WashU weekly Neuroscience publications

Orbitofrontal-striatal potentiation underlies cocaine-induced hyperactivity
(2020) Nature Communications, 11 (1), art. no. 3996, .

Bariselli, S.^a d , Miyazaki, N.L.^a , Creed, M.C.^b c , Kravitz, A.V.^a c

^a National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, United States
^b Washington University Pain Center, St Louis, MO 63110, United States
^c Departments of Psychiatry, Anesthesiology, and Neuroscience, Washington University School of Medicine, St Louis, MO 63110, United States
^d National Institute on Alcohol Abuse and Alcoholism (NIAAA), Laboratory for Integrative Neuroscience (LIN), Bethesda, MD 20892-9412, United States

Abstract
Psychomotor stimulants increase dopamine levels in the striatum and promote locomotion; however, their effects on striatal pathway function in vivo remain unclear. One model that has been proposed to account for these motor effects suggests that stimulants drive hyperactivity via activation and inhibition of direct and indirect pathway striatal neurons, respectively. Although this hypothesis is consistent with the cellular actions of dopamine receptors and received support from optogenetic and chemogenetic studies, it has been rarely tested with in vivo recordings. Here, we test this model and observe that cocaine increases the activity of both pathways in the striatum of awake mice. These changes are linked to a dopamine-dependent cocaine-induced strengthening of upstream orbitofrontal cortex (OFC) inputs to the dorsomedial striatum (DMS) in vivo. Finally, depressing OFC-DMS pathway with a high frequency stimulation protocol in awake mice over-powers the cocaine-induced potentiation of OFC-DMS pathway and attenuates the expression of locomotor sensitization, directly linking OFC-DMS potentiation to cocaine-induced hyperactivity. © 2020, The Author(s).

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

Aging alters neural activity at event boundaries in the hippocampus and Posterior Medial network
(2020) Nature Communications, 11 (1), art. no. 3980, .

Reagh, Z.M.^a b c , Delarazan, A.I.^a b , Garber, A.^b , Ranganath, C.^b d

^a Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
^b UC Davis Center for Neuroscience, University of California, Davis, CA, United States
^c Department of Neurology, University of California, Davis, CA, United States
^d Department of Psychology, University of California, Davis, CA, United States

Abstract
Recent research has highlighted a role for the hippocampus and a Posterior Medial cortical network in signaling event boundaries. However, little is known about whether or how these neural processes change over the course of healthy aging. Here, 546 cognitively normal participants 18–88 years old viewed a short movie while brain activity was measured using fMRI. The hippocampus and regions of the Posterior Medial network show increased activity at event boundaries, but these boundary-evoked responses decrease with age. Boundary-evoked activity in the posterior hippocampus predicts performance on a separate test of memory for stories, suggesting that hippocampal activity during event segmentation may be a broad indicator of individual differences in episodic memory ability. In contrast, boundary-evoked responses in the medial prefrontal cortex and middle temporal gyrus increase across the age range. These findings suggest that aging may alter neural processes for segmenting and remembering continuous real-world experiences. © 2020, The Author(s).

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

It’s complicated: The relationship between sleep and Alzheimer’s disease in humans
(2020) Neurobiology of Disease, 144, art. no. 105031, .

Lucey, B.P.^a b

^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

Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by an asymptomatic period of amyloid-β (Aβ) deposition as insoluble extracellular plaque, intracellular tau aggregation, neuronal and synaptic loss, and subsequent cognitive dysfunction and dementia. A growing public health crisis, the worldwide prevalence of AD is expected to rise from 46.8 million individuals affected in 2015 to 131.5 million in 2050. Sleep disturbances have been associated with increased future risk of AD. A bi-directional relationship is hypothesized between sleep and AD with sleep disturbances as either markers for AD pathology and/or a mechanism mediating increased risk of AD. In this review, the evidence in humans supporting this complex relationship between sleep and AD will be discussed as well as the therapeutic potential and challenges of treating sleep disturbances to prevent or delay the onset of AD. © 2020 The Author

Author Keywords
Alzheimer’s disease;  Amyloid-beta;  Sleep;  Tau

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

Effects of MS disease-modifying therapies on responses to vaccinations: A review.
(2020) Multiple Sclerosis and Related Disorders, 45, art. no. 102439, .

Ciotti, J.R., Valtcheva, M.V., Cross, A.H.

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

Abstract
Background: : Development of long-term immunologic memory relies upon humoral and cellular immune responses. Vaccinations aim to stimulate these responses against pathogens. Several studies have evaluated the impact of multiple sclerosis disease-modifying therapies on immune response to vaccines. Findings from these studies have important implications for people with multiple sclerosis who require vaccination and are using disease-modifying therapies. Methods: : Searches using PubMed and other engines were conducted in May 2020 to collect studies evaluating the impact of various disease-modifying therapies on immune responses to vaccination. Results: : Several studies demonstrated preserved immune responses in people treated with beta-interferons to multiple vaccine types. Limited data suggest vaccine responses to be preserved with dimethyl fumarate treatment, as well. Vaccine responses were reduced to varying degrees in those treated with glatiramer acetate, teriflunomide, sphingosine-1-phosphate receptor modulators, and natalizumab. The timing of vaccination played an important role in those treated with alemtuzumab. Humoral vaccine responses were significantly impaired by B cell depleting anti-CD20 monoclonal antibody therapies, particularly to a neoantigen. Data are lacking on vaccine responses in patients with multiple sclerosis taking cladribine and high-dose corticosteroids. Notably, the majority of these studies have focused on humoral responses, with few examining cellular immune responses to vaccination. Conclusions: : Prior investigations into the effects of individual disease-modifying therapies on immune responses to existing vaccines can serve as a guide to expected responses to a SARS-CoV-2 vaccine. Responses to any vaccination depend on the vaccine type, the type of response (recall versus response to a novel antigen), and the impact of the individual disease-modifying therapy on humoral and cellular immunity in response to that vaccine type. When considering a given therapy, clinicians should weigh its efficacy against MS for the individual patient versus potential impact on responses to vaccinations that may be needed in the future. © 2020 Elsevier B.V.

Author Keywords
Disease-modifying therapies;  Multiple sclerosis;  Vaccines

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

List-level control in the flanker task
(2020) Quarterly Journal of Experimental Psychology, 73 (9), pp. 1444-1459.

Bugg, J.M.^a , Gonthier, C.^b

^a Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Psychology, University of Rennes, Rennes, France

Abstract
Current theories posit multiple levels of cognitive control for resolving conflict, including list-level control: the global or proactive biasing of attention across a list of trials. However, to date, evidence for pure list-level control has largely been confined to the Stroop task. Our goals were twofold: (a) test the generality of theoretical accounts by seeking evidence for list-level control in the letter flanker task, using an established method involving diagnostic items, and investigating the conditions under which list-level control may and may not be observed and (b) develop and test a potential solution to the challenge of isolating list-level control in tasks with a relatively limited set of stimuli and responses such as arrow flanker. Our key findings were that list-level control was observed for the first time in a letter flanker task on diagnostic items (Experiment 1), and it was not observed when the design was altered to encourage learning and use of simple stimulus–response associations (Experiment 2). These findings support the generalisability of current theoretical accounts positing dual-mechanisms or multiple levels of control, and the associations as antagonists to control account positing that list-level control may be a last resort, to conflict tasks besides Stroop. List-level control was also observed in the arrow flanker task using a modified design (Experiment 3), which could be extended to other conflict tasks with limited sets of stimuli (four or fewer), although this solution is not entirely free of confounds. © Experimental Psychology Society 2020.

