WashU weekly Neuroscience publications

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, 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, 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

Spinal cord organogenesis model reveals role of Flk1+ cells in self-organization of neural progenitor cells into complex spinal cord tissue
(2018) Stem Cell Research, 33, pp. 156-165. 

Pan, B.^{a b} , Ao, H.^{e f} , Liu, S.^a , Xu, Y.^d , McDonald, J.W.^{a b} , Belegu, V.^{a b c}

^a International Center for Spinal Cord Injury, Hugo W. Moser Research Institute at Kennedy Krieger Inc, Baltimore, MD, United States
^b Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^c Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^d Department of Neurology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
^e Center for the Study of Nervous System Injury and the Restorative Treatment and Research Center, Washington University School of Medicine, St. Louis, MO 63108, United States
^f Department of Anesthesiology, Chinese Academy of Medical Sciences and Peking Union Medical College Fuwai Hospital, Beijing, 100037, China

Abstract
A platform for studying spinal cord organogenesis in vivo where embryonic stem cell (ESC)-derived neural progenitor cells (NPC) self-organize into spinal cord-like tissue after transplantation in subarachnoid space of the spinal cord has been described. We advance the applicability of this platform by imaging in vivo the formed graft through T2w magnetic resonance imaging (MRI). Furthermore, we used diffusion tensor imaging (DTI) to verify the stereotypical organization of the graft showing that it mimics the host spinal cord. Within the graft white matter (WM) we identified astrocytes that form glial limitans, myelinating oligodendrocytes, and myelinated axons with paranodes. Within the graft grey matter (GM) we identified cholinergic, glutamatergic, serotonergic and dopaminergic neurons. Furthermore, we demonstrate the presence of ESC-derived complex vasculature that includes the presence of blood brain barrier. In addition to the formation of mature spinal cord tissue, we describe factors that drive this process. Specifically, we identify Flk1+ cells as necessary for spinal cord formation, and synaptic connectivity with the host spinal cord and formation of host-graft chimeric vasculature as contributing factors. This model can be used to study spinal cord organogenesis, and as an in vivo drug discovery platform for screening potential therapeutic compounds and their toxicity. © 2018 The Authors

Author Keywords
Embryonic stem cells;  Flk1;  Neural progenitor cells;  Spinal cord organogenesis

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, 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, 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

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

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 , Ni, T.^b , Liu, D.^b , Chen, G.^c , Yan, Z.^b , Lin, H.^d , Guan, F.^b , Rice, J.P.^e

^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; 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
^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; Department of Forensic Pathology, School of Medicine & Forensics, Xi’an Jiaotong University Health Science Center, 76 Yanta West Road, Xi’an, Shaanxi, 710061, China
^d Xi’an Mental Health Center, 15 Yanyin Road, Xi’an, Shaanxi 710086, China
^e 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. Copyright © 2018 Elsevier Ltd. All rights reserved.

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

Document Type: Article
Source: Scopus

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, 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

Language delay aggregates in toddler siblings of children with autism spectrum disorder
(2018) Journal of Neurodevelopmental Disorders, 10 (1), art. no. 29, . 

Marrus, N.^a , Hall, L.P.^b , Paterson, S.J.^c , Elison, J.T.^d , Wolff, J.J.^e , Swanson, M.R.^f , Parish-Morris, J.^g , Eggebrecht, A.T.^h , Pruett, J.R.^a , Hazlett, H.C.^f , Zwaigenbaum, L.ⁱ , Dager, S.^j , Estes, A.M.^k , Schultz, R.T.^g , Botteron, K.N.^a , Piven, J.^f , Constantino, J.N.^a , Piven, J.^l , Hazlett, H.C.^l , Chappell, C.^l , Dager, S.^l , Estes, A.^l , Shaw, D.^l , Botteron, K.^l , McKinstry, R.^l , Constantino, J.^l , Pruett, J.^l , Schultz, R.T.^l , Paterson, S.^l , Zwaigenbaum, L.^l , Elison, J.^l , Evans, A.C.^l , Collins, D.L.^l , Pike, G.B.^l , Fonov, V.^l , Kostopoulos, P.^l , Das, S.^l , Gerig, G.^l , Styner, M.^l , Gu, H.^l

^a Department of Psychiatry, Washington University, School of Medicine, 660 S. Euclid Ave, Box 8504, St Louis, MO 63110, United States
^b Department of Psychology, St. Jude Children’s Research Hospital, Mail Stop 740, 262 Danny Thomas Place, Memphis, TN 38105, United States
^c Department of Psychology, Temple University, 1801 N. Broad St, Philadelphia, PA 19122, United States
^d Institute of Child Development, University of Minnesota, 51 East River Parkway, Minneapolis, MN 55455, United States
^e Department of Educational Psychology, University of Minnesota, 56 East River Road, Minneapolis, MN 55455, United States
^f Department of Psychiatry, University of North Carolina at Chapel Hill, 101 Manning Dr, Chapel Hill, NC 27514, United States
^g Children’s Hospital of Philadelphia, University of Pennsylvania, Civic Center Blvd, Philadelphia, PA 19104, United States
^h Mallinckrodt Institute of Radiology, Washington University, School of Medicine, 660 S. Euclid Ave, St Louis, MO 63110, United States
ⁱ Department of Pediatrics, University of Alberta, 1E1 Walter Mackenzie Health Sciences Centre (WMC), 8440 112 St NW, Edmonton, AB T6G 2B7, Canada
^j Department of Radiology, University of Washington, Seattle, 1410 NE Campus Parkway, Seattle, WA 98195, United States
^k Department of Speech and Hearing Sciences, University of Washington, Seattle, 1701 NE Columbia Rd, Seattle, WA 98195-7920, United States

