Arts & Sciences Brown School Engineering & Applied Science Medicine Weekly Publications

WashU weekly Neuroscience publications

"Nicotine aversion is mediated by GABAergic interpeduncular nucleus inputs to laterodorsal tegmentum" (2018) Nature Communications

Nicotine aversion is mediated by GABAergic interpeduncular nucleus inputs to laterodorsal tegmentum
(2018) Nature Communications, 9 (1), art. no. 2710, . 

Wolfman, S.L.a , Gill, D.F.a , Bogdanic, F.b , Long, K.c , Al-Hasani, R.d , McCall, J.G.d e f , Bruchas, M.R.e f , McGehee, D.S.a b

a Committee on Neurobiology, University of Chicago, Chicago, IL, United States
b Department of Anesthesia and Critical Care, University of Chicago, Chicago, IL, United States
c Interdisciplinary Scientist Training Program, University of Chicago, Chicago, IL, United States
d St. Louis College of Pharmacy, Center for Clinical Pharmacology, Division of Basic Research, Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
e Division of Basic Research, Department of Anesthesiology, Washington University Pain Center, St. Louis, MO, United States
f Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Nicotine use can lead to dependence through complex processes that are regulated by both its rewarding and aversive effects. Recent studies show that aversive nicotine doses activate excitatory inputs to the interpeduncular nucleus (IPN) from the medial habenula (MHb), but the downstream targets of the IPN that mediate aversion are unknown. Here we show that IPN projections to the laterodorsal tegmentum (LDTg) are GABAergic using optogenetics in tissue slices from mouse brain. Selective stimulation of these IPN axon terminals in LDTg in vivo elicits avoidance behavior, suggesting that these projections contribute to aversion. Nicotine modulates these synapses in a concentration-dependent manner, with strong enhancement only seen at higher concentrations that elicit aversive responses in behavioral tests. Optogenetic inhibition of the IPN-LDTg connection blocks nicotine conditioned place aversion, suggesting that the IPN-LDTg connection is a critical part of the circuitry that mediates the aversive effects of nicotine. © 2018 The Author(s).

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

"Cannabis decriminalization: A study of recent policy change in five U.S. states" (2018) International Journal of Drug Policy

Cannabis decriminalization: A study of recent policy change in five U.S. states
(2018) International Journal of Drug Policy, 59, pp. 67-75. 

Grucza, R.A.a , Vuolo, M.b , Krauss, M.J.a , Plunk, A.D.c , Agrawal, A.a , Chaloupka, F.J.d , Bierut, L.J.a

a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
b Department of Sociology, The Ohio State University, Columbus, OH, United States
c Department of Pediatrics, Eastern Virginia Medical School, Norfolk, VA, United States
d Division of Health Policy and Administration, University of Illinois at Chicago, Chicago, IL, United States

Abstract
Background: A number of public health professional organizations support the decriminalization of cannabis due to adverse effects of cannabis-related arrests and legal consequences, particularly on youth. We sought to examine the associations between cannabis decriminalization and both arrests and youth cannabis use in five states that passed decriminalization measures between the years 2008 and 2014: Massachusetts (decriminalized in 2008), Connecticut (2011), Rhode Island (2013), Vermont (2013), and Maryland (2014). Methods: Data on cannabis possession arrests were obtained from federal crime statistics; data on cannabis use were obtained from state Youth Risk Behavior Survey (YRBS) surveys, years 2007–2015. Using a “difference in difference” regression framework, we contrasted trends in decriminalization states with those from states that did not adopt major policy changes during the observation period. Results: Decriminalization was associated with a 75% reduction in the rate of drug-related arrests for youth (95% CI: 44%, 89%) with similar effects observed for adult arrests. Decriminalization was not associated with any increase in the past-30 day prevalence of cannabis use overall (relative change=−0.2%; 95% CI: −4.5%, 4.3%) or in any of the individual decriminalization states. Conclusions: Decriminalization of cannabis in Massachusetts, Connecticut, Rhode Island, Vermont, and Maryland resulted in large decreases in cannabis possession arrests for both youth and adults, suggesting that the policy change had its intended consequence. Our analysis did not find any increase in the prevalence of youth cannabis use during the observation period. © 2018 Elsevier B.V.

Document Type: Article
Source: Scopus

"Top research priorities for stroke genetics" (2018) The Lancet Neurology

Top research priorities for stroke genetics
(2018) The Lancet Neurology, 17 (8), pp. 663-665. 

