departments of Neurology, Radiology, Neuroscience, and Bioengineering, Washington University, School of Medicine, St. Louis, United States

Abstract
Understanding the relationship between large-scale structural and functional brain networks remains a crucial issue in modern neuroscience. Recently, there has been growing interest in investigating the role of homeostatic plasticity mechanisms, across different spatiotemporal scales, in regulating network activity and brain functioning against a wide range of environmental conditions and brain states (e.g., during learning, development, ageing, neurological diseases). In the present study, we investigate how the inclusion of homeostatic plasticity in a stochastic whole-brain model, implemented as a normalization of the incoming node’s excitatory input, affects the macroscopic activity during rest and the formation of functional networks. Importantly, we address the structure-function relationship both at the group and individual-based levels. In this work, we show that normalization of the node’s excitatory input improves the correspondence between simulated neural patterns of the model and various brain functional data. Indeed, we find that the best match is achieved when the model control parameter is in its critical value and that normalization minimizes both the variability of the critical points and neuronal activity patterns among subjects. Therefore, our results suggest that the inclusion of homeostatic principles lead to more realistic brain activity consistent with the hallmarks of criticality. Our theoretical framework open new perspectives in personalized brain modeling with potential applications to investigate the deviation from criticality due to structural lesions (e.g. stroke) or brain disorders. © 2018, The Author(s).

Document Type: Article
Source: Scopus
Access Type: Open Access

“TRP channels as drug targets to relieve itch” (2018) Pharmaceuticals

TRP channels as drug targets to relieve itch
(2018) Pharmaceuticals, 11 (4), art. no. 100, . 

Xie, Z., Hu, H.

Department of Anesthesiology, The Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Although acute itch has a protective role by removing irritants to avoid further damage, chronic itch is debilitating, significantly impacting quality of life. Over the past two decades, a considerable amount of stimulating research has been carried out to delineate mechanisms of itch at the molecular, cellular, and circuit levels. There is growing evidence that transient receptor potential (TRP) channels play important roles in itch signaling. The purpose of this review is to summarize our current knowledge about the role of TRP channels in the generation of itch under both physiological and pathological conditions, thereby identifying them as potential drug targets for effective anti-itch therapies. © 2018 by the authors. Licensee MDPI, Basel, Switzerland.

Author Keywords
Agonists;  Antagonists;  Itch;  Pain;  TRP channels;  TRPA1;  TRPC4;  TRPM8;  TRPV1;  TRPV3;  TRPV4

Document Type: Review
Source: Scopus
Access Type: Open Access

“A Regeneration Toolkit” (2018) Developmental Cell

A Regeneration Toolkit
(2018) Developmental Cell, 47 (3), pp. 267-280. 

Mokalled, M.H.a , Poss, K.D.b c

a Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, United States
c Regeneration Next, Duke University, Durham, NC 27710, United States

Abstract
The ability of animals to replace injured body parts has been a subject of fascination for centuries. The emerging importance of regenerative medicine has reinvigorated investigations of innate tissue regeneration, and the development of powerful genetic tools has fueled discoveries into how tissue regeneration occurs. Here, we present an overview of the armamentarium employed to probe regeneration in vertebrates, highlighting areas where further methodology advancement will deepen mechanistic findings. The emerging importance of regenerative medicine has reinvigorated investigations of innate tissue regeneration, and development of powerful genetic tools has fueled discoveries into how tissue regeneration occurs. Mokalled and Poss present an overview of the armamentarium employed to probe regeneration in vertebrates, highlighting areas where further methodology advancement will deepen mechanistic findings. © 2018 Elsevier Inc.

Author Keywords
gene editing;  lineage tracing;  mice;  model systems;  salamanders;  stem cells;  tissue regeneration;  zebrafish

Document Type: Review
Source: Scopus

“Voltage-gated calcium channel activity and complex related genes and schizophrenia: A systematic investigation based on Han Chinese population” (2018) Journal of Psychiatric Research

Voltage-gated calcium channel activity and complex related genes and schizophrenia: A systematic investigation based on Han Chinese population
(2018) Journal of Psychiatric Research, 106, pp. 99-105. 

Zhang, T.a , Zhu, L.b c , Ni, T.b c , Liu, D.b c , Chen, G.c d , Yan, Z.b c , Lin, H.e , Guan, F.b c , Rice, J.P.f

a Department of Epidemiology and Biostatistics, School of Public Health, Xi’an Jiaotong University Health Science Center, 76 Yanta West Road, Xi’an, Shaanxi 710061, China
b Department of Forensic Psychiatry, School of Medicine & Forensics, Xi’an Jiaotong University Health Science Center, 76 Yanta West Road, Xi’an, Shaanxi 710061, China
c Key Laboratory of National Ministry of Health for Forensic Sciences, School of Medicine & Forensics, Xi’an Jiaotong University Health Science Center, 76 Yanta West Road, Xi’an, Shaanxi 710061, China
d Department of Forensic Pathology, School of Medicine & Forensics, Xi’an Jiaotong University Health Science Center, 76 Yanta West Road, Xi’an, Shaanxi 710061, China
e Xi’an Mental Health Center, 15 Yanyin Road, Xi’an, Shaanxi 710086, China
f Department of Psychiatry, School of Medicine, Washington University in St. Louis63124, United States

Abstract
Schizophrenia (SCZ) is a devastating mental disorder affecting approximately 1% of the worldwide population. Early studies have indicated that genetics plays an important role in the onset and development of SCZ. Accumulating evidence supports that SCZ is linked to abnormalities of synapse transmission and synaptic plasticity. Voltage-gated calcium channel (VGCC) subunits are critical for mediating intracellular Ca2 + influx and therefore are responsible for changing neuronal excitability and synaptic plasticity. To systematically investigate the role of calcium signaling genes in SCZ susceptibility, we conducted a case-control study that included 2518 SCZ patients and 7521 healthy controls with Chinese Han ancestry. Thirty-seven VGCC genes, including 363 tag single nucleotide polymorphisms (SNPs), were examined. Our study replicated the following previously identified susceptible loci: CACNA1C, CACNB2, OPRM1, GRM7 and PDE4B. In addition, several novel loci including CACNA2D1, PDE4D, NALCN, and CACNA2D3 were also identified to be associated with SCZ in our Han Chinese sample. Combined with GTEx eQTL data, we have shown that CASQ2, ITGAV, and TMC2 can be also added into the prioritization list of SCZ susceptible genes. Two-way interaction analyses identified widespread gene-by-gene interactions among VGCC activity and complex-related genes for the susceptibility of SCZ. Further sequencing based studies are still needed to unravel potential contributions of schizophrenia risk from rare or low frequency variants of these candidate genes. © 2018 Elsevier Ltd

Author Keywords
Case-control study;  Common variants;  Han Chinese;  Schizophrenia susceptibility;  Voltage-gated calcium channels related genes

Document Type: Article
Source: Scopus

“Peli1 facilitates virus replication and promotes neuroinflammation during West Nile virus infection” (2018) The Journal of clinical investigation

Peli1 facilitates virus replication and promotes neuroinflammation during West Nile virus infection
(2018) The Journal of clinical investigation, 128 (11), pp. 4980-4991. 

Luo, H.a , Winkelmann, E.R.a , Zhu, S.b , Ru, W.c , Mays, E.a , Silvas, J.A.d , Vollmer, L.L.e , Gao, J.c , Peng, B.-H.c , Bopp, N.E.d , Cromer, C.d , Shan, C.f , Xie, G.a , Li, G.a , Tesh, R.d g , Popov, V.L.d g , Shi, P.-Y.f g , Sun, S.-C.h , Wu, P.c g , Klein, R.S.e , Tang, S.-J.c g , Zhang, W.b c g , Aguilar, P.V.d g , Wang, T.a d g

a Department of Microbiology and Immunology, United Arab Emirates
b Department of Ophthalmology and Visual Sciences, United Kingdom
c Department of Neuroscience, Cell Biology and Anatomy, Canada
d Department of Pathology, University of Texas Medical Branch (UTMB), Galveston, TX, United States
e Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
f Department of Biochemistry and Molecular Biology, Argentina
g Institute for Human Infections and Immunity, UTMB, Galveston, TX, United States
h Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, United States

Abstract
The E3 ubiquitin ligase Pellino 1 (Peli1) is a microglia-specific mediator of autoimmune encephalomyelitis. Its role in neurotropic flavivirus infection is largely unknown. Here, we report that mice deficient in Peli1 (Peli1-/-) were more resistant to lethal West Nile virus (WNV) infection and exhibited reduced viral loads in tissues and attenuated brain inflammation. Peli1 mediates chemokine and proinflammatory cytokine production in microglia and promotes T cell and macrophage infiltration into the CNS. Unexpectedly, Peli1 was required for WNV entry and replication in mouse macrophages and mouse and human neurons and microglia. It was also highly expressed on WNV-infected neurons and adjacent inflammatory cells from postmortem patients who died of acute WNV encephalitis. WNV passaged in Peli1-/- macrophages or neurons induced a lower viral load and impaired activation in WT microglia and thereby reduced lethality in mice. Smaducin-6, which blocks interactions between Peli1 and IRAK1, RIP1, and IKKε, did not inhibit WNV-triggered microglia activation. Collectively, our findings suggest a nonimmune regulatory role for Peli1 in promoting microglia activation during WNV infection and identify a potentially novel host factor for flavivirus cell entry and replication.

Author Keywords
Inflammation;  Innate immunity;  Neurological disorders;  Virology

Document Type: Article
Source: Scopus

“Incident cognitive impairment: longitudinal changes in molecular, structural and cognitive biomarkers” (2018) Brain : a journal of neurology

Incident cognitive impairment: longitudinal changes in molecular, structural and cognitive biomarkers
(2018) Brain : a journal of neurology, 141 (11), pp. 3233-3248. 

