WashU weekly Neuroscience publications | Office of Neuroscience Research

“Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy” (2020) Nature Communications

Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy
(2020) Nature Communications, 11 (1), art. no. 595, .

Hengel, H.^a ^b , Bosso-Lefèvre, C.^c ^d , Grady, G.^e , Szenker-Ravi, E.^c , Li, H.^f , Pierce, S.^g , Lebigot, É.^h , Tan, T.-T.ⁱ , Eio, M.Y.ⁱ , Narayanan, G.ⁱ , Utami, K.H.^j , Yau, M.^k , Handal, N.^l , Deigendesch, W.^l , Keimer, R.^m , Marzouqa, H.M.^l , Gunay-Aygun, M.ⁿ , Muriello, M.J.ⁿ , Verhelst, H.^o , Weckhuysen, S.^p ^q ^r , Mahida, S.^s , Naidu, S.^s , Thomas, T.G.^t , Lim, J.Y.^u ^v ^w , Tan, E.S.^u ^v ^w , Haye, D.^x , Willemsen, M.A.A.P.^y , Oegema, R.^z , Mitchell, W.G.^aa , Pierson, T.M.^ab , Andrews, M.V.^ac , Willing, M.C.^ac , Rodan, L.H.^ad , Barakat, T.S.^ae , van Slegtenhorst, M.^ae , Gavrilova, R.H.^af , Martinelli, D.^ag , Gilboa, T.^ah , Tamim, A.M.^ai , Hashem, M.O.^aj , AlSayed, M.D.^ak , Abdulrahim, M.M.^ak , Al-Owain, M.^ak , Awaji, A.^al , Mahmoud, A.A.H.^am , Faqeih, E.A.^an , Asmari, A.A.^an , Algain, S.M.^ao , Jad, L.A.^am , Aldhalaan, H.M.^ap , Helbig, I.^aq , Koolen, D.A.^ar , Riess, A.^as , Kraegeloh-Mann, I.^at , Bauer, P.^as , Gulsuner, S.^g , Stamberger, H.^p ^q ^r , Ng, A.Y.J.^au , Tang, S.^av , Tohari, S.^au , Keren, B.^aw , Schultz-Rogers, L.E.^af , Klee, E.W.^af , Barresi, S.^ag , Tartaglia, M.^ag , Mor-Shaked, H.^ax , Maddirevula, S.^aj , Begtrup, A.^ay , Telegrafi, A.^ay , Pfundt, R.^ar , Schüle, R.^a ^b , Ciruna, B.^k , Bonnard, C.^c , Pouladi, M.A.^j ^az ^ba , Stewart, J.C.^au , Claridge-Chang, A.^au ^bb , Lefeber, D.J.^bc ^bd , Alkuraya, F.S.^aj , Mathuru, A.S.^f ^au , Venkatesh, B.^d ^au , Barycki, J.J.^e , Simpson, M.A.^e , Jamuar, S.S.^u ^v ^w ^be , Schöls, L.^a ^b , Reversade, B.^c ^d ^au ^bf ^bg

^a Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
^b German Center of Neurodegenerative Diseases (DZNE), Tübingen, Germany
^c Institute of Medical Biology, A*STAR, Biopolis, Singapore, 138648, Singapore
^d National University of Singapore, Department of Paediatrics, Yong Loo Lin School of Medicine, Biopolis, Singapore, Singapore
^e Department of Molecular and Structural Biochemistry North Carolina State University, Raleigh, NC 27607, United States
^f Yale-NUS College, 12 College Avenue West, Biopolis, Singapore, Singapore
^g Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, United States
^h Service De Biochimie, Hopital Bicêtre, Assistance publique-Hôpitaux de Paris, 78 avenue du general leclerc, Le Kremlin Bicêtre, France
ⁱ Institute of Medical Biology, Singapore Stem Cell Bank, A∗STAR, Biopolis, Singapore, 138648, Singapore
^j Translational Laboratory in Genetic Medicine, Agency for Science, Technology, and Research, Singapore (A*STAR), 8A Biomedical Grove, Immunos, Level 5, Singapore, 138648, Singapore
^k Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Department of Molecular Genetics, The University of Toronto, Toronto, ON, Canada
^l Caritas Baby Hospital Bethlehem, Bethlehem, Palestine
^m Ped Neurology, Staufer Hospital, Wetzgauer Straße 85, Schwäbisch-Gmünd, Germany
ⁿ McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
^o Department of Paediatric Neurology, Ghent University Hospital, Ghent, Belgium
^p Center for Molecular Neurology, VIB, Antwerp, Belgium
^q Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
^r Department of Neurology, University Hospital Antwerp, Antwerp, Belgium
^s Division of Neurology and Neurogenetics, Kennedy Krieger Institute, Baltimore, MD, United States
^t Neurology Service, Department of Paediatrics, KK Women’s and Children’s Hospital, Singapore, Singapore
^u Genetics Service, Department of Paediatrics, KK Women’s and Children’s Hospital, Singapore, Singapore
^v Paediatric Academic Clinical Programme, Duke-NUS Medical School, Singapore, Singapore
^w SingHealth Duke-NUS Genomic Medicine Centre, Singapore, Singapore
^x Service de Génétique Médicale, CHU De Nice Hôpital de l’Archet 2, 151 route Saint Antoine de la Ginestière, CS 23079 062002, Nice, Cedex 3, France
^y Department of Pediatric Neurology, Radboud University Medical Center, Nijmegen, Netherlands
^z Department of Genetics, University Medical Center Utrecht, Utrecht, Netherlands
^aa Neurology Division, Childrens Hospital Los Angeles & Department of Neurology, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033, United States
^ab Department of Pediatrics, Department of Neurology, & the Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
^ac Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
^ad Division of Genetics and Genomics and Department of Neurology, Boston Children’s Hospital, Boston, MA, United States
^ae Department of Clinical Genetics, Erasmus MC, University Medical Center, Wytemaweg 80, Rotterdam, 3015 CN, Netherlands
^af Department of Clinical Genomics, Mayo Clinic, 200 First Street SW, Rochester, MN, United States
^ag Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, viale San Paolo 15, Rome, 00146, Italy
^ah Child Neurology Unit, Hadassah-Hebrew University Medical Center, Jerusalem, 9112001, Israel
^ai Pediatric Neurology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
^aj Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
^ak Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
^al Department of Pediatrics, King Fahad Central Hospital in Jizan, Abu Arish, Saudi Arabia
^am Pediatric Neurology Department, National Neuroscience Institute, King Fahad Medical City, Riyadh, Saudi Arabia
^an Section of Medical Genetics, Children’s Hospital, King Fahad Medical City, Riyadh, Saudi Arabia
^ao General Pediatrics and Adolescents, King Fahad Medical City, Riyadh, Saudi Arabia
^ap Neuroscience Department King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
^aq Division of Neurology, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States
^ar Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands
^as Institute of Medical Genetics and Applied Genomics (Tübingen) and Centogene AG (Rostock), Rostock, Germany
^at Department of Pediatric Neurology, University of Tübingen, Tübingen, Germany
^au Institute of Molecular and Cell Biology, A*STAR, Biopolis, Singapore, 138673, Singapore
^av Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, CA, United States
^aw APHP, GH Pitié Salpêtrière, Department of Genetics, Unit of Development Genomics, Paris, France
^ax Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, 9112001, Israel
^ay GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, United States
^az Department of Physiology, National University of Singapore, Singapore, 117597, Singapore
^ba Department of Medicine, National University of Singapore, Singapore, 117597, Singapore
^bb Program in Neuroscience and Behavioral Disorders, Duke-NUS Medical School, Singapore, Singapore
^bc Department of Neurology, Donders Center for Brain, Cognition, and Behavior, Nijmegen, Netherlands
^bd Department of Laboratory Medicine, Translational Metabolic Laboratory, Nijmegen, Netherlands
^be SingHealth Duke-NUS Institute of Precision Medicine, Singapore, Singapore
^bf Medical Genetics Department, Koç University School of Medicine, Istanbul, 34010, Turkey
^bg Reproductive Biology Laboratory, Obstetrics and Gynaecology, Academic Medical Center (AMC), Meibergdreef 9, Amsterdam-Zuidoost, 1105 AZ, Netherlands

Abstract
Developmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients’ primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy. © 2020, The Author(s).

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

“Damage to the shortest structural paths between brain regions is associated with disruptions of resting-state functional connectivity after stroke” (2020) NeuroImage

Damage to the shortest structural paths between brain regions is associated with disruptions of resting-state functional connectivity after stroke
(2020) NeuroImage, 210, art. no. 116589, .

Griffis, J.C.^a , Metcalf, N.V.^a , Corbetta, M.^a ^b ^c ^d ^e ^f , Shulman, G.L.^a ^b

^a Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO 63110, United States
^d Department of Bioengineering, Washington University School of Medicine, St. Louis, MO 63110, United States
^e Department of Neuroscience and Padua Neuroscience Center, University of Padua, Padua, Italy
^f Venetian Institute of Molecular Medicine (VIMM), Padua, Italy

Abstract
Focal brain lesions disrupt resting-state functional connectivity, but the underlying structural mechanisms are unclear. Here, we examined the direct and indirect effects of structural disconnections on resting-state functional connectivity in a large sample of sub-acute stroke patients with heterogeneous brain lesions. We estimated the impact of each patient’s lesion on the structural connectome by embedding the lesion in a diffusion MRI streamline tractography atlas constructed using data from healthy individuals. We defined direct disconnections as the loss of direct structural connections between two regions, and indirect disconnections as increases in the shortest structural path length between two regions that lack direct structural connections. We then tested the hypothesis that functional connectivity disruptions would be more severe for disconnected regions than for regions with spared connections. On average, nearly 20% of all region pairs were estimated to be either directly or indirectly disconnected by the lesions in our sample, and extensive disconnections were associated primarily with damage to deep white matter locations. Importantly, both directly and indirectly disconnected region pairs showed more severe functional connectivity disruptions than region pairs with spared direct and indirect connections, respectively, although functional connectivity disruptions tended to be most severe between region pairs that sustained direct structural disconnections. Together, these results emphasize the widespread impacts of focal brain lesions on the structural connectome and show that these impacts are reflected by disruptions of the functional connectome. Further, they indicate that in addition to direct structural disconnections, lesion-induced increases in the structural shortest path lengths between indirectly structurally connected region pairs provide information about the remote functional disruptions caused by focal brain lesions. © 2020 The Authors

Author Keywords
Functional connectivity; Lesion; Shortest path length; Stroke; Structural connectivity; Structural disconnection

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

“Exercise effects on brain and behavior in healthy mice, Alzheimer’s disease and Parkinson’s disease model—A systematic review and meta-analysis” (2020) Behavioural Brain Research

Exercise effects on brain and behavior in healthy mice, Alzheimer’s disease and Parkinson’s disease model—A systematic review and meta-analysis
(2020) Behavioural Brain Research, 383, art. no. 112488, .

da Costa Daniele, T.M.^a ^b ^c ^f , de Bruin, P.F.C.^a ^b ^c , de Matos, R.S.^a ^b ^c , de Bruin, G.S.^c ^e , Maia Chaves, C., Junior^c ^d , de Bruin, V.M.S.^a ^b ^c