Woo, D.a , Anderson, C.D.b , Maguire, J.c , Fornage, M.d , Lee, J.-M.e , Seshadri, S.f g , Markus, H.S.h , Majersik, J.J.i , Jimenez-Conde, J.j , Crawford, K.b k , Lindgren, A.G.l m , Debette, S.n o

a Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States
b Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, United States
c University of Technology Sydney, Sydney, NSW, Australia
d University of Texas Health Science Center at Houston, Brown Foundation Institute of Molecular Medicine, McGovern Medical School, Human Genetics Center, School of Public Health, Houston, TX, United States
e Department of Neurology, Radiology, and Biomedical Engineering, Washington University School of Medicine, St Louis, MO, United States
f Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio, TX, United States
g Framingham Heart Study and Department of Neurology, Boston University School of Medicine, Boston, MA, United States
h Stroke Research Group, Department of Neurosciences, University of Cambridge, Cambridge, United Kingdom
i Department of Neurology, University of Utah, Salt Lake City, UT, United States
j Neurovascular Research Group, Department of Neurology, IMIM-Institut Hospital del Mar d’Investigació Mèdica, Universitat Autonoma de Barcelona, Barcelona, Spain
k Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, United States
l Department of Clinical Sciences Lund, Neurology, Lund University, Lund, Sweden
m Department of Neurology and Rehabilitation Medicine, Skåne University Hospital, Lund, Sweden
n University of Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR 1219, Bordeaux, France
o CHU de Bordeaux, Department of Neurology, Bordeaux, France

Document Type: Letter
Source: Scopus

"The Association Between Cognitive Impairment and Patterns of Activity Engagement Among Older Adults" (2018) Research on Aging

The Association Between Cognitive Impairment and Patterns of Activity Engagement Among Older Adults
(2018) Research on Aging, 40 (7), pp. 645-667. 

Amano, T., Park, S., Morrow-Howell, N.

Brown School of Social Work, Washington University in St. Louis, St. Louis, MO, United States

Abstract
This study aims to assess the association between cognitive impairment and activity engagement patterns. Data from the 2012 Health and Retirement Study were used. A total of 3,943 participants aged 65 or older were included in analyses. Latent class analysis and multinomial logistic regression analysis were used. Four activity engagement profiles were identified: high activity (31.2%), active leisure (18.9%), passive leisure (28.2%), and low activity (21.7%). People in the high activity group engaged in all activities more than people in any other group, whereas people in the low activity group did not actively engage in most activities. Multinomial logistic regression analysis showed that cognitive impairment had an independent effect on the probability of being assigned to the low activity group compared to other groups. Cognitive impairment was associated with inactivity in a variety of activities. Future studies should examine supportive factors, which facilitate active patterns among people with cognitive impairment. © 2017, The Author(s) 2017.

Document Type: Article
Source: Scopus

"Fetal gene therapy for neurodegenerative disease of infants" (2018) Nature Medicine

Fetal gene therapy for neurodegenerative disease of infants
(2018) Nature Medicine, pp. 1-7. Article in Press. Cited 1 time.

Massaro, G.a , Mattar, C.N.Z.b , Wong, A.M.S.c , Sirka, E.d , Buckley, S.M.K.e , Herbert, B.R.f , Karlsson, S.g , Perocheau, D.P.e , Burke, D.h , Heales, S.h , Richard-Londt, A.i , Brandner, S.i , Huebecker, M.j , Priestman, D.A.j , Platt, F.M.j , Mills, K.d , Biswas, A.b , Cooper, J.D.c k l , Chan, J.K.Y.b m n , Cheng, S.H.o , Waddington, S.N.e p , Rahim, A.A.a

a UCL School of Pharmacy, University College London, London, United Kingdom
b Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
c Department of Basic and Clinical Neuroscience, King’s College London, Institute of Psychiatry, Psychology and Neuroscience, London, United Kingdom
d UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
e UCL Institute for Women’s Health, University College London, London, United Kingdom
f Institute for Reproductive and Developmental Biology, Imperial College London, London, United Kingdom
g Division of Molecular Medicine and Gene Therapy, Lund University, Lund, Sweden
h Paediatric Laboratory Medicine, Great Ormond Street Hospital and UCL Great Ormond Street Institute of Child Health, London, United Kingdom
i Department of Neurodegenerative Disease, UCL Institute of Neurology, University College London, London, United Kingdom
j Department of Pharmacology, University of Oxford, Oxford, United Kingdom
k Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor–UCLA Medical Center, David Geffen School of Medicine, University of California Los Angeles, Torrance, CA, United States
l Department of Pediatrics, Washington University School of Medicine, St Louis, MO, United States
m Department of Reproductive Medicine, KK Women’s and Children’s Hospital, Singapore, Singapore
n Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore
o Sanofi, Framingham, MA, United States
p MRC Antiviral Gene Therapy Research Unit, Faculty of Health Sciences, University of the Witswatersrand, Johannesburg, South Africa

