WashU weekly Neuroscience publications

A longitudinal study of neurocognition and behavior in patients with Hurler-Scheie syndrome heterozygous for the L238Q mutation
(2019) Molecular Genetics and Metabolism Reports, 20, art. no. 100484, . 

Ahmed, A.^a , Ou, L.^b , Rudser, K.^c , Shapiro, E.^a , Eisengart, J.B.^a , King, K.^a , Chen, A.^d , Dickson, P.^{d e} , Whitley, C.B.^{a b}

^a Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, United States
^b Gene Therapy Center, Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, United States
^c Division of Biostatistics, University of Minnesota, Minneapolis, MN 55455, United States
^d Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, United States
^e Department of Pediatrics, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Previous research has demonstrated the mutation, c.712T>A (p.L238Q) of the gene for α-L- iduronidase (IDUA) in patients with Hurler-Scheie syndrome is relatively severe when paired with a nonsense or deletion or splice-site mutation. This mutation was also found to be associated with psychiatric symptoms. This research presents longitudinal data and protein analysis to further investigate the severity and natural history of these unique patients. Methods: Six patients heterozygous for L238Q were compared to six patients with Hurler-Scheie without the L238Q mutations. Somatic burden of disease, IQ, memory, attention, adaptive functioning and behavioral measures were given yearly over 2 to 4 years from 2009 to 2014. The impact of L238Q on the IDUA enzyme was examined using 7 bioinformatics tools and a 3D structural analysis. Results: Similar to the cross sectional study, the L238Q patients had more severe abnormalities in IQ, attention, adaptive functioning, and behavioral functioning than the comparison group. There were no major differences between the two groups in change over time; IQ for both groups was stable with some behavioral areas showing improvement. Over time, both groups declined in visual spatial memory and, attention/visual processing. They also showed increased anxiety. Structural and bioinformatics analysis of the L238Q suggest that this mutation causes a significant reduction in the IDUA enzyme’s potential catalytic activity, and this mutation may be more severe than other mutations contributing to the Hurler-Scheie syndrome phenotype, presumably causing the psychiatric disease. Conclusion: L238Q patients demonstrate severe neurocognitive and neurobehavioral deficits but are relatively stable. Like the comparison group, decreasing visual spatial memory and attention and increasing anxiety suggest more intervention in life skills and emotional social supports are needed. © 2019 The Authors

Author Keywords
Hurler-Scheie syndrome;  L238Q mutation;  Mucopolysaccharidosis (MPS);  Neurocognition;  α-L-iduronidase

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

Correlates of HIV RNA concentrations in cerebrospinal fluid during antiretroviral therapy: a longitudinal cohort study
(2019) The Lancet HIV, 6 (7), pp. e456-e462. Cited 1 time.

Livelli, A.^a , Vaida, F.^c , Ellis, R.J.^{c d} , Ma, Q.^f , Ferrara, M.^b , Clifford, D.B.^g , Collier, A.C.^h , Gelman, B.B.^j , Marra, C.M.ⁱ , McArthur, J.C.^k , McCutchan, J.A.^e , Morgello, S.^{l m n} , Sacktor, N.^{k n} , Simpson, D.M.^l , Grant, I.^{c n} , Letendre, S.L.^{c e} , Abramson, I.ⁿ , Al-Lozi, M.T.ⁿ , Archibald, S.L.ⁿ , Atkinson, J.H.ⁿ , Best, B.M.ⁿ , Clifford, D.B.ⁿ , Collier, A.C.ⁿ , Cushman, C.ⁿ , Dawson, M.S.ⁿ , Ellis, R.J.ⁿ , Fennema-Notestine, C.ⁿ , Franklin, D.R.ⁿ , Gelman, B.B.ⁿ , Head, E.ⁿ , Heaton, R.K.ⁿ , Jones, T.ⁿ , Letendre, S.ⁿ , Maravilla, K.R.ⁿ , Marcotte, T.D.ⁿ , Marra, C.M.ⁿ , McArthur, J.C.ⁿ , McCutchan, J.A.ⁿ , Mintz, L.ⁿ , Naidich, T.P.ⁿ , Simpson, D.M.ⁿ , Smith, D.M.ⁿ , Stegbauer, K.C.ⁿ , Tang, C.Y.ⁿ , Teshome, M.ⁿ

^a Department of Psychology, Università degli Studi di Torino, Torino, Italy
^b Department of Medical Sciences, Università degli Studi di Torino, Torino, Italy
^c Department of Psychiatry, University of California San Diego, San Diego, CA, United States
^d Department of Neurosciences, University of California San Diego, San Diego, CA, United States
^e Department of Medicine, University of California San Diego, San Diego, CA, United States
^f Department of Pharmacy Practice, University at Buffalo, Buffalo, NY, United States
^g Department of Neurology, Washington University, St Louis, MO, United States
^h Department of Medicine, University of Washington, Seattle, WA, United States
ⁱ Department of Neurology, University of Washington, Seattle, WA, United States
^j Department of Pathology, University of Texas Medical Branch, Galveston, TX, United States
^k Department of Neurology, Johns Hopkins University, Baltimore, MD, United States
^l Department of Neurology, Mount Sinai School of Medicine, New York, NY, United States
^m Department of Pathology, Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, United States

Abstract
Background: Few large projects have evaluated the factors that influence the HIV RNA concentrations (viral load) in cerebrospinal fluid (CSF) during antiretroviral therapy (ART) over time. We aimed to determine the correlates of HIV RNA in CSF in a large cohort. Methods: We analysed longitudinal data from adults living with HIV in the US CHARTER cohort. Participants in the CHARTER study were recruited from six US academic medical centres—in Baltimore (MD), Galveston (TX), New York (NY), St Louis (MO), San Diego (C92A), and Seattle (WA). Participants in this study had been assessed at least three times between Sept 4, 2003, and Sept 14, 2010, and were taking ART and underwent venous and lumbar puncture with measurement of HIV RNA concentration at all assessments. The lower limit of quantification of the HIV RNA assays was 50 copies per mL. Data were analysed with longitudinal mixed effects logistic regression to identify correlates of HIV RNA concentration (as a binary [detectable or not] and as a continuous variable) in CSF over time. We tested demographic characteristics, plasma HIV RNA, nadir and current CD4 cell count in blood, current CD8 cell count in blood, estimated duration of HIV infection, AIDS diagnosis, duration of ART, adherence to ART, ART characteristics, and CSF characteristics as potential correlates. Findings: At the time of analysis, 2207 assessments from 401 participants met the criteria for inclusion in this study. Mean duration of observation was 33·7 months (range 12–84). HIV RNA concentrations in 710 (32·2%) plasma specimens and in 255 (11·6%) CSF specimens were greater than the lower limit of quantification. The best multivariate model of HIV RNA concentration in CSF greater than the lower limit of quantification over time included increased plasma HIV RNA concentration (odds ratio 18·0 per 1 log10 copy per mL, 95% CI 11·3 to 28·8; p<0·0001), increased CSF leucocyte count (2·01 per 5 cells per μL, 1·61 to 2·39; p<0·0001), decreased CD4 cell count (0·53 per 5 square-root cells per μL, 0·35 to 0·79; p=0·0025), decreased CNS penetration-effectiveness value (0·71 per unit, 0·56 to 0·92; p=0·0078), increased CD8 cell count (1·51 per 5 square-root cells, 1·11 to 2·06; p=0·0089), and protease inhibitor use (3·26, 1·04 to 10·23; p=0·039; model R2=0·22, p<0·0001). Analyses of continuous HIV RNA concentration in CSF that accounted for censoring below the lower limit of quantification had similar findings, although increased HIV RNA concentrations in CSF were also associated with black ethnicity (change in log10 HIV RNA concentration in CSF 0·205, 0·0367 to 0·3733; p=0·017), increased total protein in CSF (0·0025, −0·0002 to 0·0052; p=0·069), and the presence of addictive-drug metabolites in urine (0·103, −0·013 to 0·219; p=0·081). Interpretation: The identified correlates of HIV RNA concentration in CSF during ART could strengthen clinical prediction of risk for failure to achieve or maintain HIV RNA suppression in CSF. Because most participants in this analysis were ART-experienced and were taking a three-drug regimen that did not include an integrase inhibitor, future research should focus on participants who are taking their first ART regimens or regimens that include integrase inhibitors or two drugs. Funding: The work was supported by the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke. © 2019 Elsevier Ltd

Document Type: Article
Publication Stage: Final
Source: Scopus

Electroencephalography-Guided Anesthetic Administration and Postoperative Delirium – Reply
(2019) JAMA – Journal of the American Medical Association, 321 (24), pp. 2471-2472. 

Wildes, T.S., Mickle, A.M., Avidan, M.S.

Department of Anesthesiology, Washington University, School of Medicine, 660 S Euclid Ave, Campus Box 8054, St Louis, MO 63110, United States

Document Type: Letter
Publication Stage: Final
Source: Scopus

Role of the L-PGDS-PGD2-DP1 receptor axis in sleep regulation and neurologic outcomes
(2019) Sleep, 42 (6), . 