Roe, C.M.a b , Ances, B.M.a b c d , Head, D.a d e , Babulal, G.M.a b , Stout, S.H.a b , Grant, E.A.a f , Hassenstab, J.a e , Xiong, C.a f , Holtzman, D.M.a b d , Benzinger, T.L.S.a c g , Schindler, S.E.a b , Fagan, A.M.a b , Morris, J.C.a b h i j

a Charles F. and Joanne Knight Alzheimer’s disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
d The Hope Center for Neurological Disorders; Washington University School of Medicine, St. Louis, MO, USA
e Department of Psychological and Brain Sciences, Washington University School of Medicine, St. Louis, MO, United States
f Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
g Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
h Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
i Department of Occupational Therapy, Washington University School of Medicine, St. Louis, MO, United States
j Department of Physical Therapy, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Longer periods are needed to examine how biomarker changes occur relative to incident sporadic cognitive impairment. We evaluated molecular (CSF and imaging), structural, and cognitive biomarkers to predict incident cognitive impairment and examined longitudinal biomarker changes before and after symptomatic onset. Data from participants who were cognitively normal, underwent amyloid imaging using Pittsburgh compound B and/or CSF studies, and at least two clinical assessments were used. Stepwise Cox proportional hazards models tested associations of molecular (Pittsburgh compound B; CSF amyloid-β42, tau, ptau181, tau/amyloid-β42, ptau181/amyloid-β42), structural (normalized hippocampal volume, normalized whole brain volume), and cognitive (Animal Naming, Trail Making A, Trail Making B, Selective Reminding Test – Free Recall) biomarkers with time to Clinical Dementia Rating (CDR) > 0. Cognitively normal participants (n = 664), aged 42 to 90 years (mean ± standard deviation = 71.4 ± 9.2) were followed for up to 16.9 years (mean ± standard deviation = 6.2 ± 3.5 years). Of these, 145 (21.8%) participants developed a CDR > 0. At time of incident cognitive impairment, molecular, structural, and cognitive markers were abnormal for CDR > 0 compared to CDR = 0. Linear mixed models indicated rates of change in molecular biomarkers were similar for CDR = 0 and CDR > 0, suggesting that the separation in values between CDR = 0 and CDR > 0 must have occurred prior to the observation period. Rate of decline for structural and cognitive biomarkers was faster for CDR > 0 compared to CDR = 0 (P < 0.0001). Structural and cognitive biomarkers for CDR > 0 diverged from CDR 0 at 9 and 12 years before incident cognitive impairment, respectively. Within those who developed CDR > 0, a natural separation occurred for Pittsburgh compound B values. In particular, CDR > 0 who had at least one APOE ɛ4 allele had higher, and more rapid increase in Pittsburgh compound B, while APOE ɛ2 was observed to have slower increases in Pittsburgh compound B. Of molecular biomarker-positive participants followed for at least 10 years (n = 16-23), 70% remained CDR = 0 over the follow-up period. In conclusion, conversion from cognitively normal to CDR > 0 is characterized by not only the magnitude of molecular biomarkers but also rate of change in cognitive and structural biomarkers. Findings support theoretical models of biomarker changes seen during transition to cognitive impairment using longitudinal data and provide a potential time for changes seen during this transition. These findings support the use of molecular biomarkers for trial inclusion and cognitive/structural biomarkers for evaluating trial outcomes. Finally, results support a potential role for APOE ɛ in modulating amyloid accumulation in CDR > 0 with APOE ɛ4 being deleterious and APOE ɛ2 protective.

Document Type: Article
Source: Scopus
Access Type: Open Access

“Simplified Chinese translation of 13 adult item banks from the Quality of Life in Neurological Disorders (Neuro-QoL)” (2018) BMC health services research

Simplified Chinese translation of 13 adult item banks from the Quality of Life in Neurological Disorders (Neuro-QoL)
(2018) BMC health services research, 18 (1), p. 825. 

Xie, G.a b , Chen, L.c d , Yang, S.e f , Tao, J.a g , Chan, C.C.H.h , Heinemann, A.W.i , Cella, D.j , Lai, J.-S.k , Correia, H.l , Wong, A.W.K.m

a College of Rehabilitation Medicine, Fujian University of Traditional Chinese Medicine, Minhou Shangjie, 1 Huatuo Road, Fuzhou, Fujian 350122, China
b Traditional Chinese Medicine Rehabilitation Research Center of State Administration of Traditional Chinese Medicine of the P.R.C., Fuzhou, Fujian, China
c College of Rehabilitation Medicine, Fujian University of Traditional Chinese Medicine, Minhou Shangjie, 1 Huatuo Road, Fuzhou, Fujian 350122, China
d Traditional Chinese Medicine Rehabilitation Research Center of State Administration of Traditional Chinese Medicine of the P.R.C., Fuzhou, Fujian, China
e Affiliated Rehabilitation Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
f Rehabilitation Medical Technology Joint National Local Engineering Research Center, Fuzhou, Fujian, China
g Fujian Collaborative Innovation Center for Rehabilitation Technology, Fuzhou, Fujian, China
h Department of Rehabilitation Sciences, Hong Kong Polytechnic University, Hong Kong Special Administrative Region, China
i Department of Physical Medicine and Rehabilitation, Shirley Ryan Ability Lab (formerly Rehabilitation Institute of Chicago), Northwestern University Feinberg School of Medicine & Center for Rehabilitation Outcomes Research, Chicago, IL, United States
j Department of Medical Social Science & Center for Patient-Centered Outcomes, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
k Departments of Medical Social Science & Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
l Department of Medical Social Science, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
m Program in Occupational Therapy and Department of Neurology, Washington University School of Medicine, 4444 Forest Park Ave ,Campus Box 8505, St. Louis, MO 63108, United States

Abstract
BACKGROUND: The Quality of Life in Neurological Disorders (Neuro-QoL) item banks evaluate and monitor the physical, mental, and social health of individuals with neurological conditions. Neuro-QoL items can be administered via short form or computerized adaptive testing. This paper describes the English-to-Simplified Chinese translation of 299 items from 13 adult item banks, which are publicly available.

METHODS: Items were translated according to the Functional Assessment of Chronic Illness Therapy (FACIT) method, including forward and backward translation, reconciliation, expert reviews, and cognitive debriefing with both general and clinical populations in China.

RESULTS: Most of the 299 Simplified Chinese items were well understood by the respondents. Revisions were made on a small number of items after cognitive debriefing. Although some difficulties were encountered in the translation process, all 13 item banks were linguistically validated with acceptable translations.

CONCLUSION: All Chinese adult Neuro-QoL measures are linguistically equivalent to their English sources. Future work includes psychometric validation of these measures in order to create a final version of the item banks. The translation methodology used in this study can serve as a blueprint for researchers in other countries interested in translating the Neuro-QoL.

Author Keywords
Cross-cultural validation;  Item Bank;  Neuro-QoL;  Translation

Document Type: Article
Source: Scopus
Access Type: Open Access

“MRI-based assessment of function and dysfunction in myelinated axons” (2018) Proceedings of the National Academy of Sciences of the United States of America

MRI-based assessment of function and dysfunction in myelinated axons
(2018) Proceedings of the National Academy of Sciences of the United States of America, 115 (43), pp. E10225-E10234. 

Spees, W.M.a b , Lin, T.-H.a , Sun, P.a , Song, C.c , George, A.a , Gary, S.E.a , Yang, H.-C.a , Song, S.-K.a b c

a Biomedical MR Laboratory, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
b Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Biomedical Engineering, Washington University, St. Louis, MO 63110, United States

Abstract
Repetitive electrical activity produces microstructural alteration in myelinated axons, which may afford the opportunity to noninvasively monitor function of myelinated fibers in peripheral nervous system (PNS)/CNS pathways. Microstructural changes were assessed via two different magnetic-resonance-based approaches: diffusion fMRI and dynamic T2 spectroscopy in the ex vivo perfused bullfrog sciatic nerves. Using this robust, classical model as a platform for testing, we demonstrate that noninvasive diffusion fMRI, based on standard diffusion tensor imaging (DTI), can clearly localize the sites of axonal conduction blockage as might be encountered in neurotrauma or other lesion types. It is also shown that the diffusion fMRI response is graded in proportion to the total number of electrical impulses carried through a given locus. Dynamic T2 spectroscopy of the perfused frog nerves point to an electrical-activity-induced redistribution of tissue water and myelin structural changes. Diffusion basis spectrum imaging (DBSI) reveals a reversible shift of tissue water into a restricted isotropic diffusion signal component. Submyelinic vacuoles are observed in electron-microscopy images of tissue fixed during electrical stimulation. A slowing of the compound action potential conduction velocity accompanies repetitive electrical activity. Correlations between electrophysiology and MRI parameters during and immediately after stimulation are presented. Potential mechanisms and interpretations of these results are discussed. © 2018 National Academy of Sciences. All rights reserved.

Author Keywords
Action potential;  Diffusion MRI;  FMRI;  Myelin;  White matter

Document Type: Article
Source: Scopus

“Myosin V functions as a vesicle tether at the plasma membrane to control neurotransmitter release in central synapses” (2018) eLife

Myosin V functions as a vesicle tether at the plasma membrane to control neurotransmitter release in central synapses
(2018) eLife, 7, . 

Maschi, D.a b , Gramlich, M.W.a b , Klyachko, V.A.a b

a Department of Cell Biology and Physiology, Washington UniversityMO, United States
b Department of Biomedical Engineering, Washington UniversityMO, United States

Abstract
Synaptic vesicle fusion occurs at specialized release sites at the active zone. How refilling of release sites with new vesicles is regulated in central synapses remains poorly understood. Using nanoscale-resolution detection of individual release events in rat hippocampal synapses we found that inhibition of myosin V, the predominant vesicle-associated motor, strongly reduced refilling of the release sites during repetitive stimulation. Single-vesicle tracking revealed that recycling vesicles continuously shuttle between a plasma membrane pool and an inner pool. Vesicle retention at the membrane pool was regulated by neural activity in a myosin V dependent manner. Ultrastructural measurements of vesicle occupancy at the plasma membrane together with analyses of single-vesicle trajectories during vesicle shuttling between the pools suggest that myosin V acts as a vesicle tether at the plasma membrane, rather than a motor transporting vesicles to the release sites, or directly regulating vesicle exocytosis. © 2018, Maschi et al.

Author Keywords
active zone;  myosin V;  neuroscience;  neurotransmitter release;  rat;  release site;  single-vesicle imaging;  synaptic vesicle

Document Type: Article
Source: Scopus
Access Type: Open Access

“Chronic vagus nerve stimulation significantly improves quality of life in treatment-resistant major depression” (2018) Journal of Clinical Psychiatry

Chronic vagus nerve stimulation significantly improves quality of life in treatment-resistant major depression
(2018) Journal of Clinical Psychiatry, 79 (5), art. no. 18m12178, . 

