WashU weekly Neuroscience publications | Office of Neuroscience Research

"Common genetic contributions to high-risk trauma exposure and self-injurious thoughts and behaviors" (2018) Psychological Medicine

Common genetic contributions to high-risk trauma exposure and self-injurious thoughts and behaviors
(2018) Psychological Medicine, pp. 1-10. Article in Press.

Richmond-Rakerd, L.S.^a ^b , Trull, T.J.^b , Gizer, I.R.^b , McLaughlin, K.^b , Scheiderer, E.M.^b ^c , Nelson, E.C.^d , Agrawal, A.^d , Lynskey, M.T.^e , Madden, P.A.F.^d , Heath, A.C.^d , Statham, D.J.^f , Martin, N.G.^g

^a Department of Psychology & Neuroscience, Duke University, Durham, NC, USA
^b Department of Psychological Sciences, University of Missouri, Columbia, MO, USA
^c Department of Clinical and Counselling Psychology, NHS Grampian, Royal Cornhill Hospital, Aberdeen, UK
^d Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
^e National Addiction Centre, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK
^f University of the Sunshine Coast, Queensland, Australia
^g QIMR Berghofer Medical Research Institute, Brisbane, Australia

Abstract
Background: Prior research has documented shared heritable contributions to non-suicidal self-injury (NSSI) and suicidal ideation (SI) as well as NSSI and suicide attempt (SA). In addition, trauma exposure has been implicated in risk for NSSI and suicide. Genetically informative studies are needed to determine common sources of liability to all three self-injurious thoughts and behaviors, and to clarify the nature of their associations with traumatic experiences. Methods: Multivariate biometric modeling was conducted using data from 9526 twins [59% female, mean age = 31.7 years (range 24–42)] from two cohorts of the Australian Twin Registry, some of whom also participated in the Childhood Trauma Study and the Nicotine Addiction Genetics Project. Results: The prevalences of high-risk trauma exposure (HRT), NSSI, SI, and SA were 24.4, 5.6, 27.1, and 4.6%, respectively. All phenotypes were moderately to highly correlated. Genetic influences on self-injurious thoughts and behaviors and HRT were significant and highly correlated among men [rG = 0.59, 95% confidence interval (CI) (0.37–0.81)] and women [rG = 0.56 (0.49–0.63)]. Unique environmental influences were modestly correlated in women [rE = 0.23 (0.01–0.45)], suggesting that high-risk trauma may confer some direct risk for self-injurious thoughts and behaviors among females. Conclusions: Individuals engaging in NSSI are at increased risk for suicide, and common heritable factors contribute to these associations. Preventing trauma exposure may help to mitigate risk for self-harm and suicide, either directly or indirectly via reductions in liability to psychopathology more broadly. In addition, targeting pre-existing vulnerability factors could significantly reduce risk for life-threatening behaviors among those who have experienced trauma. Copyright © Cambridge University Press 2018

Author Keywords
High-risk trauma; non-suicidal self-injury; suicidal ideation; suicide attempt; twins

Document Type: Article in Press
Source: Scopus

"Evaluating the contributions of task expectancy in the testing and guessing benefits on recognition memory" (2018) Memory

Evaluating the contributions of task expectancy in the testing and guessing benefits on recognition memory
(2018) Memory, pp. 1-19. Article in Press.

Huff, M.J.^a , Yates, T.J.^b , Balota, D.A.^b

^a Department of Psychology, The University of Southern Mississippi, Hattiesburg, MS, USA
^b Department of Psychological & Brain Sciences, Washington University, St. Louis, MO, USA

Abstract
Recently, we have shown that two types of initial testing (recall of a list or guessing of critical items repeated over 12 study/test cycles) improved final recognition of related and unrelated word lists relative to restudy. These benefits were eliminated, however, when test instructions were manipulated within subjects and presented after study of each list, procedures designed to minimise expectancy of a specific type of upcoming test [Huff, Balota, & Hutchison, 2016. The costs and benefits of testing and guessing on recognition memory. Journal of Experimental Psychology: Learning, Memory, and Cognition, 42, 1559–1572. doi:10.1037/xlm0000269], suggesting that testing and guessing effects may be influenced by encoding strategies specific for the type of upcoming task. We follow-up these experiments by examining test-expectancy processes in guessing and testing. Testing and guessing benefits over restudy were not found when test instructions were presented either after (Experiment 1) or before (Experiment 2) a single study/task cycle was completed, nor were benefits found when instructions were presented before study/task cycles and the task was repeated three times (Experiment 3). Testing and guessing benefits emerged only when instructions were presented before a study/task cycle and the task was repeated six times (Experiments 4A and 4B). These experiments demonstrate that initial testing and guessing can produce memory benefits in recognition, but only following substantial task repetitions which likely promote task-expectancy processes. © 2018 Informa UK Limited, trading as Taylor & Francis Group

Author Keywords
guessing; recall; recognition; retrieval practice; Test expectancy

Document Type: Article in Press
Source: Scopus

"NAD+ cellular redox and SIRT1 regulate the diurnal rhythms of tyrosine hydroxylase and conditioned cocaine reward" (2018) Molecular Psychiatry

NAD+ cellular redox and SIRT1 regulate the diurnal rhythms of tyrosine hydroxylase and conditioned cocaine reward
(2018) Molecular Psychiatry, pp. 1-17. Article in Press.

Logan, R.W.^a ^b ^c , Parekh, P.K.^a ^b , Kaplan, G.N.^a ^b , Becker-Krail, D.D.^a ^b , Williams, W.P., III^a , Yamaguchi, S.^d , Yoshino, J.^d , Shelton, M.A.^a , Zhu, X.^a ^b , Zhang, H.^a ^e , Waplinger, S.^a , Fitzgerald, E.^a , Oliver-Smith, J.^a , Sundarvelu, P.^a , Enwright, J.F., III^a , Huang, Y.H.^a ^b , McClung, C.A.^a ^b ^c

^a Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh Medical School, Pittsburgh, PA, United States
^b Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, United States
^c Center for Systems Neurogenetics of Addiction, The Jackson Laboratory, Bar Harbor, ME, United States
^d Center for Human Nutrition, Division of Geriatrics and Nutritional Science, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
^e School of Medicine, Peking Union Medical College, Tsinghua University, Beijing, China

Abstract
The diurnal regulation of dopamine is important for normal physiology and diseases such as addiction. Here we find a novel role for the CLOCK protein to antagonize CREB-mediated transcriptional activity at the tyrosine hydroxylase (TH) promoter, which is mediated by the interaction with the metabolic sensing protein, Sirtuin 1 (SIRT1). Additionally, we demonstrate that the transcriptional activity of TH is modulated by the cellular redox state, and daily rhythms of redox balance in the ventral tegmental area (VTA), along with TH transcription, are highly disrupted following chronic cocaine administration. Furthermore, CLOCK and SIRT1 are important for regulating cocaine reward and dopaminergic (DAergic) activity, with interesting differences depending on whether DAergic activity is in a heightened state and if there is a functional CLOCK protein. Taken together, we find that rhythms in cellular metabolism and circadian proteins work together to regulate dopamine synthesis and the reward value for drugs of abuse. © 2018 Macmillan Publishers Limited, part of Springer Nature

Document Type: Article in Press
Source: Scopus

"Muscularis macrophage development in the absence of an enteric nervous system" (2018) Proceedings of the National Academy of Sciences of the United States of America

Muscularis macrophage development in the absence of an enteric nervous system
(2018) Proceedings of the National Academy of Sciences of the United States of America, 115 (18), pp. 4696-4701.