^a Programa de Pós-Graduação em Ciências Médicas, Universidade Federal do Ceará, Fortaleza, Brazil
^b Sleep and Biological Rhythms Laboratory, UFC, Brazil
^c Universidade Federal do Ceará (UFC), Brazil
^d Departamento de Clínica Odontológica, UFC, Brazil
^e Department of Neurology, Washington University in St Louis, United States
^f Universidade de Fortaleza (UNIFOR)

Abstract
This systematic review and meta-analysis examines how exercise modifies brain and behavior in healthy mice, dementia (D) and Parkinson disease (PD) models. A search was performed on the Medline and Scopus electronic databases (2008–2019). Search terms were “mice”, “brain”, “treadmill”, “exercise”, “physical exercise”. In the total, 430 were found but only 103 were included. Animals n = 1,172; exercised 4–8 weeks (Range 24 h to 32 weeks), 60 min/day (Range 8–120 min per day), and 10/12 m/min (Range 0.2 m/min to 36 m/min). Hippocampus, cerebral cortex, striatum and whole brain were more frequently investigated. Exercise improved learning and memory. Meta-analysis showed that exercise increased: cerebral BDNF in health (n = 150; z = 5.8, CI 3.43–12.05; p < 0.001 I2 = 94.3 %), D (n = 124; z = 4.18, CI = 2.22–9.12; p < 0.001; I2 = 93.7 %) and PD (n = 16 z = 4.26, CI 5.03–48.73 p < 0.001 I2 = 94.8 %). TrkB improved in health (n = 84 z = 5.49, CI 3.8–17.73 p < 0.001, I2 = 0.000) and PD (n = 22; z = 3.1, CI = 2.58–67.3, p < 0.002 I2 = 93.8 %). Neurogenesis increased in health (n = 68; z = 7.08, CI 5.65–21.25 p < 0.001; I2 17.58) and D model (n = 116; z = 4.18, CI 2.22–9.12 p < 0.001 I2 93.7 %). Exercise augmented amyloid clearance (n = 166; z = 7.51 CI = 4.86–14.85, p < 0.001 I2 = 58.72) and reduced amyloid plaques in D models (n = 49; z = 4.65, CI = 3.94–15.3 p < 0.001 I2 = 0.000). In conclusion, exercise improved brain and behavior, neurogenesis in healthy and dementia models, reduced toxicity and cerebral amyloid. Evidence regarding inflammation, oxidative stress and energy metabolism were scarce. Studies examining acute vs chronic exercise, extreme training and the durability of exercise benefit were rare. Vascular or glucose metabolism changes were seldom reported. © 2020

Author Keywords
Brain; Cognition; Neurogenesis; Neurological disorders; Treadmill exercise

Document Type: Review
Publication Stage: Final
Source: Scopus

“Light deprivation reduces the severity of experimental diabetic retinopathy” (2020) Neurobiology of Disease

Light deprivation reduces the severity of experimental diabetic retinopathy
(2020) Neurobiology of Disease, 137, art. no. 104754, .

Thebeau, C.^a , Zhang, S.^a , Kolesnikov, A.V.^a , Kefalov, V.J.^a , Semenkovich, C.F.^b ^c , Rajagopal, R.^a

^a Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, Saint Louis, MO 63110, United States
^b Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, Saint Louis, MO 63110, United States
^c Department of Cell Biology and Physiology, Washington University School of Medicine, Saint Louis, MO 63110, United States

Abstract
Illumination of the retina is a major determinant of energy expenditure by its neurons. However, it remains unclear whether light exposure significantly contributes to the pathophysiology of common retinal disease. Driven by the premise that light exposure reduces the metabolic demand of the retina, recent clinical trials failed to demonstrate a benefit for constant illumination in the treatment of diabetic retinopathy. Here, we instead ask whether light deprivation or blockade of visual transduction could modulate the severity of this common cause of blindness. We randomized adult mice with two different models of diabetic retinopathy to 1-3 months of complete dark housing. Unexpectedly, we find that diabetic mice exposed to short or prolonged light deprivation have reduced diabetes-induced retinal pathology, using measures of visual function, compared to control animals in standard lighting conditions. To corroborate these results, we performed assays of retinal vascular health in diabetic Gnat1−/− and Rpe65−/− mice, which lack phototransduction. Both mutants displayed less diabetes-associated retinal vascular disease compared to respective wild-type controls. Collectively, these results suggest that light-induced visual transduction promotes the development of diabetic retinopathy and implicate photoreceptors as an early source of visual pathology in diabetes. © 2020 The Authors

Author Keywords
Db/db; Diabetic retinopathy; Electroretinography; Gnat1; Light deprivation; Rpe65; Streptozotocin; transducin1

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

“Somatic complaints in early adulthood predict the developmental course of compassion into middle age” (2020) Journal of Psychosomatic Research

Somatic complaints in early adulthood predict the developmental course of compassion into middle age
(2020) Journal of Psychosomatic Research, 131, art. no. 109942, .

Saarinen, A.I.L.^a ^b , Keltikangas-Järvinen, L.^b , Lehtimäki, T.^c , Jula, A.^d , Cloninger, C.R.^e , Hintsanen, M.^a

^a Research Unit of Psychology, University of Oulu, Finland
^b Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Finland
^c Department of Clinical Chemistry, Fimlab Laboratories and Faculty of Medicine and Health Technology, Finnish Cardiovascular Research Center, Tampere University, Tampere, Finland
^d Department of Public Health Solutions, National Institute for Health and Welfare (THL), Helsinki, Finland
^e Department of Psychiatry, Washington University, St. Louis, United States

Abstract
Objective: The aim of the present study was to investigate (i) whether somatic complaints predict the developmental course of compassion in adulthood, and (ii) whether this association depends on alexithymic features. Methods: The participants came from the population-based Young Finns study (N = 471–1037). Somatic complaints (headache, stomachache, chest pain, backache, fatigue, exhaustion, dizziness, heartburn, heartbeat, and tension) were evaluated with a self-rating questionnaire in 1986 when participants were aged between 18 and 24 years. Compassion was assessed with the Compassion Scale of the Temperament and Character Inventory (TCI) in 1997, 2001, and 2012. The data were analyzed using growth curve models. Results: We obtained a significant compassion-age interaction (B = -0.137, p = .02) and a compassion-age squared interaction (B = 0.007, p = .006), when predicting the course of somatic complaints. Specifically, in participants without frequent somatic complaints, compassion steadily increased with age in adulthood. In participants with frequent somatic complaints, however, compassion remained at a lower level until the age of 40 years, then started to increase, and achieved the normal level of compassion approximately at the age of 50 years. The association between somatic complaints and compassion over age was found to be independent of alexithymic features. The analyses were adjusted for a variety of covariates (age, gender, use of health care in childhood, depression in childhood, parental socioeconomic factors, parental care-giving practices, stressful life events, parental alcohol intoxication, and participants’ socioeconomic factors in adulthood). Conclusion: Frequent somatic complaints may predict delayed development of compassion in adulthood. This association was found to be independent of alexithymic features. © 2020 Elsevier Inc.

Author Keywords
Compassion; Personality; Physical symptoms; Somatic complaints; Somatization

Document Type: Article
Publication Stage: Final
Source: Scopus

“Recognition memory: Tulving’s contributions and some new findings” (2020) Neuropsychologia

Recognition memory: Tulving’s contributions and some new findings
(2020) Neuropsychologia, 139, art. no. 107350, .

Roediger, H.L., III, Tekin, E.

Washington University in St. Louis, United States

Abstract
Endel Tulving has provided unparalleled contributions to the study of human memory. We consider here his contributions to the study of recognition memory and celebrate his first article on recognition, a nearly forgotten but (we argue) essential paper from 1968. We next consider his distinction between remembering and knowing, its relation to confidence, and the implications of high levels of false remembering in the DRM paradigm for using phenomenal experiences as measures of memory. We next pivot to newer work, the use of confidence accuracy characteristic plots in analyzing standard recognition memory experiments. We argue they are quite useful in such research, as they are in eyewitness research. For example, we report that even with hundreds of items, high confidence in a response indicates high accuracy, just as it does in one-item eyewitness research. Finally, we argue that amnesia (rapid forgetting) occurs in all people (not just amnesic patients) for some of their experiences. We provide evidence from three experiments revealing that subjects who fail to recognize recently studied items (miss responses) do so with high confidence 15–20% of the time. Such high confidence misses constitute our definition of everyday amnesia that can occur even in college student populations. © 2020 Elsevier Ltd

Document Type: Article
Publication Stage: Final
Source: Scopus

“Getting to the table: Agency characteristics and evidence-based intervention adoption in children’s mental health care” (2020) Children and Youth Services Review

Getting to the table: Agency characteristics and evidence-based intervention adoption in children’s mental health care
(2020) Children and Youth Services Review, 110, art. no. 104774, .

Choy-Brown, M.^a , Hamovitch, E.K.^b , Bornheimer, L.A.^c , Acri, M.C.^d , McKay, M.M.^e

^a University of Minnesota, United States
^b The McSilver Institute for Poverty Policy and Research, United States
^c University of Michigan, School of Social Work, United States
^d The McSilver Institute for Poverty Policy and Research, Adjunct Assistant Professor at New York University School of Medicine, United States
^e Brown School at Washington University in St. Louis, United States

Abstract
Scaling evidence-based interventions (EBI) for children and families across healthcare systems can expand public health impact. Research has identified EBI adoption determinants. However, less understood are characteristics of agencies that opt in across the stages of adoption. This study examined the relationship between agency (N = 69) characteristics (e.g., revenue) and four adoption stages during a large-scale trial of an EBI for children with significant behavioral difficulties and their families. 48 (70%) of agencies demonstrated interest, 28 (41%) scheduled an informational meeting, 20 (29%) received training, and 15 (22%) demonstrated EBI uptake. Analyses indicated no differences in characteristics and initial interest. However, agencies with small-sized revenue had significantly reduced odds at other adoption stages. Implications for strategies to bring EBI access to scale are discussed. © 2020 Elsevier Ltd

Author Keywords
Adoption; Implementation; Mental health; Organizations; Public data; Scale-up

Document Type: Article
Publication Stage: Final
Source: Scopus

“Patient-controlled intravenous morphine analgesia combined with transcranial direct current stimulation for post-thoracotomy pain: A cost-effectiveness study and a feasibility for its future implementation” (2020) International Journal of Environmental Research and Public Health

Patient-controlled intravenous morphine analgesia combined with transcranial direct current stimulation for post-thoracotomy pain: A cost-effectiveness study and a feasibility for its future implementation
(2020) International Journal of Environmental Research and Public Health, 17 (3), art. no. 816, .