Ahmad, A.S.^{a b c} , Ottallah, H.^{a b c} , Maciel, C.B.^d , Strickland, M.^e , Doré, S.^{a b c f g h i}

^a Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
^b Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, United States
^c McKnight Brain Institute, University of Florida, Gainesville, FL, United States
^d Department of Neurology, University of Florida College of Medicine, Gainesville, FL, United States
^e Division of Biology and Biomedical Sciences, Washington University in Saint Louis, Saint Louis, MO, United States
^f Department of Psychiatry, University of Florida, Gainesville, FL, United States
^g Department of Pharmaceutics, University of Florida, Gainesville, FL, United States
^h Department of Psychology, University of Florida, Gainesville, FL, United States
ⁱ Department of Neuroscience, University of Florida, Gainesville, FL, United States

Abstract
To meet the new challenges of modern lifestyles, we often compromise a good night’s sleep. In preclinical models as well as in humans, a chronic lack of sleep is reported to be among the leading causes of various physiologic, psychologic, and neurocognitive deficits. Thus far, various endogenous mediators have been implicated in inter-regulatory networks that collectively influence the sleep-wake cycle. One such mediator is the lipocalin-type prostaglandin D2 synthase (L-PGDS)-Prostaglandin D2 (PGD2)-DP1 receptor (L-PGDS-PGD2-DP1R) axis. Findings in preclinical models confirm that DP1R are predominantly expressed in the sleep-regulating centers. This finding led to the discovery that the L-PGDS-PGD2-DP1R axis is involved in sleep regulation. Furthermore, we showed that the L-PGDS-PGD2-DP1R axis is beneficial in protecting the brain from ischemic stroke. Protein sequence homology was also performed, and it was found that L-PGDS and DP1R share a high degree of homology between humans and rodents. Based on the preclinical and clinical data thus far pertaining to the role of the L-PGDS-PGD2-DP1R axis in sleep regulation and neurologic conditions, there is optimism that this axis may have a high translational potential in human therapeutics. Therefore, here the focus is to review the regulation of the homeostatic component of the sleep process with a special focus on the L-PGDS-PGD2-DP1R axis and the consequences of sleep deprivation on health outcomes. Furthermore, we discuss whether the pharmacological regulation of this axis could represent a tool to prevent sleep disturbances and potentially improve outcomes, especially in patients with acute brain injuries. © Sleep Research Society 2019. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.

Author Keywords
animal models;  brain injuries;  DP1 receptor;  eicosanoids;  inflammation;  outcome assessments;  poststroke sleep disturbance;  prostaglandin D2;  prostaglandin receptors;  sleep apnea

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

Septal dysembryoplastic neuroepithelial tumor: a comprehensive clinical, imaging, histopathologic, and molecular analysis
(2019) Neuro-oncology, 21 (6), pp. 800-808. 

Chiang, J.C.H.^a , Harreld, J.H.^b , Tanaka, R.^c , Li, X.^a , Wen, J.^a , Zhang, C.^{d e} , Boué, D.R.^f , Rauch, T.M.^g , Boyd, J.T.^h , Chen, J.ⁱ , Corbo, J.C.ⁱ , Bouldin, T.W.^j , Elton, S.W.^k , Liu, L.-W.L.^l , Schofield, D.^m , Lee, S.C.ⁿ , Bouffard, J.-P.^o , Georgescu, M.-M.^p , Dossani, R.H.^q , Aguiar, M.A.^m , Sances, R.A.^r , Saad, A.G.^s , Boop, F.A.^e , Qaddoumi, I.^a , Ellison, D.W.^c

^a Department of Pathology, St Jude Children’s Research Hospital, Memphis, TN, United States
^b Department of Diagnostic Imaging, St Jude Children’s Research Hospital, Memphis, TN, United States
^c Department of Oncology, Division of Neuro-Oncology, St Jude Children’s Research Hospital, Memphis, TN, United States
^d Department of Pediatric Neurosurgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
^e Department of Surgery, Division of Pediatric Neurosurgery, St Jude Children’s Research Hospital, Memphis, TN, United States
^f Department of Pathology and Laboratory Medicine, Nationwide Children’s Hospital, Columbus, OH, United States
^g Pathology Group of Louisiana, Baton Rouge, LA, United States
^h Clinical and Anatomic Pathology Laboratory, Dayton Children’s, Dayton, OH, United States
ⁱ Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, United States
^j Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, United States
^k Department of Neurosurgery, University of North Carolina, Chapel Hill, NC, United States
^l Wesley Pathology, Wichita, KS, United States
^m Department of Pathology, Children’s Hospital of The King’s Daughters, Norfolk, Virginia, USA
ⁿ Department of Surgical Pathology, Montefiore Medical Center/Moses Campus, Bronx, NY, United States
^o Atlantic Health System, Summit, NJ, United States
^p Department of Pathology, Louisiana State University Health Science Center, Shreveport, LA, United States
^q Department of Neurosurgery, Louisiana State University Health Science Center, Shreveport, LA, United States
^r Department of Pathology, East Tennessee Children’s Hospital, Knoxville, TN, United States
^s Department of Pathology, Methodist University Hospital, Memphis, TN, United States

Abstract
BACKGROUND: Dysembryoplastic neuroepithelial tumors (DNETs) are uncommon neural tumors presenting most often in children and young adults and associated with intractable seizures. Rare midline neoplasms with similar histological features to those found in DNETs have been described near the septum pellucidum and termed “DNET-like neoplasms of the septum pellucidum.” Due to their rarity, these tumors have been described in just a few reports and their genetic alterations sought only in small series. METHODS: We collected 20 of these tumors for a comprehensive study of their clinical, radiological, and pathological features. RNA sequencing or targeted DNA sequencing was undertaken on 18 tumors, and genome-wide DNA methylation profiling was possible with 11 tumors. Published cases (n = 22) were also reviewed for comparative purposes. RESULTS: The commonest presenting symptoms and signs were related to raised intracranial pressure; 40% of cases required cerebrospinal fluid diversion. Epilepsy was seen in approximately one third of cases. All patients had an indolent disease course, despite metastasis within the neuraxis in a few cases. Radiologically, the septum verum/septal nuclei were involved in all cases and are the proposed site of origin for septal DNET (sDNET). Septal DNET showed a high frequency (~80%) of mutations of platelet derived growth factor receptor A (PDGFRA), and alterations in fibroblast growth factor receptor 1 (FGFR1) and neurofibromatosis type 1 (NF1) were also identified. In a genomic DNA methylation analysis alongside other neural tumors, sDNETs formed a separate molecular group. CONCLUSIONS: Genetic alterations that are different from those of cerebral DNETs and a distinct methylome profile support the proposal that sDNET is a distinct disease entity. © The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Author Keywords
FGFR1;  NF1;  PDGFRA;  DNET;  septum verum

Document Type: Article
Publication Stage: Final
Source: Scopus

Progress in treatment and newborn screening for Duchenne muscular dystrophy and spinal muscular atrophy
(2019) World Journal of Pediatrics, 15 (3), pp. 219-225. 

Ke, Q.^a , Zhao, Z.-Y.^b , Mendell, J.R.^c , Baker, M.^d , Wiley, V.^e , Kwon, J.M.^f , Alfano, L.N.^g , Connolly, A.M.^h , Jay, C.ⁱ , Polari, H.^j , Ciafaloni, E.ⁱ , Qi, M.^k , Griggs, R.C.ⁱ , Gatheridge, M.A.^l

^a Department of Neurology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
^b Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
^c Department of Pediatrics and Neurology, Nationwide Children’s Hospital, Columbus, OH, United States
^d Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
^e Disciplines of Genetic Medicine and Pediatric and Child Health, University of Sydney, Sydney, Australia
^f Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
^g Department of Pediatrics, Nationwide Children’s Hospital, Columbus, OH, United States
^h Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
ⁱ Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, NY, United States
^j PerkinElmer Inc, Turku, Finland
^k Department of Clinical Laboratory, Zhejiang University School of Medicine, Hangzhou, China
^l Department of Neurology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave, Box 673, Rochester, NY 14642, United States

Abstract
Background: Advances in treatment for Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA) hold promise for children with these disorders. Accurate genetic diagnosis, early in the disease process, will allow these treatments to be most effective. Newborn screening (NBS) for SMA has been recommended in the United States, and a pilot DMD NBS program is underway in Hangzhou, China. Data sources: A PubMed search, limited to the past 5 years, was conducted to identify: (1) therapeutic advancements for DMD/SMA approved by the United States Food and Drug Administration or the European Medicine Agency and (2) The status of NBS for DMD/SMA. Results: We review the current state of approved treatments for DMD/SMA. We present recommendations regarding the future of NBS for these diseases, with a focus on the outcomes and challenges of SMA NBS in New York, USA, and the DMD NBS pilot program in Hangzhou, China. Conclusions: Approved treatments for DMD and SMA may change the natural history of these diseases. Long-term studies of these treatments are underway. To avoid the known diagnostic delay associated with these disorders and provide optimal effectiveness of these treatments, early identification of patients through NBS will be necessary. Establishing comprehensive follow-up plans for positively identified patients will need to be in place for NBS programs to be successful. © 2019, Children’s Hospital, Zhejiang University School of Medicine.

Author Keywords
Duchene muscular dystrophy;  Neurology;  Neuromuscular disorders;  Newborn screening;  Spinal muscular atrophy

Document Type: Review
Publication Stage: Final
Source: Scopus

Extreme Overvalued Belief and the Legacy of Carl Wernicke
(2019) The journal of the American Academy of Psychiatry and the Law, 47 (2), pp. 180-187. 

Rahman, T., Meloy, J.R., Bauer, R.