Abstract
Background: Language delay is extremely common in children with autism spectrum disorder (ASD), yet it is unclear whether measurable variation in early language is associated with genetic liability for ASD. Assessment of language development in unaffected siblings of children with ASD can inform whether decreased early language ability aggregates with inherited risk for ASD and serves as an ASD endophenotype. Methods: We implemented two approaches: (1) a meta-analysis of studies comparing language delay, a categorical indicator of language function, and language scores, a continuous metric, in unaffected toddlers at high and low familial risk for ASD, and (2) a parallel analysis of 350 unaffected 24-month-olds in the Infant Brain Imaging Study (IBIS), a prospective study of infants at high and low familial risk for ASD. An advantage of the former was its detection of group differences from pooled data across unique samples; an advantage of the latter was its sensitivity in quantifying early manifestations of language delay while accounting for covariates within a single large sample. Results: Meta-analysis showed that high-risk siblings without ASD (HR-noASD) were three to four times more likely to exhibit language delay versus low-risk siblings without ASD (LR-noASD) and had lower mean receptive and expressive language scores. Analyses of IBIS data corroborated that language delay, specifically receptive language delay, was more frequent in the HR-noASD (n = 235) versus LR-noASD group (n = 115). IBIS language scores were continuously and unimodally distributed, with a pathological shift towards decreased language function in HR-noASD siblings. The elevated inherited risk for ASD was associated with lower receptive and expressive language scores when controlling for sociodemographic factors. For receptive but not expressive language, the effect of risk group remained significant even when controlling for nonverbal cognition. Conclusions: Greater frequency of language delay and a lower distribution of language scores in high-risk, unaffected toddler-aged siblings support decreased early language ability as an endophenotype for ASD, with a more pronounced effect for receptive versus expressive language. Further characterization of language development is warranted to refine genetic investigations of ASD and to elucidate factors influencing the progression of core autistic traits and related symptoms. © 2018 The Author(s).

Author Keywords
Autism spectrum disorder;  Development;  Endophenotype;  Infant sibling;  Language

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

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

Medical cannabis, synthetic marijuana extracts, and obstructive sleep apnea
(2018) Journal of Clinical Sleep Medicine, 14 (10), pp. 1815-1816. 

Ramar, K.^a , Kirsch, D.B.^b , Carden, K.A.^c , Rosen, I.M.^d , Malhotra, R.K.^e

^a Division of Pulmonary and Critical Care Medicine, Center for Sleep Medicine, Mayo Clinic, Rochester, MN, United States
^b Carolinas Healthcare Medical Group Sleep Services, Charlotte, NC, United States
^c Saint Thomas Medical Partners – Sleep Specialists, Nashville, TN, United States
^d Division of Sleep Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^e Washington University Sleep Center, St. Louis, MO, United States

Document Type: Letter
Source: Scopus

Neurosteroids in pain management: A new perspective on an old player
(2018) Frontiers in Pharmacology, 9 (OCT), art. no. 1127, . 

Joksimovic, S.L.^a , Covey, D.F.^{b c} , Jevtovic-Todorovic, V.^a , Todorovic, S.M.^{a d}

^a Department of Anesthesiology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, United States
^b Department of Developmental Biology, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
^c Taylor Family Institute for Innovative Psychiatric Research, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
^d Neuroscience Graduate Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, United States

Abstract
Since the discovery of the nervous system’s ability to produce steroid hormones, numerous studies have demonstrated their importance in modulating neuronal excitability. These central effects are mostly mediated through different ligand-gated receptor systems such as GABAA and NMDA, as well as voltage-dependent Ca2+ or K+ channels. Because these targets are also implicated in transmission of sensory information, it is not surprising that numerous studies have shown the analgesic properties of neurosteroids in various pain models. Physiological (nociceptive) pain has protective value for an organism by promoting survival in life-threatening conditions. However, more prolonged pain that results from dysfunction of nerves (neuropathic pain), and persists even after tissue injury has resolved, is one of the main reasons that patients seek medical attention. This review will focus mostly on the analgesic perspective of neurosteroids and their synthetic 5α and 5β analogs in nociceptive and neuropathic pain conditions. © 2007 – 2018 Frontiers Media S.A. All Rights Reserved.

Author Keywords
Analgesic (activity);  Chronic pain;  Neurosteroid analogs;  Neurosteroids;  T-channel (CaV3);  T-channel calcium channel blockers

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

Intracranial vasculopathy and infarct recurrence in children with sickle cell anaemia, silent cerebral infarcts and normal transcranial Doppler velocities
(2018) British Journal of Haematology, 183 (2), pp. 324-326. Cited 2 times.

