WashU weekly Neuroscience publications

Structural basis for adhesion G protein-coupled receptor Gpr126 function
(2020) Nature Communications, 11 (1), art. no. 194, . 

Leon, K.^{a b} , Cunningham, R.L.^c , Riback, J.A.^{a d} , Feldman, E.^a , Li, J.^{a b} , Sosnick, T.R.^{a e} , Zhao, M.^a , Monk, K.R.^{c f} , Araç, D.^{a b}

^a Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, United States
^b Grossman Institute for Neuroscience, Quantitative Biology and Human Behavior, The University of Chicago, Chicago, IL 60637, United States
^c Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, United States
^d Graduate Program in Biophysical Sciences Program, The University of Chicago, Chicago, IL 60637, United States
^e Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, United States
^f Vollum Institute, Oregon Health & Science University, Portland, OR 97239, United States

Abstract
Many drugs target the extracellular regions (ECRs) of cell-surface receptors. The large and alternatively-spliced ECRs of adhesion G protein-coupled receptors (aGPCRs) have key functions in diverse biological processes including neurodevelopment, embryogenesis, and tumorigenesis. However, their structures and mechanisms of action remain unclear, hampering drug development. The aGPCR Gpr126/Adgrg6 regulates Schwann cell myelination, ear canal formation, and heart development; and GPR126 mutations cause myelination defects in human. Here, we determine the structure of the complete zebrafish Gpr126 ECR and reveal five domains including a previously unknown domain. Strikingly, the Gpr126 ECR adopts a closed conformation that is stabilized by an alternatively spliced linker and a conserved calcium-binding site. Alternative splicing regulates ECR conformation and receptor signaling, while mutagenesis of the calcium-binding site abolishes Gpr126 function in vivo. These results demonstrate that Gpr126 ECR utilizes a multi-faceted dynamic approach to regulate receptor function and provide relevant insights for ECR-targeted drug design. © 2020, The Author(s).

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

ASCOT identifies key regulators of neuronal subtype-specific splicing
(2020) Nature Communications, 11 (1), art. no. 137, . 

Ling, J.P.^{a b} , Wilks, C.^{c d} , Charles, R.^{c d} , Leavey, P.J.^b , Ghosh, D.^b , Jiang, L.^b , Santiago, C.P.^b , Pang, B.^b , Venkataraman, A.^b , Clark, B.S.^e , Nellore, A.^{f g h} , Langmead, B.^{a c d} , Blackshaw, S.^{a b i j k l}

^a Kavli Neuroscience Discovery Institute, Johns Hopkins University, Baltimore, MD, United States
^b Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, Baltimore, MD, United States
^c Department of Computer Science, Johns Hopkins University, Baltimore, MD, United States
^d Center for Computational Biology, Johns Hopkins University, Baltimore, MD, United States
^e John F. Hardesty, MD Department of Ophthalmology and Visual Sciences, Washington University, St. Louis, MO, United States
^f Department of Biomedical Engineering, Oregon Health and Science University, Portland, OR, United States
^g Department of Surgery, Oregon Health and Science University, Portland, OR, United States
^h Computational Biology Program, Oregon Health and Science University, Portland, OR, United States
ⁱ Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^j Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^k Center for Human Systems Biology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^l Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Abstract
Public archives of next-generation sequencing data are growing exponentially, but the difficulty of marshaling this data has led to its underutilization by scientists. Here, we present ASCOT, a resource that uses annotation-free methods to rapidly analyze and visualize splice variants across tens of thousands of bulk and single-cell data sets in the public archive. To demonstrate the utility of ASCOT, we identify novel cell type-specific alternative exons across the nervous system and leverage ENCODE and GTEx data sets to study the unique splicing of photoreceptors. We find that PTBP1 knockdown and MSI1 and PCBP2 overexpression are sufficient to activate many photoreceptor-specific exons in HepG2 liver cancer cells. This work demonstrates how large-scale analysis of public RNA-Seq data sets can yield key insights into cell type-specific control of RNA splicing and underscores the importance of considering both annotated and unannotated splicing events. © 2020, The Author(s).

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

Polysubstance Use: A Broader Understanding of Substance Use During the Opioid Crisis
(2020) American Journal of Public Health, 110 (2), pp. 244-250. 

Cicero, T.J., Ellis, M.S., Kasper, Z.A.