Department of Psychiatry, University of California, Washington University in St. Louis, Dr. Rahman is Associate Professor of Psychiatry ,School of Medicine. Dr. Meloy is Clinical ProfessorSchool of Medicine. Dr. Bauer is Resident Psychiatrist, San Diego, MO, United States

Abstract
Individuals with extreme overvalued beliefs often carry out abhorrent and inexplicable acts of violence. They hold odd and bizarre beliefs that are shared by others in their culture or subculture. This creates a dilemma for the forensic psychiatrist because the definition of delusion may not be adequate. We discuss the evolution of the term “overvalued idea” first described in a forensic context by neuropsychiatrist Carl Wernicke in 1892. The overvalued idea is invoked in British scholarship as a definition for beliefs seen in anorexia nervosa, morbid jealousy, paranoid litigious states, and other disorders. This is sometimes referred to as delusional disorder by psychiatrists in the United States. The concept of an extreme overvalued belief has recently been validated and is separate from an obsession or delusion. It plays an important role in identifying fixation as a warning sign in threat assessment. We use this definition in three well-known cases (i.e., Anders Breivik, John Hinckley, Jr., and Ted Kaczynski) to emphasize how form and content of beliefs are critical to understanding the mens rea in violent criminal acts. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, would be enhanced by the addition of extreme overvalued belief as a definition to differentiate it from idiosyncratic, fixed, false beliefs seen in delusion. © 2019 American Academy of Psychiatry and the Law.

Document Type: Article
Publication Stage: Final
Source: Scopus

An infant with abnormal eye movements
(2019) NeoReviews, 20 (6), art. no. e367, pp. e367-e371. 

Herco, M.^a , Soloveychik, V.^b , Vachharajani, A.^a

^a Department of Pediatrics/Newborn Medicine, Washington University at St Louis, St Louis, MO, United States
^b Department of Neonatology, Carle Foundation Hospital, Urbana, IL, United States

Document Type: Note
Publication Stage: Final
Source: Scopus

Editorial overview: The confluence of human health, psychology, and genetics: new opportunities to grow our understanding of ourselves
(2019) Current Opinion in Psychology, 27, pp. iv-vii. 

Boutwell, B.B.^{a b c} , White, M.A.^d

^a Criminology and Criminal Justice, Saint Louis University, 3550 Lindell Blvd., St. Louis, MO 63013, United States
^b Department of Epidemiology and Biostatistics, School of Medicine, United States
^c Department of Family and Community Medicine, School of Medicine, United States
^d Department of Genetics and Edison Family Center for Genome Sciences and Systems Biology, Washington University in St. Louis School of Medicine, Couch Biomedical Research Building, St. Louis, MO 63110, United States

Document Type: Editorial
Publication Stage: Final
Source: Scopus

Ultrasound Visualization of Radial Nerve Excursion during Acupuncture
(2019) Medical Acupuncture, 31 (3), pp. 185-188. 

Tang, C.-T., Cheng, A.L.

Department of Orthopedic Surgery, Division of Physical Medicine and Rehabilitation, Washington University, School of Medicine in St. Louis, St. Louis, MO, United States

Abstract
Objective: Nerves are likely to be contacted by needles somewhat regularly during acupuncture treatments. However, the effects of this are not well-known or described. The aim of this article is to describe the effects of acupuncture needling to the radial nerve in a single healthy subject. Materials and Methods: In this experiment, conducted at an academic medical center (Washington University School of Medicine in St. Louis, St. Louis, MO), ultrasound-guided acupuncture needling was performed to the radial nerve of one of the authors (C.-T.T.) in the upper arm at acupoint LI 13. The main outcome measures sought were ultrasonic visualization of the nerve during acupuncture needling and the sensations experienced during acupuncture needling of the nerve. Results: The radial nerve was seen to “roll” out of the way when it was needled. Two De Qi responses were elicited en route to the nerve, but, during nerve contact and penetration, minimal-to-no sensation was experienced. Conclusions: Healthy nerves can show side-to-side excursion when needled, and providers and patients cannot know reliably whether or not a nerve has been contacted or penetrated based on the sensations the patient experiences. © Copyright 2019, Mary Ann Liebert, Inc., publishers 2019.

Author Keywords
acupuncture;  peripheral nerves;  ultrasound

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

Clinical trials in multiple sclerosis: potential future trial designs
(2019) Therapeutic Advances in Neurological Disorders, 12, . 

Manouchehri, N.^a , Zhang, Y.^a , Salter, A.^b , Hussain, R.Z.^a , Hartung, H.-P.^c , Hemmer, B.^d , Linker, R.^e , Segal, B.M.^f , Cutter, G.^g , Stüve, O.^{h i j}

^a Department of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas, TX, United States
^b Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Neurology, UKD and Center for Neurology and Neuropsychiatry, LVR Klinikum, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
^d Department of Neurology, Klinikum rechts der Isar, Technische Universität München, Germany
^e Department of Neurology, University of Regensburg, Germany
^f Department of Neurology, University of Michigan, Ann Arbor, MI, United States
^g Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, United States
^h Neurology Section, VA North Texas Health Care System, Medical Service, 500 South Lancaster Rd, Dallas, TX 75216, United States
ⁱ Department of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas, TX, United States
^j Department of Neurology, Klinikum rechts der Isar, Technische Universität München, Germany

Abstract
Clinical trials of new treatments in multiple sclerosis (MS) currently require large sample sizes and long durations in order to yield reliable results. The differential responses of an already heterogeneous population of MS patients to individual disease-modifying therapies (DMTs) will further complicate future trials. MS trials with smaller samples and faster outcomes are conceivable through the substitution of current clinical and MRI outcomes with objectively measureable genomic and proteomic biomarkers. Currently, biomarkers that could be utilized for diagnosis and monitoring of MS disease activity are in the early validation phase. The power of single biomarkers or multiple correlated biomarkers to predict prognosis and response to treatment could initially be compared with currently accepted methods. These prospectively validated disease biomarkers could then be used to subcategorize the spectrum of MS patients into a finite number of endophenotypes with demonstrable different molecular pathogeneses and DMT response profiles. Newly developed DMT could potentially be assessed within specific endophenotypes and compared with pharmacogenomically relevant active comparator DMT. This approach may increase the efficiency of MS trials through homogenization of patient population and minimization of nonresponders in study groups, providing the potential for the development of targeted therapies. © The Author(s), 2019.

Author Keywords
Clinical trial;  Disease Modifying therapy;  Endophenotypes;  Multiple Sclerosis;  Pharmacology;  Trial design

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

Cadaveric study investigating the mechanism of action of erector spinae blockade
(2019) Regional Anesthesia and Pain Medicine, 44 (2), p. 280. 

Schoenfeldt, J., Guffey, R., Fingerman, M.

Department of Anesthesiology, Washington University, School of Medicine, 660 S Euclid Ave, St. Louis, MO 63110, United States

Author Keywords
acute pain;  anatomy;  truncal blocks

Document Type: Letter
Publication Stage: Final
Source: Scopus

Reduction of leukocyte microvascular adherence and preservation of blood-brain barrier function by superoxide-lowering therapies in a piglet model of neonatal asphyxia
(2019) Frontiers in Neurology, 10 (MAY), art. no. 447, . 

Ruden, J.B.^a , Quick, K.L.^b , Gonzales, E.R.^c , Shah, A.R.^{c d} , Park, T.S.^e , Kennedy, N.^f , Dugan, L.L.^{a g} , Gidday, J.M.^h

^a Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, United States
^b PerkinElmer, Waltham, MA, United States
^c Hope Center for Neurological Disorders and Department of Neurology, Washington University in Saint Louis School of Medicine, St. Louis, MO, United States
^d Knight Alzheimer’s Disease Research Center, Washington University in Saint Louis School of Medicine, St. Louis, MO, United States
^e Department of Neurosurgery, St. Louis Children’s Hospital, Washington University in Saint Louis School of Medicine, St. Louis, MO, United States
^f Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, TN, United States
^g Division of Geriatric Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
^h Departments of Ophthalmology, Physiology, and Neuroscience, Louisiana State University School of Medicine, New Orleans, LA, United States

Abstract
Background: Asphyxia is the most common cause of brain damage in newborns. Substantial evidence indicates that leukocyte recruitment in the cerebral vasculature during asphyxia contributes to this damage. We tested the hypothesis that superoxide radical (O2·-) promotes an acute post-asphyxial inflammatory response and blood-brain barrier (BBB) breakdown. We investigated the effects of removing O2·- by superoxide dismutase (SOD) or C3, the cell-permeable SOD mimetic, in protecting against asphyxia-related leukocyte recruitment. We also tested the hypothesis that xanthine oxidase activity is one source of this radical. Methods: Anesthetized piglets were tracheostomized, ventilated, and equipped with closed cranial windows for the assessment of post-asphyxial rhodamine 6G-labeled leukocyte-endothelial adherence and microvascular permeability to sodium fluorescein in cortical venules. Asphyxia was induced by discontinuing ventilation. SOD and C3 were administered by cortical superfusion. The xanthine oxidase inhibitor oxypurinol was administered intravenously. Results: Leukocyte-venular adherence significantly increased during the initial 2 h of post-asphyxial reperfusion. BBB permeability was also elevated relative to non-asphyxial controls. Inhibition of O2·- production by oxypurinol, or elimination of O2·- by SOD or C3, significantly reduced rhodamine 6G-labeled leukocyte-endothelial adherence and improved BBB integrity, as measured by sodium fluorescein leak from cerebral microvessels. Conclusion: Using three different strategies to either prevent formation or enhance elimination of O2·- during the post-asphyxial period, we saw both reduced leukocyte adherence and preserved BBB function with treatment. These findings suggest that agents which lower O2·- in brain may be attractive new therapeutic interventions for the protection of the neonatal brain following asphyxia. © 2019 Ruden, Quick, Gonzales, Shah, Park, Kennedy, Dugan and Gidday.