Author Keywords
Cognitive control;  flanker task;  proactive control;  proportion congruency effects

Document Type: Article
Publication Stage: Final
Source: Scopus

Rapid adaptation to fully intelligible nonnative-accented speech reduces listening effort
(2020) Quarterly Journal of Experimental Psychology, 73 (9), pp. 1431-1443.

Brown, V.A.^a , McLaughlin, D.J.^a , Strand, J.F.^b , Van Engen, K.J.^a

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

Abstract
In noisy settings or when listening to an unfamiliar talker or accent, it can be difficult to understand spoken language. This difficulty typically results in reductions in speech intelligibility, but may also increase the effort necessary to process the speech even when intelligibility is unaffected. In this study, we used a dual-task paradigm and pupillometry to assess the cognitive costs associated with processing fully intelligible accented speech, predicting that rapid perceptual adaptation to an accent would result in decreased listening effort over time. The behavioural and physiological paradigms provided converging evidence that listeners expend greater effort when processing nonnative- relative to native-accented speech, and both experiments also revealed an overall reduction in listening effort over the course of the experiment. Only the pupillometry experiment, however, revealed greater adaptation to nonnative- relative to native-accented speech. An exploratory analysis of the dual-task data that attempted to minimise practice effects revealed weak evidence for greater adaptation to the nonnative accent. These results suggest that even when speech is fully intelligible, resolving deviations between the acoustic input and stored lexical representations incurs a processing cost, and adaptation may attenuate this cost. © Experimental Psychology Society 2020.

Author Keywords
accented speech;  dual-task;  listening effort;  pupillometry;  Speech perception

Document Type: Article
Publication Stage: Final
Source: Scopus

Ofatumumab versus Teriflunomide in Multiple Sclerosis
(2020) The New England Journal of Medicine, 383 (6), pp. 546-557.

Hauser, S.L., Bar-Or, A., Cohen, J.A., Comi, G., Correale, J., Coyle, P.K., Cross, A.H., de Seze, J., Leppert, D., Montalban, X., Selmaj, K., Wiendl, H., Kerloeguen, C., Willi, R., Li, B., Kakarieka, A., Tomic, D., Goodyear, A., Pingili, R., Häring, D.A., Ramanathan, K., Merschhemke, M., Kappos, L., ASCLEPIOS I and ASCLEPIOS II Trial Groups

From the UCSF Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco (S.L.H.); the Center for Neuroinflammation and Experimental Therapeutics and Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia (A.B.-O.); the Department of Neurology, Mellen Center for Multiple Sclerosis, Neurological Institute, Cleveland Clinic, Cleveland (J.A.C.); the Institute of Experimental Neurology and Multiple Sclerosis Center IRCCS, San Raffaele Hospital, Milan (G.C.); the Department of Neurology, Fleni, Buenos Aires (J.C.); the Department of Neurology, Stony Brook University, Stony Brook, NY (P.K.C.); Washington University School of Medicine, St. Louis (A.H.C.); the University Hospital of Strasburg and Clinical Investigation Center INSERM 1434, Strasburg, France (J.S.); University Hospital Basel (D.L.), Novartis Pharma (C.K., R.W., A.K., D.T., D.A.H., K.R., M.M.), and the Neurologic Clinic and Policlinic, Departments of Medicine, Clinical Research, Biomedicine, and Biomedical Engineering, University Hospital and University of Basel (L.K.) – all in Basel, Switzerland; the Department of Neurology-Neuroimmunology, Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Hospital Universitari Vall d’Hebron, Barcelona (X.M.); the University of Warmia and Mazury, Olsztyn, and the Center of Neurology, Lodz – both in Poland (K.S.); the Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany (H.W.); and Novartis Pharmaceuticals, East Hanover, NJ (B.L., A.G., R.P.)

Abstract
BACKGROUND: Ofatumumab, a subcutaneous anti-CD20 monoclonal antibody, selectively depletes B cells. Teriflunomide, an oral inhibitor of pyrimidine synthesis, reduces T-cell and B-cell activation. The relative effects of these two drugs in patients with multiple sclerosis are not known. METHODS: In two double-blind, double-dummy, phase 3 trials, we randomly assigned patients with relapsing multiple sclerosis to receive subcutaneous ofatumumab (20 mg every 4 weeks after 20-mg loading doses at days 1, 7, and 14) or oral teriflunomide (14 mg daily) for up to 30 months. The primary end point was the annualized relapse rate. Secondary end points included disability worsening confirmed at 3 months or 6 months, disability improvement confirmed at 6 months, the number of gadolinium-enhancing lesions per T1-weighted magnetic resonance imaging (MRI) scan, the annualized rate of new or enlarging lesions on T2-weighted MRI, serum neurofilament light chain levels at month 3, and change in brain volume. RESULTS: Overall, 946 patients were assigned to receive ofatumumab and 936 to receive teriflunomide; the median follow-up was 1.6 years. The annualized relapse rates in the ofatumumab and teriflunomide groups were 0.11 and 0.22, respectively, in trial 1 (difference, -0.11; 95% confidence interval [CI], -0.16 to -0.06; P<0.001) and 0.10 and 0.25 in trial 2 (difference, -0.15; 95% CI, -0.20 to -0.09; P<0.001). In the pooled trials, the percentage of patients with disability worsening confirmed at 3 months was 10.9% with ofatumumab and 15.0% with teriflunomide (hazard ratio, 0.66; P = 0.002); the percentage with disability worsening confirmed at 6 months was 8.1% and 12.0%, respectively (hazard ratio, 0.68; P = 0.01); and the percentage with disability improvement confirmed at 6 months was 11.0% and 8.1% (hazard ratio, 1.35; P = 0.09). The number of gadolinium-enhancing lesions per T1-weighted MRI scan, the annualized rate of lesions on T2-weighted MRI, and serum neurofilament light chain levels, but not the change in brain volume, were in the same direction as the primary end point. Injection-related reactions occurred in 20.2% in the ofatumumab group and in 15.0% in the teriflunomide group (placebo injections). Serious infections occurred in 2.5% and 1.8% of the patients in the respective groups. CONCLUSIONS: Among patients with multiple sclerosis, ofatumumab was associated with lower annualized relapse rates than teriflunomide. (Funded by Novartis; ASCLEPIOS I and II ClinicalTrials.gov numbers, NCT02792218 and NCT02792231.). Copyright © 2020 Massachusetts Medical Society.

Document Type: Article
Publication Stage: Final
Source: Scopus

De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects
(2020) American Journal of Human Genetics, 107 (2), pp. 311-324.

