WashU weekly Neuroscience publications | Office of Neuroscience Research

“Testing the impact of a single nucleotide polymorphism in a Plasmodium berghei ApiAP2 transcription factor on experimental cerebral malaria in mice” (2020) Scientific Reports

Testing the impact of a single nucleotide polymorphism in a Plasmodium berghei ApiAP2 transcription factor on experimental cerebral malaria in mice
(2020) Scientific Reports, 10 (1), art. no. 13630, .

Akkaya, M.^a , Bansal, A.^b ^e , Sheehan, P.W.^a ^f , Pena, M.^a , Cimperman, C.K.^a ^g , Qi, C.F.^a , Yazew, T.^a ^h , Otto, T.D.^c , Billker, O.^d , Miller, L.H.^b , Pierce, S.K.^a

^a Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 5625 Fishers Lane, Room 4S04, Rockville, MD, United States
^b Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, United States
^c Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom
^d Laboratory for Molecular Infection Medicine Sweden and Molecular Biology Department, Umea University, Umea, Sweden
^e School of Life Sciences, Jawaharlal Nehru University, New Delhi, India
^f Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^g Department of Microbiology, University of Pennsylvania, Philadelphia, PA, United States
^h Department of Veterinary Medicine, College of Agriculture and Natural Resources, University of Maryland, College Park, MD, United States

Abstract
Cerebral malaria (CM) is the deadliest form of severe Plasmodium infections. Currently, we have limited understanding of the mechanisms by which Plasmodium parasites induce CM. The mouse model of CM, experimental CM (ECM), induced by infection with the rodent parasite, Plasmodium berghei ANKA (PbANKA) has been extensively used to study the pathophysiology of CM. Recent genomic analyses revealed that the coding regions of PbANKA and the closely related Plasmodium berghei NK65 (PbNK65), that does not cause ECM, differ in only 21 single nucleotide polymorphysims (SNPs). Thus, the SNP-containing genes might contribute to the pathogenesis of ECM. Although the majority of these SNPs are located in genes of unknown function, one SNP is located in the DNA binding site of a member of the Plasmodium ApiAP2 transcription factor family, that we recently showed functions as a virulence factor alternating the host’s immune response to the parasite. Here, we investigated the impact of this SNP on the development of ECM. Our results using CRISPR-Cas9 engineered parasites indicate that despite its immune modulatory function, the SNP is neither necessary nor sufficient to induce ECM and thus cannot account for parasite strain-specific differences in ECM phenotypes. © 2020, The Author(s).

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

“Parcel-guided rTMS for depression” (2020) Translational Psychiatry

Parcel-guided rTMS for depression
(2020) Translational Psychiatry, 10 (1), art. no. 283, .

Moreno-Ortega, M.^a ^b , Kangarlu, A.^c , Lee, S.^d , Perera, T.^e , Kangarlu, J.^f , Palomo, T.^b ^g , Glasser, M.F.^h , Javitt, D.C.^a

^a Division of Experimental Therapeutics, Department of Psychiatry, New York State Psychiatric Institute/Columbia University Medical Center, New York, NY, United States
^b Centro de Investigacion Biomedica en Red de Salud Mental (CIBERSAM), Madrid, Spain
^c Department of Psychiatry, Radiology and Biomedical Engineering, Columbia University, New York, NY, United States
^d Department of Psychiatry and Biostatistics, New York State Psychiatric Institute/Columbia University, New York, NY, United States
^e Contemporary Care, Greenwich, CT, United States
^f State University of New York (SUNY) Upstate Medical University, Syracuse, NY, United States
^g Department of Psychiatry, Complutense University, Madrid, Spain
^h Departments of Radiology and Neuroscience, Washington University Medical School, St. Louis, United States

Abstract
Transcranial magnetic stimulation (TMS) is an approved intervention for treatment-resistant depression (TRD), but current targeting approaches are only partially successful. Our objectives were (1) to examine the feasibility of MRI-guided TMS in the clinical setting using a recently published surface-based, multimodal parcellation in patients with TRD who failed standard TMS (sdTMS); (2) to examine the neurobiological mechanisms and clinical outcomes underlying MRI-guided TMS compared to that of sdTMS. We used parcel-guided TMS (pgTMS) to target the left dorsolateral prefrontal cortex parcel 46. Resting-state functional connectivity (rsfc) was assessed between parcel 46 and predefined nodes within the default mode and visual networks, following both pgTMS and sdTMS. All patients (n = 10) who had previously failed sdTMS responded to pgTMS. Alterations in rsfc between frontal, default mode, and visual networks differed significantly over time between groups. Improvements in symptoms correlated with alterations in rsfc within each treatment group. The outcome of our study supports the feasibility of pgTMS within the clinical setting. Future prospective, double-blind studies of pgTMS vs. sdTMS appear warranted. © 2020, The Author(s).

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

“The genetic architecture of human brainstem structures and their involvement in common brain disorders” (2020) Nature Communications

The genetic architecture of human brainstem structures and their involvement in common brain disorders
(2020) Nature Communications, 11 (1), art. no. 4016, .