Author Keywords
Asphyxia;  Carboxyfullerene;  Endothelium;  Inflammation;  Leukocytes;  Oxypurinol;  Superoxide;  Xanthine oxidase

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

Rev-erbs and glia—implications for neurodegenerative diseases
(2019) Journal of Experimental Neuroscience, 13, . 

Griffin, P., Dimitry, J.M., Musiek, E.S.

Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Recently, we described a role for the circadian clock protein and nuclear receptor Rev-erbα in regulating glial activation states in the brain. Deletion of Rev-erbα resulted in microglial as well as astrocytic activation, while a Rev-erbα agonist diminished the severity of lipopolysaccharide (LPS)-induced neuroinflammation. Concomitant with this glial activation is impaired neuronal health. These findings suggest that Rev-erb proteins may play critical roles in glial biology. Pertinent ideas such as the glial cell type of most importance, the translatability of these findings to human disease, and the effect of manipulating Rev-erbs in models of neurodegeneration, need to be explored further. In this commentary, we will address the potential role of Rev-erbs in neuroinflammation related to neurodegenerative diseases and speculate on Rev-erbs as potential therapeutic targets for these conditions. © The Author(s) 2019.

Author Keywords
Circadian;  Microglia;  Neuroinflammatio;  Rev-erb alpha

Document Type: Article
Publication Stage: Final
Source: Scopus

Insights into traumatic brain injury from mri of harmonic brain motion
(2019) Journal of Experimental Neuroscience, 13, . 

Okamoto, R.J.^a , Romano, A.J.^b , Johnson, C.L.^c , Bayly, P.V.^a

^a Department of Mechanical Engineering & Materials Science, Washington University in St. Louis, St. Louis, MO, United States
^b Acoustics Division, U.S. Naval Research Laboratory, Washington, DC, United States
^c Department of Biomedical Engineering, University of Delaware, Newark, DE, United States

Abstract
Measurements of dynamic deformation of the human brain, induced by external harmonic vibration of the skull, were analyzed to illuminate the mechanics of mild traumatic brain injury (TBI). Shear wave propagation velocity vector fields were obtained to illustrate the role of the skull and stiff internal membranes in transmitting motion to the brain. Relative motion between the cerebrum and cerebellum was quantified to assess the vulnerability of connecting structures. Mechanical deformation was quantified throughout the brain to investigate spatial patterns of strain and axonal stretch. Strain magnitude was generally attenuated as shear waves propagated into interior structures of the brain; this attenuation was greater at higher frequencies. Analysis of shear wave propagation direction indicates that the stiff membranes (falx and tentorium) greatly affect brain deformation during imposed skull motion as they serve as sites for both initiation and reflection of shear waves. Relative motion between the cerebellum and cerebrum was small in comparison with the overall motion of both structures, which suggests that such relative motion might play only a minor role in TBI mechanics. Strain magnitudes and the amount of axonal stretch near the bases of sulci were similar to those in other areas of the cortex, and local strain concentrations at the gray-white matter boundary were not observed. We tentatively conclude that observed differences in neuropathological response in these areas might be due to heterogeneity in the response to mechanical deformation rather than heterogeneity of the deformation itself. © The Author(s) 2019.

Author Keywords
Brain mechanics;  Brain-skull interface;  Chronic traumatic encephalopathy;  MR elastography;  Traumatic brain injury

Document Type: Article
Publication Stage: Final
Source: Scopus

T cells promote microglia-mediated synaptic elimination and cognitive dysfunction during recovery from neuropathogenic flaviviruses
(2019) Nature Neuroscience, . 

Garber, C.^a , Soung, A.^a , Vollmer, L.L.^a , Kanmogne, M.^a , Last, A.^a , Brown, J.^a , Klein, R.S.^{a b c}

^a Department of Internal Medicine, Washington University School of Medicine, St Louis, MO, United States
^b Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, United States
^c Department of Neuroscience, Washington University School of Medicine, St Louis, MO, United States

Abstract
T cells clear virus from the CNS and dynamically regulate brain functions, including spatial learning, through cytokine signaling. Here we determined whether hippocampal T cells that persist after recovery from infection with West Nile virus (WNV) or Zika virus (ZIKV) impact hippocampal-dependent learning and memory. Using newly established models of viral encephalitis recovery in adult animals, we show that in mice that have recovered from WNV or ZIKV infection, T cell-derived interferon-γ (IFN-γ) signaling in microglia underlies spatial-learning defects via virus-target-specific mechanisms. Following recovery from WNV infection, mice showed presynaptic termini elimination with lack of repair, while for ZIKV, mice showed extensive neuronal apoptosis with loss of postsynaptic termini. Accordingly, animals deficient in CD8+ T cells or IFN-γ signaling in microglia demonstrated protection against synapse elimination following WNV infection and decreased neuronal apoptosis with synapse recovery following ZIKV infection. Thus, T cell signaling to microglia drives post-infectious cognitive sequelae that are associated with emerging neurotropic flaviviruses. © 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.

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

Quantitative 18F-AV1451 brain tau PET imaging in cognitively normal older adults, mild cognitive impairment, and Alzheimer’s disease patients
(2019) Frontiers in Neurology, 10 (MAY), art. no. 486, . 

Zhao, Q.^{a b} , Liu, M.^{b c} , Ha, L.^{b d} , Zhou, Y.^{b e}

^a Department of Nuclear Medicine, General Hospital of Ningxia Medical University, Yinchuan, China
^b Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^c Department of Radiology, Xuanwu Hospital of Capital Medical University, Beijing, China
^d Center for Reproductive Medicine, General Hospital of Ningxia Medical University, Yinchuan, China
^e Mallinckrodt Institute of Radiology, Washington University in St. Louis School of Medicine, St. Louis, MO, United States

Abstract
Recent developments of tau Positron Emission Tomography (PET) allows assessment of regional neurofibrillary tangles (NFTs) deposition in human brain. Among the tau PET molecular probes, 18F-AV1451 is characterized by high selectivity for pathologic tau aggregates over amyloid plaques, limited non-specific binding in white and gray matter, and confined off-target binding. The objectives of the study are (1) to quantitatively characterize regional brain tau deposition measured by 18F-AV1451 PET in cognitively normal older adults (CN), mild cognitive impairment (MCI), and AD participants; (2) to evaluate the correlations between cerebrospinal fluid (CSF) biomarkers or Mini-Mental State Examination (MMSE) and 18F-AV1451 PET standardized uptake value ratio (SUVR); and (3) to evaluate the partial volume effects on 18F-AV1451 brain uptake. Methods: The study included total 115 participants (CN = 49, MCI = 58, and AD = 8) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Preprocessed 18F-AV1451 PET images, structural MRIs, and demographic and clinical assessments were downloaded from the ADNI database. A reblurred Van Cittertiteration method was used for voxelwise partial volume correction (PVC) on PET images. Structural MRIs were used for PET spatial normalization and region of interest (ROI) definition in standard space. The parametric images of 18F-AV1451 SUVR relative to cerebellum were calculated. The ROI SUVR measurements from PVC and non-PVC SUVR images were compared. The correlation between ROI 18F-AV1451 SUVR and the measurements of MMSE, CSF total tau (t-tau), and phosphorylated tau (p-tau) were also assessed. Results: 18F-AV1451 prominently specific binding was found in the amygdala, entorhinal cortex, parahippocampus, fusiform, posterior cingulate, temporal, parietal, and frontal brain regions. Most regional SUVRs showed significantly higher uptake of 18F-AV1451 in AD than MCI and CN participants. SUVRs of small regions like amygdala, entorhinal cortex and parahippocampus were statistically improved by PVC in all groups (p < 0.01). Although there was an increasing tendency of 18F-AV-1451 SUVRs in MCI group compared with CN group, no significant difference of 18F-AV1451 deposition was found between CN and MCI brains with or without PVC (p > 0.05). Declined MMSE score was observed with increasing 18F-AV1451 binding in amygdala, entorhinal cortex, parahippocampus, and fusiform. CSF p-tau was positively correlated with 18F-AV1451 deposition. PVC improved the results of 18F-AV-1451 tau deposition and correlation studies in small brain regions. Conclusion: The typical deposition of 18F-AV1451 tau PET imaging in AD brain was found in amygdala, entorhinal cortex, fusiform and parahippocampus, and these regions were strongly associated with cognitive impairment and CSF biomarkers. Although more deposition was observed in MCI group, the 18F-AV-1451 PET imaging could not differentiate the MCI patients from CN population. More tau deposition related to decreased MMSE score and increased level of CSF p-tau, especially in ROIs of amygdala, entorhinal cortex and parahippocampus. PVC did improve the results of tau deposition and correlation studies in small brain regions and suggest to be routinely used in 18F-AV1451 tau PET quantification. © 2019 Zhao, Liu, Ha, Zhou and Alzheimer’s Disease Neuroimaging Initiative. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Author Keywords
18F-AV1451;  Alzheimer’s disease;  Cognitively normal;  Mild cognition impairment;  Tau PET

Document Type: Article
Publication Stage: Final
Source: Scopus

CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum
(2019) Genetics in Medicine, . 