All of the authors are with Washington University in St Louis, St Louis, MO

Abstract
Objectives. To understand important changes in co-occurring opioid and nonopioid drug use (i.e., polysubstance use) within the opioid epidemic in the United States.Methods. We analyzed survey data on the past month co-use of prescription and illicit opioids and 12 nonopioid psychoactive drug classes from a national sample of 15 741 persons entering treatment of opioid use disorder.Results. Past-month illicit opioid use increased from 44.8% in 2011 to 70.1% in 2018, while the use of prescription opioids alone dropped from 55.2% to 29.9%, yet overall remained high (94.5% to 85.2%). Past-month use of at least 1 nonopioid drug occurred in nearly all participants (> 90%), with significant increases in methamphetamine (+85%) and decreases across nonopioid prescription drug classes (range: -40% to -68%).Conclusions. Viewing opioid trends in a “silo” ignores the fact not only that polysubstance use is ubiquitous among those with opioid use disorder but also that significant changes in polysubstance use should be monitored alongside opioid trends.Public Health Implications. Treatment, prevention, and policymaking must address not only the supply and demand of a singular drug class but also the global nature of substance use overall.

Document Type: Article
Publication Stage: Final
Source: Scopus

MeCP2 Represses Enhancers through Chromosome Topology-Associated DNA Methylation
(2020) Molecular Cell, 77 (2), pp. 279-293.e8. Cited 1 time.

Clemens, A.W., Wu, D.Y., Moore, J.R., Christian, D.L., Zhao, G., Gabel, H.W.

Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110-1093, United States

Abstract
The genomes of mammalian neurons contain uniquely high levels of non-CG DNA methylation that can be bound by the Rett syndrome protein, MeCP2, to regulate gene expression. How patterns of non-CG methylation are established in neurons and the mechanism by which this methylation works with MeCP2 to control gene expression is unclear. Here, we find that genes repressed by MeCP2 are often located within megabase-scale regions of high non-CG methylation that correspond with topologically associating domains of chromatin folding. MeCP2 represses enhancers found in these domains that are enriched for non-CG and CG methylation, with the strongest repression occurring for enhancers located within MeCP2-repressed genes. These alterations in enhancer activity provide a mechanism for how MeCP2 disruption in disease can lead to widespread changes in gene expression. Hence, we find that DNA topology can shape non-CG DNA methylation across the genome to dictate MeCP2-mediated enhancer regulation in the brain. © 2019 Elsevier Inc.

Clemens and Wu et al. demonstrate that DNMT3A establishes non-CG DNA methylation across topologically associating domains in neurons, resulting in broad regions of high and low methylation. Within regions of enriched DNA methylation, MeCP2 represses the activity of enhancers, regulating promoter activation for genes controlled by these enhancers. © 2019 Elsevier Inc.

Author Keywords
cerebral cortex;  DNA methylation;  enhancer;  MeCP2;  non-CG methylation;  Rett syndrome;  topologically associating domains;  transcription

Document Type: Article
Publication Stage: Final
Source: Scopus

Brain Parenchymal and Extraparenchymal Macrophages in Development, Homeostasis, and Disease
(2020) Journal of Immunology (Baltimore, Md. : 1950), 204 (2), pp. 294-305. 

Brioschi, S., Zhou, Y., Colonna, M.

Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO 63110

Abstract
Microglia are parenchymal macrophages of the CNS; as professional phagocytes they are important for maintenance of the brain’s physiology. These cells are generated through primitive hematopoiesis in the yolk sac and migrate into the brain rudiment after establishment of embryonic circulation. Thereafter, microglia develop in a stepwise fashion, reaching complete maturity after birth. In the CNS, microglia self-renew without input from blood monocytes. Recent RNA-sequencing studies have defined a molecular signature for microglia under homeostasis. However, during disease, microglia undergo remarkable phenotypic changes, which reflect the acquisition of specialized functions tailored to the pathological context. In addition to microglia, the brain-border regions host populations of extraparenchymal macrophages with disparate origins and phenotypes that have recently been delineated. In this review we outline recent findings that provide a deeper understanding of both parenchymal microglia and extraparenchymal brain macrophages in homeostasis and during disease. Copyright © 2020 by The American Association of Immunologists, Inc.

Document Type: Review
Publication Stage: Final
Source: Scopus

Incidence of Infectious Complications Following Cochlear Implantation in Children and Adults
(2020) JAMA, 323 (2), pp. 182-183. 