Elvsåshagen, T.^a ^b ^c , Bahrami, S.^a , van der Meer, D.^a ^d , Agartz, I.^e ^f ^g , Alnæs, D.^a , Barch, D.M.^h , Baur-Streubel, R.ⁱ , Bertolino, A.^j ^k , Beyer, M.K.^c ^l , Blasi, G.^j ^k , Borgwardt, S.^m ⁿ ^o , Boye, B.^p ^q , Buitelaar, J.^r ^s , Bøen, E.^p , Celius, E.G.^b ^c , Cervenka, S.^f , Conzelmann, A.^t , Coynel, D.^u ^v , Di Carlo, P.^k , Djurovic, S.^w ^x , Eisenacher, S.^y ^z , Espeseth, T.^aa ^ab , Fatouros-Bergman, H.^f , Flyckt, L.^f , Franke, B.^ac , Frei, O.^a , Gelao, B.^j , Harbo, H.F.^b ^c , Hartman, C.A.^ad , Håberg, A.^ae ^af , Heslenfeld, D.^ag ^ah , Hoekstra, P.J.^ai , Høgestøl, E.A.^b ^c , Jonassen, R.^aa ^aj , Jönsson, E.G.^a ^c ^f , Farde, L.^f , Flyckt, L.^f , Engberg, G.^bh , Erhardt S, S.^bh , Fatouros-Bergman, H.^f , Cervenka, S.^f , Schwieler, L.^bh , Piehl, F.^bi , Agartz, I.^e ^f ^g , Collste, K.^f , Victorsson, P.^f , Malmqvist, A.^bh , Hedberg, M.^bh , Orhan, F.^bh , Sellgren, C.M.^bh , Kirsch, P.^ak ^al , Kłoszewska, I.^am , Lagerberg, T.V.^a , Landrø, N.I.^e ^aa , Le Hellard, S.^x , Lesch, K.-P.^an ^ao ^ap , Maglanoc, L.A.^a ^aa , Malt, U.F.^c , Mecocci, P.^aq , Melle, I.^a ^c , Meyer-Lindenberg, A.^y , Moberget, T.^a ^aa , Nordvik, J.E.^ar , Nyberg, L.^as , Connell, K.S.O.^a , Oosterlaan, J.^ag ^at , Papalino, M.^k , Papassotiropoulos, A.^u ^v ^au ^av , Pauli, P.ⁱ , Pergola, G.^k , Persson, K.^aw ^ax , de Quervain, D.^u ^v ^au , Reif, A.^ay , Rokicki, J.^a ^aa , van Rooij, D.^r , Shadrin, A.A.^a ^c , Schmidt, A.^m , Schwarz, E.^y , Selbæk, G.^c ^aw ^ax , Soininen, H.^az ^ba , Sowa, P.^l , Steen, V.M.^x ^bb , Tsolaki, M.^bc , Vellas, B.^bd , Wang, L.^be , Westman, E.ⁿ ^bf , Ziegler, G.C.^an , Zink, M.^y ^bg , Andreassen, O.A.^a ^c , Westlye, L.T.^a ^aa , Kaufmann, T.^a ^c , Karolinska Schizophrenia Project (KaSP) consortium^bj

^a NORMENT, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
^b Department of Neurology, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway
^c Institute of Clinical Medicine, University of Oslo, Oslo, Norway
^d School of Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, Netherlands
^e Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway
^f Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet & Stockholm Health Care Services, Stockholm Region, Stockholm, Sweden
^g NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
^h Departments of Psychological & Brain Sciences, Psychiatry, and Radiology, Washington University in St. Louis, St. Louis, United States
ⁱ Department of Psychology I and Centre of Mental Health, University of Würzburg, Würzburg, Germany
^j Institute of Psychiatry, University of Bari, Bari, Italy
^k Department of Basic Medical Science, Neuroscience, and Sense Organs, University of Bari Aldo Moro, Bari, Italy
^l Division of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway
^m Department of Psychiatry (UPK), University of Basel, Basel, Switzerland
ⁿ Institute of Psychiatry, King’s College, London, United Kingdom
^o Department of Psychiatry and Psychotherapy, University of Lübeck, Lübeck, Germany
^p Psychosomatic and CL Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
^q Department of Behavioural Sciences in Medicine, University of Oslo, Oslo, Norway
^r Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, Netherlands
^s Karakter Child and Adolescent Psychiatry University Centre, Nijmegen, Netherlands
^t Children and Adolescence Psychiatry, University of Tübingen, Tübingen, Germany
^u Transfaculty Research Platform Molecular and Cognitive Neurosciences, University of Basel, Basel, CH-4055, Switzerland
^v Division of Cognitive Neuroscience, Department of Psychology, University of Basel, Basel, CH-4055, Switzerland
^w Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
^x NORMENT, Department of Clinical Science, University of Bergen, Bergen, Norway
^y Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
^z Institute of Psychiatric and Psychosomatic Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
^aa Department of Psychology, University of Oslo, Oslo, Norway
^ab Bjørknes College, Lovisenberggata, Oslo, 13, 0456, Norway
^ac Departments of Human Genetics and Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, Netherlands
^ad Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
^ae Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway
^af Department of Radiology and Nuclear Medicine, St. Olavs Hospital, Trondheim, Norway
^ag Clinical Neuropsychology section, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
^ah Department of Cognitive Psychology, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
^ai Department of Child and Adolescent Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
^aj Faculty of Health Sciences, Oslo Metropolitan University, Oslo, Norway
^ak Department of Clinical Psychology, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
^al Bernstein Center for Computational Neuroscience Heidelberg/Mannheim, Mannheim, Germany
^am Department of Old Age Psychiatry and Psychotic Disorders, Medical University of Lodz, Lodz, Poland
^an Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Würzburg, Germany
^ao Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Moscow, Russian Federation
^ap Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Maastricht, Netherlands
^aq Institute of Gerontology and Geriatrics, University of Perugia, Perugia, Italy
^ar The CatoSenteret Rehabilitation Center, Son, Norway
^as Departments of Radiation Sciences and Integrative Medical Biology, Umeå Center for Functional Brain Imaging, Umeå University, Umeå, Sweden
^at Emma Children’s Hospital Amsterdam UMC, University of Amsterdam, Emma Neuroscience Group, Department of Pediatrics, Amsterdam Reproduction & Development, Amsterdam, Netherlands
^au Psychiatric University Clinics, University of Basel, Basel, Switzerland
^av Department Biozentrum, Life Sciences Training Facility, University of Basel, Basel, Switzerland
^aw Department of Geriatric Medicine, Oslo University Hospital, Oslo, Norway
^ax Norwegian National Advisory Unit on Ageing and Health, Vestfold Hospital Trust, Tønsberg, Norway
^ay Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt am Main, Germany
^az Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland
^ba Neurocenter, Neurology, Kuopio University Hospital, Kuopio, Finland
^bb Dr. E. Martens Research Group for Biological Psychiatry, Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway
^bc 1st University Department of Neurology, Aristotle University of Thessaloniki, Makedonia, Greece
^bd INSERM U 1027, University of Toulouse, Toulouse, France
^be Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
^bf Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Stockholm, Sweden
^bg District hospital Mittelfranken, Ansbach, Germany
^bh Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
^bi Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