Konrad, E.D.H.^a , Nardini, N.^a , Caliebe, A.^b , Nagel, I.^{b c} , Young, D.^d , Horvath, G.^d , Santoro, S.L.^e , Shuss, C.^e , Ziegler, A.^f , Bonneau, D.^f , Kempers, M.^g , Pfundt, R.^g , Legius, E.^h , Bouman, A.ⁱ , Stuurman, K.E.ⁱ , Õunap, K.^{j k l} , Pajusalu, S.^{j k m} , Wojcik, M.H.^{l n} , Vasileiou, G.^a , Le Guyader, G.^o , Schnelle, H.M.^p , Berland, S.^p , Zonneveld-Huijssoon, E.^q , Kersten, S.^g , Gupta, A.^r , Blackburn, P.R.^s , Ellingson, M.S.^s , Ferber, M.J.^s , Dhamija, R.^t , Klee, E.W.^r , McEntagart, M.^u , Lichtenbelt, K.D.^v , Kenney, A.^w , Vergano, S.A.^w , Abou Jamra, R.^x , Platzer, K.^x , Ella Pierpont, M.^y , Khattar, D.^z , Hopkin, R.J.^z , Martin, R.J.^aa , Jongmans, M.C.J.^g , Chang, V.Y.^{ab ac} , Martinez-Agosto, J.A.^{ad ae} , Kuismin, O.^{af ag ah ai} , Kurki, M.I.^{af aj ak} , Pietiläinen, O.^{ak al} , Palotie, A.^{af aj ak am an} , Maarup, T.J.^ao , Johnson, D.S.^ap , Venborg Pedersen, K.^aq , Laulund, L.W.^ar , Lynch, S.A.^as , Blyth, M.^at , Prescott, K.^at , Canham, N.^au , Ibitoye, R.^au , Brilstra, E.H.^v , Shinawi, M.^av , Fassi, E.^av , Sticht, H.^ax , Gregor, A.^a , Van Esch, H.^ay , Zweier, C.^a , DDD Study^aw

^a Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
^b Institute of Human Genetics, Universitätsklinikum Schleswig Holstein Campus Kiel and Christian-Albrechts-Universität, Kiel, Germany
^c Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
^d Adult Metabolic Diseases Clinic, Vancouver General Hospital, Vancouver, BC, Canada
^e Division of Molecular and Human Genetics, Nationwide Children’s Hospital, Columbus, OH, United States
^f Département de Biochimie et Génétique, CHU Angers et Mitolab INSERM 1083—CNRS 6015, Angers, France
^g Department of Human Genetics, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences, Nijmegen, Netherlands
^h Department of Human Genetics, KU Leuven and Center for Human Genetics, University Hospital Leuven, KU Leuven, Leuven, Belgium
ⁱ Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
^j Department of Clinical Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia
^k Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia
^l The Broad Institute of MIT and Harvard, Cambridge, MA, United States
^m Department of Genetics, Yale University School of Medicine, New Haven, CT, United States
ⁿ Divisions of Genetics and Genomics and Newborn Medicine, Department of Pediatrics, Boston Children’s Hospital, Boston, MA, United States
^o Service de Génétique Clinique, CHU de Poitiers, Poitiers, France
^p Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway
^q Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
^r Center for Individualized Medicine, Mayo Clinic, Rochester, MN, United States
^s Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
^t Department of Clinical Genomics, Mayo Clinic, Scottsdale, AZ, United States
^u South West Thames Regional Genetics Centre, St. George’s Healthcare NHS Trust, St. George’s, University of London, London, United Kingdom
^v Department of Genetics, University Medical Center Utrecht, Utrecht, Netherlands
^w Division of Medical Genetics and Metabolism, Children’s Hospital of The King’s Daughters, Norfolk, VA, United States
^x Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
^y Department of Pediatrics, Division of Genetics and Metabolism, University of Minnesota, Minneapolis, MN, United States
^z Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
^aa The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
^ab Division of Pediatric Hematology-Oncology, Department of Pediatrics, David Geffen School of Medicine, Los Angeles, CA, United States
^ac Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, United States
^ad Division of Medical Genetics, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA, United States
^ae Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, United States
^af Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
^ag PEDEGO Research Unit, University of Oulu, Oulu, Finland
^ah Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland
^ai Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland
^aj Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, United States
^ak The Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, United States
^al Department of Stem Cell and Regenerative Biology, University of Harvard, Cambridge, MA, United States
^am Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, United States
^an Department of Neurology, Massachusetts General Hospital, Boston, MA, United States
^ao Department of Genetics, Kaiser Permanente, Los Angeles, CA, United States
^ap Sheffield Children’s Hospital, Sheffield, United Kingdom
^aq Department of Clinical Genetics, Odense University Hospital, Odense, Denmark
^ar Department of Pediatrics, Odense University Hospital, Odense, Denmark
^as University College Dublin and Temple Street Children’s Hospital, Dublin, Ireland
^at Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
^au North West Thames Regional Genetics Service, Northwick Park Hospital, Harrow, United Kingdom
^av Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
^aw Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom
^ax Institute of Biochemistry, Emil-Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
^ay Center for Human Genetics, University Hospital Leuven, KU Leuven, Leuven, Belgium

Abstract
Purpose: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individuals with a neurodevelopmental disorder (NDD). Methods: Through international collaboration we collected data from 39 subjects with variants in CTCF. We performed transcriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impact of Ctcf dosage alteration on nervous system development and function. Results: The individuals in our cohort carried 2 deletions, 8 likely gene-disruptive, 2 splice-site, and 20 different missense variants, most of them de novo. Two cases were familial. The associated phenotype was of variable severity extending from mild developmental delay or normal IQ to severe intellectual disability. Feeding difficulties and behavioral abnormalities were common, and variable other findings including growth restriction and cardiac defects were observed. RNA-sequencing in five individuals identified 3828 deregulated genes enriched for known NDD genes and biological processes such as transcriptional regulation. Ctcf dosage alteration in Drosophila resulted in impaired gross neurological functioning and learning and memory deficits. Conclusion: We significantly broaden the mutational and clinical spectrum of CTCF-associated NDDs. Our data shed light onto the functional role of CTCF by identifying deregulated genes and show that Ctcf alterations result in nervous system defects in Drosophila. © 2019, The Author(s).

Author Keywords
chromatin organization;  CTCF;  Drosophila melanogaster;  intellectual disability;  neurodevelopmental disorders

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

TREM2 function impedes tau seeding in neuritic plaques
(2019) Nature Neuroscience, . 

Leyns, C.E.G.^{a b c} , Gratuze, M.^{a b c} , Narasimhan, S.^d , Jain, N.^{a b c} , Koscal, L.J.^{a b c} , Jiang, H.^{a b c} , Manis, M.^{a b c} , Colonna, M.^{b c e} , Lee, V.M.Y.^d , Ulrich, J.D.^{a b c} , Holtzman, D.M.^{a b c}

^a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^b Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
^c Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, United States
^e Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Variants in the triggering receptor expressed on myeloid cells 2 (TREM2) have been associated with increased risk for sporadic, late-onset Alzheimer’s disease. Here we show that germline knockout of Trem2 or the TREM2R47H variant reduces microgliosis around amyloid-β plaques and facilitates the seeding and spreading of neuritic plaque tau aggregates. These findings demonstrate a key role for TREM2 and microglia in limiting the development of peri-plaque tau pathologies. © 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.

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

Comparing Participation Outcome Over Time Across International Stroke Cohorts: Outcomes and Methods
(2019) Archives of Physical Medicine and Rehabilitation, . 

Verberne, D.^{a b} , Tse, T.^{c d e} , Matyas, T.^{c d} , Baum, C.^f , Post, M.^{g h} , Carey, L.^{c d} , van Heugten, C.^{a b i}

^a Maastricht University Medical Center, Department of Psychiatry and Neuropsychology, Faculty of Health, Medicine and Neuroscience, School for Mental Health and Neuroscience, Maastricht, Netherlands
^b Limburg Brain Injury Centre, Maastricht, Netherlands
^c Occupational Therapy, School of Allied Health, College of Science, Health, and Engineering, La Trobe University, Melbourne, Australia
^d Neurorehabilitation and Recovery, Stroke Division Florey Institute of Neuroscience and Mental Health, Heidelberg, Australia
^e St. Vincent’s Hospital, Melbourne, Fitzroy, Australia
^f Program in Occupational Therapy, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^g Center of Excellence for Rehabilitation Medicine, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht University and De Hoogstraat Rehabilitation, Utrecht, Netherlands
^h University of Groningen, University Medical Center Groningen, Department of Rehabilitation Medicine, Groningen, Netherlands
ⁱ Maastricht University, Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht, Netherlands

Abstract
Objective: To enable a direct comparison of participation levels in the first year post-stroke, assessed by different outcome measures internationally. Design: Two prospective stroke cohort studies following persons from stroke onset to 12 months post-stroke. Setting: Community. Participants: Persons with stroke (N=495), not living at a nursing home, from Australia STroke imAging pRevention and Treatment-Prediction and Prevention to Achieve optimal Recovery Endpoints after stroke (START-PrePARE; n=100) and the Netherlands (Restore4stroke; n=395). Interventions: Not applicable. Main Outcome Measures: Activity Card Sort-Australia and Utrecht Scale for Evaluation of Rehabilitation-Participation. Activity domains were matched across measures to find common denominators and original scoring methods were recoded, hereby enabling a direct comparison of retained activities. Results: Ninety-one (START-PrePARE) and 218 (Restore4stroke) persons with stroke were included for analyses. No major differences in background characteristics were observed between the cohorts; the Dutch cohort suffered from slightly more severe stroke. A higher level of participation was observed (radar charts) in the first months post-stroke for the Australian cohort than in the Dutch cohort, especially for unpaid work (P<.003). At 12 months post-stroke, participation levels were similar, without significant differences in retained activities using the defined common denominators (P>.003). Conclusions: An international comparison of actual activities that persons re-engage in in the first year post-stroke was achieved using a new method and recoding of data. High levels of participation were observed in both cohorts. Unpaid work showed different frequencies at 2-3 months, contributing to different trajectories over time across cultures. Important insights were gained. Although valuable information is inevitably lost with recoding, the approach may assist future studies on the harmonization of data across cohorts, particularly for 1 of the key outcomes of stroke: participation. © 2019 American Congress of Rehabilitation Medicine

Author Keywords
Comparative study;  Cross-cultural comparison;  Feasibility studies;  Rehabilitation;  Social participation;  Stroke

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

High alert!
(2019) Multiple Sclerosis Journal, . 