Conway, C.R.a , Kumar, A.b , Xiong, W.a , Bunker, M.b , Aaronson, S.T.c , Rush, A.J.d e f

a Department of Psychiatry, Washington University, School of Medicine in St Louis, Campus Box 8134, 660 S. Euclid Ave, St Louis, MO 63110, United States
b LivaNova PLC (Cyberonics, Inc), Houston, TX, United States
c Sheppard Pratt Health System Clinical Research Programs, Baltimore, MD, United States
d Duke-National University of Singapore, Singapore, Singapore
e Department of Psychiatry, Duke Medical School, Durham, NC, United States
f Texas Tech University-Health Sciences Center, Permian Basin, TX, United States

Abstract
Objective: To compare quality-of-life (QOL) change associated with treatment as usual (TAU, any antidepressant treatment) versus adjunctive vagus nerve stimulation treatment (VNS + TAU) in a population of patients with treatment-resistant depression (TRD) for 5 years. Methods: Self-reported QOL assessments, using the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF), were gathered in a multicenter, longitudinal registry (January 2006- May 2015) comparing the antidepressant efficacy of VNS + TAU versus TAU in TRD. All depressed patients (N = 599), with either unipolar or bipolar depression, met DSM-IV-TR major depressive episode criteria and failed at least 4 adequate antidepressant trials. The Montgomery- Asberg Depression Rating Scale (MADRS) was administered by blinded raters. Q-LES-Q-SF scores in the treatment arms were compared via linear regression; linear regression was employed to compare QOL differences with percent decrease in MADRS. A subanalysis comparing Q-LES-Q-SF functional domain change was performed. Results: 328 VNS + TAU and 271 TAU patients with TRD were compared. On average, VNS + TAU demonstrated a significant, comparative QOL advantage over TAU (as demonstrated via nonoverlapping 95% confidence bands) that began at 3 months and was sustained through 5 years and was reinforced using a clinical global improvement measure. Patients receiving VNS + TAU, but not TAU alone, demonstrated a clinically meaningful QOL improvement (34% MADRS decrease) well below the classically defined antidepressant response (50% MADRS decrease). Exploratory post hoc subanalysis demonstrated that VNS + TAU had a significant advantage in multiple Q-LES-Q domains. Conclusion: Compared to TAU, adjunctive VNS significantly improved QOL in TRD, and this QOL advantage was sustained. Further, TRD patients treated with VNS experienced clinically meaningful QOL improvements even with depression symptom reduction less than the conventional 50% reduction used to ascribe “response.”. © 2018 Physicians Postgraduate Press, Inc.

Document Type: Article
Source: Scopus
Access Type: Open Access

“Concurrent bilateral audiometric inference” (2018) Acta Acustica united with Acustica

Concurrent bilateral audiometric inference
(2018) Acta Acustica united with Acustica, 104 (5), pp. 762-765. Cited 1 time.

Heisey, K.L.a c , Buchbinder, J.M.b c c , Barbour, D.L.c

a Program in Neuroscience, Washington University School of Medicine, 660 South Euclid Drive, St. Louis, MO 63110, United States
b Program in Audiology and Communication Sciences, Washington University School of Medicine, 660 South Euclid Drive, St. Louis, MO 63110, United States
c Laboratory of Sensory Neuroscience and Neuroengineering, Department of Biomedical Engineering, Washington University in St. Louis, 1 Brookings Drive, St. Louis, MO 63130, United States

Abstract
Conventional audiometric testing assesses hearing one ear at a time. Given that a person’s two ears often share features in common both in health and disease, this shared variability could be exploited to improve the estimation process or the estimate itself. Here we introduce the active bilateral audiogram, which simultaneously estimates the hearing functions of both ears. We show in a cohort of normal-hearing and hearing-impaired listeners that the bilateral audiogram converges to its final estimates significantly faster than sequential active unilateral audiograms in a process termed conjoint psychoacoustic estimation. © 2018 The Author(s).

Document Type: Conference Paper
Source: Scopus

“To Treat or Not to Treat?” (2018) Stroke

To Treat or Not to Treat?
(2018) Stroke, 49 (8), pp. 1933-1938. 

Levine, S.R.a b , Weingast, S.Z.c , Weedon, J.d , Stefanov, D.G.d , Katz, P.e , Hurley, D.f , Kasner, S.E.g , Khatri, P.h , Broderick, J.P.h , Grotta, J.C.i , Feldmann, E.j , Panagos, P.D.k , Romano, J.G.l , Bianchi, R.m , Meyer, B.C.n , Scott, P.A.o , Kim, D.p , Balucani, C.c

a From the Departments of Neurology and Emergency Medicine (S.R.L.)
b Department of Neurology, Kings County Medical Center, Brooklyn, Australia
c Department of Neurology (S.Z.W.
d Department of Scientific Computing (J.W.
e Department of Medicine, University of California San Francisco (P. Katz)
f Genentech, Inc, Seattle, United States
g Department of Neurology, University of Pennsylvania, Australia
h Department of Neurology, University of Cincinnati, Bulgaria
i Department of Neurology, Memorial Hermann Hospital-Texas Medical Center
j Department of Neurology, Springfield, Australia
k Department of Emergency Medicine, Washington University School of Medicine, St. Louis, United States
l Department of Neurology, University of Miami, FL (J.G.R.)
m Department of Physiology and Pharmacology (R.B.), SUNY Downstate Medical Center, Brooklyn, NY, United States
n Department of Neurology, UC San Diego Health
o Department of Emergency Medicine, University of Michigan, United States
p Department of Emergency Medicine, David Geffen School of Medicine at UCLA, Santa Monica, United States

Abstract
Background and Purpose- The 2015 updated US Food and Drug Administration alteplase package insert altered several contraindications. We thus explored clinical factors influencing alteplase treatment decisions for patients with minor stroke. Methods- An expert panel selected 7 factors to build a series of survey vignettes: National Institutes of Health Stroke Scale (NIHSS), NIHSS area of primary deficit, baseline functional status, previous ischemic stroke, previous intracerebral hemorrhage, recent anticoagulation, and temporal pattern of symptoms in first hour of care. We used a fractional factorial design (150 vignettes) to provide unconfounded estimates of the effect of all 7 main factors, plus first-order interactions for NIHSS. Surveys were emailed to national organizations of neurologists, emergency physicians, and colleagues. Physicians were randomized to 1 of 10 sets of 15 vignettes, presented randomly. Physicians reported the subjective likelihood of giving alteplase on a 0 to 5 scale; scale categories were anchored to 6 probabilities from 0% to 100%. A conjoint statistical analysis was applied. Results- Responses from 194 US physicians yielded 156 with complete vignette data: 74% male, mean age 46, 80% neurologists. Treatment mean probabilities for individual vignettes ranged from 6% to 95%. Treatment probability increased from 24% for NIHSS score =1 to 41% for NIHSS score =5. The conjoint model accounted for 25% of total observed response variance. In contrast, a model accounting for all possible interactions accounted for 30% variance. Four of the 7 factors accounted jointly for 58% of total relative importance within the conjoint model: previous intracerebral hemorrhage (18%), recent anticoagulation (17%), NIHSS (13%), and previous ischemic stroke (10%). Conclusions- Four main variables jointly account for only a small fraction (<15%) of the total variance related to deciding to treat with intravenous alteplase, reflecting high variability and complexity. Future studies should consider other variables, including physician characteristics.

Author Keywords
contraindications;  decision making;  physicians;  probability;  stroke;  tissue plasminogen activator

Document Type: Article
Source: Scopus
Access Type: Open Access

“Use of vitamins and dietary supplements by patients with multiple sclerosis a review” (2018) JAMA Neurology

Use of vitamins and dietary supplements by patients with multiple sclerosis a review
(2018) JAMA Neurology, 75 (8), pp. 1013-1021. 

Evans, E., Piccio, L., Cross, A.H.

John L. Trotter MS Center, Department of Neurology, Neuroimmunology Section, Washington University in St Louis, 660 S Euclid Ave., St Louis, MO 63110, United States

Abstract
IMPORTANCE Surveys of patients with multiple sclerosis report that most are interested in modifying their diet and using supplements to potentially reduce the severity and symptoms of the disease. This review provides an updated overview of the current state of evidence for the role that vitamins and dietary supplements play in multiple sclerosis and its animal models, with an emphasis on recent studies, and addresses biological plausibility and safety issues. OBSERVATIONS Several vitamins and dietary supplements have been recently explored both in animal models and by patients with multiple sclerosis. Most human trials have been small or nonblinded, limiting their generalizability. Biotin and Vitamin D are currently being tested in large randomized clinical trials. Smaller trials are ongoing or planned for other supplements such as lipoic acid and probiotics. The results of these studiesmay help guide clinical recommendations. CONCLUSIONS AND RELEVANCE At the present time, the only vitamin with sufficient evidence to support routine supplementation for patients with multiple sclerosis is Vitamin D. Vitamin deficiencies should be avoided. It is important for clinicians to know which supplements their patients are taking and to educate patients on any known efficacy data, along with any potential medication interactions and adverse effects of individual supplements. Given that dietary supplements and vitamins are not subject to the same regulatory oversight as prescription pharmaceuticals in the United States, it is recommended that vitamins and supplements be purchased from reputable manufacturers with the United States Pharmacopeia designation. © 2018 American Medical Association. All rights reserved.

Document Type: Review
Source: Scopus

“Structure-function analysis of the curli accessory protein CsgE defines surfaces essential for coordinating amyloid fiber formation” (2018) mBio

Structure-function analysis of the curli accessory protein CsgE defines surfaces essential for coordinating amyloid fiber formation
(2018) mBio, 9 (4), art. no. e01349-18, . 