Manole, A.^a , Efthymiou, S.^a , O’Connor, E.^a , Mendes, M.I.^b , Jennings, M.^c , Maroofian, R.^a , Davagnanam, I.^at , Mankad, K.^d , Lopez, M.R.^e , Salpietro, V.^a , Harripaul, R.^f g , Badalato, L.^h , Walia, J.^h , Francklyn, C.S.ⁱ , Athanasiou-Fragkouli, A.^a , Sullivan, R.^a , Desai, S.^j , Baranano, K.^j , Zafar, F.^k , Rana, N.^k , Ilyas, M.^l , Horga, A.^a , Kara, M.^m , Mattioli, F.^p , Goldenberg, A.^o , Griffin, H.^c , Piton, A.^p , Henderson, L.B.^q , Kara, B.^r , Aslanger, A.D.^r , Raaphorst, J.^s t , Pfundt, R.^s , Portier, R.^u , Shinawi, M.^v , Kirby, A.^w , Christensen, K.M.^w , Wang, L.^x , Rosti, R.O.^x , Paracha, S.A.^y , Sarwar, M.T.^y , Jenkins, D.^av , Ahmed, J.^y , Santoni, F.A.^z aa , Ranza, E.^z ab ac , Iwaszkiewicz, J.^ad , Cytrynbaum, C.^ae , Weksberg, R.^ae , Wentzensen, I.M.^q , Guillen Sacoto, M.J.^q , Si, Y.^q , Telegrafi, A.^q , Andrews, M.V.^v , Baldridge, D.^v , Gabriel, H.^af , Mohr, J.^af , Oehl-Jaschkowitz, B.^ag , Debard, S.ⁿ , Senger, B.ⁿ , Fischer, F.ⁿ , van Ravenwaaij, C.^ah , Fock, A.J.M.^ah , Stevens, S.J.C.^ai , Bähler, J.^e , Nasar, A.^h , Mantovani, J.F.^ar , Manzur, A.^av , Sarkozy, A.^av , Smith, D.E.C.^b , Salomons, G.S.^b , Ahmed, Z.M.^as , Riazuddin, S.^aj , Riazuddin, S.^as , Usmani, M.A.^as , Seibt, A.^ak , Ansar, M.^z au , Antonarakis, S.E.^z ab al , Vincent, J.B.^f g , Ayub, M.^h , Grimmel, M.^am , Jelsig, A.M.^an , Hjortshøj, T.D.^an , Karstensen, H.G.^an , Hummel, M.^ao , Haack, T.B.^am ap , Jamshidi, Y.^aq , Distelmaier, F.^ak , Horvath, R.^c , Gleeson, J.G.^x , Becker, H.ⁿ , Mandel, J.-L.^p , Koolen, D.A.^s , Houlden, H.^a , SYNAPS Study Group^aw

^a Department of Neuromuscular Disorders, University College London (UCL) Institute of Neurology, Queen Square, London, WC1N 3BG, United Kingdom
^b Metabolic Unit, Department of Clinical Chemistry, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam Gastroenterology and Metabolism, Amsterdam, 1081, Netherlands
^c Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0QQ, United Kingdom
^d Department of Neuroradiology, Great Ormond Street Hospital for Children, London, WC1N 3JH, United Kingdom
^e Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London (UCL), London, WC1E 6BT, United Kingdom
^f Campbell Family Mental Health Research Institute, Centre for Addiction and Mental HealthON M5T 1R8, Canada
^g Institute of Medical Science and Department of Psychiatry, University of Toronto, Toronto, ON M5T 1R8, Canada
^h Department of Pediatrics, Queen’s University, Kingston, ON K7L 2V7, Canada
ⁱ Department of Biochemistry, University of Vermont College of Medicine, Burlington, VT 05405, United States
^j Department of Neurology and Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD 21205, United States
^k Department of Pediatrics, Multan Hospital, Multan, 60000, Pakistan
^l University of Islamabad, Islamabad, 45320, Pakistan
^m Department of Pediatrics, Tripoli Children’s Hospital, Tripoli, Libyan Arab Jamahiriya
ⁿ University of Strasbourg, CNRS, GMGM UMR 7156Strasbourg 67083, France
^o Département de Génétique, centre de référence anomalies du développement et syndromes malformatifs, CHU de Rouen, Inserm U1245, UNIROUEN, Normandie Université, Centre Normand de Génomique et de Médecine Personnalisée, Rouen, 76031, France
^p Institute for Genetics and Molecular and Cellular Biology (IGBMC), University of Strasbourg, CNRS UMR7104, INSERM U1258Illkirch 67404, France
^q GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, United States
^r Bezmiâlem Vakıf Üniversitesi, Istanbul, 34093, Turkey
^s Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, 6500HB, Netherlands
^t Department of Neurology, Amsterdam Neuroscience Institute, Amsterdam University Medical Center, Amsterdam, 1105AZ, Netherlands
^u Department of Neurology, Medisch Spectrum Twente, Enschede, 7512KZ, Netherlands
^v Department of Pediatrics, Divisions of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
^w Division of Medical Genetics, SSM Health Cardinal Glennon Children’s Hospital, Saint Louis University School of Medicine, St. Louis, MO 63104, United States
^x Howard Hughes Medical Institute, University of California San Diego and Rady Children’s Hospital, La Jolla, CA 92130, United States
^y Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, 25100, Pakistan
^z Department of Genetic Medicine and Development, University of Geneva, Geneva, 1206, Switzerland
^aa Department of Endocrinology, Diabetes, and Metabolism, University Hospital of Lausanne, Lausanne, 1011, Switzerland
^ab Service of Genetic Medicine, University Hospitals of Geneva, Geneva, 1205, Switzerland
^ac Medigenome, The Swiss Institute of Genomic Medicine, Geneva, CH-1207, Switzerland
^ad Swiss Institute of Bioinformatics, Molecular Modeling Group, Batiment Genopode, Unil Sorge, Lausanne, CH-1015, Switzerland
^ae Hospital for Sick Children, Division of Clinical and Metabolic Genetics, 555 University Ave., Toronto, M5G 1X8, Canada
^af CeGaT GmbH and Praxis für Humangenetik Tuebingen, Tuebingen, 72076, Germany
^ag Biomedical Centre Cardinal-Wendel-Straße 14, Hamburg, 66424, Germany
^ah University of Groningen, University Medical Center Groningen, Department of Neurology, Groningen, 9713, Netherlands
^ai Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, 6211, Netherlands
^aj Jinnah Burn and Reconstructive Surgery Center, Allama Iqbal Medical College, University of Health Sciences, Lahore, 54550, Pakistan
^ak Department of General Pediatrics, Heinrich-Heine-University, Moorenstr. 5, Düsseldorf, 40225, Germany
^al iGE3 Institute of Genetics and Genomics of Geneva, Geneva, 1211, Switzerland
^am Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tübingen, 72076, Germany
^an Department of Clinical Genetics, University Hospital of Copenhagen, Rigshospitalet2100, Denmark
^ao Department of Pediatrics, Section of Medical Genetics, West Virginia University, Morgantown, WV 26506-9600, United States
^ap Centre for Rare Diseases, University of Tuebingen, Tübingen, 72076, Germany
^aq Genetics Centre, Molecular and Clinical Sciences Institute, St George’s University of London, London, SW17 0RE, United Kingdom
^ar Division of Child Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
^as Department of Biochemistry and Molecular Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205, United States
^at Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, United Kingdom
^au Institute of Molecular and Clinical Ophthalmology Basel, Basel, Switzerland
^av Institute of Child Health, Guilford Street and Dubowitz Neuromuscular Centre, Great Ormond Street Hospital for Children, London, WC1N 3JH, United Kingdom
^aw SYNAPS Study Group, see Supplemental Information for the study group members who contributed clinical cases and data