Avetisyan, M.^a ^b ^c , Rood, J.E.^d ^e , Lopez, S.H.^a ^b , Sengupta, R.^a ^b , Wright-Jin, E.^f , Dougherty, J.D.^g ^h , Behrens, E.M.^d ^e , Heuckeroth, R.O.^a ^b

^a Abramson Research Center, Children’s Hospital of Philadelphia Research Institute, Philadelphia, PA, United States
^b Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^c Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
^d Division of Rheumatology, Abramson Research Center, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
^e Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^f Department of Pediatric Neurology, Washington University School of Medicine, St. Louis, MO, United States
^g Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
^h Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States

Abstract
The nervous system of the bowel regulates the inflammatory phenotype of tissue resident muscularis macrophages (MM), and in adult mice, enteric neurons are the main local source of colony stimulating factor 1 (CSF1), a protein required for MM survival. Surprisingly, we find that during development MM colonize the bowel before enteric neurons. This calls into question the requirement for neuron-derived CSF1 for MM colonization of the bowel. To determine if intestinal innervation is required for MM development, we analyzed MM of neonatal Ret−/− (Ret KO) mice that have no enteric nervous system in small bowel or colon. We found normal numbers of well-patterned MM in Ret KO bowel. Similarly, the abundance and distribution of MM in aganglionic human colon obtained from Hirschsprung disease patients was normal. We also identify endothelial cells and interstitial cells of Cajal as the main sources of CSF1 in the developing bowel. Additionally, MM from neonatal Ret KOs do not differ from controls in baseline activation status or cytokine-production in response to lipopolysac-charide. Unexpectedly, these data demonstrate that the enteric nervous system is dispensable for MM colonization and patterning in the bowel, and suggest that modulatory interactions between MM and the bowel nervous system are established postnatally. © 2018 National Academy of Sciences. All rights reserved.

Author Keywords
Enteric nervous system; Hirschsprung disease; Muscularis macrophages; Neuroimmunology

Document Type: Article
Source: Scopus

"Dynamic Resting State Connectivity as a Tool for Understanding Neurobiological Correlates of Cognition Across the Psychosis Spectrum" (2018) Biological Psychiatry: Cognitive Neuroscience and Neuroimaging

Dynamic Resting State Connectivity as a Tool for Understanding Neurobiological Correlates of Cognition Across the Psychosis Spectrum
(2018) Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, 3 (5), pp. 407-408.

Sheffield, J.M.^a ^b

^a Vanderbilt University Department of Psychiatry and Behavioral Sciences, Nashville, Tennessee, United States
^b Washington University Department of Psychological and Brain Sciences, St. Louis, Missouri, United States

Document Type: Note
Source: Scopus

"Targeting of nonlipidated, aggregated apoE with antibodies inhibits amyloid accumulation" (2018) Journal of Clinical Investigation

Targeting of nonlipidated, aggregated apoE with antibodies inhibits amyloid accumulation
(2018) Journal of Clinical Investigation, 128 (5), pp. 2144-2155. Cited 1 time.

Liao, F.^d , Li, A.^d , Xiong, M.^d , Bien-Ly, N.^a , Jiang, H.^d , Zhang, Y.^a , Finn, M.B.^d , Hoyle, R.^d , Keyser, J.^d , Lefton, K.B.^d , Robinson, G.O.^d , Serrano, J.R.^d , Silverman, A.P.^a , Guo, J.L.^a , Getz, J.^a , Henne, K.^a , Leyns, C.E.G.^d , Gallardo, G.^d , Ulrich, J.D.^d , Sullivan, P.M.^b , Lerner, E.P.^c , Hudry, E.^c , Sweeney, Z.K.^a , Dennis, M.S.^a , Hyman, B.T.^c , Watts, R.J.^a , Holtzman, D.M.^d

^a Denali Therapeutics Inc., South San Francisco, CA, United States
^b Department of Medicine, Duke University, Durham, NC, United States
^c MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States
^d Department of Neurology, Hope Center for Neurological Disorders, Charles F. and Joanne Knight Alzheimer’s Disease Research Center, Washington University, School of Medicine, 660 S. Euclid Avenue, St. Louis, MO, United States

Abstract
The apolipoprotein E E4 allele of the APOE gene is the strongest genetic factor for late-onset Alzheimer disease (LOAD). There is compelling evidence that apoE influences Alzheimer disease (AD) in large part by affecting amyloid β (Aβ) aggregation and clearance; however, the molecular mechanism underlying these findings remains largely unknown. Herein, we tested whether anti-human apoE antibodies can decrease Aβ pathology in mice producing both human Aβ and apoE4, and investigated the mechanism underlying these effects. We utilized APPPS1-21 mice crossed to apoE4-knockin mice expressing human apoE4 (APPPS1-21/APOE4). We discovered an anti-human apoE antibody, anti-human apoE 4 (HAE-4), that specifically recognizes human apoE4 and apoE3 and preferentially binds nonlipidated, aggregated apoE over the lipidated apoE found in circulation. HAE-4 also binds to apoE in amyloid plaques in unfixed brain sections and in living APPPS1-21/APOE4 mice. When delivered centrally or by peripheral injection, HAE-4 reduced Aβ deposition in APPPS1-21/APOE4 mice. Using adeno-associated virus to express 2 different full-length anti-apoE antibodies in the brain, we found that HAE antibodies decreased amyloid accumulation, which was dependent on Fcγ receptor function. These data support the hypothesis that a primary mechanism for apoE-mediated plaque formation may be a result of apoE aggregation, as preferentially targeting apoE aggregates with therapeutic antibodies reduces Aβ pathology and may represent a selective approach to treat AD. © 2018 Academic Press. All rights reserved.

Document Type: Article
Source: Scopus

"Irritability Trajectories, Cortical Thickness, and Clinical Outcomes in a Sample Enriched for Preschool Depression" (2018) Journal of the American Academy of Child and Adolescent Psychiatry

Irritability Trajectories, Cortical Thickness, and Clinical Outcomes in a Sample Enriched for Preschool Depression
(2018) Journal of the American Academy of Child and Adolescent Psychiatry, 57 (5), pp. 336-342.e6.

Pagliaccio, D.^a , Pine, D.S.^b , Barch, D.M.^c , Luby, J.L.^c , Leibenluft, E.^b

^a New York State Psychiatric Institute and College of Physicians and Surgeons, Columbia University, New York, United States
^b Emotion and Development Branch, National Institute of Mental Health (NIMH), Bethesda, MD, United States
^c Washington University School of Medicine, St. Louis, MO, United States

Abstract
Objective: Cross-sectional, longitudinal, and genetic associations exist between irritability and depression. Prior studies have examined developmental trajectories of irritability, clinical outcomes, and associations with child and familial depression. However, studies have not integrated neurobiological measures. The present study examined developmental trajectories of irritability, clinical outcomes, and cortical structure among preschoolers oversampled for depressive symptoms. Method: Beginning at 3 to 5 years old, a sample of 271 children enriched for early depressive symptoms were assessed longitudinally by clinical interview. Latent class mixture models identified trajectories of irritability severity. Risk factors, clinical outcomes, and cortical thickness were compared across trajectory classes. Cortical thickness measures were extracted from 3 waves of magnetic resonance imaging at 7 to 12 years of age. Results: Three trajectory classes were identified among these youth: 53.50% of children exhibited elevated irritability during preschool that decreased longitudinally, 30.26% exhibited consistently low irritability, and 16.24% exhibited consistently elevated irritability. Compared with other classes, the elevated irritability class exhibited higher rates of maternal depression, early life adversity, later psychiatric diagnoses, and functional impairment. Further, elevated baseline irritability predicted later depression beyond adversity and personal and maternal depression history. The elevated irritability class exhibited a thicker cortex in the left superior frontal and temporal gyri and the right inferior parietal lobule. Conclusion: Irritability manifested with specific developmental trajectories in this sample enriched for early depression. Persistently elevated irritability predicted poor psychiatric outcomes, higher risk for later depression, and decreased overall function later in development. Greater frontal, temporal, and parietal cortical thickness also was found, providing neural correlates of this risk trajectory. © 2018 American Academy of Child and Adolescent Psychiatry

Author Keywords
cortical thickness; development; irritability; latent trajectory; magnetic resonance imaging

Document Type: Article
Source: Scopus

"Development of white matter circuitry in infants with fragile x syndrome" (2018) JAMA Psychiatry

Development of white matter circuitry in infants with fragile x syndrome
(2018) JAMA Psychiatry, 75 (5), pp. 505-513.