Rancic, N.^a ^b ^c , Mladenovic, K.^a ^d , Ilic, N.V.^e ^f , Dragojevic-Simic, V.^a ^b , Karanikolas, M.^g , Ilic, T.V.^a ^h , Stamenkovic, D.M.^a ^d

^a Medical Faculty Military Medical Academy, University of Defense, Belgrade, 11 000, Serbia
^b Center for Clinical Pharmacology, Military Medical Academy, Belgrade, 11 000, Serbia
^c Institute of Radiology, Military Medical Academy, Belgrade, 11 000, Serbia
^d Department of Anesthesiology and Intensive Care, Military Medical Academy, Belgrade, 11 000, Serbia
^e Medical Faculty, University of Belgrade, Belgrade, 11 000, Serbia
^f Clinic of Physical Medicine and Rehabilitation, Clinical Center of Serbia, Belgrade, 11 000, Serbia
^g Department of Anesthesiology, Washington University School of Medicine, St Louis, MO 63110, United States
^h Department of Neurology, Military Medical Academy, Belgrade, 11 000, Serbia

Abstract
This prospective randomized study aims to evaluate the feasibility and cost-effectiveness of combining transcranial direct current stimulation (tDCS) with patient controlled intravenous morphine analgesia (PCA-IV) as part of multimodal analgesia after thoracotomy. Patients assigned to the active treatment group (a-tDCS, n = 27) received tDCS over the left primary motor cortex for five days, whereas patients assigned to the control group (sham-tDCS, n = 28) received sham tDCS stimulations. All patients received postoperative PCA-IV morphine. For cost-effectiveness analysis we used data about total amount of PCA-IV morphine and maximum visual analog pain scale with cough (VASP-Cmax). Direct costs of hospitalization were assumed as equal for both groups. Cost-effectiveness analysis was performed with the incremental cost-effectiveness ratio (ICER), expressed as the incremental cost (RSD or US$) per incremental gain in mm of VASP-Cmax reduction. Calculated ICER was 510.87 RSD per VASP-Cmax 1 mm reduction. Conversion on USA market (USA data 1.325 US$ for 1 mg of morphine) revealed ICER of 189.08 US$ or 18960.39 RSD/1 VASP-Cmax 1 mm reduction. Cost-effectiveness expressed through ICER showed significant reduction of PCA-IV morphine costs in the tDCS group. Further investigation of tDCS benefits with regards to reduction of postoperative pain treatment costs should also include the long-term benefits of reduced morphine use. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Author Keywords
Acute pain; Cost and cost analysis; Morphine; Pain; Pharmacoeconomics; Postoperative; Transcranial direct current stimulation

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

“Toward Actionable Practice Parameters for “Dual Diagnosis”: Principles of Assessment and Management for Co-Occurring Psychiatric and Intellectual/Developmental Disability” (2020) Current Psychiatry Reports

Toward Actionable Practice Parameters for “Dual Diagnosis”: Principles of Assessment and Management for Co-Occurring Psychiatric and Intellectual/Developmental Disability
(2020) Current Psychiatry Reports, 22 (2), p. 9.

Constantino, J.N.^a , Strom, S.^a , Bunis, M.^a , Nadler, C.^b , Rodgers, T.^c , LePage, J.^c , Cahalan, C.^c , Stockreef, A.^c , Evans, L.^c , Jones, R.^c , Wilson, A.^d

^a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA
^b Children’s Mercy Kansas City, Kansas City, MO, USA
^c Missouri Department of Mental Health, Jefferson City, MO, USA
^d College for Public Health and Social Justice, Saint Louis University, St. Louis, MO, USA

Abstract
PURPOSE OF REVIEW: Although treatment algorithms and parameters for best practice are readily available for all major syndromes of psychiatric impairment, the occurrence of psychiatric syndromes in individuals with intellectual and developmental disability (IDD) invokes serious contextual challenges for interpretation of symptoms, diagnosis, and optimization of treatment, both for clinicians and for the service sectors in which care and support of individuals with IDD are delivered. Recognizing that there exist very few definitive resources for best practice under the circumstance of this form of “dual diagnosis,” the Missouri Department of Mental Health convened an expert panel to conduct a focused review and synthesis of the relevant scientific literature from which to develop guidance in the form of decision support to clinicians. This article summarizes the findings for three of the most common and impairing clusters of psychiatric symptoms that co-occur with IDD-aggression, depression, and addictions. RECENT FINDINGS: Individuals with IDD are at high risk for the development of psychiatric symptoms (PS), which often manifest uniquely in IDD and for which evidence for effective intervention is steadily accruing. Interventions that are commonly implemented in the IDD service sector (e.g., functional communication training and positive behavioral support planning) are capable of mitigating severe behavioral impairment, yet rarely invoked when dual diagnosis patients are seen in the psychiatric service sector. Conversely, state-of-the-art interventions for traumatic stress, pharmacotherapy, and psychotherapy have proven capable of improving behavioral impairments in IDD but are typically restricted to the psychiatric service sector, where there exist significant barriers to access for patients with IDD, including limitations imposed by diagnostic eligibility and practitioner experience. Bridging these gaps in knowledge and clinical capacity across the respective IDD and PS service sectors should be of very high priority in strategizing the care and support of IDD patients with serious co-occurring psychiatric conditions.

Author Keywords
Comorbidity; Diagnosis; Psychiatric services; Treatment

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

“Introduction. Advances and future directions in brain mapping in neurosurgery” (2020) Neurosurgical Focus

Introduction. Advances and future directions in brain mapping in neurosurgery
(2020) Neurosurgical Focus, 48 (2), p. E1.

Golby, A.J.^a , Leuthardt, E.C.^b , Duffau, H.^c , Berger, M.S.^d

^a Department of Neurosurgery, Department of Radiology, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA
^b Department of Neurological Surgery, Washington University, St. Louis, MO, United States
^c 3Department of Neurosurgery, Gui de Chauliac Hospital, Montpellier University Medical Center, National Institute for Health and Medical Research (INSERM), U1051 Laboratory, Institute for Neurosciences of Montpellier, France; and
^d Department of Neurological Surgery, Brain Tumor Research Center, University of California, San Francisco, CA, Mexico

Document Type: Article
Publication Stage: Final
Source: Scopus

“Stomach gastrin is regulated by sodium via PPAR-α and dopamine D1 receptor” (2020) Journal of Molecular Endocrinology

Stomach gastrin is regulated by sodium via PPAR-α and dopamine D1 receptor
(2020) Journal of Molecular Endocrinology, 64 (2), pp. 53-65.

Xu, P.^a , Gildea, J.J.^a , Zhang, C.^a , Konkalmatt, P.^b , Cuevas, S.^b , Bigler Wang, D.^a , Tran, H.T.^a , Jose, P.A.^b ^c , Felder, R.A.^a

^a Department of Pathology, University of Virginia, Charlottesville, VA, United States
^b Division of Renal Diseases & Hypertension, Department of Medicine, The George Washington University, School of Medicine & Health Sciences, Washington, District of Columbia, USA
^c Department of Pharmacology and Physiology, The George Washington University, School of Medicine & Health Sciences, Washington, District of Columbia, USA

Abstract
Gastrin, secreted by stomach G cells in response to ingested sodium, stimulates the renal cholecystokinin B receptor (CCKBR) to increase renal sodium excretion. It is not known how dietary sodium, independent of food, can increase gastrin secretion in human G cells. However, fenofibrate (FFB), a peroxisome proliferator-activated receptor-α (PPAR-α) agonist, increases gastrin secretion in rodents and several human gastrin-secreting cells, via a gastrin transcriptional promoter. We tested the following hypotheses: (1.) the sodium sensor in G cells plays a critical role in the sodium-mediated increase in gastrin expression/secretion, and (2.) dopamine, via the D1R and PPAR-α, is involved. Intact human stomach antrum and G cells were compared with human gastrin-secreting gastric and ovarian adenocarcinoma cells. When extra- or intracellular sodium was increased in human antrum, human G cells, and adenocarcinoma cells, gastrin mRNA and protein expression/secretion were increased. In human G cells, the PPAR-α agonist FFB increased gastrin protein expression that was blocked by GW6471, a PPAR-α antagonist, and LE300, a D1-like receptor antagonist. LE300 prevented the ability of FFB to increase gastrin protein expression in human G cells via the D1R, because the D5R, the other D1-like receptor, is not expressed in human G cells. Human G cells also express tyrosine hydroxylase and DOPA decarboxylase, enzymes needed to synthesize dopamine. G cells in the stomach may be the sodium sensor that stimulates gastrin secretion, which enables the kidney to eliminate acutely an oral sodium load. Dopamine, via the D1R, by interacting with PPAR-α, is involved in this process.

Author Keywords
dopamine D1 receptor; fenofibrate; gastrin; PPAR-α; sodium; SW626

Document Type: Article
Publication Stage: Final
Source: Scopus

“We’re not alone: Understanding the social consequences of intrinsic emotion regulation” (2020) Emotion (Washington, D.C.)

We’re not alone: Understanding the social consequences of intrinsic emotion regulation
(2020) Emotion (Washington, D.C.), 20 (1), pp. 43-47.

English, T., Eldesouky, L.

Department of Psychological and Brain Sciences, Washington University in St. Louis

Abstract
Recently, there has been a push for taking a more interpersonal approach to emotion regulation. However, most work continues to look at regulators in isolation and focus on strategies that do not involve others. Our objective is to highlight the interpersonal nature of emotion regulation by providing a targeted review of its social consequences, including effects on the regulator and their interaction partners. For illustrative purposes, we focus on one commonly used strategy that has received particular attention in this area, namely, expressive suppression. We briefly review existing research on social consequences of suppression and then delineate underlying mechanisms and potential boundary conditions. Finally, we provide recommendations for expanding this area of research, including (a) incorporating a more diverse set of strategies, especially interpersonal ones; (b) examining a wider range of relationship contexts and levels of analysis; and (c) evaluating emotion regulation as a dynamic, shared phenomenon. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Document Type: Article
Publication Stage: Final
Source: Scopus

“Deep Learning for Automated Measurement of Hemorrhage and Perihematomal Edema in Supratentorial Intracerebral Hemorrhage” (2020) Stroke

Deep Learning for Automated Measurement of Hemorrhage and Perihematomal Edema in Supratentorial Intracerebral Hemorrhage
(2020) Stroke, 51 (2), pp. 648-651.

Dhar, R.^a , Falcone, G.J.^b , Chen, Y.^a , Hamzehloo, A.^a , Kirsch, E.P.^b , Noche, R.B.^b , Roth, K.^b , Acosta, J.^b , Ruiz, A.^a , Phuah, C.-L.^a , Woo, D.^c , Gill, T.M.^d , Sheth, K.N.^b , Lee, J.-M.^a

^a From the Department of Neurology, Washington University School of Medicine, C.-L.P.
^b Department of Neurology (G.J.F., Yale School of Medicine, CT, New Haven, United States
^c Department of Neurology, University of Cincinnati
^d Department of Internal Medicine (T.M.G.), Yale School of Medicine, CT, New Haven, United States

Abstract
Background and Purpose- Volumes of hemorrhage and perihematomal edema (PHE) are well-established biomarkers of primary and secondary injury, respectively, in spontaneous intracerebral hemorrhage. An automated imaging pipeline capable of accurately and rapidly quantifying these biomarkers would facilitate large cohort studies evaluating underlying mechanisms of injury. Methods- Regions of hemorrhage and PHE were manually delineated on computed tomography scans of patients enrolled in 2 intracerebral hemorrhage studies. Manual ground-truth masks from the first cohort were used to train a fully convolutional neural network to segment images into hemorrhage and PHE. The primary outcome was automated-versus-human concordance in hemorrhage and PHE volumes. The secondary outcome was voxel-by-voxel overlap of segmentations, quantified by the Dice similarity coefficient (DSC). Algorithm performance was validated on 84 scans from the second study. Results- Two hundred twenty-four scans from 124 patients with supratentorial intracerebral hemorrhage were used for algorithm derivation. Median volumes were 18 mL (interquartile range, 8-43) for hemorrhage and 12 mL (interquartile range, 5-30) for PHE. Concordance was excellent (0.96) for automated quantification of hemorrhage and good (0.81) for PHE, with DSC of 0.90 (interquartile range, 0.85-0.93) and 0.54 (0.39-0.65), respectively. External validation confirmed algorithm accuracy for hemorrhage (concordance 0.98, DSC 0.90) and PHE (concordance 0.90, DSC 0.55). This was comparable with the consistency observed between 2 human raters (DSC 0.90 for hemorrhage, 0.57 for PHE). Conclusions- We have developed a deep learning-based imaging algorithm capable of accurately measuring hemorrhage and PHE volumes. Rapid and consistent automated biomarker quantification may accelerate powerful and precise studies of disease biology in large cohorts of intracerebral hemorrhage patients.