Abstract
Aminoacyl-tRNA synthetases (ARSs) are ubiquitous, ancient enzymes that charge amino acids to cognate tRNA molecules, the essential first step of protein translation. Here, we describe 32 individuals from 21 families, presenting with microcephaly, neurodevelopmental delay, seizures, peripheral neuropathy, and ataxia, with de novo heterozygous and bi-allelic mutations in asparaginyl-tRNA synthetase (NARS1). We demonstrate a reduction in NARS1 mRNA expression as well as in NARS1 enzyme levels and activity in both individual fibroblasts and induced neural progenitor cells (iNPCs). Molecular modeling of the recessive c.1633C>T (p.Arg545Cys) variant shows weaker spatial positioning and tRNA selectivity. We conclude that de novo and bi-allelic mutations in NARS1 are a significant cause of neurodevelopmental disease, where the mechanism for de novo variants could be toxic gain-of-function and for recessive variants, partial loss-of-function. © 2020

Author Keywords
aminoacyl-tRNA synthetase;  developmental delay;  epilepsy;  neurodevelopment;  neuropathy;  next generation sequencing

Document Type: Article
Publication Stage: Final
Source: Scopus

Comorbidity is associated with disease activity in MS: Findings from the CombiRx trial
(2020) Neurology, 95 (5), pp. e446-e456.

Salter, A., Kowalec, K., Fitzgerald, K.C., Cutter, G., Marrie, R.A.

From the Department of Biostatistics (A.S.), Washington University in St. Louis, MO; College of Pharmacy (K.K.), and Departments of Internal Medicine and Community Health Sciences (R.A.M.), Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada; Department of Medical Epidemiology and Biostatistics (K.K.), Karolinska Institutet, Solna, Sweden; Department of Neurology (K.C.F.), Johns Hopkins School of Medicine, Baltimore, MD; and Department of Biostatistics (G.C.), University of Alabama in Birmingham School of Public Health

Abstract
OBJECTIVE: To determine whether comorbidity is associated with clinical (relapses, disability worsening) and MRI outcomes in multiple sclerosis (MS) by conducting a secondary analysis of the CombiRx clinical trial. METHODS: CombiRx compared interferon beta-1a, glatiramer acetate, and the combination of these agents. For participants eligible for evaluation of 6-month confirmed disability worsening, we used medical history, concomitant medications, and adverse events to ascertain comorbidity status. Comorbid conditions evaluated included hypertension, dyslipidemia, diabetes mellitus, depression, anxiety disorders, and migraine. Clinical outcomes included disease activity consisting of protocol-defined relapses, disability worsening, and MRI activity. We summarized the prevalence of these comorbid conditions and their association with disease activity and its components using multivariable Cox regression. RESULTS: Of the 1,008 participants randomized, 959 (95.1%) were eligible for assessment of 6-month disability worsening; for this subgroup, the median length of follow-up was 3.4 years (range 0.5-6.9 years). Overall, 55.1% of participants had ≥1 comorbidity at enrollment. After adjustment, anxiety (hazard ratio [HR] 1.25, 95% confidence interval [CI] 1.01-1.55) and dyslipidemia (HR 1.32, 95% CI 1.01-1.72) were associated with an increased hazard of any disease activity, while migraine (HR 0.80, 95% CI 0.67-0.97) was associated with a decreased hazard. CONCLUSIONS: In this large trial population with rigorously obtained outcomes, comorbid conditions were common among participants and influenced disease outcomes, including relapses. The comorbidity burden of clinical trial participants with MS may be an important factor in the outcome of clinical trials. Additional investigations of the impact of comorbidity on clinical trial outcomes and response to disease-modifying therapies are warranted. © 2020 American Academy of Neurology.

Document Type: Article
Publication Stage: Final
Source: Scopus

Inhibition of DNAJ-HSP70 interaction improves strength in muscular dystrophy
(2020) The Journal of Clinical Investigation, 130 (8), pp. 4470-4485.

Bengoechea, R.^a , Findlay, A.R.^a , Bhadra, A.K.^b , Shao, H.^c , Stein, K.C.^d , Pittman, S.K.^a , Daw, J.A.^a , Gestwicki, J.E.^c , True, H.L.^b , Weihl, C.C.^a

^a Department of Neurology and
^b Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, United States
^c Institute for Neurodegenerative Diseases, UCSF, San Francisco, CA, United States
^d Department of Biology, Stanford University, Stanford, CA, United States

Abstract
Dominant mutations in the HSP70 cochaperone DNAJB6 cause a late-onset muscle disease termed limb-girdle muscular dystrophy type D1 (LGMDD1), which is characterized by protein aggregation and vacuolar myopathology. Disease mutations reside within the G/F domain of DNAJB6, but the molecular mechanisms underlying dysfunction are not well understood. Using yeast, cell culture, and mouse models of LGMDD1, we found that the toxicity associated with disease-associated DNAJB6 required its interaction with HSP70 and that abrogating this interaction genetically or with small molecules was protective. In skeletal muscle, DNAJB6 localizes to the Z-disc with HSP70. Whereas HSP70 normally diffused rapidly between the Z-disc and sarcoplasm, the rate of diffusion of HSP70 in LGMDD1 mouse muscle was diminished, probably because it had an unusual affinity for the Z-disc and mutant DNAJB6. Treating LGMDD1 mice with a small-molecule inhibitor of the DNAJ-HSP70 complex remobilized HSP70, improved strength, and corrected myopathology. These data support a model in which LGMDD1 mutations in DNAJB6 are a gain-of-function disease that is, counterintuitively, mediated via HSP70 binding. Thus, therapeutic approaches targeting HSP70-DNAJB6 may be effective in treating this inherited muscular dystrophy.

Author Keywords
Cell Biology;  Chaperones;  Muscle Biology;  Protein misfolding;  Skeletal muscle

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

Efficient Transgenesis in Caenorhabditis elegans Using Flp Recombinase-Mediated Cassette Exchange
(2020) Genetics, 215 (4), pp. 903-921.

Nonet, M.L.

Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
The application of CRISPR technology has greatly facilitated the creation of transgenic Caenorhabditis elegans lines. However, methods to insert multi-kilobase DNA constructs remain laborious even with these advances. Here, I describe a new approach for introducing large DNA constructs into the C. elegans genome at specific sites using a combination of Flp and Cre recombinases. The system utilizes specialized integrated landing sites that express GFP ubiquitously flanked by single loxP, FRT, and FRT3 sites. DNA sequences of interest are inserted into an integration vector that contains a sqt-1 self-excising cassette and FRT and FRT3 sites. Plasmid DNA is injected into the germline of landing site animals. Transgenic animals are identified as Rol progeny, and the sqt-1 marker is subsequently excised with heat shock Cre expression. Integration events were obtained at a rate of approximately one integration per three injected F0 animals-a rate substantially higher than any current approach. To demonstrate the robustness of the approach, I compared the efficiency of the Gal4/UAS, QF (and QF2)/QUAS, tetR(and rtetR)/tetO, and LexA/lexO bipartite expression systems by assessing expression levels in combinations of driver and reporter GFP constructs and a direct promoter GFP fusion each integrated at multiple sites in the genome. My data demonstrate that all four bipartite systems are functional in C. elegans Although the new integration system has several limitations, it greatly reduces the effort required to create single-copy insertions at defined sites in the C. elegans genome. Copyright © 2020 by the Genetics Society of America.