Choudhury, N.A.^{a b} , DeBaun, M.R.^b , Ponisio, M.R.^c , Jordan, L.C.^d , Rodeghier, M.^e , Pruthi, S.^f , McKinstry, R.C.^g

^a School of Medicine, Meharry Medical College, Nashville, TN, United States
^b Department of Pediatrics, Vanderbilt-Meharry Center of Excellence in Sickle Cell Disease, Vanderbilt University Medical Center, Nashville, TN, United States
^c Department of Radiology, Division of Nuclear Medicine, Washington University School of Medicine, Saint Louis, MO, United States
^d Department of Pediatrics, Division of Pediatric Neurology, Vanderbilt University Medical Center, Nashville, TN, United States
^e Rodeghier Consultants, Chicago, IL, United States
^f Department of Radiology, Divisions of Pediatric Radiology and Neuroradiology, Vanderbilt University Medical Center, Nashville, TN, United States
^g Pediatric Radiology and Neuroradiology Sections, Washington University School of Medicine, Saint Louis, MO, United States

Author Keywords
children;  intracranial vasculopathy;  sickle cell anaemia;  silent cerebral infarct;  silent stroke

Document Type: Letter
Source: Scopus
Access Type: Open Access

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

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

Predicting state transitions in brain dynamics through spectral difference of phase-space graphs
(2018) Journal of Computational Neuroscience, . Article in Press. 

Luckett, P.^a , Pavelescu, E.^b , McDonald, T.^c , Hively, L.^d , Ochoa, J.^e

^a Department of Neurology, Washington University, St. Louis, MO, United States
^b Department of Mathematics and Statistics, University of South Alabama, Mobile, AL 36688, United States
^c School of Computing, University of South Alabama, Mobile, AL 36688, United States
^d Oak Ridge National Laboratory (retired), Oak Ridge, TN 37830, United States
^e Department of Neurology, University of South Alabama, Mobile, AL 36604, United States

Abstract
Networks are naturally occurring phenomena that are studied across many disciplines. The topological features of a network can provide insight into the dynamics of a system as it evolves, and can be used to predict changes in state. The brain is a complex network whose temporal and spatial behavior can be measured using electroencephalography (EEG). This data can be reconstructed to form a family of graphs that represent the state of the brain over time, and the evolution of these graphs can be used to predict changes in brain states, such as the transition from preictal to ictal in patients with epilepsy. This research proposes objective indications of seizure onset observed from minimally invasive scalp EEG. The approach considers the brain as a complex nonlinear dynamical system whose state can be derived through time-delay embedding of the EEG data and characterized to determine change in brain dynamics related to the preictal state. This method targets phase-space graph spectra as biomarkers for seizure prediction, correlates historical degrees of change in spectra, and makes accurate prediction of seizure onset. A significant trend of normalized dissimilarity over time indicates a departure from the norm, and thus a change in state. Our methods show high sensitivity (90–100%) and specificity (90%) on 241 h of scalp EEG training data, and sensitivity and specificity of 70%–90% on test data. Moreover, the algorithm was capable of processing 12.7 min of data per second on an Intel Core i3 CPU in Matlab, showing that real-time analysis is viable. © 2018, Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Epilepsy;  Graph spectra;  Phase-space graph analysis;  Seizure prediction

Document Type: Article in Press
Source: Scopus

Stress, stressors, and substance use: Differential risk for hookah use among African American college students
(2018) Journal of Ethnicity in Substance Abuse, . Article in Press. 

Cunningham-Williams, R.M.^a , Jones, B.D.^b , Butler-Barnes, S.T.^a , Wells, A.A.^c , Williams Woodson, S.-L.L.^d , Johnson, S.D.^d , Pilar, M.R.^a

^a Brown School of Social Work, Washington University in St. Louis, St. Louis, MO, United States
^b Center for Student Success, Troy University, Troy, AL, United States
^c School of Social Work, University of Cincinnati, Cincinnati, OH, United States
^d School of Social Work, University of Missouri–St. Louis, St. Louis, MO, United States

Abstract
Using differential, multivariable risk models, we assessed the contribution of substance use and stress/traumatic events to hookah use among African American college students (n = 1,402) using data from the Fall 2012 American College Health Association-National College Health Assessment (ACHA-NCHA) II. Lifetime hookah use was 24.8%, with 34.2% of lifetime users having done so in the past 30 days. Compared to nonusers, hookah users had significantly higher use rates of alcohol, marijuana, other tobacco, and other drugs. Furthermore, hookah use was more likely among those with cumulative stress, yet less likely among older students. An implication is that prevention messages may need to be tailored for African American college students and particularly target younger students, substance users, and those with cumulative stress. These findings also inform policy discussions regarding hookah use on college campuses. © 2018, © 2018 Taylor & Francis Group, LLC.

Author Keywords
African American;  college students;  health promotion;  Hookah smoking;  stress;  substance use

Document Type: Article in Press
Source: Scopus

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

Blood exposure causes ventricular zone disruption and glial activation in vitro
(2018) Journal of Neuropathology and Experimental Neurology, 77 (9), pp. 803-813. 