Lander, D.P.^a , Durakovic, N.^a , Kallogjeri, D.^a , Jiramongkolchai, P.^a , Olsen, M.A.^b , Piccirillo, J.F.^a , Buchman, C.A.^a

^a Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine in St Louis, St Louis, MO, United States
^b Division of Infectious Diseases, Washington University School of Medicine in St Louis, St Louis, MO, United States

Document Type: Article
Publication Stage: Final
Source: Scopus

Erratum: Correction to: Comprehensive gene expression meta-analysis identifies signature genes that distinguish microglia from peripheral monocytes/macrophages in health and glioma (Acta neuropathologica communications (2019) 7 1 (20))
(2020) Acta Neuropathologica Communications, 8 (1), p. 1. 

Haage, V.^a , Semtner, M.^a , Vidal, R.O.^a , Hernandez, D.P.^a , Pong, W.W.^b , Chen, Z.^c , Hambardzumyan, D.^c , Magrini, V.^d , Ly, A.^d , Walker, J.^d , Mardis, E.^d , Mertins, P.^a , Sauer, S.^a , Kettenmann, H.^a , Gutmann, D.H.^{a b}

^a Max Delbrück Center for Molecular Medicine in the Helmholtz AssociationBerlin, Germany
^b Department of Neurology, Washington University School of Medicine, Box 8111, 660 S. Euclid Avenue, St. Louis, MO, 63110, USA
^c Department of Pediatrics, Emory University, Atlanta, United States
^d McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA

Abstract
The original publication of this article [1] contained 3 minor errors in Figs. 1, 3 and 5. In this correction article the updated figures are published. The figure captions describe the updated information in these figures.

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

Implicit Social Cognition
(2020) Annual Review of Psychology, 71, pp. 419-445. 

Greenwald, A.G.^a , Lai, C.K.^b

^a Department of Psychology, University of Washington, Seattle, Washington 98195, USA; email: agg@uw.edu
^b Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO 63130, United States

Abstract
In the last 20 years, research on implicit social cognition has established that social judgments and behavior are guided by attitudes and stereotypes of which the actor may lack awareness. Research using the methods of implicit social cognition has produced the concept of implicit bias, which has generated wide attention not only in social, clinical, and developmental psychology, but also in disciplines outside of psychology, including business, law, criminal justice, medicine, education, and political science. Although this rapidly growing body of research offers prospects of useful societal applications, the theory needed to confidently guide those applications remains insufficiently developed. This article describes the methods that have been developed, the findings that have been obtained, and the theoretical questions that remain to be answered.

Author Keywords
evaluative priming;  Implicit Association Test;  implicit bias;  implicit social cognition;  implicit–explicit relationships;  indirect measures

Document Type: Article
Publication Stage: Final
Source: Scopus

Event Perception and Memory
(2020) Annual Review of Psychology, 71, pp. 165-191. 

Zacks, J.M.

Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, Missouri 63130, USA; email:

Abstract
Events make up much of our lived experience, and the perceptual mechanisms that represent events in experience have pervasive effects on action control, language use, and remembering. Event representations in both perception and memory have rich internal structure and connections one to another, and both are heavily informed by knowledge accumulated from previous experiences. Event perception and memory have been identified with specific computational and neural mechanisms, which show protracted development in childhood and are affected by language use, expertise, and brain disorders and injuries. Current theoretical approaches focus on the mechanisms by which events are segmented from ongoing experience, and emphasize the common coding of events for perception, action, and memory. Abetted by developments in eye-tracking, neuroimaging, and computer science, research on event perception and memory is moving from small-scale laboratory analogs to the complexity of events in the wild.

Author Keywords
action control;  cognitive development;  cognitive neuroscience;  episodic memory;  event perception;  film;  media

Document Type: Article
Publication Stage: Final
Source: Scopus

Latent Profiles of Cognitive Control, Episodic Memory, and Visual Perception Across Psychiatric Disorders Reveal a Dimensional Structure
(2020) Schizophrenia Bulletin, 46 (1), pp. 154-162. 