Author Keywords
biology; biomarkers; brain edema; cerebral hemorrhage; deep learning

Document Type: Article
Publication Stage: Final
Source: Scopus

“Blood Pressure Variability and Neurologic Outcome After Endovascular Thrombectomy: A Secondary Analysis of the BEST Study” (2020) Stroke

Blood Pressure Variability and Neurologic Outcome After Endovascular Thrombectomy: A Secondary Analysis of the BEST Study
(2020) Stroke, 51 (2), pp. 511-518.

Mistry, E.A.^a , Mehta, T.^b , Mistry, A.^c , Arora, N.^d , Starosciak, A.K.^e , De Los Rios La Rosa, F.^e , Siegler, J.E., 3rd^f , Chitale, R.^c , Anadani, M.^g , Yaghi, S.^h , Khatri, P.ⁱ , de Havenon, A.^j

^a From the Department of Neurology, Vanderbilt University Medical Center, Nashville, United States
^b Department of Neurology and Neurosurgery, University of Minnesota, Minneapolis (T.M.)
^c Department of Neurosurgery, Vanderbilt University Medical Center, Nashville, United States
^d Department of Neurology, University of Missouri
^e Baptist Health Neuroscience Center, FL (A.K.S., Miami, United States
^f Department of Neurology, University of Pennsylvania
^g Department of Neurosurgery, Washington University School of Medicine, St. Louis, United States
^h Department of Neurology, New York University Langone Health
ⁱ Department of Neurology and Rehabilitation Medicine, University of Cincinnati
^j Department of Neurology, University of Utah

Abstract
Background and Purpose- Although higher blood pressure variability (BPV) is associated with worse functional outcome after stroke, this association is not as well established in large vessel occlusion strokes treated with endovascular treatment (EVT). Methods- In this post hoc analysis of BEST (Blood Pressure after Endovascular Therapy for Ischemic Stroke), a prospective, multicenter cohort study of anterior circulation acute ischemic stroke patients undergoing EVT, we determined the association of BPV with poor outcome or death (90-day modified Rankin Scale, 3-6). We calculated BPV during the first 24 hours after EVT for systolic and diastolic BP using 5 methodologies, then divided BPV into tertiles and compared the highest to lowest tertile using logistic regression. Results- Of the 443 patients included in our analysis, 259 (58.5%) had a poor outcome, and 79 (17.8%) died. All measures of BPV were significantly higher in patients with poor outcome or death, but the difference was more pronounced for systolic than diastolic BPV. In the logistic regression, the highest tertile of systolic BPV consistently predicted poor outcome (odds ratio, 1.8-3.5, all P<0.05). The rate of death within 90 days was 10.1% in the tertile with the lowest systolic BPV versus 25.2% in the tertile with the highest BPV (P<0.001). Conclusions- In EVT-treated stroke patients, higher BPV in the first 24 hours is associated with worse 90-day outcome. This association was more robust for systolic BPV. The mechanism by which BPV may exert a negative influence on neurological outcome remains unknown, but the consistency of this association warrants further investigation and potentially intervention.

Author Keywords
blood pressure; hemorrhage; hypertension; hypotension; thrombectomy

Document Type: Article
Publication Stage: Final
Source: Scopus

“Reduction in Cerebrospinal Fluid Volume as an Early Quantitative Biomarker of Cerebral Edema After Ischemic Stroke” (2020) Stroke

Reduction in Cerebrospinal Fluid Volume as an Early Quantitative Biomarker of Cerebral Edema After Ischemic Stroke
(2020) Stroke, 51 (2), pp. 462-467.

Dhar, R.^a , Chen, Y.^a , Hamzehloo, A.^a , Kumar, A.^a , Heitsch, L.^a ^b , He, J.^c , Chen, L.^c , Slowik, A.^d , Strbian, D.^e , Lee, J.-M.^a

^a From the Department of Neurology (R.D., Y.C., A.H., A.K., L.H., J.-M.L.), Washington University School of Medicine, St. Louis, MO
^b Department of Emergency Medicine (L.H.), Washington University School of Medicine, St. Louis, MO
^c Division of Biostatistics (J.H., L.C.), Washington University School of Medicine, St. Louis, MO
^d Department of Neurology, Jagiellonian University Medical College, Poland (A.S.), Krakow, Poland
^e Department of Neurology, Helsinki University Hospital, Finland (D.S.)

Abstract
Background and Purpose- Cerebral edema (CED) develops in the hours to days after stroke; the resulting increase in brain volume may lead to midline shift (MLS) and neurological deterioration. The time course and implications of edema formation are not well characterized across the spectrum of stroke. We analyzed displacement of cerebrospinal fluid (ΔCSF) as a dynamic quantitative imaging biomarker of edema formation. Methods- We selected subjects enrolled in a stroke cohort study who presented within 6 hours of onset and had baseline and ≥1 follow-up brain computed tomography scans available. We applied a neural network-based algorithm to quantify hemispheric CSF volume at each imaging time point and modeled CSF trajectory over time (using a piecewise linear mixed-effects model). We evaluated ΔCSF within the first 24 hours as an early biomarker of CED (defined as developing MLS on computed tomography beyond 24 hours) and poor outcome (modified Rankin Scale score, 3-6). Results- We had serial imaging in 738 subjects with stroke, of whom 91 (13%) developed CED with MLS. Age did not differ (69 versus 70 years), but baseline National Institutes of Health Stroke Scale was higher (16 versus 7) and baseline CSF volume lower (132 versus 161 mL, both P<0.001) in those with CED. ΔCSF was faster in those developing MLS, with the majority seen by 24 hours (36% versus 11% or 2.4 versus 0.8 mL/h; P<0.0001). Risk of CED almost doubled for every 10% ΔCSF within 24 hours (odds ratio, 1.76 [95% CI, 1.46-2.14]), adjusting for age, glucose, and National Institutes of Health Stroke Scale. Risk of neurological deterioration (1.6-point increase in National Institutes of Health Stroke Scale at 24 hours) and poor outcome (adjusted odds ratio, 1.34 [95% CI, 1.15-1.56]) was also greater for every 10% increase in ΔCSF. Conclusions- CSF volumetrics provides quantitative evaluation of early edema formation. ΔCSF from baseline to 24-hour computed tomography is a promising early biomarker for the development of MLS and worse neurological outcome.

Author Keywords
brain; edema; glucose; neuroimaging; stroke

Document Type: Article
Publication Stage: Final
Source: Scopus

“On the Continuity Between Autistic and Schizoid Personality Disorder Trait Burden: A Prospective Study in Adolescence” (2020) The Journal of Nervous and Mental Disease

On the Continuity Between Autistic and Schizoid Personality Disorder Trait Burden: A Prospective Study in Adolescence
(2020) The Journal of Nervous and Mental Disease, 208 (2), pp. 94-100.

Cook, M.L., Zhang, Y., Constantino, J.N.

Departments of Psychiatry and Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO, United States

Abstract
Although widely conceived as distinct conditions, higher-functioning autism spectrum disorder (ASD) and schizoid personality disorder (schizoid PD) share similar clinical symptomatology. This study explored the relationship between the two disorders by collecting extensively validated measures of autistic trait burden (Social Responsive Scale, Second Edition) and schizoid PD affectation (Diagnostic Interview for Genetic Studies) from clinically ascertained verbal males with and without autism ages 12 to 25 years (N = 72) via parent, teacher, and self-report. Although only a small minority of adolescents with ASD met full diagnostic criteria for schizoid PD, participants with ASD endorsed a continuous distribution of schizoid PD traits that reflected a pronounced pathological shift in comparison with those in the control group, with one half of ASD males experiencing three or more Diagnostic and Statistical Manual of Mental Disorders, 4th Edition schizoid PD criterion items “often” or “almost always.” Results suggest significant amplification of schizoid PD trait burden in adolescents with ASD. ASD-specific interventions should be considered for patients with schizoid PD with premorbid histories of ASD.

Document Type: Article
Publication Stage: Final
Source: Scopus

“Zika virus infection in the developing mouse produces dramatically different neuropathology dependent on viral strain” (2020) Journal of Neuroscience

Zika virus infection in the developing mouse produces dramatically different neuropathology dependent on viral strain
(2020) Journal of Neuroscience, 40 (5), pp. 1145-1161.

Noguchi, K.K.^a , Swiney, B.S.^a , Williams, S.L.^a , Huffman, J.N.^a , Lucas, K.^a , Wang, S.H.^a , Kapral, K.M.^a , Li, A.^a , Dikranian, K.T.^b

^a Departments of, Psychiatry, Washington University in St. Louis, St. Louis, MO 63110, United States
^b Neuroscience, Washington University in St. Louis, St. Louis, MO 63110, United States

Abstract
Zika virus (ZIKV) infection during pregnancy has been causally linked to a constellation of neurodevelopmental deformities in the fetus resulting in a disease termed congenital Zika syndrome (CZS). Here we detail how ZIKV infection produces extensive neuropathology in the developing mouse brain and spinal cord of both sexes. Surprisingly, neuropathology differs depending on viral strain with a French Polynesian isolate producing primarily excitotoxicity and a Brazilian isolate being almost exclusively apoptotic but occurring over a prolonged period that is more likely to produce severe hypoplasia. We also show exposure can produce a characteristic pattern of infection that mirrors neuropathology and ultimately results in gross morphological deformities strikingly similar to CZS. This research provides a valuable mouse model mirroring the clinical course of disease that can be used to test potential therapies to improve treatment and gain a better understanding of the disabilities associated with CZS. Copyright © 2020 the authors

Author Keywords
Apoptosis; Congenital Zika syndrome; Excitotoxicity; Microcephaly; Microencephaly; Zika virus

Document Type: Article
Publication Stage: Final
Source: Scopus

“Analysis of neurodegenerative disease-causing genes in dementia with Lewy bodies” (2020) Acta Neuropathologica Communications

Analysis of neurodegenerative disease-causing genes in dementia with Lewy bodies
(2020) Acta Neuropathologica Communications, 8 (1), p. 5.