Castaneyra-Ruiz, L.^a , Morales, D.M.^a , McAllister, J.P.^a , Brody, S.L.^b , Isaacs, A.M.^c , Strahle, J.M.^{a d} , Dahiya, S.M.^e , Limbrick, D.D.^{a d}

^a Department of Neurological Surgery, Washington University, School of Medicine, St. Louis Children’s Hospital, Campus Box 8057, 660 South Euclid Ave, St. Louis, MO 63110, United States
^b Department of Medicine, Washington University School of Medicine, St. Louis, MI, United States
^c Department of Neuroscience, Washington University School of Medicine, St. Louis, MI, United States
^d Department of Pediatrics, Washington University School of Medicine, St. Louis, MI, United States
^e Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MI, United States

Abstract
Intraventricular hemorrhage (IVH) is the most common cause of pediatric hydrocephalus in North America but remains poorly understood. Cell junction-mediated ventricular zone (VZ) disruption and astrogliosis are associated with the pathogenesis of congenital, nonhemorrhagic hydrocephalus. Recently, our group demonstrated that VZ disruption is also present in preterm infants with IVH. On the basis of this observation, we hypothesized that blood triggers the loss of VZ cell junction integrity and related cytopathology. In order to test this hypothesis, we developed an in vitro model of IVH by applying syngeneic blood to cultured VZ cells obtained from newborn mice. Following blood treatment, cells were assayed for N-cadherindependent adherens junctions, ciliated ependymal cells, and markers of glial activation using immunohistochemistry and immunoblotting. After 24-48 hours of exposure to blood, VZ cell junctions were disrupted as determined by a significant reduction in N-cadherin expression (p<0.05). This was also associated with significant decrease in multiciliated cells and increase in glial fibrillary acid protein-expressing cells (p<0.05). These observations suggest that, in vitro, blood triggers VZ cell loss and glial activation in a pattern that mirrors the cytopathology of human IVH and supports the relevance of this in vitro model to define injury mechanisms. © 2018 American Association of Neuropathologists, Inc. All rights reserved.

Author Keywords
Ependyma;  Hydrocephalus;  Intraventricular hemorrhage;  N-cadherin;  Ventricular zone

Document Type: Article
Source: Scopus

High-affinity interactions and signal transduction between Aβ oligomers and TREM2
(2018) EMBO Molecular Medicine, art. no. e201809027, . Article in Press. 

Lessard, C.B.^a , Malnik, S.L.^a , Zhou, Y.^b , Ladd, T.B.^a , Cruz, P.E.^a , Ran, Y.^a , Mahan, T.E.^c , Chakrabaty, P.^{a d} , Holtzman, D.M.^c , Ulrich, J.D.^c , Colonna, M.^b , Golde, T.E.^{a d}

^a Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, University of Florida, Gainesville, FL, United States
^b Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Neurology, Hope Center for Neurological Disorders, Knight ADRC, Washington University School of Medicine, St. Louis, MO, United States
^d McKnight Brain Institute, University of Florida, Gainesville, FL, United States

Abstract
Rare coding variants in the triggering receptor expressed on myeloid cells 2 (TREM2) are associated with increased risk for Alzheimer’s disease (AD), but how they confer this risk remains uncertain. We assessed binding of TREM2, AD-associated TREM2 variants to various forms of Aβ and APOE in multiple assays. TREM2 interacts directly with various forms of Aβ, with highest affinity interactions observed between TREM2 and soluble Aβ42 oligomers. High-affinity binding of TREM2 to Aβ oligomers is characterized by very slow dissociation. Pre-incubation with Aβ is shown to block the interaction of APOE. In cellular assays, AD-associated variants of TREM2 reduced the amount of Aβ42 internalized, and in NFAT assay, the R47H and R62H variants decreased NFAT signaling activity in response to Aβ42. These studies demonstrate i) a high-affinity interaction between TREM2 and Aβ oligomers that can block interaction with another TREM2 ligand and ii) that AD-associated TREM2 variants bind Aβ with equivalent affinity but show loss of function in terms of signaling and Aβ internalization. © 2018 The Authors. Published under the terms of the CC BY 4.0 license

Author Keywords
Alzheimer’s disease;  amyloid;  APOE;  innate immune response;  TREM2

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

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

Précis of talking to our selves: Reflection, ignorance, and agency
(2018) Behavioral and Brain Sciences, 41, art. no. e36, . 

Doris, J.M.

Philosophy-Neuroscience-Psychology Program, Philosophy Department, Washington University in St. Louis, St. Louis, MO 63130, United States

Abstract
Does it make sense for people to hold one another responsible for what they do, as happens in countless social interactions every day?One of the most unsettling lessons from recent psychological research is that people are routinely mistaken about the origins of their behavior. Yet philosophical orthodoxy holds that the exercise of morally responsible agency typically requires accurate self-awareness. If the orthodoxy is right, and the psychology is to be believed, people characteristically fail to meet the standards of morally responsible agency, and we are faced with the possibility of skepticism about agency. Unlike many philosophers, I accept the unsettling lesson from psychology. I insist, however, that we are not driven to skepticism. Instead, we should reject the requirement of accurate self-awareness for morally responsible agency. In Talking to Our Selves I develop a dialogic theory, where the exercise of morally responsible agency emerges through a collaborative conversational process by which human beings, although afflicted with a remarkable degree of self-ignorance are able to realize their values in their lives. © 2018 Cambridge University Press.