Author Keywords
bipartite expression systems;  Cre recombinase;  integration

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

Primary Care Providers And Specialists Deliver Comparable Buprenorphine Treatment Quality
(2020) Health Affairs (Project Hope), 39 (8), pp. 1395-1404.

Gertner, A.K.^a , Robertson, A.G.^b , Powell, B.J.^c , Jones, H.^d , Silberman, P.^e , Domino, M.E.^f

^a Alex K. Gertner () is an MD/PhD candidate in health policy and management at the University of North Carolina at Chapel Hill ,in Chapel HillNC
^b Duke University School of Medicine, Allison G. Robertson is an associate professor in the Department of Psychiatry and Behavioral SciencesNC
^c Washington University in St. Louis, in St. Louis, Byron J. Powell is an assistant professor at the Brown SchoolMO
^d Hendree Jones is a professor of obstetrics and gynecology at the University of North Carolina School of Medicine ,in Chapel HillNC
^e Pam Silberman is a professor of health policy and management at the University of North Carolina at Chapel Hill
^f Marisa Elena Domino is a professor of health policy and management at the University of North Carolina at Chapel Hill and the Cecil G. Sheps Center for Health Services Research

Abstract
In response to rising numbers of opioid overdose deaths, primary care providers have been called on to play a greater role in delivering buprenorphine treatment for opioid use disorder. However, policy makers and providers have raised concerns that expanding treatment access may reduce treatment quality and that primary care providers are not well equipped to deliver buprenorphine treatment. We investigated two research questions in response to these concerns: How did buprenorphine treatment use and quality change in North Carolina Medicaid from 2014 to 2017, and how did buprenorphine treatment quality differ between primary care providers and specialists in North Carolina Medicaid during this period? We measured buprenorphine treatment quality as patients’ retention in treatment and providers’ adherence to treatment guidelines. We found that the number of enrollees receiving medication treatment for opioid use disorder increased substantially, but the percentage of enrollees with the disorder receiving treatment remained low. The quality of buprenorphine treatment increased during the study period, and primary care providers provided care of comparable or higher quality compared with that of other providers. Treatment quality for buprenorphine treatment is improving, but there remains room for improvement in both use and quality. Our results support the role of primary care providers in expanding treatment for opioid use disorder.

Author Keywords
Buprenorphine;  Health care providers;  Health policy;  Medicaid;  Medication assisted treatment;  methadone;  Nonsubstance related additions;  opioid use disorder;  Patient care;  Pharmaceuticals;  Quality improvement;  Quality measurement;  Quality of care;  Substance use disorder

Document Type: Article
Publication Stage: Final
Source: Scopus

The consequences of processing goal-irrelevant information during the stroop task
(2020) Psychology and Aging, 35 (5), pp. 663-675. Cited 1 time.

Nicosia, J., Balota, D.

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

Abstract
Recent evidence indicates that older adults’ decreased ability to inhibit irrelevant information may lead to increased processing and greater memory for distractor information compared with younger adults. The present experiments examine the generality of this finding in a series of Stroop studies. In Experiment 1, participants studied a list of words then received a Stroop color naming task, with to-be-remembered words embedded within the Stroop task. Although there was evidence of a disproportionate age-related Stroop effect, there was no evidence of an age difference in episodic recognition memory for words from the Stroop task. Experiment 2 extended this paradigm to a more implicit demasking task. Again, there was evidence of an age-related disproportionate Stroop effect, however, there were no differences in memory for unattended words in demasking performance. Experiment 3 was a direct replication of a previous study which reported age differences in the influence of unattended words, via implicit priming in a general knowledge test. The results did not replicate the original study such that younger adults showed slightly more priming from distractors than older adults. The results provide converging evidence that although older adults have more difficulty inhibiting irrelevant information in the Stroop task, distractor information does not seem to disproportionately influence later memory for older adults compared with younger adults. These studies suggest that it is critical to consider the locus of memory encoding in distractor tasks to better understand the relationship between inhibitory processes during the distractor task and later memory performance. © 2020 American Psychological Association.

Author Keywords
Aging;  Attention;  Memory

Document Type: Article
Publication Stage: Final
Source: Scopus

A prospective, multi-center randomized, controlled, blinded trial of vagus nerve stimulation for difficult to treat depression: A novel design for a novel treatment
(2020) Contemporary Clinical Trials, 95, art. no. 106066, .

Conway, C.R.^a , Olin, B.^b , Aaronson, S.T.^c , Sackeim, H.A.^d , Bunker, M.^e , Kriedt, C.^a , Greco, T.^f , Broglio, K.ⁱ , Vestrucci, M.^g i , Rush, A.J.^h j k

^a Department of Psychiatry, Washington University in St. Louis, 660 S. Euclid Ave, Campus Box 8134, St. Louis, MO 63110, United States
^b LivaNova PLC, London, United Kingdom
^c Sheppard Pratt Health System, Department of Psychiatry, University of Maryland, Baltimore, MD, United States
^d Departments of Psychiatry and Radiology, Columbia University, New York, NY, United States
^e LivaNova PLC, Houston, TX, United States
^f LivaNova PLC, SORIN Group Italia S.r.l., Milano, Italy
^g Berry Consultants, Austin, TX, United States
^h Duke-NUS Medical School, Singapore
ⁱ Department of Statistics and Data Sciences, University of Texas, Austin, TX, United States
^j Duke University, Durham, NC, United States
^k Texas Tech University, Permian BasinTX, United States

Abstract
Few treatment options exist for patients with difficult-to-treat depression (DTD). One potentially efficacious treatment is vagus nerve stimulation (VNS): chronic stimulation of the vagus nerve using an implanted stimulator. Given a series of recent VNS clinical studies, including a large, five-year naturalistic investigation, the Center for Medicare and Medicaid Services (CMS) reconsidered the previous non coverage determination and announced coverage for patients participating in a “coverage with evidence” trial. This study, entitled, A PRospective, Multi-cEnter, Randomized Controlled Blinded Trial DemOnstrating the Safety and Effectiveness of VNS Therapy® System as AdjunctivE Therapy Versus a No Stimulation Control in Subjects With Treatment-Resistant Depression (RECOVER), includes DTD patients with at least four unsuccessful antidepressant treatments in the current episode and will randomize both unipolar and bipolar DTD participants, each up to 500 evaluable enrollees. Predetermined interim analyses will define the necessary sample size. All participants will be implanted with VNS devices: half receive active stimulation during year one, and half receive delayed stimulation after year one. Participants will be followed for 5 years. This RCT is unique for DTD studies: 1) large sample size and long study duration (one year of controlled comparison); 2) use of a percent time in response as the primary outcome measure, given the chronic illness and its fluctuating course (vis-à-vis meeting a response criteria at a single time point); 3) inclusion of diverse measures of VNS impact on function, including quality of life, degree of disability, health status, and suicidality. © 2020

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

The role of eye tracking technology in assessing older driver safety
(2020) Geriatrics (Switzerland), 5 (2), art. no. 36, .