Abstract
Brainstem regions support vital bodily functions, yet their genetic architectures and involvement in common brain disorders remain understudied. Here, using imaging-genetics data from a discovery sample of 27,034 individuals, we identify 45 brainstem-associated genetic loci, including the first linked to midbrain, pons, and medulla oblongata volumes, and map them to 305 genes. In a replication sample of 7432 participants most of the loci show the same effect direction and are significant at a nominal threshold. We detect genetic overlap between brainstem volumes and eight psychiatric and neurological disorders. In additional clinical data from 5062 individuals with common brain disorders and 11,257 healthy controls, we observe differential volume alterations in schizophrenia, bipolar disorder, multiple sclerosis, mild cognitive impairment, dementia, and Parkinson’s disease, supporting the relevance of brainstem regions and their genetic architectures in common brain disorders. © 2020, The Author(s).

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

“Synthesis of recurrent neural dynamics for monotone inclusion with application to Bayesian inference” (2020) Neural Networks

Synthesis of recurrent neural dynamics for monotone inclusion with application to Bayesian inference
(2020) Neural Networks, 131, pp. 231-241.

Yi, P.^a ^b , Ching, S.^c

^a Department of Control Science and Engineering, Tongji University, Shanghai, China
^b Shanghai Research Institute of Intelligent Science and Technology, Tongji University, Shanghai, China
^c Department of Electrical and Systems Engineering, Washington University in St. Louis, United States

Abstract
We propose a top-down approach to construct recurrent neural circuit dynamics for the mathematical problem of monotone inclusion (MoI). MoI in a general optimization framework that encompasses a wide range of contemporary problems, including Bayesian inference and Markov decision making. We show that in a recurrent neural circuit/network with Poisson neurons, each neuron’s firing curve can be understood as a proximal operator of a local objective function, while the overall circuit dynamics constitutes an operator-splitting system of ordinary differential equations whose equilibrium point corresponds to the solution of the MoI problem. Our analysis thus establishes that neural circuits are a substrate for solving a broad class of computational tasks. In this regard, we provide an explicit synthesis procedure for building neural circuits for specific MoI problems and demonstrate it for the specific case of Bayesian inference and sparse neural coding. © 2020 Elsevier Ltd

Author Keywords
Bayesian casual inference; Monotone inclusion; Network synthesis; Normative approach; Poisson spiking neuron; Recurrent neural networks

Document Type: Article
Publication Stage: Final
Source: Scopus

“Striatal cholinergic interneuron numbers are increased in a rodent model of dystonic cerebral palsy” (2020) Neurobiology of Disease

Striatal cholinergic interneuron numbers are increased in a rodent model of dystonic cerebral palsy
(2020) Neurobiology of Disease, 144, art. no. 105045, .