Author Keywords
Agency;  Character;  Confabulation;  Deliberation;  Ethics;  Morality;  Psychology;  Reasoning;  Reflection;  Responsibility;  Selfknowledge;  The self;  Value

Document Type: Article
Source: Scopus

BCL11B mutations in patients affected by a neurodevelopmental disorder with reduced type 2 innate lymphoid cells
(2018) Brain, 141 (8), pp. 2299-2311. 

Lessel, D.^a , Gehbauer, C.^b , Bramswig, N.C.^c , Schluth-Bolard, C.^{d e} , Venkataramanappa, S.^f , van Gassen, K.L.I.^g , Hempel, M.^a , Haack, T.B.^{h i j} , Baresic, A.^k , Genetti, C.A.^{l m} , Funari, M.F.A.ⁿ , Lessel, I.^a , Kuhlmann, L.^o , Simon, R.^f , Liu, P.^p , Denecke, J.^q , Kuechler, A.^c , De Kruijff, I.^r , Shoukier, M.^s , Lek, M.^{t u} , Mullen, T.^{t u} , Lüdecke, H.-J.^{c v} , Lerario, A.M.^{w x} , Kobbe, R.^q , Krieger, T.^y , Demeer, B.^z , Lebrun, M.^aa , Keren, B.^ab , Nava, C.^ab , Buratti, J.^ab , Afenjar, A.^ac , Shinawi, M.^ad , Guillen Sacoto, M.J.^ae , Gauthier, J.^af , Hamdan, F.F.^af , Laberge, A.-M.^ag , Campeau, P.M.^ah , Louie, R.J.^ai , Cathey, S.S.^ai , Prinz, I.^o , Jorge, A.A.L.^{n x} , Terhal, P.A.^g , Lenhard, B.^{k aj} , Wieczorek, D.^{c v} , Strom, T.M.^{h i} , Agrawal, P.B.^{l m} , Britsch, S.^f , Tolosa, E.^b , Kubisch, C.^a

^a Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, Hamburg, 20246, Germany
^b Department of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
^c Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany
^d Service de Génétique, Hospices Civils de Lyon, Lyon, France
^e Lyon Neuroscience Research Center, Inserm U1028 – CNRS UMR5292 – UCBLyon1, GENDEV Team, Bron, France
^f Institute of Molecular and Cellular Anatomy, Ulm University, Ulm, Germany
^g Department of Genetics, University Medical Center Utrecht, Utrecht, Netherlands
^h Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany
ⁱ Institute of Human Genetics, Technische Universität München, Munich, Germany
^j Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
^k Computational Regulatory Genomics Group, MRC London Institute of Medical Sciences, London, United Kingdom
^l Divisions of Genetics and Genomics and Newborn Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, United States
^m Manton Center for Orphan Disease Research, Boston Children’s Hospital, Harvard Medical School, Boston, United States
ⁿ Unidade de Endocrinologia do Desenvolvimento, Laboratorio de Hormonios e Genetica Molecular (LIM42), Hospital das Clinicas da Faculdade de Medicina, Universidade de São Paulo (USP), São Paulo, Brazil
^o Institute of Immunology, Hannover Medical School, Hannover, Germany
^p Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom
^q Department of Pediatrics, University Medical Center Eppendorf, Hamburg, Germany
^r Department of Pediatrics, St. Antonius Hospital, Nieuwegein, Netherlands
^s Pränatal-Medizin München, Munich, Germany
^t Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, United States
^u Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, United States
^v Institute of Human Genetics, University Clinic, Heinrich-Heine University, Düsseldorf, Germany
^w Unidade de Endocrinologia Genetica (LIM25), Hospital das Clinicas da Faculdade de Medicina, Universidade de São Paulo (USP), São Paulo, Brazil
^x Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, United States
^y Institute for Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
^z Unité de Génétique Clinique, CLAD Nord de France, CHU Amiens-Picardie, Amiens, France
^aa Service de Génétique Clinique, Chromosomique et Moléculaire, CHU Hôpital Nord, Saint-Etienne, France
^ab Département de Génétique, Hôpital La Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France
^ac Département de génétique médicale, Sorbonne Université, GRC n19, Pathologies Congénitales du Cervelet-LeucoDystrophies, AP-HP, Centre de Référence déficiences intellectuelles de causes rares, Hôpital Armand Trousseau, Paris, F-75012, France
^ad Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicin, St. Louis, MO, United States
^ae GeneDx, Gaithersburg, MD, United States
^af Molecular Diagnostic Laboratory, Division of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine, Montreal, Canada
^ag Division of Medical Genetics and Research Center, CHU Sainte-Justine and Department of Pediatrics, Université de Montréal, Montreal, Canada
^ah Department of Pediatrics, CHU Sainte-Justine and, University of Montreal, Montreal, Canada
^ai Greenwood Genetic Center, Greenwood, SC, United States
^aj Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, United Kingdom