Orme, T.^a , Hernandez, D.^b , Ross, O.A.^c , Kun-Rodrigues, C.^d , Darwent, L.^a , Shepherd, C.E.^e , Parkkinen, L.^f , Ansorge, O.^f , Clark, L.^g , Honig, L.S.^g , Marder, K.^g , Lemstra, A.^h , Rogaeva, E.ⁱ , St George-Hyslop, P.ⁱ , Londos, E.^j , Zetterberg, H.^a ^k , Morgan, K.^l , Troakes, C.^m , Al-Sarraj, S.^m , Lashley, T.ⁿ , Holton, J.ⁿ , Compta, Y.ⁿ ^o , Van Deerlin, V.^p , Trojanowski, J.Q.^p , Serrano, G.E.^q , Beach, T.G.^q , Lesage, S.^r ^s , Galasko, D.^s , Masliah, E.^t , Santana, I.^u , Pastor, P.^v ^w , Tienari, P.J.^x , Myllykangas, L.^y , Oinas, M.^z , Revesz, T.ⁿ , Lees, A.ⁿ , Boeve, B.F.^aa , Petersen, R.C.^ab , Ferman, T.J.^ab , Escott-Price, V.^ac , Graff-Radford, N.^ad , Cairns, N.J.^ae , Morris, J.C.^af , Pickering-Brown, S.^af , Mann, D.^af , Halliday, G.^e , Stone, D.J.^ag , Dickson, D.W.^c , Hardy, J.^a , Singleton, A.^b , Guerreiro, R.^d , Bras, J.^d

^a UK Dementia Research Institute at UCL and Department of Molecular Neuroscience, Institute of Neurology, University College London, London, United Kingdom
^b Laboratory of Neurogenetics, National Institutes on Aging, NIH, MD, Bethesda, United States
^c Department of Neuroscience, Mayo Clinic, FL, Jacksonville, United States
^d Center for Neurodegenerative Science, Van Andel Research Institute, Grand RapidsMI, United States
^e Neuroscience Research Australia, Australia and School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia
^f Nuffield Department of Clinical Neurosciences, Oxford Parkinson’s Disease Centre, University of Oxford, Oxford, United Kingdom
^g Taub Institute for Alzheimer Disease and the Aging Brain and Department of Pathology and Cell Biology and Neurology, Columbia University Medical Center, NY, NY, United States
^h Department of Neurology and Alzheimer Center, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, Netherlands
ⁱ Department of Medicine, Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, ON, Toronto, Canada
^j Clinical Memory Research Unit, Institution of Clinical Sciences Malmö, Lund University, Lund, Sweden
^k Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
^l Human Genetics, School of Life Sciences, University of Nottingham, Nottingham, United Kingdom
^m Department of Basic and Clinical Neuroscience and Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
ⁿ Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square Brain Bank, London, United Kingdom
^o Parkinson’s Disease & Movement Disorders Unit, Neurology Service, Clinical Neuroscience Institute (ICN), Hospital Clínic, Institut de Neurociències, University Universitat de Barcelona, IDIBAPS, Barcelona, Catalonia, Spain
^p Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, 3600 Spruce Street, Philadelphia, United States
^q Banner Sun Health Research Institute, AZ, 10515 W Santa Fe Drive, Sun City, 85351, United States
^r Sorbonne Université, Université Pierre et Marie Curie-Paris 06, Inserm, Centre National de la Reserche Scientifique, Institute du Cerveau et de la Moelle épinière, Paris, France
^s Hôpital de la Salpêtrière, Département de Génétique et Cytogénétique, Assistance Publique Hôpitaux de Paris, Paris, France
^t Division of Neurosciences and Laboratory of Neurogenetics, National Institute on Aging/NIH, MD, Bethesda, United States
^u Neurology Service, University of Coimbra HospitalCoimbra, Portugal
^v Memory Unit, Department of Neurology, University Hospital Mutua de Terrassa, University of Barcelona, Terrassa, Barcelona, Spain
^w Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED)Madrid, Spain
^x Translational Immunology, Research Programs Unit, Department of Neurology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
^y Department of Pathology, University of Helsinki and HUSLAB, Helsinki University Hospital, Helsinki, Finland
^z Department of Neuropathology and Neurosurgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
^aa Neurology Department, Mayo Clinic, MN, Rochester, United States
^ab Department of Psychiatry and Department of Psychology, Mayo Clinic, FL, Jacksonville, United States
^ac UK Dementia Research Institute at Cardiff and MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, United Kingdom
^ad Department of Neurology, Mayo Clinic, FL, Jacksonville, United States
^ae Department of Neurology, Washington University School of Medicine, MO, Saint Louis, United States
^af Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, University of ManchesterManchester, United Kingdom
^ag Genetics and Pharmacogenomics, Merck & Co., Inc., West Point, United States

Abstract
Dementia with Lewy bodies (DLB) is a clinically heterogeneous disorder with a substantial burden on healthcare. Despite this, the genetic basis of the disorder is not well defined and its boundaries with other neurodegenerative diseases are unclear. Here, we performed whole exome sequencing of a cohort of 1118 Caucasian DLB patients, and focused on genes causative of monogenic neurodegenerative diseases. We analyzed variants in 60 genes implicated in DLB, Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia, and atypical parkinsonian or dementia disorders, in order to determine their frequency in DLB. We focused on variants that have previously been reported as pathogenic, and also describe variants reported as pathogenic which remain of unknown clinical significance, as well as variants associated with strong risk. Rare missense variants of unknown significance were found in APP, CHCHD2, DCTN1, GRN, MAPT, NOTCH3, SQSTM1, TBK1 and TIA1. Additionally, we identified a pathogenic GRN p.Arg493* mutation, potentially adding to the diversity of phenotypes associated with this mutation. The rarity of previously reported pathogenic mutations in this cohort suggests that the genetic overlap of other neurodegenerative diseases with DLB is not substantial. Since it is now clear that genetics plays a role in DLB, these data suggest that other genetic loci play a role in this disease.

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

“Structural and Biophysical Analysis of the CLCA1 VWA Domain Suggests Mode of TMEM16A Engagement” (2020) Cell Reports

Structural and Biophysical Analysis of the CLCA1 VWA Domain Suggests Mode of TMEM16A Engagement
(2020) Cell Reports, 30 (4), pp. 1141-1151.e3.

Berry, K.N.^a ^b , Brett, T.J.^b ^c ^d ^e

^a Immunology Program and Medical Scientist Training Program, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Department of Internal Medicine, Division of Pulmonary and Critical Care, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Center for the Investigation of Membrane Excitability Diseases (CIMED), Washington University School of Medicine, St. Louis, MO 63110, United States
^d Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, United States
^e Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
The secreted protein calcium-activated chloride channel regulator 1 (CLCA1) utilizes a von Willebrand factor type A (VWA) domain to bind to and potentiate the calcium-activated chloride channel TMEM16A. To gain insight into this unique potentiation mechanism, we determined the 2.0-Å crystal structure of human CLCA1 VWA bound to Ca2+. The structure reveals the metal-ion-dependent adhesion site (MIDAS) in a high-affinity “open” conformation, engaging in crystal contacts that likely mimic how CLCA1 engages TMEM16A. The CLCA1 VWA contains a disulfide bond between α3 and α4 in close proximity to the MIDAS that is invariant in the CLCA family and unique in VWA structures. Further biophysical studies indicate that CLCA1 VWA is preferably stabilized by Mg2+ over Ca2+ and that α6 atypically extends from the VWA core. Finally, an analysis of TMEM16A structures suggests residues likely to mediate interaction with CLCA1 VWA. © 2019 The Authors

CLCA1 is a secreted potentiator of the calcium-activated chloride channel TMEM16A. Berry et al. report the structure and biophysical analysis of the human CLCA1 VWA domain, which binds to and potentiates TMEM16A. Their results suggest how the VWA MIDAS engages TMEM16A. © 2019 The Authors

Author Keywords
airway disease; calcium-activated chloride channel; calcium-activated chloride channel regulator; calcium-activated chloride channel regulator 1; CLCA; CLCA1; crystal structure; cystic fibrosis; metal-ion-dependent adhesion site motif; MIDAS; SAXS; small-angle X-ray scattering; TMEM16A; von Willebrand factor A domain; VWA

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

“Cognitive correlates of cerebellar resting-state functional connectivity in Parkinson disease” (2020) Neurology

Cognitive correlates of cerebellar resting-state functional connectivity in Parkinson disease
(2020) Neurology, 94 (4), pp. e384-e396.

Maiti, B.^a , Koller, J.M.^a , Snyder, A.Z.^a , Tanenbaum, A.B.^a , Norris, S.A.^a , Campbell, M.C.^a , Perlmutter, J.S.^b

^a From the Departments of Neurology (B.M., A.Z.S., A.T., A.B.T., S.A.N., M.C.C., J.S.P.), Radiology (A.Z.S., S.A.N., M.C.C., J.S.P), Psychiatry (J.M.K), and Neuroscience (J.S.P.) and Programs in Occupational Therapy (J.S.P.) and Physical Therapy (J.S.P.), Washington University School of Medicine, St. Louis, MO
^b From the Departments of Neurology (B.M., A.Z.S., A.T., A.B.T., S.A.N., M.C.C., J.S.P.), Radiology (A.Z.S., S.A.N., M.C.C., J.S.P), Psychiatry (J.M.K), and Neuroscience (J.S.P.) and Programs in Occupational Therapy (J.S.P.) and Physical Therapy (J.S.P.), Washington University School of Medicine, St. Louis, MO. joel@npg.wustl.edu

Abstract
OBJECTIVE: To investigate in a cross-sectional study the contributions of altered cerebellar resting-state functional connectivity (FC) to cognitive impairment in Parkinson disease (PD). METHODS: We conducted morphometric and resting-state FC-MRI analyses contrasting 81 participants with PD and 43 age-matched healthy controls using rigorous quality assurance measures. To investigate the relationship of cerebellar FC to cognitive status, we compared participants with PD without cognitive impairment (Clinical Dementia Rating [CDR] scale score 0, n = 47) to participants with PD with impaired cognition (CDR score ≥0.5, n = 34). Comprehensive measures of cognition across the 5 cognitive domains were assessed for behavioral correlations. RESULTS: The participants with PD had significantly weaker FC between the vermis and peristriate visual association cortex compared to controls, and the strength of this FC correlated with visuospatial function and global cognition. In contrast, weaker FC between the vermis and dorsolateral prefrontal cortex was found in the cognitively impaired PD group compared to participants with PD without cognitive impairment. This effect correlated with deficits in attention, executive functions, and global cognition. No group differences in cerebellar lobular volumes or regional cortical thickness of the significant cortical clusters were observed. CONCLUSION: These results demonstrate a correlation between cerebellar vermal FC and cognitive impairment in PD. The absence of significant atrophy in cerebellum or relevant cortical areas suggests that this could be related to local pathophysiology such as neurotransmitter dysfunction. © 2019 American Academy of Neurology.

Document Type: Article
Publication Stage: Final
Source: Scopus

“Neuroinflammation and White Matter Alterations in Obesity Assessed by Diffusion Basis Spectrum Imaging” (2020) Frontiers in Human Neuroscience

Neuroinflammation and White Matter Alterations in Obesity Assessed by Diffusion Basis Spectrum Imaging
(2020) Frontiers in Human Neuroscience, 13, art. no. 464, .