Swanson, M.R.^a , Wolff, J.J.^b , Shen, M.D.^c , Styner, M.^c ^d , Estes, A.^e , Gerig, G.^f , McKinstry, R.C.^g , Botteron, K.N.^h ⁱ , Piven, J.^c , Hazlett, H.C.^c

^a Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hill, Campus Box 3367, Chapel Hill, NC, United States
^b Department of Educational Psychology, University of Minnesota, Minneapolis, United States
^c Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
^d Department of Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
^e Department of Speech and Hearing Sciences, University of Washington, Seattle, United States
^f Department of Computer Science and Engineering, New York University, Brooklyn, United States
^g Mallinckrodt Institute of Radiology, Washington University in St Louis, St Louis, MO, United States
^h Department of Psychiatry, Washington University in St Louis, St Louis, MO, United States
ⁱ Department of Radiology, Washington University in St Louis, St Louis, MO, United States

Abstract
IMPORTANCE Fragile X syndrome (FXS) is a genetic neurodevelopmental disorder and the most common inherited cause of intellectual disability in males. However, there are no published data on brain development in children with FXS during infancy. OBJECTIVE To characterize the development of white matter at ages 6, 12, and 24 months in infants with FXS compared with that of typically developing controls. DESIGN, SETTING, AND PARTICIPANTS Longitudinal behavioral and brain imaging datawere collected at 1 or more time points from 27 infants with FXS and 73 typically developing controls between August 1, 2008, and June 14, 2016, at 2 academic medical centers. Infants in the control group had no first- or second-degree relatives with intellectual or psychiatric disorders, including FXS and autism spectrum disorder. MAIN OUTCOMES AND MEASURES Nineteen major white matter pathwayswere defined in common atlas space based on anatomically informed methods. Diffusion parameters, including fractional anisotropy, were compared between groups using linear mixed effects modeling. Fiber pathways showing group differences were subsequently examined in association with direct measures of verbal and nonverbal development. RESULTS There were significant differences in the development of 12 of 19 fiber tracts between the 27 infants with FXS (22 boys and 5 girls) and the 73 infants in the control group (46 boys and 27 girls), with lower fractional anisotropy in bilateral subcortical-frontal, occipital-temporal, temporal-frontal, and cerebellar-thalamic pathways, as well as 4 of 6 subdivisions of the corpus callosum. For all 12 of these pathways, there were significant main effects between groups but not for the interaction of age × group, indicating that lower fractional anisotropy was present and stable from age 6 months in infants with FXS. Lower fractional anisotropy values in the uncinate fasciculi were correlated with lower nonverbal developmental quotient in the FXS group (left uncinate, F = 10.06; false discovery rate-corrected P = .03; right uncinate, F = 21.8; P = .004). CONCLUSIONS AND RELEVANCE The results substantiate in human infants the essential role of fragile X gene expression in the early development of white matter. The findings also suggest that the neurodevelopmental effects of FXS are well established at 6 months of age. © 2018 American Medical Association.

Document Type: Article
Source: Scopus

"Medical cannabis and the treatment of obstructive sleep apnea: An American Academy of sleep Medicine position statement" (2018) Journal of Clinical Sleep Medicine

Medical cannabis and the treatment of obstructive sleep apnea: An American Academy of sleep Medicine position statement
(2018) Journal of Clinical Sleep Medicine, 14 (4), pp. 679-681.

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

^a Division of Pulmonary and Critical Care Medicine, Center for Sleep Medicine, Mayo Clinic, Rochester, MN, United States
^b Division of Sleep Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^c Carolinas Healthcare Medical Group Sleep Services, Charlotte, NC, United States
^d University of Michigan Sleep Disorders Center, Ann Arbor, MI, United States
^e Saint Thomas Medical Partners – Sleep Specialists, Nashville, TN, United States
^f School of Medicine, Johns Hopkins University, Baltimore, MD, United States
^g University of Pittsburgh, Pittsburgh, PA, United States
^h Washington University, Sleep Center, St. Louis, MO, United States
ⁱ Veterans Affairs Greater Los Angeles Healthcare System, North Hills, CA, United States
^j David Geffen School of Medicine, University of California, Los Angeles, CA, United States
^k Department of Pediatrics, Case Western Reserve University, University Hospitals, Cleveland Medical Center, Cleveland, OH, United States
^l Wayne State University, Detroit, MI, United States
^m American Academy of Sleep Medicine, 2510 N. Frontage Road, Darien, IL, United States

Abstract
The diagnosis and effective treatment of obstructive sleep apnea (OSA) in adults is an urgent health priority. Positive airway pressure (PAP) therapy remains the most effective treatment for OSA, although other treatment options continue to be explored. Limited evidence citing small pilot or proof of concept studies suggest that the synthetic medical cannabis extract dronabinol may improve respiratory stability and provide benefit to treat OSA. However, side effects such as somnolence related to treatment were reported in most patients, and the long-term effects on other sleep quality measures, tolerability, and safety are still unknown. Dronabinol is not approved by the United States Food and Drug Administration (FDA) for treatment of OSA, and medical cannabis and synthetic extracts other than dronabinol have not been studied in patients with OSA. The composition of cannabinoids within medical cannabis varies significantly and is not regulated. Synthetic medical cannabis may have differential effects, with variable efficacy and side effects in the treatment of OSA. Therefore, it is the position of the American Academy of Sleep Medicine (AASM) that medical cannabis and/or its synthetic extracts should not be used for the treatment of OSA due to unreliable delivery methods and insufficient evidence of effectiveness, tolerability, and safety. OSA should be excluded from the list of chronic medical conditions for state medical cannabis programs, and patients with OSA should discuss their treatment options with a licensed medical provider at an accredited sleep facility. Further research is needed to understand the functionality of medical cannabis extracts before recommending them as a treatment for OSA. © 2018 American Academy of Sleep Medicine. All rights reserved.

Author Keywords
Long-term effects; Medical cannabis; Obstructive sleep apnea; Pap therapy

Document Type: Article
Source: Scopus

"The risk of fatigue and sleepiness in the ridesharing industry: An American Academy of sleep Medicine position statement" (2018) Journal of Clinical Sleep Medicine

The risk of fatigue and sleepiness in the ridesharing industry: An American Academy of sleep Medicine position statement
(2018) Journal of Clinical Sleep Medicine, 14 (4), pp. 683-685.