Abstract
For inherited genetic diseases, fetal gene therapy offers the potential of prophylaxis against early, irreversible and lethal pathological change. To explore this, we studied neuronopathic Gaucher disease (nGD), caused by mutations in GBA. In adult patients, the milder form presents with hepatomegaly, splenomegaly and occasional lung and bone disease; this is managed, symptomatically, by enzyme replacement therapy. The acute childhood lethal form of nGD is untreatable since enzyme cannot cross the blood–brain barrier. Patients with nGD exhibit signs consistent with hindbrain neurodegeneration, including neck hyperextension, strabismus and, often, fatal apnea1. We selected a mouse model of nGD carrying a loxP-flanked neomycin disruption of Gba plus Cre recombinase regulated by the keratinocyte-specific K14 promoter. Exclusive skin expression of Gba prevents fatal neonatal dehydration. Instead, mice develop fatal neurodegeneration within 15 days2. Using this model, fetal intracranial injection of adeno-associated virus (AAV) vector reconstituted neuronal glucocerebrosidase expression. Mice lived for up to at least 18 weeks, were fertile and fully mobile. Neurodegeneration was abolished and neuroinflammation ameliorated. Neonatal intervention also rescued mice but less effectively. As the next step to clinical translation, we also demonstrated the feasibility of ultrasound-guided global AAV gene transfer to fetal macaque brains. © 2018 The Author(s)

Document Type: Article in Press
Source: Scopus

"Clinical Trial Protocol: Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Efficacy, and Safety Study Comparing EG-1962 to Standard of Care Oral Nimodipine in Adults with Aneurysmal Subarachnoid Hemorrhage…" (2018) Neurocritical Care

Clinical Trial Protocol: Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Efficacy, and Safety Study Comparing EG-1962 to Standard of Care Oral Nimodipine in Adults with Aneurysmal Subarachnoid Hemorrhage [NEWTON-2 (Nimodipine Microparticles to Enhance Recovery While Reducing Toxicity After Subarachnoid Hemorrhage)] (2018) Neurocritical Care, pp. 1-10. Article in Press. 

Hänggi, D.a , Etminan, N.a , Mayer, S.A.b , Aldrich, E.F.c , Diringer, M.N.d , Schmutzhard, E.e , Faleck, H.J.f , Ng, D.g , Saville, B.R.h , Macdonald, R.L.f i j k , for the NEWTON Investigatorsl

a Department of Neurosurgery, University Medical Center Mannheim, Ruprecht-Karls-University Heidelberg, Theodor-Kutzer Ufer 1-3, Mannheim, Germany
b Department of Neurology, Henry Ford Health System, Detroit, MI, United States
c Neurological Surgery, University of Maryland Medical Center, Baltimore, MD, United States
d Neurological Critical Care, Washington University School of Medicine, St. Louis, MO, United States
e Neurointensive Care Unit, Department of Neurology, Medical University Innsbruck, Innsbruck, Austria
f Edge Therapeutics, Berkeley Heights, NJ, United States
g ResearchPoint Global, Austin, TX, United States
h Berry Consultants LLC, Austin, TX, United States
i Division of Neurosurgery, Labatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan Research Centre for Biomedical Research, St. Michael’s Hospital, Toronto, Canada
j Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Canada
k Department of Surgery, University of Toronto, Toronto, Canada

Abstract
Background: Nimodipine is the only drug approved in the treatment of aneurysmal subarachnoid hemorrhage (aSAH) in many countries. EG-1962, a product developed using the Precisa™ platform, is an extended-release microparticle formulation of nimodipine that can be administered intraventricularly or intracisternally. It was developed to test the hypothesis that delivering higher concentrations of extended-release nimodipine directly to the cerebrospinal fluid would provide superior efficacy compared to systemic administration. Results: A Phase 1/2a multicenter, controlled, randomized, open-label, dose-escalation study determined the maximum tolerated dose and supported the safety and tolerability of EG-1962 in patients with aSAH. EG-1962, 600 mg, was selected for a pivotal, Phase 3 multicenter, randomized, double-blind, placebo-controlled, parallel-group efficacy, and safety study comparing it to standard of care oral nimodipine in adults with aSAH. Key inclusion criteria are patients with a ruptured saccular aneurysm repaired by clipping or coiling, World Federation of Neurological Surgeons grade 2–4, and modified Fisher score of > 1. Patients must have an external ventricular drain as part of standard of care. Patients are randomized to receive intraventricular investigational product (EG-1962 or NaCl solution) and an oral placebo or oral nimodipine in the approved dose regimen (active control) within 48 h of aSAH. The primary objective is to determine the efficacy of EG-1962 compared to oral nimodipine. Conclusions: The primary endpoint is the proportion of subjects with favorable outcome (6–8) on the Extended Glasgow Outcome Scale assessed 90 days after aSAH. The secondary endpoint is the proportion of subjects with favorable outcome on the Montreal Cognitive Assessment 90 days after aSAH. Data on safety, rescue therapy, delayed cerebral infarction, and health economics will be collected. Trail registration NCT02790632. © 2018 Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society

Document Type: Article in Press
Source: Scopus

"Polysomnography for Obstructive Sleep Apnea Should Include Arousal-Based Scoring: An American Academy of Sleep Medicine Position Statement" (2018) Journal of Clinical Sleep Medicine

Polysomnography for Obstructive Sleep Apnea Should Include Arousal-Based Scoring: An American Academy of Sleep Medicine Position Statement
(2018) Journal of Clinical Sleep Medicine, 14 (7), pp. 1245-1247. 