Smucny, J.^a , Iosif, A.-M.^a , Eaton, N.R.^b , Lesh, T.A.^a , Ragland, J.D.^a , Barch, D.M.^c , Gold, J.M.^d , Strauss, M.E.^e , MacDonald, A.W.^f , Silverstein, S.M.^g , Carter, C.S.^a

^a Department of Psychiatry and Behavioral Sciences, University of California, Davis, Davis, CA
^b Department of Psychology, State University of New York Stony Brook, Stony Brook, NY
^c Department of Psychology, Washington University in St. Louis, St. Louis, MO
^d Department of Psychiatry, Maryland Psychiatric Research Center, MD, Catonsville, United States
^e Department of Psychology, University of New Mexico, NM, Albuquerque, United States
^f Department of Psychology, University of Minnesota, MN, Minneapolis, United States
^g Departments of Psychiatry and Ophthalmology, Rutgers – The State University of New JerseyNB

Abstract
Although meta-analyses suggest that schizophrenia (SZ) is associated with a more severe neurocognitive phenotype than mood disorders such as bipolar disorder, considerable between-subject heterogeneity exists in the phenotypic presentation of these deficits across mental illnesses. Indeed, it is unclear whether the processes that underlie cognitive dysfunction in these disorders are unique to each disease or represent a common neurobiological process that varies in severity. Here we used latent profile analysis (LPA) across 3 distinct cognitive domains (cognitive control, episodic memory, and visual integration; using data from the CNTRACS consortium) to identify distinct profiles of patients across psychotic illnesses. LPA was performed on a sample of 223 psychosis patients (59 with Type I bipolar disorder, 88 with SZ, and 76 with schizoaffective disorder). Seventy-three healthy control participants were included for comparison but were not included in sample LPA. Three latent profiles (“Low,” “Moderate,” and “High” ability) were identified as the underlying covariance across the 3 domains. The 3-profile solution provided highly similar fit to a single continuous factor extracted by confirmatory factor analysis, supporting a unidimensional structure. Diagnostic ratios did not significantly differ between profiles, suggesting that these profiles cross diagnostic boundaries (an exception being the Low ability profile, which had only one bipolar patient). Profile membership predicted Brief Psychiatric Rating Scale and Young Mania Rating Scale symptom severity as well as everyday communication skills independent of diagnosis. Biological, clinical and methodological implications of these findings are discussed. © The Author(s) 2019. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Author Keywords
bipolar disorder;  cluster analysis;  schizoaffective disorder;  schizophrenia

Document Type: Article
Publication Stage: Final
Source: Scopus

Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease
(2020) Nature Medicine, 26 (1), pp. 131-142. 

Zhou, Y.^a , Song, W.M.^a , Andhey, P.S.^a , Swain, A.^a , Levy, T.^b , Miller, K.R.^c , Poliani, P.L.^d , Cominelli, M.^d , Grover, S.^e , Gilfillan, S.^a , Cella, M.^a , Ulland, T.K.^f , Zaitsev, K.^{a g} , Miyashita, A.^h , Ikeuchi, T.^h , Sainouchi, M.ⁱ , Kakita, A.ⁱ , Bennett, D.A.^j , Schneider, J.A.^j , Nichols, M.R.^e , Beausoleil, S.A.^b , Ulrich, J.D.^k , Holtzman, D.M.^k , Artyomov, M.N.^a , Colonna, M.^a

^a Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
^b Bluefin Biomedicine, MA, Beverly, United States
^c NanoString, Seattle, WA, USA
^d Pathology Unit, Molecular and Translational Medicine Department, University of Brescia, Brescia, Italy
^e Department of Chemistry & Biochemistry, University of Missouri-St. Louis, St. Louis, MO, USA
^f Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, WI, Madison, United States
^g Computer Technologies Department, ITMO University, Saint Petersburg, Russian Federation
^h Department of Molecular Genetics, Brain Research Institute, Niigata UniversityNiigata, Japan
ⁱ Department of Pathology, Brain Research Institute, Niigata UniversityNiigata, Japan
^j Rush Alzheimer’s Disease Center and Department of Neurological Sciences, Rush University Medical Center, Chicago, United States
^k Department of Neurology, Hope Center for Neurological Disorders, Knight ADRC, Washington University School of Medicine, St. Louis, MO, USA