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

^a Concentra, Inc., Grand Rapids, MI, United States
^b Division of Sleep Medicine, Perelman School of Medicine, University of Pennsylvania, 3624 Market St, Philadelphia, PA, United States
^c Carolinas Healthcare Medical Group Sleep Services, Charlotte, NC, United States
^d University of Michigan, Sleep Disorders Center, Ann Arbor, MI, United States
^e Saint Thomas Medical Partners – Sleep Specialists, Nashville, TN, United States
^f Division of Pulmonary and Critical Care Medicine, Center for Sleep Medicine, Mayo Clinic, Rochester, MN, United States
^g School of Medicine, Johns Hopkins University, Baltimore, MD, United States
^h University of Pittsburgh, Pittsburgh, PA, United States
ⁱ Washington University, Sleep Center, St. Louis, MO, United States
^j Veterans Affairs Greater Los Angeles Healthcare System, North Hills, CA, United States
^k David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
^l Department of Pediatrics, Case Western Reserve University, University Hospitals, Cleveland Medical Center, Cleveland, OH, United States
^m Wayne State University, Detroit, MI, United States
ⁿ Corporal Michael Crescenz VA Medical Center, Philadelphia, PA, United States

Abstract
The ridesharing- or ride-hailing-industry has grown exponentially in recent years, transforming quickly into a fee-for-service, unregulated taxi industry. While riders are experiencing the benefits of convenience and affordability, two key regulatory and safety issues deserve consideration. First, individuals who work as drivers in the ridesharing industry are often employed in a primary job, and they work as drivers during their “off” time. Such a schedule may lead to driving after extended periods of wakefulness or during nights, both of which are factors that increase the risk of drowsy driving accidents. Second, these drivers are often employed as “independent contractors,” and therefore they are not screened for medical problems that can reduce alertness, such as obstructive sleep apnea. Some ridesharing companies now require a rest period after an extended driving shift. This measure is encouraging, but it is insufficient to impact driving safety appreciably, particularly since many of these drivers are already working extended hours and tend to drive at non-traditional times when sleepiness may peak. Therefore, it is the position of the American Academy of Sleep Medicine (AASM) that fatigue and sleepiness are inherent safety risks in the ridesharing industry. The AASM calls on ridesharing companies, government officials, medical professionals, and law enforcement officers to work together to address this public safety risk. A collaborative effort is necessary to understand and track the scope of the problem, provide relevant education, and mitigate the risk through thoughtful regulation and effective fatigue risk management systems. © 2018 American Academy of Sleep Medicine. All rights reserved.

Author Keywords
Fatigue; Ridesharing; Sleepiness

Document Type: Article
Source: Scopus

"Metabotropic glutamate receptor 2/3 (mGluR2/3) activation suppresses TRPV1 sensitization in mouse, but not human, sensory neurons" (2018) eNeuro

Metabotropic glutamate receptor 2/3 (mGluR2/3) activation suppresses TRPV1 sensitization in mouse, but not human, sensory neurons
(2018) eNeuro, 5 (2), art. no. e0412-17.2018, .

Sheahan, T.D.^a ^b , Valtcheva, M.V.^a ^b , McIlvried, L.A.^a , Pullen, M.Y.^a , Baranger, D.A.A.^b ^c , Gereau, R.W., IV^a

^a Department of Anesthesiology, Washington University Pain Center, Washington University School of Medicine, St. Louis, MO, United States
^b Washington University School of Medicine, St. Louis, MO, United States
^c BRAIN Laboratory, Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States

Abstract
The use of human tissue to validate putative analgesic targets identified in rodents is a promising strategy for improving the historically poor translational record of preclinical pain research. We recently demonstrated that in mouse and human sensory neurons, agonists for metabotropic glutamate receptors 2 and 3 (mGluR2/3) reduce membrane hyperexcitability produced by the inflammatory mediator prostaglandin E2 (PGE2). Previous rodent studies indicate that mGluR2/3 can also reduce peripheral sensitization by suppressing inflammation-induced sensitization of TRPV1. Whether this observation similarly translates to human sensory neurons has not yet been tested. We found that activation of mGluR2/3 with the agonist APDC suppressed PGE2-induced sensitization of TRPV1 in mouse, but not human, sensory neurons. We also evaluated sensory neuron expression of the gene transcripts for mGluR2 (Grm2), mGluR3 (Grm3), and TRPV1 (Trpv1). The majority of Trpv1+ mouse and human sensory neurons expressed Grm2 and/or Grm3, and in both mice and humans, Grm2 was expressed in a greater percentage of sensory neurons than Grm3. Although we demonstrated a functional difference in the modulation of TRPV1 sensitization by mGluR2/3 activation between mouse and human, there were no species differences in the gene transcript colocalization of mGluR2 or mGluR3 with TRPV1 that might explain this functional difference. Taken together with our previous work, these results suggest that mGluR2/3 activation suppresses only some aspects of human sensory neuron sensitization caused by PGE2. These differences have implications for potential healthy human voluntary studies or clinical trials evaluating the analgesic efficacy of mGluR2/3 agonists or positive allosteric modulators. © 2018 Sheahan et al.

Author Keywords
Dorsal root ganglia; Glutamate; Human neurons; Metabotropic; Nociceptors; Pain

Document Type: Article
Source: Scopus

"Gaussian processes with optimal kernel construction for neuro-degenerative clinical onset prediction" (2018) Progress in Biomedical Optics and Imaging – Proceedings of SPIE

Gaussian processes with optimal kernel construction for neuro-degenerative clinical onset prediction
(2018) Progress in Biomedical Optics and Imaging – Proceedings of SPIE, 10575, art. no. 105750G, .

Canas, L.S.^a , Yvernault, B.^a , Cash, D.M.^a ^b , Molteni, E.^a , Veale, T.^a , Benzinger, T.^b , Ourselin, S.^a , Mead, S.^c ^d ^e , Modat, M.^a ^b

^a Translational Imaging Group, Centre for Medical Image Computing, University College London, United Kingdom
^b Dementia Research Centre, UCL Institute of Neurology, London, United Kingdom
^c Institute of Neurology, University College London, United Kingdom
^d Washington University School of Medicine, St. Louis, MO, United States
^e MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom

Abstract
Gaussian Processes (GP) are a powerful tool to capture the complex time-variations of a dataset. In the context of medical imaging analysis, they allow a robust modelling even in case of highly uncertain or incomplete datasets. Predictions from GP are dependent of the covariance kernel function selected to explain the data variance. To overcome this limitation, we propose a framework to identify the optimal covariance kernel function to model the data.The optimal kernel is defined as a composition of base kernel functions used to identify correlation patterns between data points. Our approach includes a modified version of the Compositional Kernel Learning (CKL) algorithm, in which we score the kernel families using a new energy function that depends both the Bayesian Information Criterion (BIC) and the explained variance score. We applied the proposed framework to model the progression of neurodegenerative diseases over time, in particular the progression of autosomal dominantly-inherited Alzheimer’s disease, and use it to predict the time to clinical onset of subjects carrying genetic mutation. © 2018 SPIE.

Author Keywords
Clinical onset prediction; Compositional kernel Learning; Covariance kernel functions; Disease progression model; Gaussian Process; Neurodegenerative Diseases

Document Type: Conference Paper
Source: Scopus

"An Introduction to the Forum: Cognitive Perspectives on the Assessment of Professional Competence" (2018) Journal of Applied Research in Memory and Cognition

An Introduction to the Forum: Cognitive Perspectives on the Assessment of Professional Competence
(2018) Journal of Applied Research in Memory and Cognition, . Article in Press.

Butler, A.C.

Washington University in St. Louis, United States

Author Keywords
Assessment; Cognitive psychology; Professional competence

Document Type: Article in Press
Source: Scopus

"Everolimus dosing recommendations for tuberous sclerosis complex-associated refractory seizures" (2018) Epilepsia

Everolimus dosing recommendations for tuberous sclerosis complex-associated refractory seizures
(2018) Epilepsia, . Article in Press.