Samara, A.^a , Murphy, T.^a , Strain, J.^b , Rutlin, J.^a , Sun, P.^c , Neyman, O.^a , Sreevalsan, N.^a , Shimony, J.S.^c , Ances, B.M.^b , Song, S.-K.^c , Hershey, T.^a ^b ^c ^d , Eisenstein, S.A.^a ^c

^a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^c Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Psychological Brain Sciences, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Human obesity is associated with low-grade chronic systemic inflammation, alterations in brain structure and function, and cognitive impairment. Rodent models of obesity show that high-calorie diets cause brain inflammation (neuroinflammation) in multiple regions, including the hippocampus, and impairments in hippocampal-dependent memory tasks. To determine if similar effects exist in humans with obesity, we applied Diffusion Basis Spectrum Imaging (DBSI) to evaluate neuroinflammation and axonal integrity. We examined diffusion-weighted magnetic resonance imaging (MRI) data in two independent cohorts of obese and non-obese individuals (Cohort 1: 25 obese/21 non-obese; Cohort 2: 18 obese/41 non-obese). We applied Tract-based Spatial Statistics (TBSS) to allow whole-brain white matter (WM) analyses and compare DBSI-derived isotropic and anisotropic diffusion measures between the obese and non-obese groups. In both cohorts, the obese group had significantly greater DBSI-derived restricted fraction (DBSI-RF; an indicator of neuroinflammation-related cellularity), and significantly lower DBSI-derived fiber fraction (DBSI-FF; an indicator of apparent axonal density) in several WM tracts (all corrected p < 0.05). Moreover, using region of interest analyses, average DBSI-RF and DBSI-FF values in the hippocampus were significantly greater and lower, respectively, in obese relative to non-obese individuals (Cohort 1: p = 0.045; Cohort 2: p = 0.008). Hippocampal DBSI-FF and DBSI-RF and amygdalar DBSI-FF metrics related to cognitive performance in Cohort 2. In conclusion, these findings suggest that greater neuroinflammation-related cellularity and lower apparent axonal density are associated with human obesity and cognitive performance. Future studies are warranted to determine a potential role for neuroinflammation in obesity-related cognitive impairment. © Copyright © 2020 Samara, Murphy, Strain, Rutlin, Sun, Neyman, Sreevalsan, Shimony, Ances, Song, Hershey and Eisenstein.

Author Keywords
diffusion basis spectrum imaging; diffusion tensor imaging; neuroinflammation; obesity; white matter

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

“Application of N-palmitoyl-O-phosphocholineserine for diagnosis and assessment of response to treatment in Niemann-Pick type C disease” (2020) Molecular Genetics and Metabolism

Application of N-palmitoyl-O-phosphocholineserine for diagnosis and assessment of response to treatment in Niemann-Pick type C disease
(2020) Molecular Genetics and Metabolism, .

Sidhu, R.^a , Kell, P.^a , Dietzen, D.J.^b , Farhat, N.Y.^c , Do, A.N.D.^c , Porter, F.D.^c , Berry-Kravis, E.^d , Vite, C.H.^e , Reunert, J.^f , Marquardt, T.^f , Giugliani, R.^g , Lourenço, C.M.^h , Bodamer, O.ⁱ , Wang, R.Y.^j ^k , Plummer, E.^l , Schaffer, J.E.^a , Ory, D.S.^a , Jiang, X.^a

^a Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Section on Molecular Dysmorphology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS, Bethesda, MD 20892, United States
^d Rush University Medical Center, Chicago, IL 60612, United States
^e Department of Clinical Studies, University of Pennsylvania School of Veterinary MedicinePA 19104, United States
^f Klinik und Poliklinik für Kinder- und Jugendmedizin – Allgemeine Pädiatrie, Universitätsklinikum Münster, Albert-Schweitzer-Campus 1, Gebäude A1, Münster, 48149, Germany
^g Department of Genetics, Universidade Federal do Rio Grande do Sul, Medical Genetics Service, Hospital de Clínicas de Porto Alegre, National Institute of Population Medical Genetics – INAGEMP, Porto Alegre, RS 90035-903, Brazil
^h Faculdade de Medicina – Centro Universitario Estácio de Ribeirão Preto, Rua Abrahão Issa Halach, 980 – Ribeirânia, Ribeirão Preto, SP, Brazil
ⁱ Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA 02115, United States
^j Division of Metabolic Disorders, CHOC Children’s Specialists, Orange, CA 92868, United States
^k Department of Pediatrics, University of California-Irvine School of Medicine, Orange, CA 92868, United States
^l Asante Pediatric Hematology and Oncology – Medford, Medford, OR 97504, United States

Abstract
Niemann-Pick type C (NPC) disease is a rare lysosomal storage disorder caused by mutations in either the NPC1 or the NPC2 gene. A new class of lipids, N-acyl-O-phosphocholineserines were recently identified as NPC biomarkers. The most abundant species in this class of lipid, N-palmitoyl-O-phosphocholineserine (PPCS), was evaluated for diagnosis of NPC disease and treatment efficacy assessment with 2-hydroxypropyl-β-cyclodextrin (HPβCD) in NPC. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods were developed and validated to measure PPCS in human plasma and cerebrospinal fluid (CSF). A cutoff of 248 ng/mL in plasma provided a sensitivity of 100.0% and specificity of 96.6% in identifying NPC1 patients from control and NPC1 carrier subjects. PPCS was significantly elevated in CSF from NPC1 patients, and CSF PPCS levels were significantly correlated with NPC neurological disease severity scores. Plasma and CSF PPCS did not change significantly in response to intrathetical (IT) HPβCD treatment. In an intravenous (IV) HPβCD trial, plasma PPCS in all patients was significantly reduced. These results demonstrate that plasma PPCS was able to diagnose NPC1 patients with high sensitivity and specificity, and to evaluate the peripheral treatment efficacy of IV HPβCD treatment. © 2020 Elsevier Inc.

Author Keywords
2-Hydroxypropyl-β-cyclodextrin; Diagnosis; LysoSM-509; N-palmitoyl-O-phosphocholineserine; Niemann-Pick disease type C; Treatment assessment

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

“Sensory Hypersensitivity Symptoms in Migraine With vs Without Aura: Results From the American Registry for Migraine Research” (2020) Headache

Sensory Hypersensitivity Symptoms in Migraine With vs Without Aura: Results From the American Registry for Migraine Research
(2020) Headache, .

Pearl, T.A.^a , Dumkrieger, G.^b , Chong, C.D.^b , Dodick, D.W.^b , Schwedt, T.J.^b

^a Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^b Department of Neurology, Mayo Clinic, Phoenix, AZ, United States

Abstract
Background and Objectives: Migraine with aura (MwA) is associated with increased brain hyper-responsiveness to visual stimuli and increased visual network connectivity relative to migraine without aura (MwoA). Despite this, prior studies have provided conflicting results regarding whether MwA is associated with higher photophobia symptom scores compared to MwoA. The relationships between MwA and other types of sensory hypersensitivity, such as phonophobia and cutaneous allodynia (CA), have not been previously investigated. The purpose of this cross-sectional observational study was to investigate whether MwA is associated with greater symptoms of photophobia, phonophobia, and CA compared to MwoA. Methods: This analysis included 321 migraine patients (146 MwA; 175 MwoA) who had been enrolled into the American Registry for Migraine Research. The diagnosis of either MwoA or MwA was determined by headache specialists using ICHD diagnostic criteria. Patients completed the Photosensitivity Assessment Questionnaire, the Hyperacusis Questionnaire, and the Allodynia Symptom Checklist. Mean or median values were compared between groups. Regression models were created to analyze the relationship between MwA with photophobia scores, hyperacusis scores, and the presence of interictal CA. Results: Those with MwA had higher mean photophobia scores than those with MwoA (4.1 vs 3.0, P =.0003). MwA was positively associated with photophobia symptom severity (B = 0.50 [SE = 0.14], P =.0003), after controlling for age, patient sex, and headache frequency. Aura was not associated with hyperacusis symptom severity (B = 0.07 [SE = 0.08], P =.346) or the presence of interictal CA (OR 1.33 [95% CI 0.70-2.53], P =.381). Conclusion: MwA is associated with higher photophobia symptom scores compared to MwoA. Aura is not associated with greater hyperacusis or interictal allodynia scores. These findings complement prior imaging and neurophysiologic studies that demonstrated MwA to be associated with hyper-responsiveness of brain visual processing regions. The findings suggest that MwA is associated specifically with visual hypersensitivity, as opposed to being associated with a general hypersensitivity to multiple types of sensory stimuli. © 2020 American Headache Society

Author Keywords
allodynia; aura; hyperacusis; interictal; migraine; photophobia

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

“Astrocyte-T cell crosstalk regulates region-specific neuroinflammation” (2020) GLIA

Astrocyte-T cell crosstalk regulates region-specific neuroinflammation
(2020) GLIA, .

Williams, J.L.^a ^b , Manivasagam, S.^b , Smith, B.C.^a , Sim, J.^c , Vollmer, L.L.^b , Daniels, B.P.^b , Russell, J.H.^c , Klein, R.S.^b ^d ^e

^a Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, United States
^b Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
During multiple sclerosis (MS), an inflammatory and neurodegenerative disease of the central nervous system (CNS), symptoms, and outcomes are determined by the location of inflammatory lesions. While we and others have shown that T cell cytokines differentially regulate leukocyte entry into perivascular spaces and regional parenchymal localization in murine models of MS, the molecular mechanisms of this latter process are poorly understood. Here, we demonstrate that astrocytes exhibit region-specific responses to T cell cytokines that promote hindbrain versus spinal cord neuroinflammation. Analysis of cytokine receptor expression in human astrocytes showed region-specific responsiveness to Th1 and Th17 inflammatory cytokines. Consistent with this, human and murine astrocytes treated with these cytokines exhibit differential expression of the T cell localizing molecules VCAM-1 and CXCR7 that is both cytokine and CNS region-specific. Using in vivo models of spinal cord versus brain stem trafficking of myelin-specific T cells and astrocyte-specific deletion strategies, we confirmed that Th1 and Th17 cytokines differentially regulate astrocyte expression of VCAM-1 and CXCR7 in these locations. Finally, stereotaxic injection of individual cytokines into the hindbrain or spinal cord revealed region- and cytokine-specific modulation of localizing cue expression by astrocytes. These findings identify a role for inflammatory cytokines in mediating local astrocyte-dependent mechanisms of immune cell trafficking within the CNS during neuroinflammation. © 2020 The Authors. Glia published by Wiley Periodicals, Inc.

Author Keywords
astrocyte; CXCR7; cytokine; neuroinflammation; regional heterogeneity; T cell; VCAM-1

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

“Depression and anxiety mediate the relationship between insomnia and eating disorders in college women” (2020) Journal of American College Health

Depression and anxiety mediate the relationship between insomnia and eating disorders in college women
(2020) Journal of American College Health, .

Goel, N.J.^a ^b , Sadeh-Sharvit, S.^c ^d ^e , Trockel, M.^d , Flatt, R.E.^f , Fitzsimmons-Craft, E.E.^g , Balantekin, K.N.^h , Monterubio, G.E.^g , Firebaugh, M.-L.^g , Wilfley, D.E.^g , Taylor, C.B.^d ^e

^a Department of Psychology, Virginia Commonwealth University, Richmond, VA, United States
^b Institute for Inclusion, Inquiry and Innovation (iCubed), Virginia Commonwealth University, Richmond, VA, United States
^c Baruch Ivcher School of Psychology, Interdisciplinary Center, Herzliya, Israel
^d Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, United States
^e Center for m<sup>2</sup>Health, Palo Alto University, Palo Alto, CA, United States
^f Department of Psychology and Neurosciences, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
^g Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^h Department of Exercise and Nutrition Sciences, University at Buffalo, Buffalo, NY, United States

Abstract
Objective: This study examined the associations between insomnia, anxiety, and depression in college women with eating disorders (EDs). Participants: Six hundred and ninety women from 28 US colleges who screened positive for an ED were assessed for psychiatric comorbidities. Women were, on average, 22.12 years old, mostly White (60.1%) and undergraduates (74.3%). Methods: Two mediation models were tested to determine if depression and/or anxiety mediated the relationship between insomnia and ED symptomatology. Results: One-fifth of the sample (21.7%) reported clinically moderate and severe levels of insomnia. Both depression (B =.13, p <. 001) and anxiety (B =.13, p <. 001) significantly mediated the relationship between insomnia and ED psychopathology. Conclusions: Insomnia is relatively common in college-age women with EDs. Findings suggest that this association between ED and sleep disturbances can be explained, in part, by changes in depression and anxiety. Clinicians should consider incorporating mental health assessments for insomnia, depression, and anxiety into current ED prevention, intervention, and screening efforts on college campuses. © 2020, © 2020 Taylor & Francis Group, LLC.