Abstract
The transcription factor BCL11B is essential for development of the nervous and the immune system, and Bcl11b deficiency results in structural brain defects, reduced learning capacity, and impaired immune cell development in mice. However, the precise role of BCL11B in humans is largely unexplored, except for a single patient with a BCL11B missense mutation, affected by multisystem anomalies and profound immune deficiency. Using massively parallel sequencing we identified 13 patients bearing heterozygous germline alterations in BCL11B. Notably, all of them are affected by global developmental delay with speech impairment and intellectual disability; however, none displayed overt clinical signs of immune deficiency. Six frameshift mutations, two nonsense mutations, one missense mutation, and two chromosomal rearrangements resulting in diminished BCL11B expression, arose de novo. A further frameshift mutation was transmitted from a similarly affected mother. Interestingly, the most severely affected patient harbours a missense mutation within a zinc-finger domain of BCL11B, probably affecting the DNA-binding structural interface, similar to the recently published patient. Furthermore, the most C-terminally located premature termination codon mutation fails to rescue the progenitor cell proliferation defect in hippocampal slice cultures from Bcl11b-deficient mice. Concerning the role of BCL11B in the immune system, extensive immune phenotyping of our patients revealed alterations in the T cell compartment and lack of peripheral type 2 innate lymphoid cells (ILC2s), consistent with the findings described in Bcl11b-deficient mice. Unsupervised analysis of 102 T lymphocyte subpopulations showed that the patients clearly cluster apart from healthy children, further supporting the common aetiology of the disorder. Taken together, we show here that mutations leading either to BCL11B haploinsufficiency or to a truncated BCL11B protein clinically cause a non-syndromic neurodevelopmental delay. In addition, we suggest that missense mutations affecting specific sites within zinc-finger domains might result in distinct and more severe clinical outcomes. © The Author(s) (2018). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.

Author Keywords
BCL11B;  Developmental delay;  Intellectual disability;  Neurodevelopment;  Type 2 innate lymphoid cells

Document Type: Article
Source: Scopus

Asymmetric sensorineural hearing loss is a risk factor for late-onset hearing loss in pediatric cancer survivors following cisplatin treatment
(2018) Pediatric Blood and Cancer, art. no. e27494, . Article in Press. 

Robertson, M.S.^a , Hayashi, S.S.^b , Camet, M.L.^c , Trinkaus, K.^d , Henry, J.^e , Hayashi, R.J.^{e f}

^a Davis Audiology, Greenville, SC, United States
^b Audiology Division, St. Louis Children’s Hospital, St. Louis, MO, United States
^c Program in Audiology and Communication Sciences, Washington University School of Medicine, St. Louis, MO, United States
^d Biostatistics Shared Resource, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, United States
^e Division of Pediatric Hematology/Oncology, Department of Pediatrics Washington University School of Medicine, St. Louis, MO, United States
^f St. Louis Children’s Hospital, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Background: Ototoxicity is a significant complication of cisplatin treatment. Hearing loss can be symmetric or asymmetric, and may decline after therapy. This study examined the risks of asymmetric and late-onset hearing loss (LOHL) in cisplatin-treated pediatric patients with cancer. Methods: A retrospective review of 993 patients’ medical and audiological charts from August 1990 to March 2015 was conducted using stringent criteria to characterize patients with asymmetric hearing loss (AHL) or LOHL. Audiologic data were reviewed for 248 patients that received cisplatin to assess cisplatin-induced sensorineural hearing loss and its associated risk factors. Results: Of the patients evaluable for AHL, 26% exhibited this finding. Of those evaluable for LOHL, 42% of the patients’ hearing worsened more than 6 months after therapy completion. Radiation and type of cancer diagnosis were major risk factors for both AHL and LOHL. Furthermore, LOHL was linked to age of diagnosis, noncranial radiation, and longer audiologic follow-up. AHL was strongly associated with LOHL—60% of patients with AHL also had LOHL. Logistic regression analysis revealed that patients with AHL (OR 6.3, 95% CI: 2.2-17.8, P = 0.0005) or those receiving radiation (OR 3.2, 95% CI: 1.2-8.6, P = 0.02) were at greatest risk for LOHL. Conclusion: Children receiving cisplatin therapy are at risk for developing AHL and LOHL. Those that have received radiation and/or with AHL are at increased risk for further hearing decline. Long-term monitoring of these patients is important for early intervention as hearing diminishes. © 2018 Wiley Periodicals, Inc.

Author Keywords
asymmetric;  cisplatin;  hearing loss;  late-onset;  pediatric

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, 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

A Regeneration Toolkit
(2018) Developmental Cell, . Article in Press. 

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: Article in Press
Source: Scopus

Role of resting state MRI temporal latency in refractory pediatric extratemporal epilepsy lateralization
(2018) Journal of Magnetic Resonance Imaging, . Article in Press. 