Franz, D.N.^a , Lawson, J.A.^b , Yapici, Z.^c , Brandt, C.^d , Kohrman, M.H.^e , Wong, M.^f , Milh, M.^g , Wiemer-Kruel, A.^h , Voi, M.ⁱ , Coello, N.^j , Cheung, W.ⁱ , Grosch, K.^j , French, J.A.^k

^a Department of Neurology Cincinnati Children’s Hospital Medical Center Cincinnati, OH USA
^b Tuberous Sclerosis Multidisciplinary Management Clinic Sydney Children’s Hospital Randwick, New South Wales Australia
^c Division of Child Neurology Department of Neurology Istanbul Faculty of Medicine Istanbul University Istanbul Turkey
^d Bethel Epilepsy Center Mara Hospital Bielefeld Germany
^e NeuroDevelopmental Science Center University of Chicago Chicago, IL USA
^f Department of Neurology Washington University School of Medicine St. Louis, MO USA
^g Pediatric Neurology Service Aix-Marseille University Marseille France
^h Epilepsy Center Kork/TSC Center Kehl-Kork Germany
ⁱ Novartis Pharmaceuticals Corporation East Hanover, NJ USA
^j Novartis Pharmaceuticals AG Basel Switzerland
^k New York University Comprehensive Epilepsy Center New York, NY USA

Abstract
Objective: The present analysis examined the exposure-response relationship by means of the predose everolimus concentration (Cmin) and the seizure response in patients with tuberous sclerosis complex-associated seizures in the EXIST-3 study. Recommendations have been made for the target Cmin range of everolimus for therapeutic drug monitoring (TDM) and the doses necessary to achieve this target Cmin. Methods: A model-based approach was used to predict patients’ daily Cmin. Time-normalized Cmin (TN-Cmin) was calculated as the average predicted Cmin in a time interval. TN-Cmin was used to link exposure to efficacy and safety end points via model-based approaches. A conditional logistic regression stratified by age subgroup was used to estimate the probability of response in relation to exposure. A multiplicative linear regression model was used to estimate the exposure-response relationship for seizure frequency (SF). An extended Cox regression model was used to link exposure to the time to first adverse event. Results: There was a strong, consistent, and highly significant relationship between everolimus exposure and efficacy, measured by TN-Cmin and SF, regardless of patient’s age and concomitant use of cytochrome P450 3A4 (CYP3A4) inhibitors/inducers. Results of an extended Cox regression analyses indicated that twofold increases in TN-Cmin were not associated with statistically significant increases in the risk of stomatitis or infections. Significance: The recommended TDM is to target everolimus Cmin within a range of 5-7 ng/mL initially and 5-15 ng/mL in the event of an inadequate clinical response, and safety is consistent with previous reports. Starting doses depend on age and the concomitant use of CYP3A4/P-glycoprotein inducers/inhibitors. © 2018 International League Against Epilepsy.

Author Keywords
Dose; Refractory; Seizures; TDM; TSC

Document Type: Article in Press
Source: Scopus

"Angiographic and clinical outcomes of balloon remodeling versus unassisted coil embolization in the ruptured aneurysm cohort of the GEL the NEC study" (2018) Journal of NeuroInterventional Surgery

Angiographic and clinical outcomes of balloon remodeling versus unassisted coil embolization in the ruptured aneurysm cohort of the GEL the NEC study
(2018) Journal of NeuroInterventional Surgery, 10 (5), pp. 447-451.

Dabus, G.^a , Brinjikji, W.^b , Amar, A.P.^c , Almandoz, J.E.D.^d , Diaz, O.M.^e ^f , Jabbour, P.^g , Hanel, R.^h , Hui, F.ⁱ , Kelly, M.^j , Layton, K.F.^k , Miller, J.W.^l , Levy, E.I.^m , Moran, C.J.ⁿ , Suh, D.C.^o , Woo, H.^p , Sellar, R.^q , Hoh, B.^r , Evans, A.^s , Kallmes, D.F.^b

^a NeuroInterventional Surgery, Miami Cardiac and Vascular Institute, Baptist Neuroscience Center, Miami, FL, United States
^b Departments of Radiology and Neurosurgery, Mayo Clinic, Rochester, MN, United States
^c Department of Neurosurgery, University of Southern California, Los Angeles, CA, United States
^d Neuroscience Institute, Abbott Northwestern Hospital, Minneapolis, MN, United States
^e Division of Interventional Neuroradiology, Methodist Hospital, Houston, TX, United States
^f Department of Neurosurgery, Weill Cornell Medical College, New York City, NY, United States
^g Department of Neurosurgery, Thomas Jefferson University Hospital, Philadelphia, PA, United States
^h Department of Cerebrovascular and Stroke, Baptist Health System, Jacksonville, FL, United States
ⁱ Department of Radiology, Johns Hopkins Hospital, Baltimore, MD, United States
^j Department of Neurosurgery, Univeristy of Saskatchewan, Saskatoon, Canada
^k Department of Radiology, Baylor University Medical Center, Dallas, TX, United States
^l Department of Neurosurgery, Western Michigan University, Kalamazoo, MI, United States
^m Department of Neurosurgery, University at Buffalo, Buffalo, NY, United States
ⁿ Department of Radiology, Washington University School of Medicine, St Louis, MO, United States
^o Department of Radiology, Asan Medical Center, Seoul, South Korea
^p Departments of Radiology and Neurosurgery, Stony Brook University Medical Center, Stony Brook, NY, United States
^q Department of Minimally Invasive Surgery, Edinburgh University, Edinburgh, United Kingdom
^r Department of Neurosurgery, University of Florida, Gainesville, FL, United States
^s Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA, United States

Abstract
Background and purpose GEL THE NEC (GTN) was a multicenter prospective registry developed to assess the safety and efficacy of HydroSoft coils in treating intracranial aneurysms. We compared the angiographic and clinical outcomes of aneurysms treated with balloon assisted coil embolization (BACE) versus unassisted coil embolization (CE) in the ruptured aneurysm cohort. Materials and methods GTN was performed at 27 centers in five countries. Patients aged 21-90 years with a ruptured aneurysm 3-15 mm in size were eligible for enrollment. We analyzed demographics/comorbidities, aneurysm location, and geometry, including maximum diameter, neck size, and dome to neck ratio, immediate and long term angiographic outcomes (graded by an independent core laboratory using the modified Raymond Scale), and procedure related adverse events. Angiographic and clinical outcomes were studied using χ2 and t tests. Results Of the 599 patients in the GTN, 194 met the inclusion criteria. 84 were treated with BACE and 110 with CE. There were more prior smokers in the BACE group (p=0.01). The BACE group also had more vertebrobasilar aneurysms (p=0.006) and a larger mean neck size (p=0.02). More aneurysms were immediately completely occluded in the BACE group (p=0.02) Procedure- related major morbidity and mortality were no different between the techniques (p=0.4 and p=1, respectively). Conclusions In this prospective ruptured aneurysm cohort from the GTN, BACE resulted in greater occlusion rates compared with unassisted CE with similar morbi-mortality. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved.

Author Keywords
aneurysm; balloon; coil; hemorrhage; subarachnoid

Document Type: Article
Source: Scopus

"Individual Choose-to-Transmit Decisions Reveal Little Preference for Transmitting Negative or High-Arousal Content" (2018) Journal of Cognition and Culture

Individual Choose-to-Transmit Decisions Reveal Little Preference for Transmitting Negative or High-Arousal Content
(2018) Journal of Cognition and Culture, 18 (1-2), pp. 124-153.