Abstract
Glia have been implicated in Alzheimer’s disease (AD) pathogenesis. Variants of the microglia receptor triggering receptor expressed on myeloid cells 2 (TREM2) increase AD risk, and activation of disease-associated microglia (DAM) is dependent on TREM2 in mouse models of AD. We surveyed gene-expression changes associated with AD pathology and TREM2 in 5XFAD mice and in human AD by single-nucleus RNA sequencing. We confirmed the presence of Trem2-dependent DAM and identified a previously undiscovered Serpina3n+C4b+ reactive oligodendrocyte population in mice. Interestingly, remarkably different glial phenotypes were evident in human AD. Microglia signature was reminiscent of IRF8-driven reactive microglia in peripheral-nerve injury. Oligodendrocyte signatures suggested impaired axonal myelination and metabolic adaptation to neuronal degeneration. Astrocyte profiles indicated weakened metabolic coordination with neurons. Notably, the reactive phenotype of microglia was less evident in TREM2-R47H and TREM2-R62H carriers than in non-carriers, demonstrating a TREM2 requirement in both mouse and human AD, despite the marked species-specific differences.

Document Type: Article
Publication Stage: Final
Source: Scopus

Developing retinal biomarkers for the earliest stages of Alzheimer’s disease: What we know, what we don’t, and how to move forward
(2020) Alzheimer’s & Dementia : the Journal of the Alzheimer’s Association, 16 (1), pp. 229-243. 

Alber, J.^{a b c d} , Goldfarb, D.^e , Thompson, L.I.^{c d} , Arthur, E.^{a b d} , Hernandez, K.^f , Cheng, D.^g , DeBuc, D.C.^h , Cordeiro, F.^{i j k} , Provetti-Cunha, L.^{l m n} , den Haan, J.^o , Van Stavern, G.P.^p , Salloway, S.P.^{c d q} , Sinoff, S.^r , Snyder, P.J.^{a b s}

^a Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island, USA
^b George and Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, Rhode Island, USA
^c Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, United States
^d Butler Hospital Memory & Aging Program, Providence, RI, United States
^e Banner Alzheimer’s Institute, Phoenix, AZ, United States
^f Women & Infants Hospital, Providence, RI, United States
^g Alpert Medical School of Brown University, Providence, RI, United States
^h Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami, Miami, FL, United States
ⁱ Imperial College London, London, United Kingdom
^j University College London, London, United Kingdom
^k Western Eye Hospital, London, United Kingdom
^l Federal University of Juiz de Fora Medical School, Juiz de Fora, Minas Gerais, Brazil
^m Juiz de Fora Eye Hospital, Juiz de Fora, Minas Gerais, Brazil
ⁿ University of São Paulo Medical School, São Paulo, Brazil
^o Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
^p Department of Ophthalmology and Visual Sciences, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
^q Department of Neurology, Alpert Medical School of Brown University, Providence, RI, United States
^r BayCare Health, Clearwater, FL, United States
^s Department of Neurology and Department of Surgery (Ophthalmology), Alpert Medical School of Brown University, Providence, RI, United States

Abstract
The last decade has seen a substantial increase in research focused on the identification, development, and validation of diagnostic and prognostic retinal biomarkers for Alzheimer’s disease (AD). Sensitive retinal biomarkers may be advantageous because they are cost and time efficient, non-invasive, and present a minimal degree of patient risk and a high degree of accessibility. Much of the work in this area thus far has focused on distinguishing between symptomatic AD and/or mild cognitive impairment (MCI) and cognitively normal older adults. Minimal work has been done on the detection of preclinical AD, the earliest stage of AD pathogenesis characterized by the accumulation of cerebral amyloid absent clinical symptoms of MCI or dementia. The following review examines retinal structural changes, proteinopathies, and vascular alterations that have been proposed as potential AD biomarkers, with a focus on studies examining the earliest stages of disease pathogenesis. In addition, we present recommendations for future research to move beyond the discovery phase and toward validation of AD risk biomarkers that could potentially be used as a first step in a multistep screening process for AD risk detection. © 2020 the Alzheimer’s Association.

Author Keywords
Alzheimer’s disease;  amyloid;  biomarkers;  early detection;  optical coherence tomography;  preclinical AD;  retina

Document Type: Review
Publication Stage: Final
Source: Scopus

Comparison of sporadic and familial behavioral variant frontotemporal dementia (FTD) in a North American cohort
(2020) Alzheimer’s & Dementia : the Journal of the Alzheimer’s Association, 16 (1), pp. 60-70. 