Author Keywords
Anxiety; college students; depression; eating disorders; insomnia

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

“Adherence to Consolidated Standards of Reporting Trials (CONSORT) Guidelines for Reporting Safety Outcomes in Trials of Medical Cannabis and Cannabis-based Medicines for Chronic Noncancer Pain: A Systematic Review” (2020) Clinical Journal of Pain

Adherence to Consolidated Standards of Reporting Trials (CONSORT) Guidelines for Reporting Safety Outcomes in Trials of Medical Cannabis and Cannabis-based Medicines for Chronic Noncancer Pain: A Systematic Review
(2020) Clinical Journal of Pain, .

Mohiuddin, M.M.^a , Mizubuti, G.B.^a , Haroutounian, S.^b , Smith, S.M.^c , Rice, A.S.C.^d , Campbell, F.^e ^f ^g , Park, R.^a , Gilron, I.^a

^a Department of Anesthesiology and Perioperative Medicine, Queen’s University, 76 Stuart Street, Kingston, ON K7L 2V7, Canada
^b Washington University Pain Center, Washington University School of Medicine, St. Louis, MO, United States
^c University of Rochester Medical Center, School of Medicine and Dentistry, University of Rochester, Rochester, NY, United States
^d Pain Research Group, Dept Surgery and Cancer, Faculty of Medicine, Imperial College London, United Kingdom
^e Department of Anesthesia and Pain Medicine, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
^f Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada
^g Centre for Neuroscience Studies, Queen’s University, Kingston, ON, Canada

Abstract
Objective: Current treatments for chronic pain have limited effectiveness and tolerability. With growing interest in the potential of cannabinoids, there is a need to inform risk-benefit considerations. Thus, this focused systematic review assesses the quality of safety assessment and reporting in chronic noncancer pain cannabinoid trials. Methods: The protocol for this review has been published, and, registered in PROSPERO. We searched MEDLINE, EMBASE, The Cochrane Library, Scopus and PsychINFO for double-blind, placebo-controlled, randomized controlled trials of cannabinoids for chronic pain, with a primary outcome related to pain. The primary review outcome is adherence to the 2004 CONSORT Harms extension. Secondary outcomes included type, reporting method, frequency and severity of AEs, trial participant withdrawals, and reasons for withdrawals. Results: In total, 43 studies (4,436 participants) were included. Type of cannabinoid (number of studies) included nabiximols (12), dronabinol (8), nabilone (7), oral cannabis extract preparations (5), smoked THC (5), vaporised THC (3), novel synthetic cannabinoids (2), sublingual cannabis extract preparations (1). The median CONSORT score was 7. On average, 3-4 recommendations of the CONSORT guidelines were not being met in trials. Seventeen trials did not provide their method of adverse event (AE) assessment, fourteen trials did not report on serious adverse events (SAEs) and, seven trials provided no quantitative data about AEs. Discussion: Better harms assessment and reporting are needed in chronic pain cannabinoid trials. Improvements may be achieved through: expanded education/knowledge translation, increased research regulation by ethics boards, funding agencies and journals, and greater emphasis on safety assessment and reporting throughout research training. Copyright © 2020 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.

Author Keywords
adverse events; cannabinoids; cannabis; chronic pain; clinical trials; systematic review

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

“Neuroticism predicts fear of falling after hip fracture” (2020) International Journal of Geriatric Psychiatry

Neuroticism predicts fear of falling after hip fracture
(2020) International Journal of Geriatric Psychiatry, .

Bower, E.S.^a ^c , Wetherell, J.L.^b ^c , Petkus, A.J.^d , Lenze, E.J.^e

^a SDSU/UCSD Joint Doctoral Program in Clinical Psychology, San Diego, CA, United States
^b VA San Diego Healthcare System, University of California, San Diego, CA, United States
^c Psychiatry, University of California, San Diego, CA, United States
^d Department of Neurology, University of Southern California, Los Angeles, CA, United States
^e Healthy Mind Lab, Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States

Abstract
Objectives: Fear of falling (FoF) is common and associated with poorer functional outcomes after hip fracture. We sought to differentiate patterns of FoF at 4 and 12 weeks after surgical repair for hip fracture and examine predictors of FoF. Methods/design: Secondary analysis of existing data from a 52-week prospective study examining recovery after hip fracture. Participants (N = 263) were aged 60 and older with recent hip fracture recruited from eight hospitals. FoF was measured 4 and 12 weeks postfracture with the Short Falls Efficacy Scale-International. Latent class mixed models were constructed to identify distinct patterns of FoF from 4 to 12 weeks postfracture and predictors of FoF. Predictors examined included age, gender, neuroticism, depression, negative affect, perceived social support, medical comorbidity, functional ability, cognition, and pain. Results: Three latent classes of FoF were identified: a group with minimal FoF at weeks 4 and 12 (72%), a group with high FoF that decreased (17%), and a group with high FoF that increased from week 4 to 12 (11%). In a multivariate model, higher neuroticism was associated with greater risk for high FoF (increasing or decreasing), whereas higher premorbid medical comorbidity was associated with increasing FoF, poorer premorbid functional ability was associated with decreasing FoF, and social support was not significantly associated. Conclusions: Older adults with higher neuroticism are more likely to have FoF in the first 12 weeks after a hip fracture. Screening for neuroticism in health care settings might identify individuals who would benefit from interventions to improve outcomes during recovery. © 2020 John Wiley & Sons Ltd

Author Keywords
falls; Falls Efficacy Scale International; fear of falling; femoral fractures; hip fracture; intertrochanteric fractures; neuroticism; personality

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

“Maternal Milk and Relationships to Early Neurobehavioral Outcome in Preterm Infants” (2020) The Journal of Perinatal & Neonatal Nursing

Maternal Milk and Relationships to Early Neurobehavioral Outcome in Preterm Infants
(2020) The Journal of Perinatal & Neonatal Nursing, 34 (1), pp. 72-79.

Pineda, R., Muñoz, R., Chrzastowski, H., Dunsirn-Baillie, S., Wallendorf, M., Smith, J.

Program in Occupational Therapy (Dr Pineda and Ms Muñoz) and Department of Pediatrics (Dr Pineda), Washington University School of Medicine, Saint Louis, Missouri; Spotsylvania Regional Medical Center, Fredericksburg, Virginia (Dr Chrzastowski); Children’s Hospital of Wisconsin, Madison (Dr Dunsirn-Baillie); Division of Biostatistics, Washington University, Saint Louis, Missouri (Dr Wallendorf); and Department of Quality, Safety, and Practice Excellence, St Louis Children’s Hospital, St Louis, Missouri (Dr Smith)

Abstract
The purpose of this study was to (1) define medical and sociodemographic factors related to maternal milk feedings and (2) explore relationships between maternal milk feeding and early neurobehavioral outcome. Ninety-two preterm infants born ≤ 32 weeks gestation had maternal milk feeding and breastfeeding tracked in this retrospective analysis. At 34 to 41 weeks postmenstrual age (PMA), neurobehavior was assessed with the NICU Network Neurobehavioral Scale. Maternal milk feeding was often delayed by the use of total parenteral nutrition, administered for a median of 11 (7-26) days, impacting the timing of gastric feeding initiation. Seventy-nine (86%) infants received some maternal milk during neonatal intensive care unit (NICU) hospitalization. Twenty-one (27%) infants continued to receive maternal milk at 34 to 41 weeks PMA, with 10 (48%) of those receiving maternal milk exclusively. Among mothers who initiated maternal milk feeds, 20 (25%) put their infants directly at the breast at least once during hospitalization. Mothers who were younger (P = .02), non-Caucasian (P < .001), or on public insurance (P < .001) were less likely to provide exclusive maternal milk feedings by 34 to 41 weeks PMA. Infants who received maternal milk at 34 to 41 weeks PMA demonstrated better orientation (P = .03), indicating they had better visual and auditory attention to people and objects in the environment. Our findings demonstrate a relationship between maternal milk feedings and better neurobehavior, which is evident before the infant is discharged home from the NICU.

Document Type: Article
Publication Stage: Final
Source: Scopus

“The pheromone darcin drives a circuit for innate and reinforced behaviours” (2020) Nature

The pheromone darcin drives a circuit for innate and reinforced behaviours
(2020) Nature, .

Demir, E.^a ^b , Li, K.^a , Bobrowski-Khoury, N.^a ^b , Sanders, J.I.^b ^c , Beynon, R.J.^d , Hurst, J.L.^e , Kepecs, A.^b ^f ^g , Axel, R.^a ^h

^a Department of Neuroscience, Columbia University, Mortimer B. Zuckerman Mind Brain Behavior Institute, New York, NY, United States
^b Department of Neuroscience, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, United States
^c Sanworks LLC, Stony Brook, NY, United States
^d Centre for Proteome Research, Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom
^e Mammalian Behaviour and Evolution Group, Institute of Integrative Biology, University of Liverpool, Leahurst Campus, Neston, United Kingdom
^f Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
^g Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^h Howard Hughes Medical Institute, Columbia University, New York, NY, United States

Abstract
Organisms have evolved diverse behavioural strategies that enhance the likelihood of encountering and assessing mates1. Many species use pheromones to communicate information about the location, sexual and social status of potential partners2. In mice, the major urinary protein darcin—which is present in the urine of males—provides a component of a scent mark that elicits approach by females and drives learning3,4. Here we show that darcin elicits a complex and variable behavioural repertoire that consists of attraction, ultrasonic vocalization and urinary scent marking, and also serves as a reinforcer in learning paradigms. We identify a genetically determined circuit—extending from the accessory olfactory bulb to the posterior medial amygdala—that is necessary for all behavioural responses to darcin. Moreover, optical activation of darcin-responsive neurons in the medial amygdala induces both the innate and the conditioned behaviours elicited by the pheromone. These neurons define a topographically segregated population that expresses neuronal nitric oxide synthase. We suggest that this darcin-activated neural circuit integrates pheromonal information with internal state to elicit both variable innate behaviours and reinforced behaviours that may promote mate encounters and mate selection. © 2020, The Author(s), under exclusive licence to Springer Nature Limited.

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

“New applications for independent activities of daily living in measuring disability in multiple sclerosis” (2020) Multiple Sclerosis Journal

New applications for independent activities of daily living in measuring disability in multiple sclerosis
(2020) Multiple Sclerosis Journal, .