Klein, R.D.a b , Shu, Q.c f , Cusumano, Z.T.a b g , Nagamatsu, K.d , Gualberto, N.C.a b , Lynch, A.J.L.a b , Wu, C.e , Wang, W.e , Jain, N.d h , Pinkner, J.S.a b , Amarasinghe, G.K.e , Hultgren, S.J.a b , Frieden, C.c , Chapman, M.R.d

a Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, United States
b Center for Women’s Infectious Disease Research (CWIDR), Washington University, School of Medicine, St. Louis, MO, United States
c Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, United States
d Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI, United States
e Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
f U.S. Food and Drug Administration, St. Louis, MO, United States
g NextCure Inc., Beltsville, MD, United States
h Biological and Life Sciences, School of Arts and Sciences, Ahmedabad University, Navrangpura, Ahmedabad, Gujarat, India

Abstract
Curli amyloid fibers are produced as part of the extracellular biofilm matrix and are composed primarily of the major structural subunit CsgA. The CsgE chaperone facilitates the secretion of CsgA through CsgG by forming a cap at the base of the nonameric CsgG outer membrane pore. We elucidated a series of finely tuned nonpolar and charge-charge interactions that facilitate the oligomerization of CsgE and its ability to transport unfolded CsgA to CsgG for translocation. CsgE oligomerization in vitro is temperature dependent and is disrupted by mutations in the W48 and F79 residues. Using nuclear magnetic resonance (NMR), we identified two regions of CsgE involved in the CsgE-CsgA interaction: a head comprising a positively charged patch centered around R47 and a stem comprising a negatively charged patch containing E31 and E85. Negatively charged residues in the intrinsically disordered N-and C-terminal “tails” were not implicated in this interaction. Head and stem residues were mutated and interrogated using in vivo measurements of curli production and in vitro amyloid polymerization assays. The R47 head residue of CsgE is required for stabilization of CsgA-and CsgE-mediated curli fiber formation. Mutation of the E31 and E85 stem residues to positively charged side chains decreased CsgE-mediated curli fiber formation but increased CsgE-mediated stabilization of CsgA. No single-amino-acid substitutions in the head, stem, or tail regions affected the ability of CsgE to cap the CsgG pore as determined by a bile salt sensitivity assay. These mechanistic insights into the directed assembly of functional amyloids in extracellular biofilms elucidate possible targets for biofilm-associated bacterial infections. IMPORTANCE Curli represent a class of functional amyloid fibers produced by Escherichia coli and other Gram-negative bacteria that serve as protein scaffolds in the extracellular biofilm matrix. Despite the lack of sequence conservation among different amyloidogenic proteins, the structural and biophysical properties of functional amyloids such as curli closely resemble those of amyloids associated with several common neurodegenerative diseases. These parallels are underscored by the observation that certain proteins and chemicals can prevent amyloid formation by the major curli subunit CsgA and by alpha-synuclein, the amyloid-forming protein found in Lewy bodies during Parkinson’s disease. CsgA subunits are targeted to the CsgG outer membrane pore by CsgE prior to secretion and assembly into fibers. Here, we use biophysical, biochemical, and genetic approaches to elucidate a mechanistic understanding of CsgE function in curli biogenesis. © 2018 Klein et al.

Author Keywords
Bioassembly;  Biofilms;  Curli;  Escherichia coli;  Extracellular matrix;  Functional amyloid;  Nuclear magnetic resonance;  Nucleation-precipitation

Document Type: Article
Source: Scopus
Access Type: Open Access

“Effects of ketamine compared with urethane anesthesia on vestibular sensory evoked potentials and systemic physiology in mice” (2018) Journal of the American Association for Laboratory Animal Science

Effects of ketamine compared with urethane anesthesia on vestibular sensory evoked potentials and systemic physiology in mice
(2018) Journal of the American Association for Laboratory Animal Science, 57 (3), pp. 268-277. 

Lee, C.a b , Jones, T.A.a

a Department of Special Education and Communication Disorders, University of Nebraska-Lincoln, Lincoln, NE, United States
b Department of Otolaryngology, Washington University School of Medicine, St Louis, MO, United States

Abstract
The injectable anesthetic mixture ketamine-xylazine is commonly used for electrophysiologic experiments in laboratory animals, especially rodents. General anesthesia can induce significant changes in systemic physiology, including those that compromise neural function, thus introducing research confounds. The extent of such concerns varies by agent. Here in mice, we compared the effects of ketamine-xylazine and urethane-xylazine anesthesia on systemic physiologic parameters and the vestibular sensory evoked potential (VsEP), a tool used commonly to assess peripheral vestibular function. Urethane-xylazine anesthesia provided longer anesthesia, prolonged survival times, and less compromised respiratory and cardiovascular function, compared with ketamine-xylazine. In the absence of countermeasures, mice anesthetized with either ketamine-xylazine or urethane-xylazine showed evidence of hypoxemia and fluctuations in brain temperature, heart rate, respiration rate, and VsEP response latency. The levels of hypoxemia had no effect on VsEP response parameters over the period of study (2 to 5 h). Hypoxemia was effectively countered with O2 supplementation, which stabilized respiratory rates and improved mean survival times by 160% in mice anesthetized with ketamine-xylazine. Monitoring and controlling brain temperature reduced variation in VsEP latency. VsEP thresholds, latencies, and amplitudes did not differ between mice under ketamine-xylazine compared with urethane-xylazine when the brain temperature was held at the same set point. These findings demonstrate that urethane-xylazine provides improved systemic physiologic conditions during anesthesia in mice and may be substituted for ketamine-xylazine in studies using the VsEP to evaluate peripheral vestibular function. Such advantages may prove useful to research in other neuroscience areas and might reduce the number of animals used to achieve adequate sample sizes. © 2018 by the American Association for Laboratory Animal Science.

Author Keywords
Vestibular sensory evoked potential;  VsEP

Document Type: Article
Source: Scopus

“The Electrically Evoked Auditory Change Complex Evoked by Temporal Gaps Using Cochlear Implants or Auditory Brainstem Implants in Children With Cochlear Nerve Deficiency” (2018) Ear and hearing

The Electrically Evoked Auditory Change Complex Evoked by Temporal Gaps Using Cochlear Implants or Auditory Brainstem Implants in Children With Cochlear Nerve Deficiency
(2018) Ear and hearing, 39 (3), pp. 482-494. 

He, S.a , McFayden, T.C.b , Shahsavarani, B.S.a , Teagle, H.F.B.c , Ewend, M.d , Henderson, L.c , Buchman, C.A.e

a Center for Hearing Research, Boys Town National Research Hospital, Omaha, NE, United States
b Department of Psychology, Virginia Polytechnic Institute and State University, Blacksburg, VA, United States
c Department of Otolaryngology/Head & Neck Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
d Department of Neurosurgery, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
e Department of Otolaryngology – Head and Neck Surgery, Washington University, St. Louis, MO, United States

Abstract
OBJECTIVES: This study aimed to (1) establish the feasibility of measuring the electrically evoked auditory change complex (eACC) in response to temporal gaps in children with cochlear nerve deficiency (CND) who are using cochlear implants (CIs) and/or auditory brainstem implants (ABIs); and (2) explore the association between neural encoding of, and perceptual sensitivity to, temporal gaps in these patients.

DESIGN: Study participants included 5 children (S1 to S5) ranging in age from 3.8 to 8.2 years (mean: 6.3 years) at the time of testing. All subjects were unilaterally implanted with a Nucleus 24M ABI due to CND. For each subject, two or more stimulating electrodes of the ABI were tested. S2, S3, and S5 previously received a CI in the contralateral ear. For these 3 subjects, at least two stimulating electrodes of their CIs were also tested. For electrophysiological measures, the stimulus was an 800-msec biphasic pulse train delivered to individual electrodes at the maximum comfortable level (C level). The electrically evoked responses, including the onset response and the eACC, were measured for two stimulation conditions. In the standard condition, the 800-msec pulse train was delivered uninterrupted to individual stimulating electrodes. In the gapped condition, a temporal gap was inserted into the pulse train after 400 msec of stimulation. Gap durations tested in this study ranged from 2 up to 128 msec. The shortest gap that could reliably evoke the eACC was defined as the objective gap detection threshold (GDT). For behavioral GDT measures, the stimulus was a 500-msec biphasic pulse train presented at the C level. The behavioral GDT was measured for individual stimulating electrodes using a one-interval, two-alternative forced-choice procedure.

RESULTS: The eACCs to temporal gaps were recorded successfully in all subjects for at least one stimulating electrode using either the ABI or the CI. Objective GDTs showed intersubject variations, as well as variations across stimulating electrodes of the ABI or the CI within each subject. Behavioral GDTs were measured for one ABI electrode in S2 and for multiple ABI and CI electrodes in S5. All other subjects could not complete the task. S5 showed smaller behavioral GDTs for CI electrodes than those measured for ABI electrodes. One CI and two ABI electrodes in S5 showed comparable objective and behavioral GDTs. In contrast, one CI and two ABI electrodes in S5 and one ABI electrode in S2 showed measurable behavioral GDTs but no identifiable eACCs.

CONCLUSIONS: The eACCs to temporal gaps were recorded in children with CND using either ABIs or CIs. Both objective and behavioral GDTs showed inter- and intrasubject variations. Consistency between results of eACC recordings and psychophysical measures of GDT was observed for some but not all ABI or CI electrodes in these subjects.

Document Type: Article
Source: Scopus

“Characterization of a Mouse Model of Börjeson-Forssman-Lehmann Syndrome” (2018) Cell Reports

Characterization of a Mouse Model of Börjeson-Forssman-Lehmann Syndrome
(2018) Cell Reports, . Article in Press. 

Cheng, C.a b , Deng, P.-Y.c d , Ikeuchi, Y.a , Yuede, C.e , Li, D.f g , Rensing, N.e , Huang, J.a , Baldridge, D.h , Maloney, S.E.g i , Dougherty, J.D.g i , Constantino, J.j , Jahani-Asl, A.k l , Wong, M.e , Wozniak, D.F.i , Wang, T.f g , Klyachko, V.A.c d , Bonni, A.a b

a Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
b Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Biomedical Engineering, Washington University, St. Louis, MO 63110, United States
d Department of Cell Biology and Physiology, Washington University, St. Louis, MO 63110, United States
e Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
f The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63108, United States
g Department of Genetics, Washington University School of Medicine, 4515 McKinley Ave., St. Louis, MO 63108, United States
h Department of Pediatrics, Division of Newborn Medicine, Washington University School of Medicine, St. Louis, MO 63108, United States
i Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63108, United States
j Department of Psychiatry, Division of Child Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
k Department of Oncology, Faculty of Medicine, McGill University, Montreal, QC H3T 1E2, Canada
l Lady Davis Research Institute, Jewish General Hospital, Montreal, QC H3T 1E2, Canada

Abstract
Mutations of the transcriptional regulator PHF6 cause the X-linked intellectual disability disorder Börjeson-Forssman-Lehmann syndrome (BFLS), but the pathogenesis of BFLS remains poorly understood. Here, we report a mouse model of BFLS, generated using a CRISPR-Cas9 approach, in which cysteine 99 within the PHD domain of PHF6 is replaced with phenylalanine (C99F). Mice harboring the patient-specific C99F mutation display deficits in cognitive functions, emotionality, and social behavior, as well as reduced threshold to seizures. Electrophysiological studies reveal that the intrinsic excitability of entorhinal cortical stellate neurons is increased in PHF6 C99F mice. Transcriptomic analysis of the cerebral cortex in C99F knockin mice and PHF6 knockout mice show that PHF6 promotes the expression of neurogenic genes and represses synaptic genes. PHF6-regulated genes are also overrepresented in gene signatures and modules that are deregulated in neurodevelopmental disorders of cognition. Our findings advance our understanding of the mechanisms underlying BFLS pathogenesis. Cheng et al. generated a mouse model of Börjeson-Forssman-Lehmann syndrome containing a patient-specific mutation of PHF6. PHF6 knockin mice display cognitive impairments, neuronal hyperexcitability, and seizure susceptibility. PHF6 promotes neurogenic and repressed synaptic genes in the cortex. This study advances understanding of the cellular and molecular underpinnings of BFLS. © 2018 The Authors

Author Keywords
gene expression;  mouse models;  neuronal excitability;  PHF6;  X-linked intellectual disability

Document Type: Article in Press
Source: Scopus

“Predicting cognitive functioning, activities of daily living, and participation 6 months after mild to moderate stroke” (2018) Archives of Clinical Neuropsychology

Predicting cognitive functioning, activities of daily living, and participation 6 months after mild to moderate stroke
(2018) Archives of Clinical Neuropsychology, 33 (5), pp. 562-576. 