Van Leeuwen, F.^a , Parren, N.^b , Miton, H.^c , Boyer, P.^d

^a Aarhus University, Leiden University, Netherlands
^b University of Lyon, France
^c Central European University, France
^d Washington University in St. Louis, United States

Abstract
Research on social transmission suggests that people preferentially transmit information about threats and social interactions. Such biases might be driven by the arousal that is experienced as part of the emotional response triggered by information about threats or social relationships. The current studies tested whether preferences for transmitting threat-relevant information are consistent with a functional motive to recruit social support. USA residents were recruited for six online studies. Studies 1a and 1B showed that participants more often chose to transmit positive, low-arousal vignettes (rather than negative, high-arousal vignettes involving threats and social interactions). Studies 2A and 2B showed higher intentions to transmit emotional vignettes (triggering disgust, fear, anger, or sadness) to friends (rather than to strangers or disliked acquaintances). Study 4 showed a preference for transmitting stories that participants had modified and were therefore novel and unique. Studies 2A and 3 (but not Studies 2B and 4) suggest that motivations for seeking social support might influence transmission preferences. Overall, the findings are not easily accounted for by any of the major theories of social transmission. We discuss limitations of the current studies and directions for further research. © 2018 Koninklijke Brill NV, Leiden, The Netherlands.

Author Keywords
anxiety; cultural transmission; negativity bias; social support; threat detection

Document Type: Article
Source: Scopus

"Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study" (2018) The Lancet Neurology

Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study
(2018) The Lancet Neurology, . Article in Press.

Pottier, C.^a , Zhou, X.^a , Perkerson, R.B., III^a , Baker, M.^a , Jenkins, G.D.^d , Serie, D.J.^b , Ghidoni, R.^f , Benussi, L.^f , Binetti, G.^f ^h , López de Munain, A.^g ⁱ ^j , Zulaica, M.^g ^j , Moreno, F.^g ⁱ ^j , Le Ber, I.^k ^l , Pasquier, F.^m , Hannequin, D.ⁿ , Sánchez-Valle, R.^o , Antonell, A.^o , Lladó, A.^o , Parsons, T.M.^a , Finch, N.A.^a , Finger, E.C.^p , Lippa, C.F.^q , Huey, E.D.^r , Neumann, M.^u ^v , Heutink, P.^w ^x , Synofzik, M.^w ^x , Wilke, C.^w ^x , Rissman, R.A.^y ^z , Slawek, J.^aa , Sitek, E.^aa , Johannsen, P.^ab , Nielsen, J.E.^ab , Ren, Y.^b , van Blitterswijk, M.^a , DeJesus-Hernandez, M.^a , Christopher, E.^a , Murray, M.E.^a , Bieniek, K.F.^a , Evers, B.M.^ac , Ferrari, C.^ad , Rollinson, S.^ae , Richardson, A.^af , Scarpini, E.^ag , Fumagalli, G.G.^ag ^ah , Padovani, A.^ai , Hardy, J.^aj , Momeni, P.^al , Ferrari, R.^aj , Frangipane, F.^am , Maletta, R.^am , Anfossi, M.^am , Gallo, M.^am , Petrucelli, L.^a , Suh, E.^an , Lopez, O.L.^ap , Wong, T.H.^ar , van Rooij, J.G.J.^ar , Seelaar, H.^ar , Mead, S.^as , Caselli, R.J.^at , Reiman, E.M.^au , Noel Sabbagh, M.^av , Kjolby, M.^aw , Nykjaer, A.^aw , Karydas, A.M.^ax , Boxer, A.L.^ax , Grinberg, L.T.^ax ^ay , Grafman, J.^az , Spina, S.^bd ^be , Oblak, A.^be , Mesulam, M.-M.^ba , Weintraub, S.^ba ^bb ^bc , Geula, C.^ba , Hodges, J.R.^bf ^bh , Piguet, O.^bf ^bi , Brooks, W.S.^bg ^bj , Irwin, D.J.^an ^ao , Trojanowski, J.Q.^an , Lee, E.B.^an , Josephs, K.A.^e , Parisi, J.E.^e , Ertekin-Taner, N.^a ^c , Knopman, D.S.^e , Nacmias, B.^ah , Piaceri, I.^ah , Bagnoli, S.^ah , Sorbi, S.^ad ^ah , Gearing, M.^bk , Glass, J.^bk , Beach, T.G.^bl , Black, S.E.^bm , Masellis, M.^bm , Rogaeva, E.^bn , Vonsattel, J.-P.^r ^s , Honig, L.S.^r ^t , Kofler, J.^aq , Bruni, A.C.^am , Snowden, J.^af , Mann, D.^bo , Pickering-Brown, S.^ae , Diehl-Schmid, J.^bp , Winkelmann, J.^bq , Galimberti, D.^ag , Graff, C.^br ^bs , Öijerstedt, L.^br ^bs , Troakes, C.^bt , Al-Sarraj, S.^bt ^bu , Cruchaga, C.^bv ^bx , Cairns, N.J.^bw , Rohrer, J.D.^ak , Halliday, G.M.^bf ^bh , Kwok, J.B.^bf , van Swieten, J.C.^ar ^by , White, C.L., III^ac , Ghetti, B.^be , Murell, J.R.^be , Mackenzie, I.R.A.^bz , Hsiung, G.-Y.R.^ca ^cb , Borroni, B.^ai , Rossi, G.^cc , Tagliavini, F.^cd , Wszolek, Z.K.^c , Petersen, R.C.^e , Bigio, E.H.^ba , Grossman, M.^an ^ao , Van Deerlin, V.M.^an , Seeley, W.W.^ax ^ay , Miller, B.L.^ax , Graff-Radford, N.R.^c , Boeve, B.F.^e , Dickson, D.W.^a , Biernacka, J.M.^d , Rademakers, R.^a