Malhotra, R.K.l , Kirsch, D.B.a , Kristo, D.A.b , Olson, E.J.c , Aurora, R.N.d , Carden, K.A.e , Chervin, R.D.f , Martin, J.L.g h , Ramar, K.c , Rosen, C.L.i , Rowley, J.A.j , Rosen, I.M.k

a Carolinas Healthcare Medical Group Sleep Services, Charlotte, NC, United States
b University of Pittsburgh, Pittsburgh, PA, United States
c Division of Pulmonary and Critical Care Medicine, Center for Sleep Medicine, Mayo Clinic, Rochester, MN, United States
d Johns Hopkins School of Medicine, Baltimore, MD, United States
e Saint Thomas Medical Partners – Sleep Specialists, Nashville, TN, United States
f University of Michigan Sleep Disorders Center, Ann Arbor, MI, United States
g Veterans Affairs Greater Los Angeles Healthcare System, North Hills, CA, United States
h David Geffen School of Medicine, University of California, Los Angeles, CA, United States
i Department of Pediatrics, Case Western Reserve University, University Hospitals – Cleveland Medical Center, Cleveland, OH, United States
j Wayne State University, Detroit, MI, United States
k Division of Sleep Medicine, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
l Washington University Sleep Center, 1600 South Brentwood Boulevard, #600, St. Louis, MO, United States

Abstract
The diagnostic criteria for obstructive sleep apnea (OSA) in adults, as defined in the International Classification of Sleep Disorders, Third Edition, requires an increased frequency of obstructive respiratory events demonstrated by in-laboratory, attended polysomnography (PSG) or a home sleep apnea test (HSAT). However, there are currently two hypopnea scoring criteria in The AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology and Technical Specifications (AASM Scoring Manual). This dichotomy results in differences among laboratory reports, patient treatments and payer policies. Confusion occurs regarding recognizing and scoring “arousal-based respiratory events” during OSA testing. “Arousal-based scoring” recognizes hypopneas associated with electroencephalography-based arousals, with or without significant oxygen desaturation, when calculating an apnea-hypopnea index (AHI), or it includes respiratory effort-related arousals (RERAs), in addition to hypopneas and apneas, when calculating a respiratory disturbance index (RDI). Respiratory events associated with arousals, even without oxygen desaturation, cause significant, and potentially dangerous, sleep apnea symptoms. During PSG, arousal-based respiratory scoring should be performed in the clinical evaluation of patients with suspected OSA, especially in those patients with symptoms of excessive daytime sleepiness, fatigue, insomnia, or other neurocognitive symptoms. Therefore, it is the position of the AASM that the RECOMMENDED AASM Scoring Manual scoring criteria for hypopneas, which includes diminished airflow accompanied by either an arousal or ≥ 3% oxygen desaturation, should be used to calculate the AHI. If the ACCEPTABLE AASM Scoring Manual criteria for scoring hypopneas, which includes only diminished airflow plus ≥ 4% oxygen desaturation (and does not allow for arousal-based scoring alone), must be utilized due to payer policy requirements, then hypopneas as defined by the RECOMMENDED AASM Scoring Manual criteria should also be scored. Alternatively, the AASM Scoring Manual includes an option to report an RDI which also provides an assessment of the sleep-disordered breathing that results in arousal from sleep. Furthermore, given the inability of most HSAT devices to capture arousals, a PSG should be performed in any patient with an increased risk for OSA whose HSAT is negative. If the PSG yields an AHI of 5 or more events/h, or if the RDI is greater than or equal to 5 events/h, then treatment of symptomatic patients is recommended to improve quality of life limit neurocognitive symptoms and reduce accident risk. © 2018 American Academy of Sleep Medicine. All rights reserved.

Document Type: Article
Source: Scopus

"Dropout from interpersonal psychotherapy for mental health disorders: A systematic review and meta-analysis" (2018) Psychotherapy Research

Dropout from interpersonal psychotherapy for mental health disorders: A systematic review and meta-analysis
(2018) Psychotherapy Research, pp. 1-12. Article in Press. 