Carr, D.B.^a , Grover, P.^b

^a Department of Medicine and Neurology, Washington University, School of Medicine, St Louis, MO 63110, United States
^b Department of Neurology, Washington University, School of Medicine, St Louis, MO 63110, United States

Abstract
A growing body of literature is focused on the use of eye tracking (ET) technology to understand the association between objective visual parameters and higher order brain processes such as cognition. One of the settings where this principle has found practical utility is in the area of driving safety. Methods: We reviewed the literature to identify the changes in ET parameters with older adults and neurodegenerative disease. Results: This narrative review provides a brief overview of oculomotor system anatomy and physiology, defines common eye movements and tracking variables that are typically studied, explains the most common methods of eye tracking measurements during driving in simulation and in naturalistic settings, and examines the association of impairment in ET parameters with advanced age and neurodegenerative disease. Conclusion: ET technology is becoming less expensive, more portable, easier to use, and readily applicable in a variety of clinical settings. Older adults and especially those with neurodegenerative disease may have impairments in visual search parameters, placing them at risk for motor vehicle crashes. Advanced driver assessment systems are becoming more ubiquitous in newer cars and may significantly reduce crashes related to impaired visual search, distraction, and/or fatigue. © 2020 by the authors.

Author Keywords
Alzheimer’s disease (AD);  Driving;  Eye tracking;  Older adults;  Rehabilitation

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

Self-Reporting Transposons Enable Simultaneous Readout of Gene Expression and Transcription Factor Binding in Single Cells
(2020) Cell, .

Moudgil, A.^a b c , Wilkinson, M.N.^a b , Chen, X.^a b , He, J.^a b , Cammack, A.J.^d , Vasek, M.J.^a e , Lagunas, T., Jr.^a e , Qi, Z.^a b , Lalli, M.A.^a , Guo, C.^a c f , Morris, S.A.^a f g , Dougherty, J.D.^a e , Mitra, R.D.^a b

^a Department of Genetics, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
^b Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
^c Medical Scientist Training Program, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
^d Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
^e Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
^f Department of Developmental Biology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
^g Center of Regenerative Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States

Abstract
Moudgil et al. present a single-cell method for simultaneously capturing gene expression and transcription factor binding site data from the same cells, first in cell lines and then in the mouse brain. © 2020 Elsevier Inc.

Cellular heterogeneity confounds in situ assays of transcription factor (TF) binding. Single-cell RNA sequencing (scRNA-seq) deconvolves cell types from gene expression, but no technology links cell identity to TF binding sites (TFBS) in those cell types. We present self-reporting transposons (SRTs) and use them in single-cell calling cards (scCC), a novel assay for simultaneously measuring gene expression and mapping TFBS in single cells. The genomic locations of SRTs are recovered from mRNA, and SRTs deposited by exogenous, TF-transposase fusions can be used to map TFBS. We then present scCC, which map SRTs from scRNA-seq libraries, simultaneously identifying cell types and TFBS in those same cells. We benchmark multiple TFs with this technique. Next, we use scCC to discover BRD4-mediated cell-state transitions in K562 cells. Finally, we map BRD4 binding sites in the mouse cortex at single-cell resolution, establishing a new method for studying TF biology in situ. © 2020 Elsevier Inc.

Author Keywords
bromodomains;  calling cards;  cell state;  mouse cortex;  single cell;  transcription factors;  transposons

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

TREM2 activation on microglia promotes myelin debris clearance and remyelination in a model of multiple sclerosis
(2020) Acta Neuropathologica, .

Cignarella, F.^a j , Filipello, F.^a b , Bollman, B.^a , Cantoni, C.^a , Locca, A.^a , Mikesell, R.^a , Manis, M.^a , Ibrahim, A.^c , Deng, L.^a d , Benitez, B.A.^e f g , Cruchaga, C.^e f g , Licastro, D.^h , Mihindukulasuriya, K.^e g , Harari, O.^e f g , Buckland, M.ⁱ , Holtzman, D.M.^a f , Rosenthal, A.^c , Schwabe, T.^c , Tassi, I.^c , Piccio, L.^a g i

^a Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8111, St. Louis, MO 63110, United States
^b Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele – Milan, 20090, Italy
^c Alector, 131 Oyster Point Blvd #600, South San Francisco, CA 94080, United States
^d Department of Anesthesiology, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China
^e Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
^f Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States
^g NeuroGenomics and Informatics, Washington University School of Medicine, St. Louis, MO 63110, United States
^h ARGO Open Lab Platform for Genome sequencing, AREA Science Park, Padriciano 99, Trieste, 34149, Italy
ⁱ Brain and Mind Centre, University of Sydney, 94 Mallett St Camperdown, Sydney, NSW 2050, Australia
^j Alector, 131 Oyster Point Blvd #600, South San Francisco, CA 94080, United States

Abstract
Multiple sclerosis (MS) is an inflammatory, demyelinating, and neurodegenerative disease of the central nervous system (CNS) triggered by autoimmune mechanisms. Microglia are critical for the clearance of myelin debris in areas of demyelination, a key step to allow remyelination. TREM2 is expressed by microglia and promotes microglial survival, proliferation, and phagocytic activity. Herein we demonstrate that TREM2 was highly expressed on myelin-laden phagocytes in active demyelinating lesions in the CNS of subjects with MS. In gene expression studies, macrophages from subjects with TREM2 genetic deficiency displayed a defect in phagocytic pathways. Treatment with a new TREM2 agonistic antibody promoted the clearance of myelin debris in the cuprizone model of CNS demyelination. Effects included enhancement of myelin uptake and degradation, resulting in accelerated myelin debris removal by microglia. Most importantly, antibody-dependent TREM2 activation on microglia increased density of oligodendrocyte precursors in areas of demyelination, as well as the formation of mature oligodendrocytes thus enhancing remyelination and axonal integrity. These results are relevant as they propose TREM2 on microglia as a potential new target to promote remyelination. © 2020, The Author(s).

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

Higher CSF sTREM2 and microglia activation are associated with slower rates of beta-amyloid accumulation
(2020) EMBO Molecular Medicine, . 

Ewers, M.^a b , Biechele, G.^c , Suárez-Calvet, M.^d e f , Sacher, C.^c , Blume, T.^b , Morenas-Rodriguez, E.^g , Deming, Y.^h , Piccio, L.^i j k , Cruchaga, C.^j l , Kleinberger, G.^g m , Shaw, L.ⁿ , Trojanowski, J.Q.^o , Herms, J.^b , Dichgans, M.^a b p , Brendel, M.^c , Haass, C.^b g p , Franzmeier, N.^a

^a Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig Maximilian University (LMU), Munich, Germany
^b German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
^c Department of Nuclear Medicine, University Hospital Munich, Ludwig Maximilian University Munich, Munich, Germany
^d Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain
^e IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
^f Servei de Neurologia, Hospital del Mar, Barcelona, Spain
^g Chair of Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany
^h Department of Population Health Sciences, University of Wisconsin-Madison, Madison, WI, United States
ⁱ Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
^j Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
^k Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia
^l Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^m ISAR Bioscience GmbH, Planegg, Germany
ⁿ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^o Center for Neurodegenerative Disease Research, Institute on Aging, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^p Munich Cluster for Systems Neurology (SyNergy), Munich, Germany