Bertolin, M.a b , Van Patten, R.a , Greif, T.a , Fucetola, R.b

a Department of Psychology, Saint Louis University, 3700 Lindell Boulevard, Saint Louis, MO 63108, United States
b Department of Neurology, Washington University, School of Medicine, St. Louis, MO 63108, United States

Abstract
Objective: Predicting neurocognitive and functional outcomes in stroke is an important clinical task, especially in rehabilitation settings. We assessed acute predictors of cognitive and functional outcomes 6 months after mild to moderate stroke. Methods: We conducted a retrospective analysis of acute clinical data and 6-month follow-up telephone interviews for 498 mild to moderate stroke patients. Predictors were sociodemographic variables, the National Institute of Health Stroke Scale (NIHSS), basic physical measures, the Mesulam Cancellation Test, the Short Blessed Test (SBT), Trails A/B, and the Boston Naming Test. The outcome variables were the Communication, Memory and Thinking, ADL/IADLs, and Participation subscales from the Stroke Impact Scale. We conducted four hierarchical multiple regression analyses with demographic variables and the NIHSS score entered into the first step, followed by physical variables in the second step, and neuropsychological variables in the final step. Results: Physical variables explained more variance in ADL/IADLs and Participation outcomes than in Communication and Memory and Thinking outcomes, while cognitive predictors exhibited the opposite trend. The SBT was the only significant independent predictor of Communication and Memory and Thinking (p’s < .001), while the NIHSS was the only measure that significantly predicted ADL/IADLs (p < .001) and Participation (p = .002). Poorer performance on screening measures predicted worse cognitive and functional outcomes 6 months post-stroke. Conclusions: These results support the clinical utility of administering brief screening instruments during acute recovery from mild to moderate stroke. Neuropsychologists should prioritize performance on screening measures assessing acute neurologic status and cognitive dysfunction when making recommendations for post-stroke rehabilitation. © The Author 2017.

Author Keywords
Assessment;  Everyday functioning;  Rehabilitation;  Stroke

Document Type: Article
Source: Scopus

“A longitudinal study of parent-reported sensory responsiveness in toddlers at-risk for autism” (2018) Journal of Child Psychology and Psychiatry and Allied Disciplines

A longitudinal study of parent-reported sensory responsiveness in toddlers at-risk for autism
(2018) Journal of Child Psychology and Psychiatry and Allied Disciplines, . Article in Press. 

Wolff, J.J.a , Dimian, A.F.b , Botteron, K.N.c , Dager, S.R.d , Elison, J.T.e , Estes, A.M.f , Hazlett, H.C.g h , Schultz, R.T.i , Zwaigenbaum, L.j , Piven, J.g h , Chappell, C.k , Shaw, D.k , McKinstry, R.k , Constantino, J.k , Pruett, J.k , Pandey, J.k , Paterson, S.k , Elison, J.k , Evans, A.C.k , Collins, D.L.k , Pike, G.B.k , Fonov, V.k , Kostopoulos, P.k , Das, S.k , MacIntyre, L.k , Gerig, G.k , Styner, M.k , Gu, H.k , the IBIS Networkk

a Department of Educational Psychology, University of Minnesota, Minneapolis, MN, United States
b Institute on Community Integration, University of Minnesota, Minneapolis, MN, United States
c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
d Department of Radiology, University of Washington, Seattle, WA, United States
e Institute of Child Development, University of Minnesota, Minneapolis, MN, United States
f Department of Speech and Hearing Sciences, University of Washington, Seattle, WA, United States
g Department of Psychiatry, University of North Carolina, Chapel Hill, NC, United States
h Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, NC, United States
i Center for Autism Research, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
j Department of Pediatrics, University of Alberta, Edmonton, AB, Canada

Abstract
Background: Atypical sensory responsivity and sensory interests are now included in the DSM 5 diagnostic criteria for autism spectrum disorder (ASD) under the broad domain of restricted and repetitive behavior (RRB). However, relatively little is known about the emergence of sensory-related features and their relation to conventionally defined RRB in the first years of life. Methods: Prospective, longitudinal parent-report data using the Sensory Experiences Questionnaire (SEQ) were collected for 331 high-risk toddlers (74 of whom met diagnostic criteria for ASD at age 2) and 135 low-risk controls. Longitudinal profiles for SEQ scores were compared between groups across ages 12–24 months. Associations between SEQ measures and measures of RRB subtypes (based on the Repetitive Behavior Scale, Revised) were also examined. Results: Longitudinal profiles for all SEQ scores significantly differed between groups. SEQ scores were elevated for the ASD group from age 12 months, with differences becoming more pronounced across the 12–24 month interval. At both 12 and 24 months, most measures derived from the SEQ were significantly associated with all subtypes of RRB. Conclusions: These findings suggest that differences in sensory responsivity may be evident in high-risk infants later diagnosed with ASD in early toddlerhood, and that the magnitude of these differences increases over the second year of life. The high degree of association between SEQ scores and RRB supports the conceptual alignment of these features but also raises questions as to explanatory mechanisms. © 2018 Association for Child and Adolescent Mental Health.

Author Keywords
development;  longitudinal;  repetitive behavior;  Sensory

Document Type: Article in Press
Source: Scopus

“Cognitive Deficits in Psychotic Disorders: A Lifespan Perspective” (2018) Neuropsychology Review

Cognitive Deficits in Psychotic Disorders: A Lifespan Perspective
(2018) Neuropsychology Review, . Article in Press. 

Sheffield, J.M.a , Karcher, N.R.b , Barch, D.M.b c d

a Department of Psychiatry & Behavioral Sciences, Vanderbilt University Medical Center, 1601 23rd Ave S, Nashville, TN 37212, United States
b Department of Psychological & Brain Sciences, Washington University St. Louis, 1 Brookings Dr., St. Louis, MO 63130, United States
c Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
d Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Individuals with disorders that include psychotic symptoms (i.e. psychotic disorders) experience broad cognitive impairments in the chronic state, indicating a dimension of abnormality associated with the experience of psychosis. These impairments negatively impact functional outcome, contributing to the disabling nature of schizophrenia, bipolar disorder, and psychotic depression. The robust and reliable nature of cognitive deficits has led researchers to explore the timing and profile of impairments, as this may elucidate different neurodevelopmental patterns in individuals who experience psychosis. Here, we review the literature on cognitive deficits across the life span of individuals with psychotic disorder and psychotic-like experiences, highlighting the dimensional nature of both psychosis and cognitive ability. We identify premorbid generalized cognitive impairment in schizophrenia that worsens throughout development, and stabilizes by the first-episode of psychosis, suggesting a neurodevelopmental course. Research in affective psychosis is less clear, with mixed evidence regarding premorbid deficits, but a fairly reliable generalized deficit at first-episode, which appears to worsen into the chronic state. In general, cognitive impairments are most severe in schizophrenia, intermediate in bipolar disorder, and the least severe in psychotic depression. In all groups, cognitive deficits are associated with poorer functional outcome. Finally, while the generalized deficit is the clearest and most reliable signal, data suggests specific deficits in verbal memory across all groups, specific processing speed impairments in schizophrenia and executive functioning impairments in bipolar disorder. Cognitive deficits are a core feature of psychotic disorders that provide a window into understanding developmental course and risk for psychosis. © 2018, Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Bipolar Disorder;  Cognitive Impairment;  Depression;  Development;  Psychosis;  Schizophrenia

Document Type: Article in Press
Source: Scopus

“Most Current Smokers Desire Genetic Susceptibility Testing and Genetically-Efficacious Medication” (2018) Journal of Neuroimmune Pharmacology

Most Current Smokers Desire Genetic Susceptibility Testing and Genetically-Efficacious Medication
(2018) Journal of Neuroimmune Pharmacology, . Article in Press. 

Chiu, A., Hartz, S., Smock, N., Chen, J., Qazi, A., Onyeador, J., Ramsey, A.T., Bierut, L.J., Chen, L.-S.

Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8134, St. Louis, MO 63110, United States

Abstract
The clinical translation of genetic research on nicotine dependence and treatment response requires acceptance of genetic testing by smokers. This study determines (1) which current smokers are receptive to genetic susceptibility testing for nicotine dependence and (2) to what potential extent smokers motivated to quit desire to take smoking cessation medication when hypothetical genetic results predict their pharmacogenetic medication response. Current smokers from a genetic nicotine dependence study (n = 1306) and an ongoing smoking cessation trial (n = 209) were surveyed on their hypothetical interest in seeing genetic testing results related to risk of nicotine dependence. Most current smokers (84.8%) reported high interest in receiving genetic testing results. Factors associated with high interest included age ≥ 40 years, having a college degree, and a positive medical history (≥1 medical condition). In the ongoing smoking cessation trial, current smokers motivated to quit (n = 474) were surveyed on their desire to take smoking cessation medication given hypothetical below or above average pharmacogenetic responses to the medication. When the hypothetical medication response changed from below to above average, significantly more smokers reported a desire to take medication (from 61.0% to 97.5%, p <.0001). These preliminary findings suggest that genetic testing for personalized smoking cessation treatment is well-received by smokers and that a positive hypothetical pharmacogenetic response increases desire to take smoking cessation medication among current smokers motivated to quit. [Figure not available: see fulltext.]. © 2018, Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Genetic predisposition testing;  Interest in genetic testing;  Pharmacogenomic testing;  Precision medicine;  Smoking cessation

Document Type: Article in Press
Source: Scopus

“β2-adrenoreceptor medications and risk of Parkinson disease” (2018) Annals of Neurology

β2-adrenoreceptor medications and risk of Parkinson disease
(2018) Annals of Neurology, . Article in Press. 