Shah, M.N.^a , Nguyen, R.D.^a , Pao, L.P.^a , Zhu, L.^b , CreveCoeur, T.S.^c , Mitra, A.^d , Smyth, M.D.^c

^a Departments of Pediatric Surgery and Neurosurgery, McGovern Medical School at UTHealth, Houston, TX, United States
^b Department of Internal Medicine, Clinical and Translational Sciences, McGovern Medical School at UTHealth, Houston, TX, United States
^c Department of Neurological Surgery, Washington University School of Medicine, Saint Louis, MO, United States
^d Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, MO, United States

Abstract
Background: Pediatric epilepsy affects 0.5–1% of children, with 10–30% of these children refractory to medical anticonvulsant therapy and potentially requiring surgical intervention. Analysis of resting state functional MRI (rsMRI) signal temporal differences (latency) has been proposed to study the pathological cognitive processes. Purpose/Hypothesis: To quantitatively and qualitatively analyze the correlation of rsMRI signal latency to pediatric refractory extratemporal epilepsy seizure foci lateralization. Study Type: Retrospective review. Population: With Institutional Review Board approval, rsMRI and anatomical MRI scans were obtained from 38 registered pediatric epilepsy surgery patients from Washington University and 259 healthy control patients from the ADHD-200 dataset. Field Strength/Sequence: 3 T echo planar imaging (EPI) blood oxygenation level-dependent (BOLD) sequence. Assessment: The images were transformed to pediatric atlases in Talairach space. Preoperative voxelwise latency maps were generated with parabolic interpolation of the rsMRI signal lateness or earliness when compared with the global mean signal (GMS) using cross-covariance analysis. Statistical Tests: Latency z-score maps were created for each epilepsy patient by voxelwise calculation using healthy control mean and standard deviation maps. Voxelwise hypothesis testing was performed via multiple comparisons corrected (false discovery and familywise error rate) and uncorrected methods to determine significantly late and early voxels. Significantly late and/or early voxels were counted for the right and left hemisphere separately. The hemisphere with the greater proportion of significantly late and/or early voxels was hypothesized to contain the seizure focus. Preoperative rsMRI latency analysis hypotheses were compared with postoperative seizure foci lateralization determined by resection images. Results: Preoperative rsMRI latency analysis correctly identified seizure foci lateralization of 64–85% of postoperative epilepsy resections with the proposed methods. RsMRI latency lateralization analysis was 77–100% sensitive and 58–79% specific. In some patients, qualitative analysis yielded preoperative rsMRI latency patterns specific to procedure performed. Data Conclusion: Preoperative rsMRI signal latency of pediatric epilepsy patients was correlated with seizure foci lateralization. J. Magn. Reson. Imaging 2018. © 2018 International Society for Magnetic Resonance in Medicine

Author Keywords
hemispherotomy;  lesionectomy;  resting state functional MRI;  seizure foci;  temporal latency

Document Type: Article in Press
Source: Scopus

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 Investigators^v

^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

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

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 Network^k

^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

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 &lt; 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 &lt; 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

Genetic Predisposition vs Individual-Specific Processes in the Association between Psychotic-like Experiences and Cannabis Use
(2018) JAMA Psychiatry, . Article in Press. 

Karcher, N.R.^a , Barch, D.M.^{a b} , Demers, C.H.^b , Baranger, D.A.A.^b , Heath, A.C.^a , Lynskey, M.T.^c , Agrawal, A.^a

^a Department of Psychiatry, Washington University, School of Medicine, St Louis, MO, United States
^b Department of Psychological and Brain Sciences, Washington University in St Louis, St Louis, MO, United States
^c Addictions Department, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, United Kingdom

Abstract
Importance: Previous research indicates that cannabis use is associated with psychotic-like experiences (PLEs). However, it is unclear whether this association results from predispositional (ie, shared genetic) factors or individual-specific factors (eg, causal processes, such as cannabis use leading to PLEs). Objectives: To estimate genetic and environmental correlations between cannabis use and PLEs, and to examine PLEs in twin and nontwin sibling pairs discordant for exposure to cannabis use to disentangle predispositional from individual-specific effects. Design, Setting, and Participants: In this cross-sectional analysis, diagnostic interviews and self-reported data were collected from 2 separate population-based samples of twin and nontwin sibling pairs. Data from the Human Connectome Project were collected between August 10, 2012, and September 29, 2015, and data from the Australian Twin Registry Cohort 3 (ATR3) were collected between August 1, 2005, and August 31, 2010. Data were analyzed between August 17, 2017, and July 6, 2018. The study included data from 1188 Human Connectome Project participants and 3486 ATR3 participants, totaling 4674 participants. Main Outcomes and Measures: Three cannabis-involvement variables were examined: frequent use (ie, ≥100 times), a DSM-IV lifetime cannabis use disorder diagnosis, and current cannabis use. Genetic and environmental correlations between cannabis involvement and PLEs were estimated. Generalized linear mixed models examined PLE differences in twin and nontwin sibling pairs discordant for cannabis use. Results: Among the 4674 participants, the mean (SD) age was 30.5 (3.2) years, and 2923 (62.5%) were female. Data on race/ethnicity were not included as a covariate owing to lack of variability within the ATR3 sample; among the 1188 participants in the Human Connectome Project, 875 (73.7%) were white. Psychotic-like experiences were associated with frequent cannabis use (β = 0.11; 95% CI, 0.08-0.14), cannabis use disorder (β = 0.13; 95% CI, 0.09-0.16), and current cannabis use (β = 0.07; 95% CI, 0.04-0.10) even after adjustment for covariates. Correlated genetic factors explained between 69.2% and 84.1% of this observed association. Within discordant pairs of twins/siblings (Npairs, 308-324), Psychotic-like experiences were more common in cannabis-exposed individuals compared with their relative who used cannabis to a lesser degree (β ≥.23, P <.05; eg, frequent and infrequent cannabis-using relatives significantly differed, z = -5.41; P <.001). Conclusions and Relevance: Despite the strong contribution of shared genetic factors, frequent and problem cannabis use also appears to be associated with PLEs via person-specific pathways. This study’s findings suggest that policy discussions surrounding legalization should consider the influence of escalations in cannabis use on traitlike indices of vulnerability, such as PLEs, which could contribute to pervasive psychological and interpersonal burden. © 2018 American Medical Association. All rights reserved.