Heuer, H.W.^a , Wang, P.^a , Rascovsky, K.^b , Wolf, A.^a , Appleby, B.^c , Bove, J.^b , Bordelon, Y.^d , Brannelly, P.^e , Brushaber, D.E.^f , Caso, C.^g , Coppola, G.^d , Dickerson, B.^h , Dickinson, S.ⁱ , Domoto-Reilly, K.^g , Faber, K.^j , Ferrall, J.^k , Fields, J.^f , Fishman, A.^l , Fong, J.^a , Foroud, T.^j , Forsberg, L.K.^f , Gearhart, D.^f , Ghazanfari, B.^m , Ghoshal, N.ⁿ , Goldman, J.^o , Graff-Radford, J.^f , Graff-Radford, N.^p , Grant, I.^q , Grossman, M.^b , Haley, D.^p , Hsiung, G.-Y.^r , Huey, E.^o , Irwin, D.^b , Jones, D.^f , Kantarci, K.^f , Karydas, A.^a , Kaufer, D.^k , Kerwin, D.^s , Knopman, D.^f , Kornak, J.^a , Kramer, J.H.^a , Kraft, R.^f , Kremers, W.K.^f , Kukull, W.^t , Litvan, I.^u , Ljubenkov, P.^a , Mackenzie, I.R.^r , Maldonado, M.^d , Manoochehri, M.^o , McGinnis, S.^h , McKinley, E.^v , Mendez, M.F.^d , Miller, B.L.^a , Onyike, C.^l , Pantelyat, A.^l , Pearlman, R.^w , Petrucelli, L.^p , Potter, M.^j , Rademakers, R.^p , Ramos, E.M.^d , Rankin, K.P.^a , Roberson, E.D.^v , Rogalski, E.^q , Sengdy, P.^r , Shaw, L.^b , Syrjanen, J.^f , Tartaglia, M.C.^m , Tatton, N.ⁱ , Taylor, J.^a , Toga, A.^x , Trojanowski, J.^c , Weintraub, S.^q , Wong, B.^h , Wszolek, Z.^p , Boeve, B.F.^f , Rosen, H.J.^a , Boxer, A.L.^a , ARTFL and LEFFTDS consortia^y

^a University of California, San Francisco, CA, Mexico
^b University of Pennsylvania, Philadelphia, PA, United States
^c Case Western Reserve University, Cleveland, OH, United States
^d University of California, Los Angeles, CA, Mexico
^e Rainwater Charitable Foundation, Fort Worth, TX, United States
^f Mayo Clinic, Rochester, MN
^g Washington, Seattle, United States
^h Boston, MA
ⁱ Association for Frontotemporal Degeneration, Radnor, PA, United States
^j National Centralized Repository for Alzheimer’s Disease and Related Disorders (NCRAD), Indiana University, Indianapolis, IN, United States
^k University of North Carolina, Chapel HillNC
^l Johns Hopkins University, Baltimore, MD, United States
^m University of Toronto, Toronto, ON, Canada
ⁿ Washington University, St. Louis, MO, United States
^o Columbia UniversityNY
^p Mayo Clinic, Jacksonville, FL, United States
^q Northwestern University, Chicago, IL, Mexico
^r University of British Columbia, Vancouver, BC, Canada
^s University of Texas, Southwestern Medical Center at Dallas, Dallas, TX, United States
^t National Alzheimer Coordinating Center (NACC), University of Washington, Seattle, WA, United States
^u University of California, San Diego, CA, Mexico
^v University of Alabama at Birmingham, Birmingham, AL
^w Bluefield Project, San Francisco, CA, Mexico
^x Laboratory of Neuroimaging (LONI), USC, Los Angeles, CA, Mexico

Abstract
INTRODUCTION: Behavioral variant frontotemporal dementia (bvFTD) may present sporadically or due to an autosomal dominant mutation. Characterization of both forms will improve understanding of the generalizability of assessments and treatments. METHODS: A total of 135 sporadic (s-bvFTD; mean age 63.3 years; 34% female) and 99 familial (f-bvFTD; mean age 59.9; 48% female) bvFTD participants were identified. f-bvFTD cases included 43 with known or presumed chromosome 9 open reading frame 72 (C9orf72) gene expansions, 28 with known or presumed microtubule-associated protein tau (MAPT) mutations, 14 with known progranulin (GRN) mutations, and 14 with a strong family history of FTD but no identified mutation. RESULTS: Participants with f-bvFTD were younger and had earlier age at onset. s-bvFTD had higher total Neuropsychiatric Inventory Questionnaire (NPI-Q) scores due to more frequent endorsement of depression and irritability. DISCUSSION: f-bvFTD and s-bvFTD cases are clinically similar, suggesting the generalizability of novel biomarkers, therapies, and clinical tools developed in either form to the other. © 2020 the Alzheimer’s Association.