Clifford, D.B.

Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States

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

What are the threats to successful brain and cognitive aging?
(2019) Neurobiology of Aging, . 

Gallagher, M.^a , Okonkwo, O.C.^b , Resnick, S.M.^c , Jagust, W.J.^d , Benzinger, T.L.S.^e , Rapp, P.R.^c

^a Department of Psychological and Brain Sciences, Johns Hopkins University, Baltimore, MD, United States
^b Department of Medicine and Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
^c Laboratory of Behavioral Neuroscience, National Institute on Aging, Baltimore, MD, United States
^d Helen Wills Neuroscience Institute, University of California, Berkeley, CA, United States
^e Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
The structure and function of the brain change over the life span. Aged brains often accumulate pathologic lesions, such as amyloid plaques and tau tangles, which lead to diminished cognitive ability in some, but not all, individuals. The basis of this vulnerability and resilience is unclear. Age-related changes can alter neural firing patterns and ability to form new memories. Risk factors for cognitive decline include male sex and apolipoprotein E genotype. Physical activity seems to be protective against cognitive decline. Longitudinal studies have shown that, although the onset of amyloid pathology and associated cognitive decline can vary greatly, once it begins, the rate of deposition is similar among affected individuals. This session of the Cognitive Aging Summit III explored fixed and modifiable factors that can threaten cognitive function in aging adults and approaches to modulate at least some of these risks. © 2019

Author Keywords
Compensation;  Maintenance;  Modifiable factors;  Pathology;  Reserve;  Resilience

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

Thoughts About Electroconvulsive Therapy and New Potential Treatments for Treatment-Resistant Depression in the Elderly
(2019) American Journal of Geriatric Psychiatry, . 

Rubin, E.H.

Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States

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

Observed Personality in Preschool: Associations with Current and Longitudinal Symptoms
(2019) Journal of Abnormal Child Psychology, . 

^a Department of Psychiatry, Washington University, 660 S. Euclid Ave, St. Louis, MO 63110, United States
^b The Program in Neuroscience, Washington University, 1 Brookings Drive, St. Louis, MO 63130, United States
^c Department of Psychological and Brain Sciences, Washington University, 1 Brookings Drive, St. Louis, MO 63130, United States
^d Department of Radiology, Washington University, 660 S. Euclid Ave, St. Louis, MO 63110, United States

Abstract
Personality is consistently associated with psychopathology across the lifespan. However, little is known of how observed personality dimensions in preschoolers are associated with concurrent or longitudinal symptoms across development. Spectrum, vulnerability, and pathopolasty models theorize how child personality and psychopathology are related across development. The current study tests these three models using observationally coded personality dimensions in a longitudinal sample of preschoolers. A validated ‘thin slice’ technique was used to code observed Five Factor Model (FFM) personality dimensions of extraversion, agreeableness, conscientiousness, neuroticism, and openness to experience in a clinically enriched preschool sample oversampled for depression (N = 299). Children were followed longitudinally for 9 years while assessing dimensional psychological symptoms and global functioning. Longitudinal multilevel models testing the spectrum, or shared underlying factor model, indicated depressive symptoms in adolescence were predicted by higher preschool extraversion and lower agreeableness and conscientiousness, externalizing symptoms were predicted by lower agreeableness and higher neuroticism, and worse global functioning was predicted by higher extraversion and neuroticism, and lower agreeableness and conscientiousness. Some associations held after accounting for the influence of baseline psychological symptoms, indicating support for a vulnerability relationship between personality and later psychopathology. No support was demonstrated for pathoplasty models such that personality did not influence the developmental course or change of psychopathology over time. Findings indicate personality dimensions measured as early as the preschool period prospectively impact psychopathology and functioning across child development, demonstrating support for both a spectrum and vulnerability relationship between youth personality and psychopathology. © 2019, Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Five factor model;  Personality development;  Preschool;  Psychopathology

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

Shared environment effects on children’s emotion recognition
(2019) Frontiers in Psychiatry, 10 (APR), art. no. 215, . 

Schapira, R.^{a b} , Elfenbein, H.A.^c , Amichay-Setter, M.^d , Zahn-Waxler, C.^e , Knafo-Noam, A.^d

^a Mofet Institute, Tel-Aviv, Israel
^b Levinsky College of Education, Tel-Aviv, Israel
^c Washington University, St. Louis, MI, United States
^d Hebrew University of Jerusalem, Jerusalem, Israel
^e University of Wisconsin-Madison, Madison, WI, United States

Abstract
Empathy is relevant to many psychiatric conditions. Empathy involves the natural ability to perceive and be sensitive to the emotional states of others. Thus, emotion recognition (ER) abilities are key to understanding empathy. Despite the importance of ER to normal and abnormal social interactions, little is known about how it develops throughout childhood. We examined genetic and environmental influences on children’s ER via facial and vocal cues in 344 7-year-old twin children [59 monozygotic (MZ) and 113 same-sex dizygotic (DZ) pairs], who were part of the Longitudinal Israeli Study of Twins. ER was assessed with the child version of the Diagnostic Assessment of Nonverbal Accuracy. For both facial and vocal cues of emotion, twin correlations were not higher for MZ twins than for DZ twins, suggesting no heritability for ER in this population. In contrast, correlations were positive for both types of twins, indicating a shared environmental effect. This was supported by a bivariate genetic analysis. This pattern was robust to controlling for twins being of the same sex and age. Effects remained after controlling for background variables such as family income and number of additional siblings. The analysis found a shared environmental correlation between facial and vocal ER (rc = .63), indicating that the shared environmental factors contributed to the overlap between vocal and facial ER. The study highlights the importance of the shared environment to children’s ER. Copyright © 2019 Schapira, Anger Elfenbein, Amichay-Setter, Zahn-Waxler and Knafo-Noam. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Author Keywords
Childhood;  Emotion recognition;  Empathy;  Individual differences;  Shared environment effect

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

FeatSNP: An interactive database for brain-specific epigenetic annotation of human SNPs
(2019) Frontiers in Genetics, 10 (APR), art. no. 262, . 

Ma, C.-Y.^a , Madden, P.^b , Gontarz, P.^a , Wang, T.^c , Zhang, B.^a

^a Center of Regenerative Medicine, Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Genetics, Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
FeatSNP is an online tool and a curated database for exploring 81 million common SNPs’ potential functional impact on the human brain. FeatSNP uses the brain transcriptomes of the human population to improve functional annotation of human SNPs by integrating transcription factor binding prediction, public eQTL information, and brain specific epigenetic landscape, as well as information of Topologically Associating Domains (TADs). FeatSNP supports both single and batched SNP searching, and its interactive user interface enables users to explore the functional annotations and generate publication-quality visualization results. FeatSNP is freely available on the internet at FeatSNP.org with all major web browsers supported. © 2007 – 2019 Frontiers Media S.A. All Rights Reserved.

Author Keywords
Brain;  Database;  Epigenetics;  SNP;  Transcription factor

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

The course of emotional distress and late mortality following myocardial infarction: Implications for depression screening and treatment
(2019) European Journal of Preventive Cardiology, . 

Carney, R.M.

Department of Psychiatry, Washington University School of MedicineMO, United States

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

Behavioral inhibition corresponds to white matter fiber bundle integrity in older adults
(2019) Brain Imaging and Behavior, . 

Garcia-Egan, P.M.^a , Preston-Campbell, R.N.^b , Salminen, L.E.^c , Heaps-Woodruff, J.M.^b , Balla, L.^b , Cabeen, R.P.^d , Laidlaw, D.H.^e , Conturo, T.E.^f , Paul, R.H.^{a b}

^a Department of Psychological Sciences, University of Missouri, St. Louis, MO 63121, United States
^b Missouri Institute of Mental Health, St. Louis, MO 63134, United States
^c Imaging Genetics Center, Stevens Neuroimaging and Informatics Institute, University of Southern California, Marina del Rey, CA 90292, United States
^d Laboratory of Neuro Imaging, Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, University of Southern California, LosAngeles, CA 90033, United States
^e Department of Computer Science, Brown University, Providence, RI 02906, United States
^f Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Little is known about the contribution of white matter integrity to inhibitory cognitive control, particularly in healthy aging. The present study examines the correspondence between white matter fiber bundle length and behavioral inhibition in 37 community-dwelling older adults (aged 51–78 years). Participants underwent neuroimaging with 3 Tesla MRI, and completed a behavioral test of inhibition (i.e., Go/NoGo task). Quantitative tractography derived from diffusion tensor imaging (qtDTI) was used to measure white matter fiber bundle lengths (FBLs) in tracts known to innervate frontal brain regions, including the anterior corpus callosum (AntCC), the cingulate gyrus segment of the cingulum bundle (CING), uncinate fasciculus (UNC), and the superior longitudinal fasciculus (SLF). Performance on the Go/NoGo task was measured by the number of commission errors standardized to reaction time. Hierarchical regression models revealed that shorter FBLs in the CING (p < 0.05) and the bilateral UNC (p < 0.01) were associated with lower inhibitory performance after adjusting for multiple comparisons, supporting a disconnection model of response inhibition in older adults. Prospective longitudinal studies are needed to examine the evolution of inhibitory errors in older adult populations and potential for therapeutic intervention. © 2019, Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Aging;  Go/NoGo;  Inhibition;  MRI fiber bundle length;  Quantitative diffusion tensor imaging;  White matter

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

Pre-injury comorbidities are associated with functional impairment and post-concussive symptoms at 3- And 6-months after mild traumatic brain injury: A TracK-TBI study
(2019) Frontiers in Neurology, 10 (APR), art. no. 343, . 