Document Type: Article in Press
Source: Scopus

Impact of Connector Placement and Design on Bending Stiffness of Spinal Constructs
(2018) World Neurosurgery, . Article in Press. 

Godzik, J.^a , Hool, N.^b , Dalton, J.F.^c , Whiting, A.C.^a , Newcomb, A.G.U.S.^b , Kelly, B.P.^b , Crawford, N.R.^b

^a Department of Neurosurgery, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, United States
^b Spinal Biomechanics Laboratory, Department of Neurosurgery Research, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, United States
^c Washington University Medical School, St. Louis, MO, United States

Abstract
Objective: To evaluate the stability of multiple rod–connector construct designs using a mechanical 4-point bending testing frame. Methods: A mechanical study was used to evaluate the bending stiffness of 3 connectors across 12 different configurations of rod–connector–rod constructs. Stability was evaluated in flexion–extension and lateral bending. Combinations of rods having 1 of 3 diameters (4.0 mm, 5.5 mm, and 6.0 mm) connected by 1 of 3 connector types (parallel open, snap-on, and hinged) were compared. Configurations with single connectors and with double connectors with variable spacing were also compared to simulate revision surgery conditions. Results: Constructs consisting of 4.0-mm rods connected to 4.0-mm rods were significantly less stiff as the total number of connectors used in a series exceeded 2. When single-connector configurations were compared, parallel open rod connectors demonstrated greater stiffness in flexion–extension than hinged open connectors, whereas hinged open connectors demonstrated greater stiffness in lateral bending. Using double connectors increased stiffness of 4.0- to 4.0-mm rod configurations in flexion–extension and lateral bending, 4.0- to 6.0-mm rod configurations in flexion–extension, and 5.5- to 6.0-mm rod configurations in lateral bending. Spacing the double connectors significantly improved lateral bending stiffness of 4.0- to 4.0-mm and 5.5- to 6.0-mm rod configurations. Conclusions: Our data indicate that the design, number, and placement of rod connectors have a significant impact on the bending stiffness of a surgical construct. Such mechanical data may influence construct design in primary and revision surgeries of the cervical spine and cervicothoracic junction. © 2018 Elsevier Inc.

Author Keywords
Bending stiffness;  Biomechanics;  Cervical spine;  Component testing;  Instrumentation;  Spinal fixation implant

Document Type: Article in Press
Source: Scopus

Local and Global Dynamics in Intrinsically Disordered Synuclein
(2018) Angewandte Chemie – International Edition, . Article in Press. 

Rezaei-Ghaleh, N.^a , Parigi, G.^b , Soranno, A.^{c d} , Holla, A.^d , Becker, S.^e , Schuler, B.^d , Luchinat, C.^b , Zweckstetter, M.^a

^a University Medical Center Göttingen &, German Center for Neurodegenerative Diseases (DZNE) &, MPI for Biophysical Chemistry, Von-Siebold-Strasse 3a, Göttingen, 37075, Germany
^b Magnetic Resonance Center (CERM) &, Department of Chemistry “Ugo Schiff”, University of Florence, via Sacconi 6, Sesto Fiorentino, 50121, Italy
^c Washington University in St. Louis, St. Louis, MO 63110, United States
^d University of Zurich, Zurich, 8057, Switzerland
^e Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, Göttingen, 37077, Germany

Abstract
Intrinsically disordered proteins (IDPs) experience a diverse spectrum of motions that are difficult to characterize with a single experimental technique. Herein we combine high- and low-field nuclear spin relaxation, nanosecond fluorescence correlation spectroscopy (nsFCS), and long molecular dynamics simulations of alpha-synuclein, an IDP involved in Parkinson disease, to obtain a comprehensive picture of its conformational dynamics. The combined analysis shows that fast motions below 2 ns caused by local dihedral angle fluctuations and conformational sampling within and between Ramachandran substates decorrelate most of the backbone N−H orientational memory. However, slow motions with correlation times of up to ca. 13 ns from segmental dynamics are present throughout the alpha-synuclein chain, in particular in its C-terminal domain, and global chain reconfiguration occurs on a timescale of ca. 60 ns. Our study demonstrates a powerful strategy to determine residue-specific protein dynamics in IDPs at different time and length scales. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Author Keywords
intrinsically disordered proteins;  NMR spectroscopy;  protein dynamics

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, . 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, . 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