Gandham, S.^a , Tak, Y.^b , Aravamuthan, B.R.^a

^a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^b St. Louis College of Pharmacy, St. Louis, MO, United States

Abstract
Neonatal brain injury leading to cerebral palsy (CP) is the most common cause of childhood dystonia, a painful and functionally debilitating movement disorder. Rare monogenic etiologies of dystonia have been associated with striatal cholinergic interneuron (ChI) pathology. However it is unclear whether striatal ChI pathology is also associated with dystonia following neonatal brain injury. We used unbiased stereology to estimate striatal ChI and parvalbumin-positive GABAergic interneuron (PVI) numbers in a rodent model of neonatal brain injury that demonstrates electrophysiological markers of dystonia and spasticity. Striatal ChI numbers are increased following neonatal brain injury while PVI numbers are unchanged. These numbers do not correlate with electrophysiologic measures of dystonia severity. This suggests that striatal ChI pathology, though present, may not be the primary pathophysiologic contributor to dystonia following neonatal brain injury. Increased striatal ChI numbers could instead represent a passenger or protective phenomenon in the setting of dystonic CP. © 2020

Author Keywords
Cerebral palsy; Dystonia; Neonatal brain injury; Spasticity

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

“Metal-chelating benzothiazole multifunctional compounds for the modulation and 64Cu PET imaging of Aβ aggregation” (2020) Chemical Science

Metal-chelating benzothiazole multifunctional compounds for the modulation and 64Cu PET imaging of Aβ aggregation
(2020) Chemical Science, 11 (30), pp. 7789-7799.

Huang, Y.^a , Cho, H.-J.^a , Bandara, N.^b , Sun, L.^a , Tran, D.^b , Rogers, B.E.^b , Mirica, L.M.^a ^c

^a Department of Chemistry, University of Illinois at Urbana-Champaign, 600 S. Mathews Avenue, Urbana, IL 61801, United States
^b Department of Radiation Oncology, Washington University, School of Medicine, St. Louis, MO 63108, United States
^c Hope Center for Neurological Disorders, Washington University, School of Medicine, St. Louis, MO 63110, United States

Abstract
While Alzheimer’s Disease (AD) is the most common neurodegenerative disease, there is still a dearth of efficient therapeutic and diagnostic agents for this disorder. Reported herein are a series of new multifunctional compounds (MFCs) with appreciable affinity for amyloid aggregates that can be potentially used for both the modulation of Aβ aggregation and its toxicity, as well as positron emission tomography (PET) imaging of Aβ aggregates. Firstly, among the six compounds tested HYR-16 is shown to be capable to reroute the toxic Cu-mediated Aβ oligomerization into the formation of less toxic amyloid fibrils. In addition, HYR-16 can also alleviate the formation of reactive oxygen species (ROS) caused by Cu2+ ions through Fenton-like reactions. Secondly, these MFCs can be easily converted to PET imaging agents by pre-chelation with the 64Cu radioisotope, and the Cu complexes of HYR-4 and HYR-17 exhibit good fluorescent staining and radiolabeling of amyloid plaques both in vitro and ex vivo. Importantly, the 64Cu-labeled HYR-17 is shown to have a significant brain uptake of up to 0.99 ± 0.04 %ID per g. Overall, by evaluating the various properties of these MFCs valuable structure-activity relationships were obtained that should aid the design of improved therapeutic and diagnostic agents for AD. This journal is © The Royal Society of Chemistry.

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

“A History of Corollary Discharge: Contributions of Mormyrid Weakly Electric Fish” (2020) Frontiers in Integrative Neuroscience

A History of Corollary Discharge: Contributions of Mormyrid Weakly Electric Fish
(2020) Frontiers in Integrative Neuroscience, 14, art. no. 42, .

Fukutomi, M., Carlson, B.A.

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

Abstract
Corollary discharge is an important brain function that allows animals to distinguish external from self-generated signals, which is critical to sensorimotor coordination. Since discovery of the concept of corollary discharge in 1950, neuroscientists have sought to elucidate underlying neural circuits and mechanisms. Here, we review a history of neurophysiological studies on corollary discharge and highlight significant contributions from studies using African mormyrid weakly electric fish. Mormyrid fish generate brief electric pulses to communicate with other fish and to sense their surroundings. In addition, mormyrids can passively locate weak, external electric signals. These three behaviors are mediated by different corollary discharge functions including inhibition, enhancement, and predictive “negative image” generation. Owing to several experimental advantages of mormyrids, investigations of these mechanisms have led to important general principles that have proven applicable to a wide diversity of animal species. © Copyright © 2020 Fukutomi and Carlson.

Author Keywords
communication; comparative physiology; efference copy; electrolocation; electrosensory; prediction; sensorimotor integration

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

“The Road to Recovery: A Pilot Study of Driving Behaviors Following Antibody-Mediated Encephalitis” (2020) Frontiers in Neurology

The Road to Recovery: A Pilot Study of Driving Behaviors Following Antibody-Mediated Encephalitis
(2020) Frontiers in Neurology, 11, art. no. 678, .

Day, G.S.^a ^b , Babulal, G.M.^a ^b , Rajasekar, G.^a , Stout, S.^a , Roe, C.M.^a ^b

^a The Charles F. and Joanne Knight Alzheimer Disease Research Center, St. Louis, MO, United States
^b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Introduction: Safe driving requires integration of higher-order cognitive and motor functions, which are commonly compromised in patients with antibody-mediated encephalitis (AME) associated with N-methyl-D-aspartate receptors or leucine-rich glioma-inactivated 1 autoantibodies. How these deficits influence the return to safe driving is largely unknown. Recognizing this, we piloted non-invasive remote monitoring technology to longitudinally assess driving behaviors in recovering AME patients. Methods: Five recovering AME patients [median age, 52 years (range 29–67); two females] were recruited from tertiary care clinics at Washington University (St. Louis, MO). Trip data and aggressive actions (e.g., hard braking, sudden acceleration, speeding) were continuously recorded using a commercial Global Positioning System data logger when the patient’s vehicle was driven by the designated driver. Longitudinal driving data were compared between AME patients and cognitively normal older adults (2:1 sex-matched) enrolled within parallel studies. Results: Driving behaviors were continuously monitored for a median of 29 months (range, 21–32). AME patients took fewer daily trips during the last vs. the first 6 months of observation, with a greater proportion of trips exceeding 10 miles. Compared to cognitively normal individuals, AME patients were more likely to experience hard braking events as recovery progressed. Despite this, no accidents were self-reported or captured by the data logger. Conclusion: Driving behaviors can be continuously monitored in AME patients using non-invasive means for protracted periods. Longitudinal changes in driving behavior may parallel functional recovery, warranting further study in expanded cohorts of recovering AME patients. © Copyright © 2020 Day, Babulal, Rajasekar, Stout and Roe.