Author Keywords
bvFTD;  C9orf72;  clinical trials;  frontotemporal dementia;  genetics;  GRN;  MAPT

Document Type: Article
Publication Stage: Final
Source: Scopus

Active lifestyles moderate clinical outcomes in autosomal dominant frontotemporal degeneration
(2020) Alzheimer’s & Dementia : the Journal of the Alzheimer’s Association, 16 (1), pp. 91-105. 

Casaletto, K.B.^a , Staffaroni, A.M.^a , Wolf, A.^a , Appleby, B.^b , Brushaber, D.^c , Coppola, G.^d , Dickerson, B.^e , Domoto-Reilly, K.^f , Elahi, F.M.^a , Fields, J.^c , Fong, J.C.^a , Forsberg, L.^b , Ghoshal, N.^g , Graff-Radford, N.^c , Grossman, M.^h , Heuer, H.W.^a , Hsiung, G.-Y.ⁱ , Huey, E.D.^j , Irwin, D.^h , Kantarci, K.^c , Kaufer, D.^k , Kerwin, D.^l , Knopman, D.^c , Kornak, J.^m , Kramer, J.H.^a , Litvan, I.ⁿ , Mackenzie, I.R.ⁱ , Mendez, M.^d , Miller, B.^a , Rademakers, R.^o , Ramos, E.M.^p , Rascovsky, K.^h , Roberson, E.D.^q , Syrjanen, J.A.^c , Tartaglia, M.C.^r , Weintraub, S.^s , Boeve, B.^c , Boxer, A.L.^a , Rosen, H.^a , Yaffe, K.^{a t} , ARTFL/LEFFTDS Study^u

^a Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, United States
^b Case Western Reserve University, Cleveland, OH, United States
^c Mayo Clinic, Rochester, MN, United States
^d University of California, Los Angeles, CA, United States
^e Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
^f University of Washington, Seattle, WA, United States
^g Washington University, St. Louis, IL, United States
^h University of Pennsylvania, Philadelphia, PA, United States
ⁱ University of British Columbia, Vancouver, BC, Canada
^j Columbia UniversityNY, United States
^k University of North Carolina, Chapel HillNC, United States
^l University of Texas Southwestern, Dallas, TX, United States
^m Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, United States
ⁿ Department of Neuroscience, University of California, Parkinson and Other Movement Disorder Center, San Diego, CA, United States
^o Mayo Clinic, Jacksonville, FL, United States
^p University of California, Los Angeles, United States
^q University of Alabama, Birmingham, AL, United States
^r University of Toronto, Toronto, ON, Canada
^s Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Northwestern University, Chicago, IL, United States
^t San Francisco Department of Psychiatry, University of California, San Francisco, CA, United States

Abstract
INTRODUCTION: Leisure activities impact brain aging and may be prevention targets. We characterized how physical and cognitive activities relate to brain health for the first time in autosomal dominant frontotemporal lobar degeneration (FTLD). METHODS: A total of 105 mutation carriers (C9orf72/MAPT/GRN) and 69 non-carriers reported current physical and cognitive activities at baseline, and completed longitudinal neurobehavioral assessments and brain magnetic resonance imaging (MRI) scans. RESULTS: Greater physical and cognitive activities were each associated with an estimated >55% slower clinical decline per year among dominant gene carriers. There was also an interaction between leisure activities and frontotemporal atrophy on cognition in mutation carriers. High-activity carriers with frontotemporal atrophy (-1 standard deviation/year) demonstrated >two-fold better cognitive performances per year compared to their less active peers with comparable atrophy rates. DISCUSSION: Active lifestyles were associated with less functional decline and moderated brain-to-behavior relationships longitudinally. More active carriers “outperformed” brain volume, commensurate with a cognitive reserve hypothesis. Lifestyle may confer clinical resilience, even in autosomal dominant FTLD. © 2020 the Alzheimer’s Association.