Linardon, J.a , Fitzsimmons-Craft, E.E.b , Brennan, L.c , Barillaro, M.c , Wilfley, D.E.b

a School of Psychology, Deakin University, Burwood, VIC, Australia
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
c School of Psychology, Australian Catholic University, Melbourne, VIC, Australia

Abstract
Objective: Dropout is one factor that might limit the effectiveness of interpersonal psychotherapy (IPT). Improved understanding of IPT dropout is an important research priority. This meta-analysis examined dropout rates from IPT in randomized controlled trials. Method: Seventy-two trials met inclusion criteria. Results: The weighted mean dropout rate from IPT was 20.6% (95% CI = 17.4–24.2). Dropout rates were similar for depressive (20.9%; 95% CI = 17.2–25.2), anxiety (16.1%; 95% CI = 11.1–22.9), and eating disorders (18.7%; 95% CI = 11.6–28.8). Dropout was highest when more stringent definitions of dropout were applied (e.g., failure to complete the entire IPT protocol versus failure to complete at least 50% of sessions) and was lowest when adolescent patients were sampled. There was some evidence that IPT was associated with significantly lower rates of dropout than both CBT and non-specific supportive therapies. These effects were generally replicated when analysing trials that provided a clear definition of treatment (rather than study) dropout. Conclusions: Overall, findings provide preliminary evidence to suggest that IPT may be an accepted and tolerated treatment option for patients with common mental health disorders. This review also highlights the need for future trials to rigorously report detail pertaining to patient dropout. © 2018 Society for Psychotherapy Research

Document Type: Article in Press
Source: Scopus

"Inhibiting autophagy reduces retinal degeneration caused by protein misfolding" (2018) Autophagy

Inhibiting autophagy reduces retinal degeneration caused by protein misfolding
(2018) Autophagy, pp. 1-13. Article in Press. 

Yao, J.a , Qiu, Y.b , Frontera, E.a , Jia, L.a , Khan, N.W.a , Klionsky, D.J.c , Ferguson, T.A.d , Thompson, D.A.a e , Zacks, D.N.a

a Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI, USA
b Department of Ophthalmology, Xiangya School of medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
c Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA
d Department of Ophthalmology and Visual Sciences, Washington University, St. Louis, MO, USA
e Department of Biological Chemistry, University of Michigan, Ann Arbor, MI, USA

Abstract
Mutations in the genes necessary for the structure and function of vertebrate photoreceptor cells are associated with multiple forms of inherited retinal degeneration. Mutations in the gene encoding RHO (rhodopsin) are a common cause of autosomal dominant retinitis pigmentosa (adRP), with the Pro23His variant of RHO resulting in a misfolded protein that activates endoplasmic reticulum stress and the unfolded protein response. Stimulating macroautophagy/autophagy has been proposed as a strategy for clearing misfolded RHO and reducing photoreceptor death. We found that retinas from mice heterozygous for the gene encoding the RHOP23H variant (hereafter called P23H) exhibited elevated levels of autophagy flux, and that pharmacological stimulation of autophagy accelerated retinal degeneration. In contrast, reducing autophagy flux pharmacologically or by rod-specific deletion of the autophagy-activating gene Atg5, improved photoreceptor structure and function. Furthermore, proteasome levels and activity were reduced in the P23H retina, and increased when Atg5 was deleted. Our findings suggest that autophagy contributes to photoreceptor cell death in P23H mice, and that decreasing autophagy shifts the degradation of misfolded RHO protein to the proteasome and is protective. These observations suggest that modulating the flux of misfolded proteins from autophagy to the proteasome may represent an important therapeutic strategy for reducing proteotoxicity in adRP and other diseases caused by protein folding defects. © 2018 Informa UK Limited, trading as Taylor & Francis Group

Document Type: Article in Press
Source: Scopus

"Histopathological correlation of diffusion basis spectrum imaging metrics of a biopsy-proven inflammatory demyelinating brain lesion: A brief report" (2018) Multiple Sclerosis Journal

Histopathological correlation of diffusion basis spectrum imaging metrics of a biopsy-proven inflammatory demyelinating brain lesion: A brief report
(2018) Multiple Sclerosis Journal, . Article in Press. 

Shirani, A.a , Sun, P.b , Schmidt, R.E.c , Trinkaus, K.d , Naismith, R.T.a , Song, S.-K.b , Cross, A.H.a

a John L. Trotter Multiple Sclerosis Center and Neuroimmunology Section, Department of Neurology, School of Medicine, Washington University in St. Louis, St Louis, MO, USA
b Department of Radiology, Mallinckrodt Institute of Radiology, School of Medicine, Washington University in St. Louis, St Louis, MO, USA
c Department of Pathology & Immunology, School of Medicine, Washington University in St. Louis, St Louis, MO, USA
d Siteman Biostatistics Shared Resource, Siteman Cancer Center and School of Medicine, Washington University in St. Louis, St Louis, MO, USA

Abstract
Diffusion basis spectrum imaging (DBSI) models diffusion-weighted magnetic resonance imaging (MRI) signals as a combination of discrete anisotropic diffusion tensors and a spectrum of isotropic diffusion tensors. Here, we report the histopathological correlates of DBSI in the biopsied brain tissue of a patient with an inflammatory demyelinating lesion typical of multiple sclerosis (MS). Increased radial diffusivity (marker of demyelination), decreased fiber fraction (apparent axonal density), elevated nonrestricted isotropic fraction (marker of vasogenic edema), but unchanged axial diffusivity (marker of integrity of residual axons) seen in the lesion appeared consistent with histopathological findings of inflammatory demyelination with relative axonal sparing. Our report supports the application of DBSI as a biomarker in human studies of MS. © 2018, The Author(s), 2018.