Author Keywords
antibody-mediated; autoantibodies; autoimmune; driving; encephalitis; LGI1; N-methyl-D-aspartate (NMDA) receptor

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

“Fetal brain ultrasound measures and maternal nutrition: A feasibility study in Ecuador” (2020) American Journal of Human Biology

Fetal brain ultrasound measures and maternal nutrition: A feasibility study in Ecuador
(2020) American Journal of Human Biology, .

Sibbald, C.A.^a , Nicholas, J.L.^b , Chapnick, M.^c , Ross, N.^d , Gandor, P.L.^e , Waters, W.F.^f , Palacios, I.^f , Iannotti, L.L.^c

^a Washington University, School of Medicine, St. Louis, MO, United States
^b Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^c Brown School, Institute for Public Health, Washington University in St. Louis, St. Louis, MO, United States
^d Columbia University Vagelos College of Physicians and Surgeons, New York, NY, United States
^e Department of Sonography, Harper College, PalatineIL, United States
^f Institute for Research in Health and Nutrition, Universidad San Francisco de Quito, Quito, Pichincha, Ecuador

Abstract
Objective: Nutrition during pregnancy is an important modifiable determinant of fetal growth and development. This pilot study aimed to characterize the association between fetal anthropometry, fetal brain development, and maternal diet among women in Ecuador using portable ultrasound in resource-limited clinics, including measurements of brain structures not typically imaged in this setting. Methods: Pregnant women (n = 47) from four resource-limited health centers were surveyed on demographic, socioeconomic, morbidity, and dietary information. Maternal height, weight, and blood pressure were taken. A sonographer took 15 images per participant, including those standardly assessed during the fetal survey and additional brain structures identified as potentially responsive to maternal nutrition, but not part of the standard fetal survey. Results: Mean percentiles for all standard fetal survey measurements generated from WHO Fetal Growth Curves fell below 50%, and negative mean Z scores were found for biparietal diameter (-0.95 ± 1.11) and femur length (-0.22 ± 1.10). Generalized linear modeling adjusting for gestational age and other covariates showed frequency of seafood consumption was positively associated with fetal biparietal diameter Z score (P = 0.005), beans and legumes positively associated with femur length (P = 0.006), and a negative association was found for soda consumption and fetal head circumference (P = 0.013). Conclusions: This pilot study demonstrated the feasibility of capturing images of nutrition-relevant fetal brain structures not part of the standard fetal survey in resource-limited settings using portable ultrasound. Our study revealed associations between anthropometry, brain structure size, and maternal diet demonstrating potential for prenatal nutrition research using ultrasound in the field. © 2020 Wiley Periodicals LLC

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

“Effectiveness of non-pharmacological interventions for treating post-stroke depressive symptoms: Systematic review and meta-analysis of randomized controlled trials” (2020) Topics in Stroke Rehabilitation

Effectiveness of non-pharmacological interventions for treating post-stroke depressive symptoms: Systematic review and meta-analysis of randomized controlled trials
(2020) Topics in Stroke Rehabilitation, .

Lee, Y.^a , Chen, B.^a , Fong, M.W.M.^b , Lee, J.-M.^b , Nicol, G.E.^c , Lenze, E.J.^c , Connor, L.T.^d , Baum, C.^d , Wong, A.W.K.^e

^a Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^d Program in Occupational Therapy $and, Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^e Program in Occupational Therapy, Department of Neurology Department of Psychiatry, Washington University School of Medicine, , St. Louis, MO, United States

Abstract
Objective: To compare the effectiveness of non-pharmacological interventions on depressive symptoms in people after stroke. Data Sources: A literature search was performed through databases from January 2000 to August 2018: MEDLINE; CINAHL Plus; Scopus; Academic Search Complete; Cochrane Central Register of Controlled Trials; Scopus; and Library, Information Science and Technology Abstracts. Search terms included depression, stroke, non-pharmacologic, and intervention. Study Selection: We included randomized controlled trials comparing non-pharmacological interventions to controls for depressive symptoms in people after stroke. Of 1703 identified articles, 22 trials were included in narrative synthesis, of which 13 were eligible for meta-analysis. Data Extraction: Two reviewers extracted characteristics of participants, interventions, and results from all included trials. Data Synthesis: Thirteen interventions were categorized into four types: complementary and alternative therapy (five trials, n=228), exercise (four trials, n=263), psychosocial therapy (two trials, n=216), and multifactorial therapy (two trials, n=358). Overall beneficial effects of non-pharmacological interventions on depressive symptoms were found both post-intervention (effect size [ES] = -0.24, 95% confidence Interval [CI]: -0.37 to -0.11, p < 0.05) and at follow-up (ES = -0.22, CI: -0.36 to -0.07, p< 0.05). We found individual beneficial effects for complementary and alternative therapy (ES = -0.29, CI: -0.55 to -0.02, p < 0.05) and psychosocial therapy (ES = – 0.33, CI: -0.60 to -0.06, p < 0.05) post-intervention. Conclusions: Complementary and alternative therapy and psychosocial therapy appear to be promising strategies for improving post-stroke depression. Future studies target a personalized approach for people with specific conditions such as cognitive impairment. © 2020 Taylor & Francis Group, LLC.