^a Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
^b Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, United States
^c Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
^d Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States
^e Department of Neurology, Mayo Clinic, Rochester, MN, United States
^f Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio-Fatebenefratelli, Brescia, Italy
^g Biodonostia Health Research Institute-CIBERNED-UPV-EHU, San Sebastian, Spain
^h MAC Memory Center, IRCCS Istituto Centro San Giovanni di Dio-Fatebenefratelli, Brescia, Italy
ⁱ Department of Neurology, Hospital Universitario Donostia, UPV/EHU, San Sebastian, Spain
^j Center for Networked Biomedical Research on Neurodegenerative Diseases, Institute of Health Carlos III, ISCIII, San Sebastian, Spain
^k Department of Neurology, Reference Center for Rare and Young Dementias, Institute of Memory and Alzheimer’s Disease (IM2A), Hopital Pitié-Salpêtrière, Paris, France
^l Sorbonne Universités, UPMC Univ Paris 06, Inserm U1127, CNRS UMR 7225, Institut du Cerveau et la Moelle épinière (ICM), Hopital Pitié-Salpêtrière, Paris, France
^m University of Lille, INSERM U1171, CHU, National Reference Center for Young Onset Dementia, DISTALZ, Lille, France
ⁿ Centre National de Référence pour les Malades Alzheimer Jeunes, CNR-MAJ, INSERM 1245, Centre Hospitalier Universitaire de Rouen, Rouen, France
^o Alzheimer’s Disease and Other Cognitive Disorders Unit, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi I Sunyer, Barcelona, Spain
^p Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada
^q Cognitive Disorders and Comprehensive Alzheimer’s Disease Center, Thomas Jefferson University Hospital, Philadelphia, PA, United States
^r Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center, New York, NY, United States
^s Department of Pathology, Columbia University Medical Center, New York, NY, United States
^t Department of Neurology, Columbia University Medical Center, New York, NY, United States
^u German Center for Neurodegenerative Diseases (DZNE), Molecular Neuropathology of Neurodegenerative Diseases, Tübingen, Germany
^v Department of Neuropathology, University of Tübingen, Tübingen, Germany
^w Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center for Neurology, Tübingen, Germany
^x German Center for Neurodegenerative Diseases (DZNE), Genome Biology of Neurodegenerative Diseases, Tübingen, Germany
^y Veterans Affairs San Diego Healthcare System San Diego, La Jolla, CA, United States
^z Department of Neurosciences, University of California San Diego, La Jolla, CA, United States
^aa Department of Neurological-Psychiatric Nursing, Medical University of Gdansk, Gdansk, Poland
^ab Department of Neurology, Rigshospitalet, Danish Dementia Research Centre, University of Copenhagen, Copenhagen, Denmark
^ac Division of Neuropathology, University of Texas Southwestern Medical Center, Dallas, TX, United States
^ad IRCCS Don Gnocchi, Florence, Italy
^ae Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
^af Cerebral Function Unit, Greater Manchester Neurosciences Centre, Salford Royal Hospital, Salford, United Kingdom
^ag Department of Pathophysiology and Transplantation, Neurodegenerative Disease Unit, University of Milan, Centro Dino Ferrari, Fondazione Ca’ Granda, IRCCS Ospedale Policlinico, Milan, Italy
^ah Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy
^ai Department of Clinical and Experimental Sciences, Neurology Unit, University of Brescia, Brescia, Italy
^aj Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom
^ak Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom
^al Rona Holdings, Silicon Valley, CA, United States
^am Regional Neurogenetic Centre, ASP Catanzaro, Lamezia Terme, Italy
^an Department of Pathology and Laboratory Medicine, Perelman School of Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, PA, United States
^ao Department of Neurology, Penn Frontotemporal Degeneration Center, University of Pennsylvania, Philadelphia, PA, United States
^ap Department of Neurology, University of Pittsburgh, Pittsburgh, PA, United States
^aq Department of Pathology, University of Pittsburgh, Pittsburgh, PA, United States
^ar Department of Neurology, Erasmus Medical Centre, Rotterdam, Netherlands
^as MCR Prion Unit at UCL, Institute of Prion Diseases, London, United Kingdom
^at Department of Neurology, Mayo Clinic, Scottsdale, AZ, United States
^au Banner Alzheimer’s Institute, Phoenix, AZ, United States
^av Barrow Neurological Institute, University of Arizona College of Medicine Phoenix, Creighton University School of Medicine, Phoenix, AZ, United States
^aw Department of Biomedicine, The Lundbeck Foundation Research Center MIND, The Danish National Research Foundation Center of Excellence PROMEMO, DANDRITE, Aarhus University, Department of Neurosurgery, Aarhus University Hospital, Aarhus, Denmark
^ax Department of Neurology, University of California, Memory and Aging Center, San Francisco, CA, United States
^ay Department of Pathology, University of California, Memory and Aging Center, San Francisco, CA, United States
^az Shirley Ryan AbilityLab and Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
^ba Cognitive Neurology and Alzheimer Disease Center, Northwestern University, Chicago, IL, United States
^bb Department of Psychiatry and Behavioral Sciences, Northwestern University, Chicago, IL, United States
^bc Department of Neurosciences Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
^bd University of California Memory and Aging Center, San Francisco, CA, United States
^be Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
^bf Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia
^bg Neuroscience Research Australia, University of Sydney, Sydney, NSW, Australia
^bh Sydney Medical School, University of Sydney, Sydney, NSW, Australia
^bi School of Psychology, University of Sydney, Sydney, NSW, Australia
^bj University of New South Wales, Sydney, NSW, Australia
^bk Department of Pathology and Laboratory Medicine and Department of Neurology, Emory University, Atlanta, GA, United States
^bl Banner Sun Health Research Institute, Civin Laboratory for Neuropathology, Sun City, AZ, United States
^bm Department of Medicine (Neurology), University of Toronto and Sunnybrook Health Sciences Centre, Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, Toronto, ON, Canada
^bn Department of Medicine Neurology, University of Toronto, Tanz Centre for Research in Neurodegenerative Disease, Toronto, ON, Canada
^bo Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Salford Royal Hospital, Salford, United Kingdom
^bp Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany
^bq Institute of Neurogenomics, Helmholtz Zentrum München, Neurologische Klinik und Poliklinik und Institut für Humangenetik, Klinikum rechts der Isar, Technical University of Munich, Munich Cluster for Systems Neurology, SyNergy, Munich, Germany
^br Division of Neurogeriatrics, Alzheimer Research Center, Karolinska Institutet, Solna, Sweden
^bs Genetics Unit, Theme Aging, Karolinska University Hospital, Stockholm, Sweden
^bt Department of Basic and Clinical Neuroscience, London Neurodegenerative Diseases Brain Bank, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
^bu Department of Clinical Neuropathology King’s College Hospital, NHS Foundation Trust, London, United Kingdom
^bv Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, MO, United States
^bw Department of Neurology, Knight Alzheimer Disease Research Center, Washington University School of Medicine, St Louis, MO, United States
^bx Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
^by Department of Neurology, VU Medical Centre, Amsterdam, Netherlands
^bz Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
^ca Division of Neurology, University of British Columbia, Vancouver, BC, Canada
^cb Department of Medicine, University of British Columbia, Vancouver, BC, Canada
^cc Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
^cd Scientific Directorate, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

Abstract
Background: Loss-of-function mutations in GRN cause frontotemporal lobar degeneration (FTLD). Patients with GRN mutations present with a uniform subtype of TAR DNA-binding protein 43 (TDP-43) pathology at autopsy (FTLD-TDP type A); however, age at onset and clinical presentation are variable, even within families. We aimed to identify potential genetic modifiers of disease onset and disease risk in GRN mutation carriers. Methods: The study was done in three stages: a discovery stage, a replication stage, and a meta-analysis of the discovery and replication data. In the discovery stage, genome-wide logistic and linear regression analyses were done to test the association of genetic variants with disease risk (case or control status) and age at onset in patients with a GRN mutation and controls free of neurodegenerative disorders. Suggestive loci (p<1 × 10−5) were genotyped in a replication cohort of patients and controls, followed by a meta-analysis. The effect of genome-wide significant variants at the GFRA2 locus on expression of GFRA2 was assessed using mRNA expression studies in cerebellar tissue samples from the Mayo Clinic brain bank. The effect of the GFRA2 locus on progranulin concentrations was studied using previously generated ELISA-based expression data. Co-immunoprecipitation experiments in HEK293T cells were done to test for a direct interaction between GFRA2 and progranulin. Findings: Individuals were enrolled in the current study between Sept 16, 2014, and Oct 5, 2017. After quality control measures, statistical analyses in the discovery stage included 382 unrelated symptomatic GRN mutation carriers and 1146 controls free of neurodegenerative disorders collected from 34 research centres located in the USA, Canada, Australia, and Europe. In the replication stage, 210 patients (67 symptomatic GRN mutation carriers and 143 patients with FTLD without GRN mutations pathologically confirmed as FTLD-TDP type A) and 1798 controls free of neurodegenerative diseases were recruited from 26 sites, 20 of which overlapped with the discovery stage. No genome-wide significant association with age at onset was identified in the discovery or replication stages, or in the meta-analysis. However, in the case-control analysis, we replicated the previously reported TMEM106B association (rs1990622 meta-analysis odds ratio [OR] 0·54, 95% CI 0·46–0·63; p=3·54 × 10−16), and identified a novel genome-wide significant locus at GFRA2 on chromosome 8p21.3 associated with disease risk (rs36196656 meta-analysis OR 1·49, 95% CI 1·30–1·71; p=1·58 × 10−8). Expression analyses showed that the risk-associated allele at rs36196656 decreased GFRA2 mRNA concentrations in cerebellar tissue (p=0·04). No effect of rs36196656 on plasma and CSF progranulin concentrations was detected by ELISA; however, co-immunoprecipitation experiments in HEK293T cells did suggest a direct binding of progranulin and GFRA2. Interpretation: TMEM106B-related and GFRA2-related pathways might be future targets for treatments for FTLD, but the biological interaction between progranulin and these potential disease modifiers requires further study. TMEM106B and GFRA2 might also provide opportunities to select and stratify patients for future clinical trials and, when more is known about their potential effects, to inform genetic counselling, especially for asymptomatic individuals. Funding: National Institute on Aging, National Institute of Neurological Disorders and Stroke, Canadian Institutes of Health Research, Italian Ministry of Health, UK National Institute for Health Research, National Health and Medical Research Council of Australia, and the French National Research Agency. © 2018 Elsevier Ltd