Searles Nielsen, S.a , Gross, A.a , Camacho-Soto, A.a , Willis, A.W.b c , Racette, B.A.a d

a Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
b Departments of Neurology and of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
c Center for Pharmacoepidemiology Research and Training, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
d School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Parktown, South Africa

Abstract
Objective: A recent study observed a 2-fold greater risk of Parkinson disease (PD) in relation to the β2-adrenoreceptor antagonist propranolol and a markedly lower risk of PD for the β2-adrenoreceptor agonist salbutamol. We examined whether confounding by clinical indication for these medications, that is, tremor and smoking-related pulmonary conditions, explained these associations. Methods: In a large, population-based case–control study of United States Medicare beneficiaries in 2009 with diagnosis codes, procedure codes, and prescription data (48,295 incident PD cases, 52,324 controls), we examined the risk of PD in relation to use of selected β antagonists (propranolol, carvedilol, metoprolol), the β2 agonist salbutamol, and other medications used for the same clinical indications (primidone, inhaled corticosteroids). We adjusted for demographics, smoking, and overall use of medical care. We then examined the effect of also adjusting for clinical indication and applying medication exposure lagging. Results: Propranolol appeared to increase PD risk (odds ratio [OR] = 3.62, 95% confidence interval [CI] = 3.31–3.96). When we adjusted for tremor or abnormal involuntary movement prior to the PD diagnosis/reference date and lagged propranolol exposure, the association was 0.97 (95% CI = 0.80–1.18). Primidone, also used for tremor, was similarly sensitive to this adjustment and lagging. β Antagonists not indicated for tremor appeared to reduce PD risk (carvedilol: OR = 0.77, 95% CI = 0.73–0.81; metoprolol: OR = 0.94, 95% CI = 0.91–0.97) and were insensitive to adjustment for indications and lagging. Neither salbutamol nor inhaled corticosteroids were consistently associated with PD risk. Interpretation: β2-adrenoreceptor agonists and antagonists do not appear to alter PD risk. Ann Neurol 2018. © 2018 American Neurological Association

Document Type: Article in Press
Source: Scopus

“Phase Separation of Intrinsically Disordered Proteins” (2018) Methods in Enzymology

Phase Separation of Intrinsically Disordered Proteins
(2018) Methods in Enzymology, . Article in Press. 

Posey, A.E., Holehouse, A.S., Pappu, R.V.

Department of Biomedical Engineering and Center for Biological Systems Engineering, Washington University in St. Louis, St. Louis, MO, United States

Abstract
There is growing interest in the topic of intracellular phase transitions that lead to the formation of biologically regulated biomolecular condensates. These condensates are membraneless bodies formed by phase separation of key protein and nucleic acid molecules from the cytoplasmic or nucleoplasmic milieus. The drivers of phase separation are referred to as scaffolds whereas molecules that preferentially partition into condensates formed by scaffolds are known as clients. Recent advances have shown that it is possible to generate physical and functional facsimiles of many biomolecular condensates in vitro. This is achieved by titrating the concentration of key scaffold proteins and solution parameters such as salt concentration, pH, or temperature. The ability to reproduce phase separation in vitro allows one to compare the relationships between information encoded in the sequences of scaffold proteins and the driving forces for phase separation. Many scaffold proteins include intrinsically disordered regions whereas others are entirely disordered. Our focus is on comparative assessments of phase separation for different scaffold proteins, specifically intrinsically disordered linear multivalent proteins. We highlight the importance of coexistence curves known as binodals for quantifying phase behavior and comparing driving forces for sequence-specific phase separation. We describe the information accessible from full binodals and highlight different methods for—and challenges associated with—mapping binodals. In essence, we provide a wish list for in vitro characterization of phase separation of intrinsically disordered proteins. Fulfillment of this wish list through key advances in experiment, computation, and theory should bring us closer to being able to predict in vitro phase behavior for scaffold proteins and connect this to the functions and features of biomolecular condensates. © 2018 Elsevier Inc.

Author Keywords
Binodal;  Coexistence curve;  Intrinsically disordered proteins;  Multivalency;  Phase separation

Document Type: Article in Press
Source: Scopus

“Genome-wide association study of brain amyloid deposition as measured by Pittsburgh Compound-B (PiB)-PET imaging” (2018) Molecular Psychiatry

Genome-wide association study of brain amyloid deposition as measured by Pittsburgh Compound-B (PiB)-PET imaging
(2018) Molecular Psychiatry, . Article in Press. 

Yan, Q.a b , Nho, K.c d , Del-Aguila, J.L.e , Wang, X.a , Risacher, S.L.c d , Fan, K.-H.a , Snitz, B.E.f g , Aizenstein, H.J.h , Mathis, C.A.g i , Lopez, O.L.f g h , Demirci, F.Y.a , Feingold, E.a , Klunk, W.E.f g h , Saykin, A.J.c d , Cruchaga, C.e , Kamboh, M.I.a g h , for the Alzheimer’s Disease Neuroimaging Initiative (ADNI)j

a Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, United States
b Department of Pediatrics, Children’s Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, PA, United States
c Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, United States
d Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, United States
e Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
f Department of Neurology, University of Pittsburgh, Pittsburgh, PA, United States
g Alzheimer Disease Research Center, University of Pittsburgh, Pittsburgh, PA, United States
h Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
i Department of Radiology, University of Pittsburgh, Pittsburgh, PA, United States

Abstract
Deposition of amyloid plaques in the brain is one of the two main pathological hallmarks of Alzheimer’s disease (AD). Amyloid positron emission tomography (PET) is a neuroimaging tool that selectively detects in vivo amyloid deposition in the brain and is a reliable endophenotype for AD that complements cerebrospinal fluid biomarkers with regional information. We measured in vivo amyloid deposition in the brains of ~1000 subjects from three collaborative AD centers and ADNI using 11C-labeled Pittsburgh Compound-B (PiB)-PET imaging followed by meta-analysis of genome-wide association studies, first to our knowledge for PiB-PET, to identify novel genetic loci for this endophenotype. The APOE region showed the most significant association where several SNPs surpassed the genome-wide significant threshold, with APOE*4 being most significant (P-meta = 9.09E-30; β = 0.18). Interestingly, after conditioning on APOE*4, 14 SNPs remained significant at P < 0.05 in the APOE region that were not in linkage disequilibrium with APOE*4. Outside the APOE region, the meta-analysis revealed 15 non-APOE loci with P < 1E-05 on nine chromosomes, with two most significant SNPs on chromosomes 8 (P-meta = 4.87E-07) and 3 (P-meta = 9.69E-07). Functional analyses of these SNPs indicate their potential relevance with AD pathogenesis. Top 15 non-APOE SNPs along with APOE*4 explained 25–35% of the amyloid variance in different datasets, of which 14–17% was explained by APOE*4 alone. In conclusion, we have identified novel signals in APOE and non-APOE regions that affect amyloid deposition in the brain. Our data also highlights the presence of yet to be discovered variants that may be responsible for the unexplained genetic variance of amyloid deposition. © 2018, The Author(s).

Document Type: Article in Press
Source: Scopus

“Relative neuron loss in hippocampal sclerosis of aging and Alzheimer’s disease” (2018) Annals of Neurology

Relative neuron loss in hippocampal sclerosis of aging and Alzheimer’s disease
(2018) Annals of Neurology, . Article in Press. 

Ihara, R.a b , Vincent, B.D.b c , Baxter, M.R.b c , Franklin, E.E.b c , Hassenstab, J.J.b c , Xiong, C.b d , Morris, J.C.b c , Cairns, N.J.b c e

a Department of Neuropathology, the University of Tokyo, Tokyo, Japan
b Knight Alzheimer Disease Research Center, Washington University School of Medicine, St Louis, MO, United States
c Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
d Department of Biostatistics, Washington University School of Medicine, St Louis, MO, United States
e Department of Pathology & Immunology, Washington University School of Medicine, St Louis, MO, United States

Abstract
Objective: To characterize the pattern of neuron loss in hippocampal sclerosis of aging (HS-Aging) and age-related diseases and to evaluate its contribution to cognitive impairment in the elderly. Methods: Participants (n = 1,361) came from longitudinal observational studies of aging at the Knight Alzheimer Disease Research Center, Washington University (St. Louis, MO). Relative neuron loss in the hippocampus of HS-Aging was measured using unbiased stereological methods. Transactive response DNA-binding protein of 43 kDa (TDP-43) proteinopathy, a putative marker of HS-Aging, was assessed. Clinical and cognitive data were analyzed using parametric statistical methods. Results: Ninety-three cases had HS-Aging (6.8%), 8 cases had “pure” HS-Aging, and 37 cases had comorbid intermediate or high Alzheimer’s disease neuropathological change (i/h ADNC). Relative neuron loss (ratio of neuron number in hippocampal subfield CA1 to the neuron number in parahippocampal gyrus) was 0.15 for HS-Aging; this was significantly lower than 0.64 for i/h ADNC and 0.66 for control cases (Kruskal-Wallis test, p < 0.0001; p = 0.0003, respectively). TDP-43 proteinopathy was present in 92.4% of HS-Aging cases, higher than that in i/h ADNC (52%) and control (25%) cases. Pure HS-Aging cases were more likely to have cognitive impairment in the memory domain. Interpretation: Relative neuron loss in the hippocampus compared to the parahippocampus gyrus may be useful in distinguishing HS-Aging in the context of comorbid ADNC. HS-Aging contributes to cognitive impairment, which phenotypically resembles AD dementia. TDP proteinopathy is a frequent comorbidity in HS-Aging and may contribute to cognitive impairment to a modest degree. Ann Neurol 2018. © 2018 American Neurological Association

Document Type: Article in Press
Source: Scopus

“SIRT1 Activation: A potential strategy for harnessing endogenous protection against delayed cerebral ischemia after subarachnoid hemorrhage” (2018) Clinical Neurosurgery

SIRT1 Activation: A potential strategy for harnessing endogenous protection against delayed cerebral ischemia after subarachnoid hemorrhage
(2018) Clinical Neurosurgery, 65, pp. 1-5. 

Vellimana, A.K.a , Diwan, D.a , Clarke, J.a , Gidday, J.M.b , Zipfel, G.J.a

a Department of Neurological Surgery, Washington University, School of Medicine, 660 S Euclid Avenue, St. Louis, MO 63110, United States
b Department of Ophthalmology, Louisiana State University Health Sciences Center, New Orleans, LA, United States

Document Type: Conference Paper
Source: Scopus

“Disorganized patterns of sulcal position in fetal brains with agenesis of corpus callosum” (2018) Cerebral Cortex

Disorganized patterns of sulcal position in fetal brains with agenesis of corpus callosum
(2018) Cerebral Cortex, 28 (9), pp. 3192-3203. 