Author Keywords
behavior therapy; complementary therapies; depression; meta-analysis; neuropsychiatry; Non-pharmacological interventions; psychosocial therapy; stroke; systematic review

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

“Dissecting the genetic overlap of smoking behaviors, lung cancer, and chronic obstructive pulmonary disease: A focus on nicotinic receptors and nicotine metabolizing enzyme” (2020) Genetic Epidemiology

Dissecting the genetic overlap of smoking behaviors, lung cancer, and chronic obstructive pulmonary disease: A focus on nicotinic receptors and nicotine metabolizing enzyme
(2020) Genetic Epidemiology, .

Bray, M.J.^a , Chen, L.-S.^a ^b , Fox, L.^a , Hancock, D.B.^c , Culverhouse, R.C.^d ^e , Hartz, S.M.^a , Johnson, E.O.^c ^f , Liu, M.^g , McKay, J.D.^h , Saccone, N.L.^e ⁱ , Hokanson, J.E.^j , Vrieze, S.I.^g , Tyndale, R.F.^k ^l , Baker, T.B.^m , Bierut, L.J.^a ^b

^a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^b The Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, United States
^c GenOmics, Bioinformatics, and Translational Research Center, Biostatistics & Epidemiology Division, RTI International, Research Triangle Park, NC, United States
^d 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 Fellow Program, RTI International, Research Triangle Park, NC, United States
^g Department of Psychology, University of Minnesota, Minneapolis, MN, United States
^h International Agency for Research on Cancer, World Health Organization, Lyon, France
ⁱ Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
^j Department of Epidemiology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
^k Centre for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada
^l Department of Pharmacology & Toxicology, and Department of Psychiatry, University of Toronto, Toronto, ON, Canada
^m Department of Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, WI, United States

Abstract
Smoking is a major contributor to lung cancer and chronic obstructive pulmonary disease (COPD). Two of the strongest genetic associations of smoking-related phenotypes are the chromosomal regions 15q25.1, encompassing the nicotinic acetylcholine receptor subunit genes CHRNA5-CHRNA3-CHRNB4, and 19q13.2, encompassing the nicotine metabolizing gene CYP2A6. In this study, we examined genetic relations between cigarettes smoked per day, smoking cessation, lung cancer, and COPD. Data consisted of genome-wide association study summary results. Genetic correlations were estimated using linkage disequilibrium score regression software. For each pair of outcomes, z-score-z-score (ZZ) plots were generated. Overall, heavier smoking and decreased smoking cessation showed positive genetic associations with increased lung cancer and COPD risk. The chromosomal region 19q13.2, however, showed a different correlational pattern. For example, the effect allele-C of the sentinel SNP (rs56113850) within CYP2A6 was associated with an increased risk of heavier smoking (z-score = 19.2; p = 1.10 × 10−81), lung cancer (z-score = 8.91; p = 5.02 × 10−19), and COPD (z-score = 4.04; p = 5.40 × 10−5). Surprisingly, this allele-C (rs56113850) was associated with increased smoking cessation (z-score = −8.17; p = 2.52 × 10−26). This inverse relationship highlights the need for additional investigation to determine how CYP2A6 variation could increase smoking cessation while also increasing the risk of lung cancer and COPD likely through increased cigarettes smoked per day. © 2020 Wiley Periodicals LLC

Author Keywords
addiction; genetics; smoking; smoking cessation

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

“Interpretation of psychiatric genome-wide association studies with multispecies heterogeneous functional genomic data integration” (2020) Neuropsychopharmacology

Interpretation of psychiatric genome-wide association studies with multispecies heterogeneous functional genomic data integration
(2020) Neuropsychopharmacology, .

Reynolds, T.^a ^b , Johnson, E.^c , Huggett, S.^d , Bubier, J.A.^a , Palmer, R.H.C.^d , Agrawal, A.^c , Baker, E.J.^b , Chesler, E.J.^a

^a The Jackson Laboratory, Bar Harbor, ME, United States
^b Computer Science Department, Baylor University, Waco, TX, United States
^c Department of Psychiatry, Washington University in St Louis, St Louis, MO, United States
^d Emory University, Atlanta, GA, United States

Abstract
Genome-wide association studies and other discovery genetics methods provide a means to identify previously unknown biological mechanisms underlying behavioral disorders that may point to new therapeutic avenues, augment diagnostic tools, and yield a deeper understanding of the biology of psychiatric conditions. Recent advances in psychiatric genetics have been made possible through large-scale collaborative efforts. These studies have begun to unearth many novel genetic variants associated with psychiatric disorders and behavioral traits in human populations. Significant challenges remain in characterizing the resulting disease-associated genetic variants and prioritizing functional follow-up to make them useful for mechanistic understanding and development of therapeutics. Model organism research has generated extensive genomic data that can provide insight into the neurobiological mechanisms of variant action, but a cohesive effort must be made to establish which aspects of the biological modulation of behavioral traits are evolutionarily conserved across species. Scalable computing, new data integration strategies, and advanced analysis methods outlined in this review provide a framework to efficiently harness model organism data in support of clinically relevant psychiatric phenotypes.[Figure not available: see fulltext.][Figure not available: see fulltext.]. © 2020, The Author(s).