Salter, A.^a , Fox, R.J.^b , Tyry, T.^c , Cutter, G.^d , Marrie, R.A.^e

^a Division of Biostatistics, Washington University in St. Louis, St. Louis, MO, United States
^b Mellen Center for Multiple Sclerosis, Cleveland Clinic Foundation, Cleveland, OH, United States
^c Dignity Health, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, United States
^d Department of Biostatistics, School of Public Health, The University of Alabama in Birmingham, Birmingham, AL, United States
^e Departments of Internal Medicine and Community Health Sciences, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada

Abstract
Background: Disability outcome measures in multiple sclerosis (MS) focus heavily on ambulation; however, limitations in performing everyday activities encompass another type of disability. Objectives: The aim of this study was to examine the ability of instrumental activities of daily living (IADL) scale to discriminate between different levels of disability and to predict disability progression. Methods: The North American Research Committee on Multiple Sclerosis (NARCOMS) registry fall 2006 semi-annual survey asked participants to complete the RAND-12, Performance Scales, Patient Determined Disease Steps (PDDS), and IADL questionnaires. We modeled the trajectory of disability change, using the PDDS, over 12 years. Analyses used linear and repeated measures regression methods. Results: Of respondents (n = 9931), 9559 (96%) completed the PDDS and IADL scale. Respondents were mostly female (76%), Caucasian (92%), and 52.3 (10.5) years old with moderate disability (median PDDS 4 (early cane)). Mean (SD) IADL total score was 20.5 (3.7). Discriminant ability of the IADL scale was higher than other measures considered at higher levels of disability. Adjusted longitudinal models showed that needing greater assistance on IADLs was independently predictive of trajectories of greater disability change. Conclusion: IADL scale had a greater ability to discriminate between higher disability levels than RAND-12 domains. The IADL scale may provide a useful and clinically relevant tool to measure disability in progressive MS populations. © The Author(s), 2020.

Author Keywords
Activities of daily living; disability; multiple sclerosis; patient-reported outcomes

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

“The Development of Social Exclusion Detection in Early Childhood: Awareness of Social Exclusion Does Not Always Align with Social Preferences” (2020) Journal of Cognition and Development

The Development of Social Exclusion Detection in Early Childhood: Awareness of Social Exclusion Does Not Always Align with Social Preferences
(2020) Journal of Cognition and Development, .

Hwang, H.G.^a ^b , Markson, L.^a

^a Washington University in St. Louis, United States
^b University of Chicago, United States

Abstract
Starting in the preschool years, children show socially exclusive behaviors, such as intentionally leaving out another child from a ball game. Prior research investigating social exclusion understanding in preschoolers primarily used interview methods and it is clear that the verbal and cognitive skills necessary to identify and reason about social exclusion become more sophisticated with age. Yet it is unknown how children’s ability to identify social exclusion relates to their own behavior, such as their social preference for socially inclusive or exclusive individuals. Further, whether such social preferences remain stable or change across development is an open question. Thus, the current study investigated whether the ability to identify social exclusion develops in tandem with social preference behavior by assessing 3- to 6-year-old children’s (N = 256) identification of social exclusion and preferences between socially exclusive and inclusive agents. Five- to six-year-old children correctly identified social exclusion and preferred inclusive agents over exclusive agents across two experiments. Three- to four-year-old children could correctly identify social exclusion, but did not show evidence of a preference for inclusive agents over exclusive agents. Children were also able to detect implicit, nonverbalized social exclusion equally well as explicit, verbalized social exclusion across development. These findings suggest that young children’s social preferences are not wholly dictated by their ability to identify socially exclusive agents. This divergent pattern of social preference from identification has implications for interpreting social preference behavior in young children. © 2020, © 2020 Taylor & Francis.

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

“Responsive Parenting Behaviors and Cognitive Function in Children With Sickle Cell Disease” (2019) Journal of Pediatric Psychology

Responsive Parenting Behaviors and Cognitive Function in Children With Sickle Cell Disease
(2019) Journal of Pediatric Psychology, 44 (10), pp. 1234-1243.

Yarboi, J.^a , Prussien, K.V.^a , Bemis, H.^a , Williams, E.^a , Watson, K.H.^a , McNally, C.^a , Henry, L.^a , King, A.A.^b , DeBaun, M.R.^c , Compas, B.E.^a

^a Department of Psychology of Human Development, Vanderbilt University
^b Department of Pediatrics, Washington University School of Medicine
^c Department of Pediatrics, Vanderbilt University School of Medicine

Abstract
OBJECTIVE: Children with sickle cell disease (SCD) are at increased risk for cognitive impairment as a result in part from biological characteristics of the disease; however, limited research has explored possible social and contextual factors associated with risk for cognitive problems. The primary aim of the present study was to examine the relation between children’s cognitive functioning and responsive parenting, a potentially important contextual factor in children with SCD, accounting for family socioeconomic disadvantage, child disease severity, and caregivers’ perceived stress. METHODS: Forty-eight children completed standardized cognitive assessments and caregivers provided self-reports of general and disease-related stress. Parent-child dyads completed a video recorded puzzle-solving task and observed parenting was quantified using two coding systems. Bivariate Pearson correlations were used to assess preliminary hypotheses, and linear multiple regression analyses were used to assess the primary hypothesis. RESULTS: Results suggested that increased levels of parental stress were related to fewer observations of responsive parenting and provided evidence of an association between children’s cognitive function and responsive parenting. Specifically, increased disease-related parent stress and reduced parental use of expansive language were associated with significantly lower cognitive functioning in children with SCD. CONCLUSIONS: Findings suggest that social environmental factors along with disease characteristics are sources of risk for cognitive problems with children with SCD. Further, these findings highlight the need to develop targeted interventions for parents of children with SCD to decrease levels of stress and enhance parenting skills, with the aim improving cognitive functioning in youth. © The Author(s) 2019. Published by Oxford University Press on behalf of the Society of Pediatric Psychology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Author Keywords
cognitive function; parenting; sickle cell disease

Document Type: Article
Publication Stage: Final
Source: Scopus

“Novel neuroactive steroid with hypnotic and T-type calcium channel blocking properties exerts effective analgesia in a rodent model of post-surgical pain” (2019) British Journal of Pharmacology

Novel neuroactive steroid with hypnotic and T-type calcium channel blocking properties exerts effective analgesia in a rodent model of post-surgical pain
(2019) British Journal of Pharmacology, .

Joksimovic, S.L.^a ^f , Joksimovic, S.M.^a , Manzella, F.M.^a ^e , Asnake, B.^g , Orestes, P.^a , Raol, Y.H.^b , Krishnan, K.^c , Covey, D.F.^c ^d , Jevtovic-Todorovic, V.^a , Todorovic, S.M.^a ^e

^a Department of Anesthesiology, University of Colorado Denver, Anschutz Medical Campus, Aurora, Co, United States
^b Department of Pediatrics, Division of Neurology, Translational Epilepsy Research Program, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States
^d Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, United States
^e Neuroscience Graduate Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, United States
^f Pharmacology Graduate Program, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
^g Department of Anesthesiology and Pain Medicine, University of California, Davis, CA, United States

Abstract
Background and Purpose: Neuroactive steroid (3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile (3β-OH) is a novel hypnotic and voltage-dependent blocker of T-type calcium channels. Here, we examine its potential analgesic effects and adjuvant anaesthetic properties using a post-surgical pain model in rodents. Experimental Approach: Analgesic properties of 3β-OH were investigated in thermal and mechanical nociceptive tests in sham or surgically incised rats and mice, with drug injected either systemically (intraperitoneal) or locally via intrathecal or intraplantar routes. Hypnotic properties of 3β-OH and its use as an adjuvant anaesthetic in combination with isoflurane were investigated using behavioural experiments and in vivo EEG recordings in adolescent rats. Key Results: A combination of 1% isoflurane with 3β-OH (60 mg·kg−1, i.p.) induced suppression of cortical EEG and stronger thermal and mechanical anti-hyperalgesia during 3 days post-surgery, when compared to isoflurane alone and isoflurane with morphine. 3β-OH exerted prominent enantioselective thermal and mechanical antinociception in healthy rats and reduced T-channel-dependent excitability of primary sensory neurons. Intrathecal injection of 3β-OH alleviated mechanical hyperalgesia, while repeated intraplantar application alleviated both thermal and mechanical hyperalgesia in the rats after incision. Using mouse genetics, we found that CaV3.2 T-calcium channels are important for anti-hyperalgesic effect of 3β-OH and are contributing to its hypnotic effect. Conclusion and Implications: Our study identifies 3β-OH as a novel analgesic for surgical procedures. 3β-OH can be used to reduce T-channel-dependent excitability of peripheral sensory neurons as an adjuvant for induction and maintenance of general anaesthesia while improving analgesia and lowering the amount of volatile anaesthetic needed for surgery. © 2019 The British Pharmacological Society

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

“G protein-biased kratom-alkaloids and synthetic carfentanil-amide opioids as potential treatments for alcohol use disorder” (2019) British Journal of Pharmacology

G protein-biased kratom-alkaloids and synthetic carfentanil-amide opioids as potential treatments for alcohol use disorder
(2019) British Journal of Pharmacology, .

Gutridge, A.M.^a , Robins, M.T.^a , Cassell, R.J.^a , Uprety, R.^e , Mores, K.L.^a , Ko, M.J.^a ^d , Pasternak, G.W.^e , Majumdar, S.^e ^f , van Rijn, R.M.^a ^b ^c ^d

^a Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, IN, United States
^b Purdue Institute for Drug Discovery, Purdue University, West Lafayette, IN, United States
^c Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN, United States
^d Purdue Interdisciplinary Life Sciences Graduate Program, Purdue University, West Lafayette, IN, United States
^e Department of Neurology and Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, NY, United States
^f Center for Clinical Pharmacology, St. Louis College of Pharmacy and Washington University School of Medicine, St. Louis, MO, United States

Abstract
Background and Purpose: Mitragyna speciosa, more commonly known as kratom, is a plant that contains opioidergic alkaloids but is unregulated in most countries. Kratom is used in the self-medication of chronic pain and to reduce illicit and prescription opioid dependence. Kratom may be less dangerous than typical opioids because of the stronger preference of kratom alkaloids to induce receptor interaction with G proteins over β-arrestin proteins. We hypothesized that kratom (alkaloids) can also reduce alcohol intake. Experimental Approach: We pharmacologically characterized kratom extracts, kratom alkaloids (mitragynine, 7-hydroxymitragynine, paynantheine, and speciogynine) and synthetic carfentanil-amide opioids for their ability to interact with G proteins and β-arrestin at μ, δ, and κ opioid receptors in vitro. We used C57BL/6 mice to assess to which degree these opioids could reduce alcohol intake and whether they had rewarding properties. Key Results: Kratom alkaloids were strongly G protein-biased at all three opioid receptors and reduced alcohol intake, but kratom and 7-hydroxymitragynine were rewarding. Several results indicated a key role for δ opioid receptors, including that the synthetic carfentanil-amide opioid MP102—a G protein-biased agonist with modest selectivity for δ opioid receptors—reduced alcohol intake, whereas the G protein-biased μ opioid agonist TRV130 did not. Conclusion and Implications: Our results suggest that kratom extracts can decrease alcohol intake but still carry significant risk upon prolonged use. Development of more δ opioid-selective synthetic opioids may provide a safer option than kratom to treat alcohol use disorder with fewer side effects. © 2019 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

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