Abstract
Microglia activation is the brain’s major immune response to amyloid plaques in Alzheimer’s disease (AD). Both cerebrospinal fluid (CSF) levels of soluble TREM2 (sTREM2), a biomarker of microglia activation, and microglia PET are increased in AD; however, whether an increase in these biomarkers is associated with reduced amyloid-beta (Aβ) accumulation remains unclear. To address this question, we pursued a two-pronged translational approach. Firstly, in non-demented and demented individuals, we tested CSF sTREM2 at baseline to predict (i) amyloid PET changes over ∼2 years and (ii) tau PET cross-sectionally assessed in a subset of patients. We found higher CSF sTREM2 associated with attenuated amyloid PET increase and lower tau PET. Secondly, in the AppNL-G-F mouse model of amyloidosis, we studied baseline 18F-GE180 microglia PET and longitudinal amyloid PET to test the microglia vs. Aβ association, without any confounding co-pathologies often present in AD patients. Higher microglia PET at age 5 months was associated with a slower amyloid PET increase between ages 5-to-10 months. In conclusion, higher microglia activation as determined by CSF sTREM2 or microglia PET shows protective effects on subsequent amyloid accumulation. © 2020 The Authors. Published under the terms of the CC BY 4.0 license

Author Keywords
beta-amyloid accumulation;  microglia;  protective;  tau;  TREM2

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

Mapping language function with task-based vs. resting-state functional MRI
(2020) PloS One, 15 (7), p. e0236423.

Park, K.Y.^a , Lee, J.J.^a , Dierker, D.^a , Marple, L.M.^a , Hacker, C.D.^b , Roland, J.L.^c , Marcus, D.S.^a , Milchenko, M.^a , Miller-Thomas, M.M.^a , Benzinger, T.L.^a , Shimony, J.S.^a , Snyder, A.Z.^a , Leuthardt, E.C.^b

^a Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Neurosurgery, University of California San Francisco, San Francisco, CA, United States

Abstract
BACKGROUND: Use of functional MRI (fMRI) in pre-surgical planning is a non-invasive method for pre-operative functional mapping for patients with brain tumors, especially tumors located near eloquent cortex. Currently, this practice predominantly involves task-based fMRI (T-fMRI). Resting state fMRI (RS-fMRI) offers an alternative with several methodological advantages. Here, we compare group-level analyses of RS-fMRI vs. T-fMRI as methods for language localization. PURPOSE: To contrast RS-fMRI vs. T-fMRI as techniques for localization of language function. METHODS: We analyzed data obtained in 35 patients who had both T-fMRI and RS-fMRI scans during the course of pre-surgical evaluation. The RS-fMRI data were analyzed using a previously trained resting-state network classifier. The T-fMRI data were analyzed using conventional techniques. Group-level results obtained by both methods were evaluated in terms of two outcome measures: (1) inter-subject variability of response magnitude and (2) sensitivity/specificity analysis of response topography, taking as ground truth previously reported maps of the language system based on intraoperative cortical mapping as well as meta-analytic maps of language task fMRI responses. RESULTS: Both fMRI methods localized major components of the language system (areas of Broca and Wernicke) although not with equal inter-subject consistency. Word-stem completion T-fMRI strongly activated Broca’s area but also several task-general areas not specific to language. RS-fMRI provided a more specific representation of the language system. CONCLUSION: We demonstrate several advantages of classifier-based mapping of language representation in the brain. Language T-fMRI activated task-general (i.e., not language-specific) functional systems in addition to areas of Broca and Wernicke. In contrast, classifier-based analysis of RS-fMRI data generated maps confined to language-specific regions of the brain.

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

Checkpoint therapy for progressive multifocal leukoencephalopathy: pointless?
(2020) European Journal of Neurology, .

Clifford, D.B.

Melba and Forest Seay of Clinical Neuropharmacology in Neurology, Department of Neurology, Washington University in St Louis, St Louis, MO, United States

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

Impact of Depression and Anxiety Symptoms on Patient-Reported Outcomes in Patients With Migraine: Results From the American Registry for Migraine Research (ARMR)
(2020) Headache, .

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

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

Abstract
Background and Objectives: The association between migraine, depression, and anxiety has been established, but the impact of these psychiatric comorbidities on functional impairment in people with migraine has been under-investigated. The purpose of this cross-sectional observational study was to investigate the relationship between anxiety and depression symptoms on migraine-related disability, pain interference, work interference, and career success in a cohort of patients with migraine. Methods: This analysis included 567 migraine patients who had been enrolled into the American Registry for Migraine Research (ARMR) between February 2016 and June 2019. Patients completed the Generalized Anxiety Disorder-7 (GAD-7) and Patient Health Questionnaire-2 (PHQ-2) to measure symptoms of anxiety and depression, respectively. Patients completed the Migraine Disability Assessment Scale (MIDAS), Pain Interference (PROMIS pain short) questionnaire, and Work Productivity and Activity Interference (WPAI) questionnaire to measure levels of functional impairment at work and in daily activities. In addition, patients answered questions designed for ARMR regarding education and career interference. Models were created to describe the relationship between severity of psychiatric symptoms (anxiety and depression), and each outcome of interest (WPAI, MIDAS, pain interference, reporting that migraine had interfered with career success). Each model was controlled for age, sex, headache frequency, years with migraine, and average headache intensity. Results: Among the 567 patients with migraine, mean (SD) age was 47.1 (13.7), 87.3% were female, and average headache frequency was 19.1 (9.3) days/month. PHQ-2 scores were positively associated with scores on MIDAS (b = 0.06, SE = 0.01, P ≤.001), pain interference (b = 1.4, SE = 0.2, P <.001), and WPAI including absenteeism (b = 0.16, SE = 0.04, P =.007), presenteeism (b = 2.7, SE = 1.1, P =.012), overall work productivity impairment (b = 3.7, SE = 1.2, P =.001), and activity impairment (b = 3.0, SE = 1.2, P =.009). PHQ-2 scores were also associated with reporting that migraine interfered with career success (b = 0.34, SE = 0.08, P ≤.001). GAD-7 scores were not associated with MIDAS, pain interference, WPAI, or reduced career success. Conclusions: Severity of depression symptoms in patients with migraine is associated with migraine-related disability, work interference, pain interference, and reduced career success. Patients with more severe symptoms of depression are more likely to have greater functional impairment. A management approach that addresses depression in those with migraine may lead to improvements in patient functioning. © 2020 American Headache Society

Author Keywords
anxiety;  depression;  disability;  migraine;  pain interference;  work productivity

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

Dementia Diagnosis Documentation in Patients Presenting to the Emergency Department with Chest Pain
(2020) Journal of the American Geriatrics Society, .

Keller, S.A.^a b c , Shah, M.N.^a c d , Holden, T.R.^e , Kind, A.J.H.^b c f

^a Department of Population Health Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
^b Health Services and Care Research Program, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
^c Department of Medicine, Geriatrics Division, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
^d Berbee Walsh Department of Emergency Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
^e Department of Medicine, Division of Geriatrics and Nutritional Science, Washington University School of Medicine, St. Louis, MO, United States
^f William S. Middleton VA Hospital, VA Geriatrics Research Education and Clinical Center, Madison, WI, United States

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

Genetic Variant in CHRNA5 and Response to Varenicline and Combination Nicotine Replacement in a Randomized Placebo-Controlled Trial
(2020) Clinical Pharmacology and Therapeutics, .