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

“Enhanced MAPK1 Function Causes a Neurodevelopmental Disorder within the RASopathy Clinical Spectrum” (2020) American Journal of Human Genetics

Enhanced MAPK1 Function Causes a Neurodevelopmental Disorder within the RASopathy Clinical Spectrum
(2020) American Journal of Human Genetics, .

Motta, M.^a , Pannone, L.^a ^b , Pantaleoni, F.^a , Bocchinfuso, G.^c , Radio, F.C.^a , Cecchetti, S.^d , Ciolfi, A.^a , Di Rocco, M.^b ^e , Elting, M.W.^f , Brilstra, E.H.^g , Boni, S.^h , Mazzanti, L.ⁱ , Tamburrino, F.ⁱ , Walsh, L.^j , Payne, K.^j , Fernández-Jaén, A.^k , Ganapathi, M.^l , Chung, W.K.^m , Grange, D.K.ⁿ , Dave-Wala, A.^o , Reshmi, S.C.^o ^p , Bartholomew, D.W.^o , Mouhlas, D.^o , Carpentieri, G.^a ^b , Bruselles, A.^b , Pizzi, S.^a , Bellacchio, E.^a , Piceci-Sparascio, F.^q , Lißewski, C.^r , Brinkmann, J.^r , Waclaw, R.R.^s , Waisfisz, Q.^f , van Gassen, K.^g , Wentzensen, I.M.^t , Morrow, M.M.^t , Álvarez, S.^u , Martínez-García, M.^u , De Luca, A.^q , Memo, L.^v , Zampino, G.^w , Rossi, C.^x , Seri, M.^x , Gelb, B.D.^y , Zenker, M.^r , Dallapiccola, B.^a , Stella, L.^c , Prada, C.E.^s ^z , Martinelli, S.^b , Flex, E.^b , Tartaglia, M.^a

^a Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, 00146, Italy
^b Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, 00161, Italy
^c Department of Chemical Science and Technologies, University of Rome Tor Vergata, Rome, 00133, Italy
^d Microscopy Area, Core Facilities, Istituto Superiore di Sanità, Rome, 00161, Italy
^e Department of Biochemical Science “A. Rossi Fanelli, ” Sapienza University of Rome, Rome, 00185, Italy
^f Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit, Amsterdam, 1117, Netherlands
^g Department of Genetics, University Medical Center Utrecht, CX Utrecht, 3584, Netherlands
^h Medical Genetics Unit, S. Martino HospitalBelluno 32100, Italy
ⁱ Department of Medical and Surgical Sciences, Policlinico S. Orsola-Malpighi Hospital, University of Bologna, Bologna, 40138, Italy
^j Indiana University Health at Riley Hospital for Children, Indianapolis, IN 46202, United States
^k Department of Pediatrics Neurology, Hospital Universitario Quirón de Madrid, Universidad Europea de Madrid, Madrid, 28223, Spain
^l Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, United States
^m Departments of Pediatrics and Medicine, Columbia University Medical Center, New York, NY 10032, United States
ⁿ Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
^o Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH, 43215, United States
^p Department of Pediatrics, Nationwide Children’s Hospital, Columbus, OH, 43215, United States
^q Medical Genetics Division, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, 71013, Italy
^r Institute of Human Genetics, University Hospital Magdeburg, Magdeburg, 39120, Germany
^s Department of Pediatrics, University of Cincinnati College of Medicine, CincinnatiOH 45229, United States
^t GeneDx, GaithersburgMD 20877, United States
^u Medical Department, NimGenetics, Madrid, 28049, Spain
^v Ambulatorio Genetica Clinica, Ospedale San Bortolo, Vicenza, 36100, Italy
^w Center for Rare Disease and Congenital Defects, Fondazione Policlinico Universitario Gemelli, Università Cattolica del Sacro Cuore, Rome, 00168, Italy
^x Medical Genetics Unit, Policlinico S. Orsola-Malpighi, University of Bologna, Bologna, 40138, Italy
^y Mindich Child Health and Development Institute and Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
^z Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, CincinnatiOH 45229, United States