Tarui, T.a b e f , Madan, N.g , Farhat, N.a b , Kitano, R.e , Tanritanir, A.C.a b , Graham, G.h , Gagoski, B.a c , Craig, A.i , Rollins, C.K.d , Ortinau, C.j k , Iyer, V.e , Pienaar, R.a c , Bianchi, D.W.l , Grant, P.E.a b c , Im, K.a b

a Fetal Neonatal Neuroimaging and Developmental Science Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, United States
b Division of Newborn Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, United States
c Department of Radiology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, United States
d Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, United States
e Mother Infant Research Institute, Tufts Medical Center, Tufts University School of Medicine, Boston, MA 02111, United States
f Department of Pediatrics, Tufts Medical Center, Tufts University School of Medicine, Boston, MA 02111, United States
g Department of Radiology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA 02111, United States
h Department of Obstetrics and Gynecology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA 02111, United States
i Department of Pediatrics, Maine Medical CenterME 04102, United States
j Department of Pediatrics Newborn Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, United States
k Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, United States
l Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD 20892, United States

Abstract
Fetuses with isolated agenesis of the corpus callosum (ACC) are associated with a broad spectrum of neurodevelopmental disability that cannot be specifically predicted in prenatal neuroimaging. We hypothesized that ACC may be associated with aberrant cortical folding. In this study, we determined altered patterning of early primary sulci development in fetuses with isolated ACC using novel quantitative sulcal pattern analysis which measures deviations of regional sulcal features (position, depth, and area) and their intersulcal relationships in 7 fetuses with isolated ACC (27.1 ± 3.8 weeks of gestation, mean ± SD) and 17 typically developing (TD) fetuses (25.7 ± 2.0 weeks) from normal templates. Fetuses with ACC showed significant alterations in absolute sulcal positions and relative intersulcal positional relationship compared to TD fetuses, which were not detected by traditional gyrification index. Our results reveal altered sulcal positional development even in isolated ACC that is present as early as the second trimester and continues throughout the fetal period. It might originate from altered white matter connections and portend functional variances in later life. © The Author 2017.

Author Keywords
Agenesis of corpus callosum;  Fetus;  Prenatal diagnosis;  Quantitative MRI;  Sulcal development

Document Type: Article
Source: Scopus

“TLR5 decoy receptor as a novel anti-amyloid therapeutic for Alzheimer’s disease” (2018) Journal of Experimental Medicine

TLR5 decoy receptor as a novel anti-amyloid therapeutic for Alzheimer’s disease
(2018) Journal of Experimental Medicine, 215 (9), pp. 2247-2264. 

Chakrabarty, P.a b c , Li, A.a b g , Ladd, T.B.a b , Strickland, M.R.a b h , Koller, E.J.a b , Burgess, J.D.d , Funk, C.C.e , Cruz, P.E.a b , Allen, M.d , Yaroshenko, M.a b , Wang, X.d , Younkin, C.d , Reddy, J.d , Lohrer, B.d , Mehrke, L.d , Moore, B.D.a , Liu, X.a b , Ceballos‑Diaz, C.a b , Rosario, A.M.a b , Medway, C.d , Janus, C.a b , Li, H.D.i , Dickson, D.W.d , Giasson, B.I.a b c , Price, N.D.e , Younkin, S.G.d , Ertekin‑Taner, N.d f , Golde, T.E.a b c

a Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, University of Florida, Gainesville, FL, United States
b University of Florida, Gainesville, FL, United States
c McKnight Brain Institute, United States
d Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
e Institute for Systems Biology, Seattle, WA; Neurology, Mayo Clinic, Jacksonville, FL, United States
f Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
g Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, United States
h Department of Neuroscience, Washington University, St. Louis, MN, United States

Abstract
There is considerable interest in harnessing innate immunity to treat Alzheimer’s disease (AD). Here, we explore whether a decoy receptor strategy using the ectodomain of select TLRs has therapeutic potential in AD. AAV-mediated expression of human TLR5 ectodomain (sTLR5) alone or fused to human IgG4 Fc (sTLR5Fc) results in robust attenuation of amyloid β (Aβ) accumulation in a mouse model of Alzheimer-type Aβ pathology. sTLR5Fc binds to oligomeric and fibrillar Aβ with high affinity, forms complexes with Aβ, and blocks Aβ toxicity. Oligomeric and fibrillar Aβ modulates flagellin-mediated activation of human TLR5 but does not, by itself, activate TLR5 signaling. Genetic analysis shows that rare protein coding variants in human TLR5 may be associated with a reduced risk of AD. Further, transcriptome analysis shows altered TLR gene expression in human AD. Collectively, our data suggest that TLR5 decoy receptor-based biologics represent a novel and safe Aβ-selective class of biotherapy in AD. © 2018 Chakrabarty et al.

Document Type: Article
Source: Scopus

“Utility of perfusion PET measures to assess neuronal injury in Alzheimer’s disease” (2018) Alzheimer’s and Dementia: Diagnosis, Assessment and Disease Monitoring

Utility of perfusion PET measures to assess neuronal injury in Alzheimer’s disease
(2018) Alzheimer’s and Dementia: Diagnosis, Assessment and Disease Monitoring, 10, pp. 669-677. 

Joseph-Mathurin, N.a , Su, Y.b , Blazey, T.M.a , Jasielec, M.c , Vlassenko, A.a , Friedrichsen, K.a , Gordon, B.A.a , Hornbeck, R.C.a , Cash, L.a , Ances, B.M.d , Veale, T.e , Cash, D.M.e , Brickman, A.M.f , Buckles, V.d , Cairns, N.J.d , Cruchaga, C.g , Goate, A.h , Jack, C.R., Jr.i , Karch, C.d , Klunk, W.j , Koeppe, R.A.k , Marcus, D.S.a , Mayeux, R.f , McDade, E.d , Noble, J.M.f , Ringman, J.l , Saykin, A.J.m , Thompson, P.M.n , Xiong, C.c , Morris, J.C.d , Bateman, R.J.d , Benzinger, T.L.S.a , Dominantly Inherited Alzheimer Networko

a Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, MO, United States
b Banner Alzheimer’s Institute, Phoenix, AZ, United States
c Division of Biostatistics, Washington University School of Medicine, Saint Louis, MO, United States
d Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States
e Dementia Research Centre, UCL Institute of Neurology, London, United Kingdom
f Department of Neurology, Columbia University Medical Center, New York, NY, United States
g Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, United States
h Neuroscience Department Laboratories, Mount Sinai School of Medicine, New York, NY, United States
i Department of Radiology, Mayo Clinic, Rochester, MN, United States
j Departments of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
k Department of Radiology, University of Michigan, Ann Arbor, MI, United States
l Memory and Aging Center, Department of Neurology, Keck School of Medicine at the University of Southern California, Los Angeles, CA, United States
m Center for Neuroimaging, Department of Radiology and Imaging Science, Indiana University School of Medicine, Indianapolis, IN, United States
n Laboratory of Neuroimaging, David Geffen School of Medicine, University of California, Los Angeles, CA, United States

Abstract
Introduction: 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is commonly used to estimate neuronal injury in Alzheimer’s disease (AD). Here, we evaluate the utility of dynamic PET measures of perfusion using 11C-Pittsburgh compound B (PiB) to estimate neuronal injury in comparison to FDG PET. Methods: FDG, early frames of PiB images, and relative PiB delivery rate constants (PiB-R1) were obtained from 110 participants from the Dominantly Inherited Alzheimer Network. Voxelwise, regional cross-sectional, and longitudinal analyses were done to evaluate the correlation between images and estimate the relationship of the imaging biomarkers with estimated time to disease progression based on family history. Results: Metabolism and perfusion images were spatially correlated. Regional PiB-R1 values and FDG, but not early frames of PiB images, significantly decreased in the mutation carriers with estimated year to onset and with increasing dementia severity. Discussion: Hypometabolism estimated by PiB-R1 may provide a measure of brain perfusion without increasing radiation exposure. © 2018 The Authors

Author Keywords
Alzheimer’s disease;  FDG;  Neuronal injury;  Perfusion;  PiB

Document Type: Article
Source: Scopus
Access Type: Open Access

“Motor Function Test Reliability During the NeuroNEXT Spinal Muscular Atrophy Infant Biomarker Study” (2018) Journal of neuromuscular diseases

Motor Function Test Reliability During the NeuroNEXT Spinal Muscular Atrophy Infant Biomarker Study
(2018) Journal of neuromuscular diseases, 5 (4), pp. 509-521. 

Krosschell, K.J.a b , Bosch, M.c , Nelson, L.d , Duong, T.e , Lowes, L.P.f , Alfano, L.N.f , Benjamin, D.g , Carry, T.B.h , Devine, G.i , Kelley, C.h , Gadekan, R.j , Malkus, E.C.k , Pasternak, A.l m , Provance-Orr, S.n , Roemeiser-Logan, L.o , Nicorici, A.p , Trussell, D.q , Young, S.D.r , Fetterman, J.R.o , Montes, J.r , Powers, P.J.i , Quinones, R.s , Quigley, J.l m , Coffey, C.S.c , Yankey, J.W.c , Bartlett, A.t , Kissel, J.T.t , Kolb, S.J.t u , NeuroNEXT Clinical Trial Network and on behalf of the NN101 SMA Biomarker Investigatorsv

a Department of Physical Therapy and Human Movement Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
b Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
c Department of Biostatistics, NeuroNEXT Data Coordinating Center, University of Iowa, Iowa City, IA, United States
d Physical Therapy, UT Southwestern Medical Center, Dallas, TX, United States
e Department of Neurology, Stanford University, Palo Alto, CA, United States
f Neurology, Nationwide Children’s Hospital, Columbus, OH, United States
g Physical Therapy, Oregon Health and Science University, Portland, OR, United States
h Physical Therapy, Children’s Hospital Colorado, Aurora, CO, United States
i Pi Beta Phi Rehabilitation Institute, Vanderbilt University Medical Center, Nashville, TN, United States
j Neuromuscular Division, Washington University School of Medicine, St. Louis, MO, United States
k Ultragenyx, Novato, CA, United States
l Department of Physical Therapy and Occupational Therapy Services, Boston Children’s Hospital, Boston, MA, United States
m Department of Neurology, Boston Children’s Hospital, Boston, MA, United States
n Physical and Occupational Therapy, Children’s Mercy Hospital, Kansas City, MO, United States
o SUNY Upstate Medical University, Syracuse, NY, United States
p Physical Medicine and Rehabilitation, University of California – Davis, Davis, CA, United States
q University of Utah, Salt Lake City, UT, United States
r Departments of Neurology and Rehabilitation and Regenerative Medicine, Columbia University Medical Center, New York, NY, USA
s Physical and Occupational Therapy, Duke Health, Durham, NC, United States
t Department of Neurology, Ohio State University Wexner Medical Center, Columbus, OH, United States
u Department of Biological Chemistry and Pharmacology, Ohio State University Wexner Medical Center, Columbus, OH, United States

Abstract
BACKGROUND: The NeuroNEXT SMA Infant Biomarker Study, a two year, longitudinal, multi-center study of infants with SMA type 1 and healthy infants, presented a unique opportunity to assess multi-site rater reliability on three infant motor function tests (MFTs) commonly used to assess infants with SMA type 1.