Yue, J.K.^{a b p} , Cnossen, M.C.^c , Winkler, E.A.^{a b} , Deng, H.^{a b} , Phelps, R.R.L.^{a b} , Coss, N.A.^{a b} , Sharma, S.^{a b} , Robinson, C.K.^{a b} , Suen, C.G.^{a b d} , Vassar, M.J.^{a b} , Schnyer, D.M.^e , Puccio, A.M.^f , Gardner, R.C.^{g h} , Yuh, E.L.^{b i} , Mukherjee, P.^{b i} , Valadka, A.B.^j , Okonkwo, D.O.^f , Lingsma, H.F.^c , Manley, G.T.^{a b} , Cooper, S.R.^k , Dams-O’Connor, K.^l , Gordon, W.A.^l , Hricik, A.J.^f , Maas, A.I.R.^m , Menon, D.K.ⁿ , Morabito, D.J.^o

^a Department of Neurosurgery, University of California, San Francisco, San Francisco, CA, United States
^b Brain and Spinal Injury Center, Zuckerberg San Francisco General Hospital, San Francisco, CA, United States
^c Department of Public Health, Erasmus Medical Center, Rotterdam, Netherlands
^d Department of Neurology, University of Utah, Salt Lake City, UT, United States
^e Department of Psychology, University of Texas in Austin, Austin, TX, United States
^f Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
^g Department of Neurology, University of California, San Francisco, San Francisco, CA, United States
^h Department of Neurology, Veterans Affairs Medical Center, San Francisco, CA, United States
ⁱ Department of Radiology, University of California, San Francisco, San Francisco, CA, United States
^j Department of Neurosurgery, Virginia Commonwealth University, Richmond, VA, United States
^k Department of Psychology, Washington University in St. Louis, St. Louis, MO, United States
^l Department of Rehabilitation Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^m Department of Neurosurgery, University Hospital Antwerp, Edegem, Belgium
ⁿ Division of Anaesthesia, University of Cambridge, Cambridge, United Kingdom
^o Department of Neurosurgery, University of California San Francisco, San Francisco, CA, United States

Abstract
Introduction: Over 70% of traumatic brain injuries (TBI) are classified as mild (mTBI), which present heterogeneously. Associations between pre-injury comorbidities and outcomes are not well-understood, and understanding their status as risk factors may improve mTBI management and prognostication. Methods: mTBI subjects (GCS 13–15) from TRACK-TBI Pilot completing 3- and 6-month functional [Glasgow Outcome Scale-Extended (GOSE)] and post-concussive outcomes [Acute Concussion Evaluation (ACE) physical/cognitive/sleep/emotional subdomains] were extracted. Pre-injury comorbidities >10% incidence were included in regressions for functional disability (GOSE ≤ 6) and post-concussive symptoms by subdomain. Odds ratios (OR) and mean differences (B) were reported. Significance was assessed at p < 0.0083 (Bonferroni correction). Results: In 260 subjects sustaining blunt mTBI, mean age was 44.0-years and 70.4% were male. Baseline comorbidities >10% incidence included psychiatric-30.0%, cardiac (hypertension)-23.8%, cardiac (structural/valvular/ischemic)-20.4%, gastrointestinal-15.8%, pulmonary-15.0%, and headache/migraine-11.5%. At 3- and 6-months separately, 30.8% had GOSE ≤ 6. At 3-months, psychiatric (GOSE ≤ 6: OR = 2.75, 95% CI [1.44–5.27]; ACE-physical: B = 1.06 [0.38–1.73]; ACE-cognitive: B = 0.72 [0.26–1.17]; ACE-sleep: B = 0.46 [0.17–0.75]; ACE-emotional: B = 0.64 [0.25–1.03]), headache/migraine (GOSE ≤ 6: OR = 4.10 [1.67–10.07]; ACE-sleep: B = 0.57 [0.15–1.00]; ACE-emotional: B = 0.92 [0.35–1.49]), and gastrointestinal history (ACE-physical: B = 1.25 [0.41–2.10]) were multivariable predictors of worse outcomes. At 6-months, psychiatric (GOSE ≤ 6: OR = 2.57 [1.38–4.77]; ACE-physical: B = 1.38 [0.68–2.09]; ACE-cognitive: B = 0.74 [0.28–1.20]; ACE-sleep: B = 0.51 [0.20–0.83]; ACE-emotional: B = 0.93 [0.53–1.33]), and headache/migraine history (ACE-physical: B = 1.81 [0.79–2.84]) predicted worse outcomes. Conclusions: Pre-injury psychiatric and pre-injury headache/migraine symptoms are risk factors for worse functional and post-concussive outcomes at 3- and 6-months post-mTBI. mTBI patients presenting to acute care should be evaluated for psychiatric and headache/migraine history, with lower thresholds for providing TBI education/resources, surveillance, and follow-up/referrals. © 2019 Yue, Cnossen, Winkler, Deng, Phelps, Coss, Sharma, Robinson, Suen, Vassar, Schnyer, Puccio, Gardner, Yuh, Mukherjee, Valadka, Okonkwo, Lingsma, Manley and TRACK-TBI Investigators. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Author Keywords
Functional impairment;  Mild traumatic brain injury;  Post-concussive symptoms;  Pre-injury comorbidities;  Prognosis

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

Preoperative Anxiety Effect on Patient-Reported Outcomes Following Foot and Ankle Surgery
(2019) Foot and Ankle International, . 

Nixon, D.C., Schafer, K.A., Cusworth, B., McCormick, J.J., Johnson, J.E., Klein, S.E.

Department of Orthopedic Surgery, Washington University in St. Louis, St Louis, MO, United States

Abstract
Background: Preoperative emotional distress has been shown to negatively influence joint arthroplasty and spine surgery, but limited data exist for foot and ankle outcomes. Emotional distress can be captured through modern tools like the Patient-Reported Outcomes Instrument Measurement System (PROMIS) anxiety domain. We hypothesized that patients with greater preoperative PROMIS anxiety scores would report greater pain and less function after foot and ankle surgery than patients with lower preoperative anxiety levels. Methods: Elective foot and ankle surgeries from May 2016 to December 2017 were retrospectively identified. PROMIS anxiety, pain interference (PI), and physical function (PF) scores were collected before and after surgery. Patients were grouped based on preoperative PROMIS scores greater or less than 59.4. A cutoff of PROMIS anxiety above 59.4 was selected as the threshold that corresponds to traditional measures of anxiety. Results: Compared to patients with less preoperative anxiety (average: 47.2, n=146), patients with higher preoperative anxiety (average: 63.9, n=59) had greater preoperative pain (PROMIS PI: 63.5 vs 59.1, P <.001) and lower physical function (PROMIS PF: 37.9 vs 42.0, P =.001). Postoperatively, patients with higher preoperative anxiety had more residual pain and greater functional disability as compared to patients with less preoperative emotional distress (PROMIS PI: 58.6 vs 52.9, P <.001; PROMIS PF: 39.8 vs 44.4, P <.001; respectively). Conclusion: Our evidence showed that preoperative emotional anxiety predicted worse pain and function at early operative follow-up. Measures of preoperative anxiety could be useful in identifying patients at risk for poorer operative outcomes, but continued study is necessary. Level of Evidence: Level III, retrospective comparative study. © The Author(s) 2019.

Author Keywords
anxiety;  patient-reported outcomes;  PROMIS

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

Post-traumatic stress in the postoperative period: current status and future directions [Stress post-traumatique en période postopératoire : état de la situation et orientations futures]
(2019) Canadian Journal of Anesthesia, . 

El-Gabalawy, R.^{a b f} , Sommer, J.L.^a , Pietrzak, R.^{c d} , Edmondson, D.^e , Sareen, J.^f , Avidan, M.S.^g , Jacobsohn, E.^a

^a Department of Anesthesiology, Perioperative and Pain Medicine, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada
^b Department of Clinical Health Psychology, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada
^c Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States
^d U.S. Department of Veterans Affairs National Center for Posttraumatic Stress Disorder, West Haven, CT, United States
^e Center for Behavioral Cardiovascular Health, Department of Medicine, Columbia University Medical Center, New York, NY, United States
^f Department of Psychiatry, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada
^g Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Purpose: This narrative review summarizes the current literature on postoperative traumatic stress, namely post-traumatic stress disorder (PTSD), including defining features, epidemiology, identification of patient and perioperative risk factors, assessment tools, intervention recommendations, and future directions. Principal findings: Postoperative traumatic stress occurs in approximately 20% of patients following surgery, with additionally elevated rates in specific surgical groups. Potential risk factors include the perceived uncontrollable nature of high-risk surgery, psychiatric history, intraoperative awareness, dissociation, surgical complications, medication administration, delirium, and pain. PTSD after surgery may manifest in ways that are distinct from traditional conceptualizations of PTSD. Identification of perioperative risk factors and stress symptoms in the early postoperative period may provide opportunities for intervention. Conclusion: Research on postoperative traumatic stress, including PTSD, is in its infancy. Current evidence shows elevated incidence rates of postoperative traumatic stress, which can worsen overall physical and mental health outcomes. Future research on assessment, prevention, and treatment is warranted. © 2019, Canadian Anesthesiologists’ Society.