Document Type: Article in Press
Source: Scopus

"A decade of natalizumab and PML: Has there been a tacit transfer of risk acceptance?" (2017) Multiple Sclerosis Journal

A decade of natalizumab and PML: Has there been a tacit transfer of risk acceptance?
(2017) Multiple Sclerosis Journal, 23 (7), pp. 934-936.

Clifford, D.B.^a , Yousry, T.A.^b , Major, E.O.^c

^a Department of Neurology, Washington University, School of Medicine, St. Louis, MO, United States
^b UCL Institute of Neurology, Neuroradiology Academic Unit, Queen Square, London, United Kingdom
^c Division of NeuroImmunology and NeuroVirology, NINDS, NIH, Bethesda, MD, United States

Abstract
The interplay between each of the stakeholder’s responsibilities and desires clearly has resulted in continued widespread use of natalizumab with substantial risks and an ongoing quest for better risk mitigation. In the United States, regulatory actions codified the process of risk acceptance—and risk transfer—by escalating monitoring and information transfer to physicians and patients. Management of medication-related risks is a core function of regulatory agencies such as the Food and Drug Administration (FDA), European Medicines Agency (EMA), and the medical community. The interaction among stakeholders in medicine, pharma, regulatory bodies, physicians, and patients, sometimes has changed without overt review and discussion. Such is the case for natalizumab, an important and widely used disease-modifying therapy for multiple sclerosis. A rather silent but very considerable shift, effectively transferring increased risk for progressive multifocal leukoencephalopathy (PML) to the physicians and patients, has occurred in the past decade. We believe this changed risk should be clearly recognized and considered by all the stakeholders. © The Author(s), 2016.

Author Keywords
Natalizumab; Progressive multifocal leukoencephalopathy risk; Stakeholders

Document Type: Article
Source: Scopus

"An exploration of brain science and its potential contributions to strategic management and strategic thinking" (2017) 2017 Annual Meeting of the Academy of Management

An exploration of brain science and its potential contributions to strategic management and strategic thinking
(2017) 2017 Annual Meeting of the Academy of Management, AOM 2017, 2017-August, .

Cummings, T.^a , Nickerson, J.^b

^a Olin Business School, Washington University in St. Louis, St. Louis, MO, United States
^b Washington University, St. Louis, United States

Abstract
This paper explores how recent advances in brain science provide new insights for strategic management and strategic thinking. The paper develops four propositions with key insights that strategic problems are precisely the situations that can lead to maladaptive strategic thinking and normatively designed processes may help mitigate these maladaptive responses. © 2017 Academy of Management. All Rights Reserved.

Document Type: Conference Paper
Source: Scopus

"A connectomic approach to the lateral geniculate nucleus" (2017) Visual neuroscience

A connectomic approach to the lateral geniculate nucleus
(2017) Visual neuroscience, 34, p. E014.

Morgan, J.L.

Department of Ophthalmology and Visual Sciences,Department of Neuroscience,Washington University School of Medicine,Saint Louis,Missouri 63110

Abstract
Although the core functions and structure of the lateral geniculate nucleus (LGN) are well understood, this core is surrounded by questions about the integration of feedforward and feedback connections, interactions between different channels of information, and how activity dependent development restructures synaptic networks. Our understanding of the organization of the mouse LGN is particularly limited given how important it has become as a model system. Advances in circuit scale electron microscopy (cellular connectomics) have made it possible to reconstruct the synaptic connectivity of hundreds of neurons within in a circuit the size of the mouse LGN. These circuit reconstructions can reveal cell type-to-cell type canonical wiring diagrams as well as the higher order wiring motifs that are only visible in reconstructions of intact networks. Connectomic analysis of the LGN therefore not only can answer longstanding questions about the organization of the visual thalamus but also presents unique opportunities for investigating fundamental properties of mammalian circuit formation.

Author Keywords
Connectomics; Electron microscopy; Lateral geniculate nucleus; LGN; RGC

Document Type: Article
Source: Scopus

"Baseline EDSS proportions in MS clinical trials affect the overall outcome and power: A cautionary note" (2017) Multiple Sclerosis Journal

Baseline EDSS proportions in MS clinical trials affect the overall outcome and power: A cautionary note
(2017) Multiple Sclerosis Journal, 23 (7), pp. 982-987.

Wang, G.^a , Cutter, G.R.^b , Cofield, S.S.^b , Lublin, F.^c , Wolinsky, J.S.^d , Gustafson, T.^c , Krieger, S.^c , Salter, A.^a

^a Division of Biostatistics, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Biostatistics, The University of Alabama at Birmingham, Birmingham, AL, United States
^c Icahn School of Medicine at Mount Sinai, New York City, NY, United States
^d McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States

Abstract
Background: In randomized clinical trials, when treatments do not work equally effectively across stratifications of participants, observed event rates may differ from those hypothesized leading to deviations in estimated power. Objectives: To investigate the effect of distributions of baseline Expanded Disability Status Scale (EDSS) proportions in relapsing-remitting multiple sclerosis (RRMS) on the trial outcome, confirmed disability progression rate (CDPR), and power. Methods: We reported CDPRs in the CombiRx trial by baseline EDSS and by groups (1st (0, 1), 2nd (1.5, 2), 3rd (2.5, 3), and 4th (⩾3.5)) and investigated the effect of different combinations of baseline EDSS proportions on the trial outcome and power. Results: There were 244 (25.4%) participants in the 1st group, 368 (38.4%) in the 2nd group, 223 (23.3%) in the 3rd group, and 124 (12.9%) in the 4th group with CDPRs of 40.1%, 13.9%, 11.2%, and 16.9%, respectively. Both CDPR and power increased when the proportion of the 1st group increased in hypothetical trials with equal sample sizes in each arm, and a 10% increase in the 1st group led to a 5% increase in power. Conclusion: Various baseline EDSS proportions yielded different CDPRs and power, suggesting caution in interpretation of treatment effects across trials that enrolled participants with different proportions of baseline EDSS. © The Author(s), 2016.

Author Keywords
Confirmed disability progression rate; Expanded Disability Status Scale; Multiple sclerosis; Relapsing-remitting multiple sclerosis

Document Type: Article
Source: Scopus