OBJECTIVE: To determine the effect of prospective MFT rater training and the effect of rater experience on inter-rater and intra-rater reliability for the Test of Infant Motor Performance Screening Items (TIMPSI), the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) and the Alberta Infant Motor Scale (AIMS).

METHODS: Training was conducted utilizing a novel set of motor function test (MFT) videos to optimize accurate MFT administration and reliability for the study duration. Inter- and intra-rater reliability of scoring for the TIMPSI and inter-rater reliability of scoring for the CHOP INTEND and the AIMS was assessed using intraclass correlation coefficients (ICC). Effect of rater experience on reliability was examined using ICC. Agreement with ‘expert’ consensus scores was examined using Pearson’s correlation coefficients.

RESULTS: Inter-rater reliability on all MFTs was good to excellent. Intra-rater reliability for the primary MFT, the TIMPSI, was excellent for the study duration. Agreement with ‘expert’ consensus was within predetermined limits (≥85%) after training. Evaluator experience with SMA and MFTs did not affect reliability.

CONCLUSIONS: Reliability of scores across evaluators was demonstrated for all three study MFTs and scores were reproducible on repeated administration. Evaluator experience had no effect on reliability.

Author Keywords
AIMS;  CHOP-INTEND;  clinical evaluator;  motor function testing;  neuromuscular diseases;  NeuroNEXT;  outcome measures;  reliability;  Spinal muscular atrophy;  TIMPSI

Document Type: Article
Source: Scopus

“Symptomatic overlap in overactive bladder and interstitial cystitis/bladder pain syndrome: development of a new algorithm” (2018) BJU International

Symptomatic overlap in overactive bladder and interstitial cystitis/bladder pain syndrome: development of a new algorithm
(2018) BJU International, . Article in Press. 

Ackerman, A.L.a , Lai, H.H.b , Parameshwar, P.S.a , Eilber, K.S.a , Anger, J.T.a

a Division of Urology, Department of Surgery, Cedars–Sinai Medical Center, Los Angeles, CA, United States
b Departments of Surgery (Urology) and Anesthesiology, Washington University School of Medicine in St Louis, St. Louis, MO, United States

Abstract
Objectives: To address challenges in the diagnosis and classification of storage lower urinary tract symptoms (LUTS), we sought to define the fundamental features of overactive bladder (OAB) and interstitial cystitis/bladder pain syndrome (IC/BPS), two conditions with considerable symptomatic overlap. Through retrospective comparison of self-reported symptoms in women with a range of clinical presentations and symptom severities, we have attempted to refine the diagnostic features of OAB and IC/BPS and to develop a novel clinical nomogram to improve patient screening and classification. Materials and Methods: We performed a univariate analysis comparing responses to the female Genitourinary Pain Index (fGUPI), the OAB Questionnaire and O’Leary–Sant Indices (the Interstitial Cystitis Symptom Index and Interstitial Cystitis Problem Index) in an initial cohort of 50 patients with OAB, patients with IC/BPS and control subjects. Only eight questions differed significantly between the IC/BPS and OAB groups; we used five unique questions and three measuring bother to generate a novel composite scoring system and nomogram that included urgency incontinence, bladder pain and symptomatic bother domains to differentiate these populations, which was validated in a second cohort of 150 patients. The addition of a self-reported bother index resulted in the creation of a diagnostic algorithm to identify and classify LUTS clusters across the total population. Results: While all validated questionnaires could distinguish between controls and patients with storage LUTS, no combined symptom scores differed significantly between the IC/BPS and OAB groups. These results are reflective of the prevalence of significant bladder pain (35%) in patients with OAB and the presence of urge incontinence (25%) in patients with IC/BPS. Only the fGUPI pain domain scores differed between patients in the OAB and IC/BPS groups, but it was not accurate enough for diagnostic evaluation (68% accuracy). Our composite scores and nomogram gave a much-improved diagnostic accuracy (94%) and demonstrated utility as a screening tool to identify storage LUTS in patients presenting for unrelated complaints, e.g. microhaematuria. Conclusions: There is significant overlap of urinary tract symptoms between OAB and IC/BPS. We present a novel algorithm that provides a binary output capable of guiding clinical diagnosis. Future studies aimed at assessing the diagnostic value of novel classification schemes that address symptoms rather than specific diagnoses may improve patient prognosis. © 2018 The Authors BJU International © 2018 BJU International Published by John Wiley & Sons Ltd

Author Keywords
#InterstitialCystitis;  #OAB;  bladder hypersensitivity;  diagnosis;  interstitial cystitis;  overactive bladder;  questionnaires

Document Type: Article in Press
Source: Scopus

“Late Effects of Radiation Prime the Brain Microenvironment for Accelerated Tumor Growth” (2018) International Journal of Radiation Oncology Biology Physics

Late Effects of Radiation Prime the Brain Microenvironment for Accelerated Tumor Growth
(2018) International Journal of Radiation Oncology Biology Physics, . Article in Press. 

Duan, C.a , Yang, R.b c , Yuan, L.d , Engelbach, J.A.b , Tsien, C.I.e , Rich, K.M.d e , Dahiya, S.M.f , Johanns, T.M.g , Ackerman, J.J.H.a b g h , Garbow, J.R.b h

a Department of Chemistry, Washington University, St Louis, MO, United States
b Department of Radiology, Washington University, St Louis, MO, United States
c Department of Radiology, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China
d Department of Neurosurgery, Washington University, St Louis, MO, United States
e Department of Radiation Oncology, Washington University, St Louis, MO, United States
f Department of Neuropathology, Washington University, St Louis, MO, United States
g Department of Medicine, Washington University, St Louis, MO, United States
h Alvin J Siteman Cancer Center, Washington University, St Louis, MO, United States

Abstract
Purpose: Glioblastoma (GBM) remains incurable, despite state-of-the-art treatment involving surgical resection, chemotherapy, and radiation. GBM invariably recurs as a highly invasive and aggressive phenotype, with the majority of recurrences within the radiation therapy treatment field. Although a large body of literature reporting on primary GBM exists, comprehensive studies of how prior irradiation alters recurrent tumor growth are lacking. An animal model that replicates the delayed effects of radiation therapy on the brain microenvironment, and its impact on the development of recurrent GBM, would be a significant advance. Methods and Materials: Cohorts of mice received a single fraction of 0, 20, 30, or 40 Gy Gamma Knife irradiation. Naïve, nonirradiated mouse GBM tumor cells were implanted into the ipsilateral hemisphere 6 weeks postirradiation. Tumor growth was measured by magnetic resonance imaging, and animal survival was assessed by monitoring weight loss. Magnetic resonance imaging results were supported by hemotoxylin and eosin histology. Results: Tumorous lesions generated from orthotopic implantation of nonirradiated mouse GBM tumor cells into irradiated mouse brain grew far more aggressively and invasively than implantation of these same cells into nonirradiated brain. Lesions in irradiated brain tissue were significantly larger, more necrotic, and more vascular than those in control animals with increased invasiveness of tumor cells in the periphery, consistent with the histologic features commonly observed in recurrent high-grade tumors in patients. Conclusions: Irradiation of normal brain primes the targeted cellular microenvironment for aggressive tumor growth when naïve (not previously irradiated) cancer cells are subsequently introduced. The resultant growth pattern is similar to the highly aggressive pattern of tumor regrowth observed clinically after therapeutic radiation therapy. The mouse model offers an avenue for determining the cellular and molecular basis for the aggressiveness of recurrent GBM. © 2018

Document Type: Article in Press
Source: Scopus

“Progressive loss of brain volume in children with sickle cell anemia and silent cerebral infarct: A report from the silent cerebral infarct transfusion trial” (2018) American Journal of Hematology

Progressive loss of brain volume in children with sickle cell anemia and silent cerebral infarct: A report from the silent cerebral infarct transfusion trial
(2018) American Journal of Hematology, . Article in Press. 

Darbari, D.S.a b , Eigbire-Molen, O.c , Ponisio, M.R.d , Milchenko, M.V.d , Rodeghier, M.J.e , Casella, J.F.f , McKinstry, R.C.g , DeBaun, M.R.h

a Division of Hematology, Children’s National Medical Center, Washington, DC, United States
b The George Washington University School of Medicine and Health Sciences, Washington, DC, United States
c Division of Pathology, St Louis University, St Louis, MO, United States
d Department of Radiology, Washington University School of Medicine, St Louis, MO, United States
e Rodeghier Consultants, Chicago, IL, United States
f Department of Pediatrics, Division of Hematology, Johns Hopkins School of Medicine, Baltimore, MD, United States
g Pediatric Radiology and Neuroradiology Sections, Washington University School of Medicine, St. Louis, MO, United States
h Department of Pediatrics, Vanderbilt-Meharry Center of Excellence in Sickle Cell Disease, Vanderbilt University Medical Center, Nashville, TN, United States

Document Type: Article in Press
Source: Scopus

“The stigmatization of nonsuicidal self-injury” (2018) Journal of Clinical Psychology

The stigmatization of nonsuicidal self-injury
(2018) Journal of Clinical Psychology, . Article in Press. 

Burke, T.A.a , Piccirillo, M.L.a b , Moore-Berg, S.L.a c , Alloy, L.B.a , Heimberg, R.G.a

a Department of Psychology, Temple University, United States
b Department of Psychological and Brain Sciences, Washington University, St. Louis, MO, United States
c Annenberg School for Communication, University of Pennsylvania, Philadelphia, PA, United States

Abstract
Objective: Despite the high prevalence of nonsuicidal self-injury (NSSI), no research has systematically studied the occurrence and effects of stigmatization by others towards NSSI scarring. Methods: The current study measured implicit and explicit attitudes among undergraduates towards NSSI scarring using the implicit association test and questionnaires to compare implicit and explicit biases towards NSSI with biases towards tattoos, a culturally sanctioned form of self-determined marking, as well as nonintentional disfigurement. Results: Our study demonstrated strong negative implicit and explicit biases towards NSSI when comparing NSSI to tattoos and nonintentional disfigurement. Conclusions: Results extend previous research describing stigma towards mental illness and suggest a large negative bias towards NSSI. The importance of studying how stigma affects those who bear scarring from NSSI is discussed. © 2018 Wiley Periodicals, Inc.

Author Keywords
explicit attitudes;  implicit attitudes;  nonsuicidal self-injury;  stigma

Document Type: Article in Press
Source: Scopus