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

Developing a crosswalk between the RAND-12 and the health utilities index for multiple sclerosis
(2019) Multiple Sclerosis Journal, . 

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

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

Abstract
Background: Researchers studying health-related quality of life (HRQOL) in multiple sclerosis (MS) can choose from many instruments, but findings from studies which use different instruments cannot be easily combined. We aimed to develop a crosswalk that associates scores from the RAND-12 to scores on the Health Utilities Index—Mark III (HUI3) in persons with MS. Methods: In 2018, participants in the North American Research Committee on Multiple Sclerosis (NARCOMS) registry completed the RAND-12 and the HUI3 to assess HRQOL. We used item-response theory (IRT) and equipercentile linking approaches to develop a crosswalk between instruments. We compared predicted scores for the HUI3 from each crosswalk to observed scores using Pearson correlations, intraclass correlation coefficients (ICCs), and Bland–Altman plots. Results: Of 11,389 invited participants, 7129 (62.6%) responded. Predicted and observed values of the HUI3 from the IRT-linking method were moderately correlated (Pearson r = 0.76) with good concordance (ICC = 0.72). However, the Bland–Altman plots suggested biased prediction. Predicted and observed values from the equipercentile linking method were also moderately correlated (Pearson r = 0.78, ICC = 0.78). The Bland–Altman plots suggested no bias. Conclusion: We developed a crosswalk between the RAND-12 and the HUI3 in the MS population which will facilitate data harmonization efforts. © The Author(s), 2019.

Author Keywords
health utilities index;  Multiple sclerosis;  quality of life

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

“Paying” attention to audiovisual speech: Do incongruent stimuli incur greater costs?
(2019) Attention, Perception, and Psychophysics, . 

Brown, V.A.^a , Strand, J.F.^b

^a Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
^b Carleton College, Northfield, MN, United States

Abstract
The McGurk effect is a multisensory phenomenon in which discrepant auditory and visual speech signals typically result in an illusory percept. McGurk stimuli are often used in studies assessing the attentional requirements of audiovisual integration, but no study has directly compared the costs associated with integrating congruent versus incongruent audiovisual speech. Some evidence suggests that the McGurk effect may not be representative of naturalistic audiovisual speech processing – susceptibility to the McGurk effect is not associated with the ability to derive benefit from the addition of the visual signal, and distinct cortical regions are recruited when processing congruent versus incongruent speech. In two experiments, one using response times to identify congruent and incongruent syllables and one using a dual-task paradigm, we assessed whether congruent and incongruent audiovisual speech incur different attentional costs. We demonstrated that response times to both the speech task (Experiment 1) and a secondary vibrotactile task (Experiment 2) were indistinguishable for congruent compared to incongruent syllables, but McGurk fusions were responded to more quickly than McGurk non-fusions. These results suggest that despite documented differences in how congruent and incongruent stimuli are processed, they do not appear to differ in terms of processing time or effort, at least in the open-set task speech task used here. However, responses that result in McGurk fusions are processed more quickly than those that result in non-fusions, though attentional cost is comparable for the two response types. © 2019, The Psychonomic Society, Inc.

Author Keywords
Audiovisual integration;  Dual-task;  Listening effort;  McGurk effect;  Response time

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

Functional connectivity of the raphe nucleus as a predictor of the response to selective serotonin reuptake inhibitors in obsessive-compulsive disorder
(2019) Neuropsychopharmacology, . 

Kim, M.^{a b} , Kwak, S.^c , Yoon, Y.B.^d , Kwak, Y.B.^c , Kim, T.^c , Cho, K.I.K.^c , Lee, T.Y.^a , Kwon, J.S.^{a b c e}

^a Department of Neuropsychiatry, Seoul National University Hospital, Seoul, South Korea
^b Department of Psychiatry, Seoul National University College of Medicine, 101 Daehak-no, Chongno-gu, Seoul, 03080, South Korea
^c Department of Brain and Cognitive Sciences, Seoul National University College of Natural Science, Seoul, South Korea
^d Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
^e Institute of Human Behavioral Medicine, SNU-MRC, Seoul, South Korea

Abstract
Selective serotonin reuptake inhibitors (SSRIs) are first-line pharmacological agents for treating obsessive-compulsive disorder (OCD). However, because nearly half of patients show insufficient SSRI responses, serotonergic dysfunction in heterogeneous OCD patients should be investigated for precision medicine. We aimed to determine whether functional connectivity (FC) of the raphe nucleus (RN), the major source of most serotonergic neurons, was altered in OCD patients and could predict the SSRI response. A total of 102 medication-free OCD patients and 101 matched healthy control (HC) subjects participated in resting-state functional magnetic resonance imaging. Among them, 54 OCD patients were treated with SSRIs for 16 weeks, resulting in 26 responders and 28 nonresponders. Seed-based whole brain FC with the RN as a seed region was compared between the OCD and HC groups, as well as between SSRI responders and nonresponders. FC cluster values showing significant group differences were used to investigate factors correlated with symptomatic severity before treatment and predictive of SSRI response. Compared to HCs, OCD patients exhibited significantly larger FC between the RN and temporal cortices including the middle temporal gyrus (MTG), paracingulate gyrus, amygdala, hippocampus, putamen, thalamus, and brain stem. Greater RN-left MTG FC was positively correlated with OC symptom severity at baseline. In addition, larger FC of the RN-left MTG was also found in SSRI nonresponders compared to responders, which was a significant predictor of SSRI response after 16 weeks. The FC of RN may reflect the neurobiological underpinning of OCD and could aid future precision medicine as a differential brain-based biomarker. © 2019, American College of Neuropsychopharmacology.

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

Comparison of Myelin-Associated Glycoprotein with Vincristine for Facial Nerve Inhibition after Bilateral Axotomy in a Transgenic Thy1-Gfp Rat Model
(2019) JAMA Facial Plastic Surgery, . 

Ali, S.A.^a , Hanks, J.E.^a , Stebbins, A.W.^{a b} , Cohen, S.T.^a , Hunter, D.A.^c , Snyder-Warwick, A.K.^c , MacKinnon, S.E.^c , Kupfer, R.A.^a , Hogikyan, N.D.^a , Feldman, E.L.^b , Brenner, M.J.^a

^a Department of Otolaryngology-Head and Neck Surgery, Michigan Medicine, Taubman Center, 1500 E Medical Center Dr, SPC 5312 1904, Ann Arbor, MI 48109-5312, United States
^b Department of Neurology, Michigan Medicine, Ann Arbor, United States
^c Division of Plastic and Reconstructive Surgery, Department of Surgery, Washington University School of Medicine in St Louis, St Louis, MO, United States

Abstract
Importance: Aberrant synkinetic movement after facial nerve injury can lead to prominent facial asymmetry and resultant psychological distress. The current practices of neuroinhibition to promote greater facial symmetry are often temporary in nature and require repeated procedures. Objective: To determine whether myelin-associated glycoprotein (MAG), a specific neuroinhibitor, can prevent neuroregeneration with efficacy comparable with that of vincristine, a well-established neurotoxin. Design, Setting, and Participants: Rats transgenic for Thy-1 cell surface antigen-green fluorescent protein (Thy1-Gfp) were randomized into 3 groups. Each rat received bilateral crush axotomy injuries to the buccal and marginal mandibular branches of the facial nerves. The animals received intraneural injection of saline, MAG, or vincristine. Main Outcomes and Measures: The animals were imaged via fluorescent microscopy at weeks 1, 3, 4, and 5 after surgery. Quantitative fluorescent data were generated as mean intensities of nerve segments proximal and distal to the axotomy site. Electrophysiological analysis, via measurement of compound muscle action potentials, was performed at weeks 0, 3, 4, and 5 after surgery. Results: A total of 12 rats were included in the study. Administration of MAG significantly reduced fluorescent intensity of the distal nerve in comparison with the control group at week 3 (mean [SD], MAG group: 94 [11] intensity units vs control group: 130 [11] intensity units; P <.001), week 4 (MAG group: 81 [19] intensity units vs control group: 103 [9] intensity units; P =.004), and week 5 (MAG group: 76 [10] intensity units vs control group: 94 [10] intensity units; P <.001). In addition, rats treated with MAG had greater fluorescent intensity than those treated with vincristine at week 3 (mean [SD], MAG group: 94 [11] intensity units vs vincristine group: 76 [6] intensity units; P =.03), although there was no significant difference for weeks 4 and 5. At week 5, both MAG and vincristine demonstrated lower distal nerve to proximal nerve intensity ratios than the control group (control group, 0.94; vs MAG group, 0.82; P =.01; vs vincristine group; 0.77; P <.001). There was no significant difference in amplitude between the experimental groups at week 5 of electrophysiological testing. Conclusions and Relevance: Lower facial asymmetry and synkinesis are common persistent concerns to patients after facial nerve injury. Using the Thy1-Gfp rat, this study demonstrates effective inhibition of neuroregeneration via intraneural application of MAG in a crush axotomy model, comparable with results with vincristine. By potentially avoiding systemic toxic effects of vincristine, MAG demonstrates potential as an inhibitor of neural regeneration for patients with synkinesis. Level of Evidence: NA.. © 2019 American Medical Association. All rights reserved.

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