Document Type: Article in Press
Source: Scopus

"Compound Motor Action Potential Measures Acute Changes in Laryngeal Innervation" (2018) Annals of Otology, Rhinology and Laryngology

Compound Motor Action Potential Measures Acute Changes in Laryngeal Innervation
(2018) Annals of Otology, Rhinology and Laryngology, . Article in Press. 

Bhatt, N.K., Kao, W.T.K., Paniello, R.C.

Department of Otolaryngology–Head and Neck Surgery, Washington University in Saint Louis, Saint Louis, Missouri, USA

Abstract
Objective: Vocal fold paralysis is caused by injury to the recurrent laryngeal nerve (RLN). Current clinical measures of laryngeal innervation are often nonquantitative. Compound motor action potentials (CMAP) measure motor innervation. The goal of this study was to determine whether CMAP can quantify laryngeal innervation following acute nerve injury. Study Design: Animal study. Methods: Twelve canine hemilaryngeal preparations were used. The RLN was serially stimulated with increasing intensities until the nerve was maximally stimulated. The CMAP amplitude was measured for each intensity stimulation and correlated. Next, the RLN was incompletely transected, and the reduction in CMAP amplitude was correlated to the percentage of transected axons. The percentage of transected axons was determined using horseradish peroxidase (HRP) staining. Results: Combining all hemilaryngeal preparations, the submaximal stimulation of the RLN linearly correlated with the resultant CMAP amplitude (r = 0.83; 95% CI, 0.76-0.88). Following partial RLN transection, the percentage of remaining axons linearly correlated with the CMAP amplitude (r = 0.87; 95% CI, 0.34-0.98). Conclusions: CMAP amplitude is a quantitative measure that may correlate with the degree of vocal fold innervation in canines. Following RLN injury, CMAP may help clinicians quantify the number of intact axons, assess the likelihood of recovery, and counsel patients on their prognosis. © 2018, The Author(s) 2018.

Document Type: Article in Press
Source: Scopus

"Dual-axis illumination for virtually augmenting the detection view of optical-resolution photoacoustic microscopy" (2018) Journal of Biomedical Optics

Dual-axis illumination for virtually augmenting the detection view of optical-resolution photoacoustic microscopy
(2018) Journal of Biomedical Optics, 23 (7), art. no. 076001, . 

Hsu, H.-C.a b , Li, L.b , Yao, J.a , Wong, T.T.W.a , Shi, J.b , Chen, R.c , Zhou, Q.d , Wang, L.V.b

a Washington University in St. Louis, Department of Biomedical Engineering, Optical Imaging Laboratory, St. Louis, MO, United States
b California Institute of Technology, Andrew and Peggy Cherng Department of Medical Engineering, Department of Electrical Engineering, Caltech Optical Imaging Laboratory, Pasadena, CA, United States
c University of Southern California, Resource Center for Medical Ultrasonic Transducer Technology, Department of Biomedical Engineering, Los Angeles, CA, United States
d Duke University, Department of Biomedical Engineering, Durham, NC, United States

Abstract
Optical-resolution photoacoustic microscopy (OR-PAM) has demonstrated fast, label-free volumetric imaging of optical-absorption contrast within the quasiballistic regime of photon scattering. However, the limited numerical aperture of the ultrasonic transducer restricts the detectability of the photoacoustic waves, thus resulting in incomplete reconstructed features. To tackle the limited-view problem, we added an oblique illumination beam to the original coaxial optical-acoustic scheme to provide a complementary detection view. The virtual augmentation of the detection view was validated through numerical simulations and tissue-phantom experiments. More importantly, the combination of top and oblique illumination successfully imaged a mouse brain in vivo down to 1 mm in depth, showing detailed brain vasculature. Of special note, it clearly revealed the diving vessels that were long missing in images from original OR-PAM. © 2018 Society of Photo-Optical Instrumentation Engineers (SPIE).

Document Type: Article
Source: Scopus

"Learning Efficiency: Identifying Individual Differences in Learning Rate and Retention in Healthy Adults" (2018) Psychological Science

Learning Efficiency: Identifying Individual Differences in Learning Rate and Retention in Healthy Adults
(2018) Psychological Science, . Article in Press. 