Chen, L.-S.^a b , Baker, T.B.^c , Miller, J.P.^a , Bray, M.^a , Smock, N.^a , Chen, J.^a , Stoneking, F.^a , Culverhouse, R.C.^d e , Saccone, N.L.^f , Amos, C.I.^g h , Carney, R.M.^a , Jorenby, D.E.^c , Bierut, L.J.^a b

^a Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
^b Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital, Washington University School of Medicine, St Louis, MO, United States
^c Division of General Internal Medicine, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
^d John T. Milliken Department of Medicine, Washington University School of Medicine, St Louis, MO, United States
^e Division of Biostatistics, Washington University School of Medicine, St Louis, MO, United States
^f Department of Genetics, Washington University School of Medicine, St Louis, MO, United States
^g Department of Biomedical Data Science, Geisel School of Medicine, Dartmouth College, Hanover, NH, United States
^h Department of Medicine, Baylor College of Medicine, Institute for Clinical and Translational Research, Houston, TX, United States

Abstract
It is unclear if genetic variants affect smoking cessation treatment response. This study tested whether variants in the cholinergic receptor nicotinic alpha 5 subunit (CHRNA5) predict response to smoking cessation medication by directly comparing the two most effective smoking cessation pharmacotherapies. In this genotype-stratified randomized, double-blind, placebo-controlled clinical trial (May 2015–August 2019 in St Louis, Missouri), smokers were randomized by genotype in blocks of six (1:1:1 ratio) to three conditions: 12 weeks of placebo (n = 273), combination nicotine patch and lozenge (combination nicotine replacement therapy, cNRT, n = 275), or varenicline (n = 274). All participants received counseling and were followed for 12 months. The primary end point was biochemically verified 7-day point prevalence abstinence at the end of treatment (EOT, week 12). Trial registration and eligibility criteria are on clinicaltrials.gov (https://clinicaltrials.gov/) (NCT02351167). We conducted the genetic analyses separately for 516 European ancestry (EA) smokers and 306 non-EA smokers (including 270 African American smokers). In African American smokers, there was a genotype-by-treatment interaction for EOT abstinence (χ2 = 10.7, degrees of freedom = 2. P = 0.0049): specifically, cNRT was more effective in smokers with rs16969968 GG genotype than was placebo, while varenicline was more effective in smokers of GA/AA genotypes. In EA ancestry smokers, there was no significant genotype-by-treatment interaction. In the whole sample, although both were effective at EOT, only varenicline, and not cNRT, was significantly effective relative to placebo at 6-month follow-up. Importantly, this study suggests that genetic information can further enhance smoking cessation treatment effectiveness. © 2020 The Authors Clinical Pharmacology & Therapeutics © 2020 American Society for Clinical Pharmacology and Therapeutics

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

ACMT Position Statement: Caring for Patients with Opioid Use Disorder during Coronavirus Disease Pandemic
(2020) Journal of Medical Toxicology, .

Stolbach, A.^a , Mazer-Amirshahi, M.^b , Schwarz, E.S.^c , Juurlink, D.^d , Wiegand, T.J.^e , Nelson, L.S.^f

^a Johns Hopkins University School of Medicine, Baltimore, MD, United States
^b Department of Emergency Medicine, MedStar Washington Hospital Center and Georgetown University School of Medicine, Washington, DC, United States
^c Division of Emergency Medicine, Washington University School of Medicine, St. Louis, MO, United States
^d Departments of Medicine and Pediatrics, University of Toronto, Toronto, Canada
^e University of Rochester Medical Center, Rochester, NY, United States
^f Rutgers New Jersey Medical School, Newark, NJ, United States

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

Anticoagulation Timing in Cardioembolic Stroke and Recurrent Event Risk
(2020) Annals of Neurology, .

Yaghi, S.^a , Trivedi, T.^a , Henninger, N.^b c , Giles, J.^d , Liu, A.^d , Nagy, M.^b , Kaushal, A.^e , Azher, I.^e , Mac Grory, B.^e , Fakhri, H.^f , Brown Espaillat, K.^f , Asad, S.D.^g , Pasupuleti, H.^h , Martin, H.^h , Tan, J.^h , Veerasamy, M.^h , Liberman, A.L.ⁱ , Esenwa, C.ⁱ , Cheng, N.ⁱ , Moncrieffe, K.ⁱ , Moeini-Naghani, I.^j , Siddu, M.^j , Scher, E.^a , Leon Guerrero, C.R.^j , Khan, M.^h , Nouh, A.^g , Mistry, E.^f , Keyrouz, S.^b , Furie, K.^e

^a Department of Neurology, New York Langone Health, New York, NY, United States
^b Department of Neurology, University of Massachusetts, Worcester, MA, United States
^c Department of Psychiatry, University of Massachusetts, Worcester, MA, United States
^d Department of Neurology, Washington University, Saint Louis, MO, United States
^e Department of Neurology, Brown University, Providence, RI, United States
^f Department of Neurology, Vanderbilt University, Nashville, TN, United States
^g Department of Neurology, Hartford Hospital, Hartford, CT, United States
^h Department of Neurology, Spectrum Health, Grand Rapids, MI, United States
ⁱ Department of Neurology, Montefiore Medical Center, New York, NY, United States
^j Department of Neurology, George Washington University, Washington, District of Columbia, United States

Abstract
Objective: Guidelines recommend initiating anticoagulation within 4 to 14 days after cardioembolic stroke. Data supporting this did not account for key factors potentially affecting the decision to initiate anticoagulation, such as infarct size, hemorrhagic transformation, or high-risk features on echocardiography. Methods: We pooled data from stroke registries of 8 comprehensive stroke centers across the United States. We included consecutive patients admitted with ischemic stroke and atrial fibrillation. The primary predictor was timing of initiating anticoagulation (0–3 days, 4–14 days, or >14 days), and outcomes were recurrent stroke/transient ischemic attack/systemic embolism, symptomatic intracerebral hemorrhage (sICH), and major extracranial hemorrhage (ECH) within 90 days. Results: Among 2,084 patients, 1,289 met the inclusion criteria. The combined endpoint occurred in 10.1% (n = 130) subjects (87 ischemic events, 20 sICH, and 29 ECH). Overall, there was no significant difference in the composite endpoint between the 3 groups (0–3 days: 10.3%, 64/617; 4–14 days: 9.7%, 52/535; >14 days: 10.2%, 14/137; p = 0.933). In adjusted models, patients started on anticoagulation between 4 and 14 days did not have a lower rate of sICH (vs 0–3 days; odds ratio [OR] = 1.49, 95% confidence interval [CI] = 0.50–4.43), nor did they have a lower rate of recurrent ischemic events (vs >14 days; OR = 0.76, 95% CI = 0.36–1.62, p = 0.482). Interpretation: In this multicenter real-world cohort, the recommended (4–14 days) time frame to start oral anticoagulation was not associated with reduced ischemic and hemorrhagic outcomes. Randomized trials are required to determine the optimal timing of anticoagulation initiation. ANN NEUROL 2020. © 2020 American Neurological Association

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