Abstract
Signal transduction through the RAF-MEK-ERK pathway, the first described mitogen-associated protein kinase (MAPK) cascade, mediates multiple cellular processes and participates in early and late developmental programs. Aberrant signaling through this cascade contributes to oncogenesis and underlies the RASopathies, a family of cancer-prone disorders. Here, we report that de novo missense variants in MAPK1, encoding the mitogen-activated protein kinase 1 (i.e., extracellular signal-regulated protein kinase 2, ERK2), cause a neurodevelopmental disease within the RASopathy phenotypic spectrum, reminiscent of Noonan syndrome in some subjects. Pathogenic variants promote increased phosphorylation of the kinase, which enhances translocation to the nucleus and boosts MAPK signaling in vitro and in vivo. Two variant classes are identified, one of which directly disrupts binding to MKP3, a dual-specificity protein phosphatase negatively regulating ERK function. Importantly, signal dysregulation driven by pathogenic MAPK1 variants is stimulus reliant and retains dependence on MEK activity. Our data support a model in which the identified pathogenic variants operate with counteracting effects on MAPK1 function by differentially impacting the ability of the kinase to interact with regulators and substrates, which likely explains the minor role of these variants as driver events contributing to oncogenesis. After nearly 20 years from the discovery of the first gene implicated in Noonan syndrome, PTPN11, the last tier of the MAPK cascade joins the group of genes mutated in RASopathies. © 2020 American Society of Human Genetics

Author Keywords
C. elegans; ERK2; exome sequencing; intracellular signaling; MAPK cascade; MKP3; Noonan syndrome; RAS signaling; RASopathies; RSK

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

“Publisher Correction: Distinct synchronization, cortical coupling and behavioral function of two basal forebrain cholinergic neuron types (Nature Neuroscience, (2020), 23, 8, (992-1003), 10.1038/s41593-020-0648-0)” (2020) Nature Neuroscience

Publisher Correction: Distinct synchronization, cortical coupling and behavioral function of two basal forebrain cholinergic neuron types (Nature Neuroscience, (2020), 23, 8, (992-1003), 10.1038/s41593-020-0648-0)
(2020) Nature Neuroscience, .

Laszlovszky, T.^a ^b , Schlingloff, D.^b ^c , Hegedüs, P.^a ^b , Freund, T.F.^c , Gulyás, A.^c , Kepecs, A.^d ^e , Hangya, B.^a

^a Lendület Laboratory of Systems Neuroscience, Institute of Experimental Medicine, Budapest, Hungary
^b János Szentágothai Doctoral School of Neurosciences, Semmelweis University, Budapest, Hungary
^c Laboratory of Cerebral Cortex Research, Institute of Experimental Medicine, Budapest, Hungary
^d Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, United States
^e Departments of Neuroscience and Psychiatry, Washington University in St Louis, St Louis, MO, United States

Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.

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

“Biological age is a novel biomarker to predict stroke recurrence” (2020) Journal of Neurology

Biological age is a novel biomarker to predict stroke recurrence
(2020) Journal of Neurology, .

Soriano-Tárraga, C.^a ^b ^c ^d , Lazcano, U.^a , Jiménez-Conde, J.^a , Ois, A.^a ^d , Cuadrado-Godia, E.^a , Giralt-Steinhauer, E.^a , Rodríguez-Campello, A.^a , Gomez-Gonzalez, A.^a , Avellaneda-Gómez, C.^a , Vivanco-Hidalgo, R.M.^a , Roquer, J.^a

^a Department of Neurology, Hospital del Mar; Neurovascular Research Group, IMIM (Institut Hospital del Mar d’Investigacions Mèdiques), Universitat Autònoma de Barcelona/DCEXS-Universitat Pompeu Fabra, Barcelona, Spain
^b Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Avenue, Saint-Louis, MO 63110, United States
^c NeuroGenomics and Informatics, Washington University School of Medicine, 425 S. Euclid Avenue, Saint-Louis, MO 63110, United States
^d Servicio de Neurología, Hospital del Mar, Passeig Maritim 25-29, Barcelona, 08003, Spain

Abstract
Background: Stroke recurrence (SR) after an ischemic stroke is an important cause of death and disability. We conducted a hospital-based study to evaluate the role of biological age (b-Age: age-related DNA-methylation changes) as a risk factor for SR. Methods: We included 587 patients in the acute phase of stroke, assessed at one tertiary stroke center (Hospital del Mar: Barcelona, Spain). B-Age was estimated with 5 different methods based on DNA methylation, and Hannum’s method was the one that better performed. We analyzed the relationships between b-Age, chronological age, sex, vascular risk factors, coronary and peripheral arterial disease, atrial fibrillation, initial neurological severity assessed by National Institutes of Health Stroke Scale (NIHSS), transient ischemic attack (TIA) in the 7 days preceding the index stroke, and symptomatic atherosclerosis. Stroke recurrence definition include: new symptoms that suggest a new ischemic event had occurred within 3 months after stroke onset and worsening by four points in the initial neurological severity (measured by National Institutes of Health Stroke Scale (NIHSS) score). Results: Logistic regression analysis associated b-Age with SR [p = 0.003; OR = 1.06 (95% CI: 1.02–1.09)], independently of chronological age [p = 0.022; OR = 0.96 (95% CI 0.94–1.00)], symptomatic atherosclerosis (stenosis > 50% in the symptomatic territory), transient ischemic attack (TIA) in the 7 days preceding the index stroke, and initial NIHSS. The b-Age of patients with SR was 2.7 years older than patients without SR. Conclusions: Patients with SR were biologically older than those without SR. B-Age was independently associated with high risk of developing SR. © 2020, Springer-Verlag GmbH Germany, part of Springer Nature.

Author Keywords
Biological age; Biomarker; DNA methylation; Epigenetics; Recurrence; Stroke

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