Zerr, C.L.a , Berg, J.J.a , Nelson, S.M.b c d , Fishell, A.K.e , Savalia, N.K.c , McDermott, K.B.a e

a Department of Psychological & Brain Sciences, Washington University in St. Louis
b VISN 17 Center of Excellence for Research on Returning War Veterans, Waco, Texas
c Center for Vital Longevity, School of Behavioral and Brain Sciences, University of Texas at Dallas
d Department of Psychology and Neuroscience, Baylor University
e Department of Radiology, Washington University in St. Louis

Abstract
People differ in how quickly they learn information and how long they remember it, yet individual differences in learning abilities within healthy adults have been relatively neglected. In two studies, we examined the relation between learning rate and subsequent retention using a new foreign-language paired-associates task (the learning-efficiency task), which was designed to eliminate ceiling effects that often accompany standardized tests of learning and memory in healthy adults. A key finding was that quicker learners were also more durable learners (i.e., exhibited better retention across a delay), despite studying the material for less time. Additionally, measures of learning and memory from this task were reliable in Study 1 (N = 281) across 30 hr and Study 2 (N = 92; follow-up n = 46) across 3 years. We conclude that people vary in how efficiently they learn, and we describe a reliable and valid method for assessing learning efficiency within healthy adults. © 2018, The Author(s) 2018.

Document Type: Article in Press
Source: Scopus

"The Mechanism of Action of Vagus Nerve Stimulation in Treatment-Resistant Depression: Current Conceptualizations" (2018) Psychiatric Clinics of North America

The Mechanism of Action of Vagus Nerve Stimulation in Treatment-Resistant Depression: Current Conceptualizations
(2018) Psychiatric Clinics of North America, . Article in Press. 

Conway, C.R., Xiong, W.

Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8134, St Louis, MO, United States

Abstract
Stimulation of the left cervical vagus nerve, or vagus nerve stimulation (VNS), brings about an antidepressant response in a subset of treatment-resistant depression (TRD) patients. How this occurs is poorly understood; however, knowledge of the neuroanatomic vagal pathways, in conjunction with functional brain imaging studies, suggests several brain regions associated with mood regulation are critical: brainstem nuclei (locus coeruleus, dorsal raphe, and ventral tegmental area), thalamus, and insular and prefrontal cortex. Furthermore, animal studies suggest that VNS enhances neuroplasticity and changes in neuronal firing patterns. Continued study to better understand the mechanism of action of VNS in TRD is warranted. © 2018

Document Type: Article in Press
Source: Scopus

"Height Growth Impairment in Children With Neurofibromatosis Type 1 Is Characterized by Decreased Pubertal Growth Velocity in Both Sexes" (2018) Journal of Child Neurology

Height Growth Impairment in Children With Neurofibromatosis Type 1 Is Characterized by Decreased Pubertal Growth Velocity in Both Sexes
(2018) Journal of Child Neurology, . Article in Press. 

Zessis, N.R.a , Gao, F.b , Vadlamudi, G.a , Gutmann, D.H.c , Hollander, A.S.a

a Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA
b Division of Biostatistics, Washington University School of Medicine, St Louis, MO, USA
c Department of Neurology, Washington University School of Medicine, St Louis, MO, USA

Abstract
Previous studies have suggested that children with neurofibromatosis type 1 are shorter than their unaffected counterparts as an effect of a germline NF1 gene mutation. The pathophysiology of this effect is still uncertain. The purpose of this study was to characterize longitudinal growth in children with neurofibromatosis type 1 in order to assess growth velocity and its influence on stature. Longitudinal height data were collected for 188 patients with a confirmed clinical diagnosis of neurofibromatosis type 1. Children with neurofibromatosis type 1 had population mean heights statistically different from the general population, with a reduced peak height velocity during pubertal growth. In addition, there were no significant differences in the timing of peak height velocity during puberty between the general population and those with neurofibromatosis type 1. These data demonstrate that short stature in neurofibromatosis type 1 is due in part to subnormal height acquisition during puberty. © 2018, The Author(s) 2018.

Document Type: Article in Press
Source: Scopus

"Obstructive sleep apnea as an independent predictor of postoperative delirium and pain: Protocol for an observational study of a surgical cohort… (2018) F1000Research

Obstructive sleep apnea as an independent predictor of postoperative delirium and pain: Protocol for an observational study of a surgical cohort [version 2; referees: 2 approved] (2018) F1000Research, 7, art. no. 328, . 

Avidan, M.S., Strutz, P., Tzeng, W., Arrington, B., Kronzer, V., McKinnon, S., Ben Abdallah, A., Haroutounian, S.

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

Abstract
Introduction: Postoperative delirium and pain are common complications in adults, and are difficult both to prevent and treat. Obstructive sleep apnea (OSA) is prevalent in surgical patients, and has been suggested to be a risk factor for postoperative delirium and pain. OSA also might impact pain perception, and alter pain medication requirements. This protocol describes an observational study, with the primary aim of testing whether OSA is an independent predictor of postoperative complications, focusing on (i) postoperative incident delirium and (ii) acute postoperative pain severity. We secondarily hypothesize that compliance with prescribed treatment for OSA (typically continuous positive airway pressure or CPAP) might decrease the risk of delirium and the severity of pain. Methods and analysis: We will include data from patients who have been enrolled into three prospective studies: ENGAGES, PODCAST, and SATISFY-SOS. All participants underwent general anesthesia for a non-neurosurgical inpatient operation, and had a postoperative hospital stay of at least one day at Barnes Jewish Hospital in St. Louis, Missouri, from February 2013 to May 2018. Patients included in this study have been assessed for postoperative delirium and pain severity as part of the parent studies. In the current study, determination of delirium diagnosis will be based on the Confusion Assessment Method, and the Visual Analogue Pain Scale will be used for pain severity. Data on OSA diagnosis, OSA risk and compliance with treatment will be obtained from the preoperative assessment record. Other variables that are candidate risk factors for delirium and pain will also be extracted from this record. We will use logistic regression to test whether OSA independently predicts postoperative delirium and linear regression to assess OSAs relationship to acute pain severity. We will conduct secondary analyses with subgroups to explore whether these relationships are modified by compliance with OSA treatment. © 2018 Strutz P et al.

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

"Differential cued-Stroop performance in cognitively asymptomatic older adults with biomarker-identified risk for Alzheimer’s disease: A pilot study" (2018) Current Alzheimer Research

Differential cued-Stroop performance in cognitively asymptomatic older adults with biomarker-identified risk for Alzheimer’s disease: A pilot study
(2018) Current Alzheimer Research, 15 (9), pp. 820-827. 

Van Patten, R.a b , Fagan, A.M.c , Kaufman, D.A.S.a

a Department of Psychology, Saint Louis University, St. Louis, MO, United States
b Warren Alpert Medical School, Brown University, Providence, RI, United States
c Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Background: There exists a need for more sensitive measures capable of detecting subtle cognitive decline due to Alzheimer’s disease. Objective: To advance the literature in Alzheimer’s disease by demonstrating that performance on a cued-Stroop task is impacted by preclinical Alzheimer’s disease neuropathology. Method: Twenty-nine cognitively asymptomatic older adults completed a computerized, cued-Stroop task in which accuracy rates and intraindividual variability in reaction times were the outcomes of interest. Cerebrospinal fluid biomarkers of Aβ42 and tau were measured and participants were then grouped according to a published p-tau/Aβ42 cutoff reflecting risk for Alzheimer’s disease (preclinical Alzheimer’s disease = 14; control = 15). Results: ANOVAs indicated that accuracy rates did not differ between the groups but 4-second delay incongruent color-naming Stroop coefficient of variation reaction times were higher in the preclinical Alzheimer’s disease group compared to the control group, reflecting increased within-person variability. Moreover, partial correlations showed no relationships between cerebrospinal fluid biomarkers and accuracy rates. However, increases in coefficient of variation reaction times correlated with decreased Aβ42 and increases in p-tau and the p-tau/Aβ42 ratio. Conclusion: Results supported the ability of the computerized, cued-Stroop task to detect subtle Alzheimer’s disease neuropathology using a small cohort of cognitively asymptomatic older adults. The ongoing measurement of cued-Stroop coefficient of variation reaction times has both scientific and clinical utility in preclinical Alzheimer’s disease. © 2018 Bentham Science Publishers.

Document Type: Article
Source: Scopus

"Myointimal Hyperplasia in a Patient with Neuromyelitis Optica (Devic's Disease) after the Creation of an Arteriovenous Graft" (2017) Case Reports in Neurology

Myointimal Hyperplasia in a Patient with Neuromyelitis Optica (Devic’s Disease) after the Creation of an Arteriovenous Graft
(2017) Case Reports in Neurology, 9 (3), pp. 252-255. 

Rao, C.a , Fox, S.b , Desai, S.S.b

a Washington University of St. Louis, St. Louis, MO, United States
b Department of Vascular Surgery, Northwest Community Hospital, Busse Center, 880 W Central Road, Arlington Heights, IL, United States

Abstract
Neuromyelitis optica, also known as Devic’s disease, is an autoimmune disorder that leads to the inflammation and demyelination of nerves. Devic’s disease primarily affects the optic nerve and spinal cord, but can lead to a significant loss of function throughout the body if not treated with steroid therapy or plasmapheresis. We recently saw a 62-year-old patient who received plasmapheresis for Devic’s disease through a PTFE arteriovenous graft in her left arm. Her graft clotted without warning, and percutaneous thrombolysis was not successful. A new vascular access was achieved with the use of an immediate-cannulation PTFE graft, and the patient received plasmapheresis immediately after her operation. However, the patient returned within 2 weeks with a thrombosed graft. Extensive myointimal fibrosis was noted within the brachial artery and axillary vein during a graft thrombectomy. Subsequent placement of a new arteriovenous fistula in her contralateral arm was eventually successful. Myointimal fibrosis may be a sequela of symptomatic antibody-positive Devic’s disease, and avoidance of synthetic materials may be indicated in this patient population to avoid exacerbation of an autoimmune response. © 2017 The Author(s). Published by S. Karger AG, Basel.

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