Author Keywords
cognitive activity;  cognitive reserve;  exercise;  frontotemporal dementia;  physical activity

Document Type: Article
Publication Stage: Final
Source: Scopus

Concordance of Lumipulse cerebrospinal fluid t-tau/Aβ42 ratio with amyloid PET status
(2020) Alzheimer’s & Dementia : the Journal of the Alzheimer’s Association, 16 (1), pp. 144-152. 

Kaplow, J.^a , Vandijck, M.^b , Gray, J.^c , Kanekiyo, M.^a , Huyck, E.^b , Traynham, C.J.^d , Esquivel, R.^d , Fagan, A.M.^c , Luthman, J.^a

^a Eisai Inc., Woodcliff Lake, United States
^b Fujirebio Europe, Ghent, Belgium
^c Department of Neurology, Knight Alzheimer’s Disease Research Center, Washington University, St. Louis, MO, USA
^d Fujirebio Diagnostics Inc., Malvern, United States

Abstract
INTRODUCTION: Cerebrospinal fluid (CSF) biomarkers can identify individuals with Alzheimer’s disease (AD) pathology (eg, amyloid plaques, neurofibrillary tangles), but defined analyte cut-points using high-throughput automated assays are necessary for general clinical use. METHODS: CSF amyloid β42 peptide (Aβ42), t-tau, and t-tau/Aβ42 were quantified by the Lumipulse platform in two test cohorts (A/B: Eisai BAN2401-201/MISSION AD E2609-301/302, n = 138; C: Knight Alzheimer’s Disease Research Center (ADRC), n = 198), and receiver operating characteristic (ROC) curve analyses defined cut-points corresponding best to amyloid determinations using positron emission tomography (PET) imaging. The best-performing cut-point was then validated as a predictor of amyloid status in an independent cohort (D: MISSION AD E2609-301/302, n = 240). RESULTS: Virtually identical t-tau/Aβ42 cut-points (∼0.54) performed best in both test cohorts and with similar accuracy (areas under ROC curve [AUCs] [A/B: 0.95; C: 0.94]). The cut-point yielded an overall percent agreement with amyloid PET of 85.0% in validation cohort D. DISCUSSION: Lumipulse CSF biomarker measures with validated cut-points have clinical utility in identifying AD pathology. © 2020 the Alzheimer’s Association.

Author Keywords
Alzheimer’s disease;  amyloid PET;  assay validation;  biomarker;  cerebrospinal fluid;  cut-point;  Lumipulse;  t-tau/Aβ42 ratio

Document Type: Article
Publication Stage: Final
Source: Scopus

Genetic screening of a large series of North American sporadic and familial frontotemporal dementia cases
(2020) Alzheimer’s & Dementia : the Journal of the Alzheimer’s Association, 16 (1), pp. 118-130. 

Ramos, E.M.^a , Dokuru, D.R.^a , Van Berlo, V.^a , Wojta, K.^a , Wang, Q.^a , Huang, A.Y.^a , Deverasetty, S.^a , Qin, Y.^a , van Blitterswijk, M.^b , Jackson, J.^b , Appleby, B.^c , Bordelon, Y.^d , Brannelly, P.^e , Brushaber, D.E.^f , Dickerson, B.^g , Dickinson, S.^h , Domoto-Reilly, K.ⁱ , Faber, K.^j , Fields, J.^f , Fong, J.^k , Foroud, T.^j , Forsberg, L.K.^f , Gavrilova, R.^f , Ghoshal, N.^l , Goldman, J.^m , Graff-Radford, J.^f , Graff-Radford, N.^b , Grant, I.ⁿ , Grossman, M.^o , Heuer, H.W.^k , Hsiung, G.-Y.R.^p , Huey, E.^m , Irwin, D.^o , Kantarci, K.^f , Karydas, A.^k , Kaufer, D.^q , Kerwin, D.^r , Knopman, D.^f , Kornak, J.^k , Kramer, J.H.^k , Kremers, W.^f , Kukull, W.^s , Litvan, I.^t , Ljubenkov, P.^k , Lungu, C.^u , Mackenzie, I.^p , Mendez, M.F.^d , Miller, B.L.^k , Onyike, C.^v , Pantelyat, A.^v , Pearlman, R.^w , Petrucelli, L.^b , Potter, M.^j , Rankin, K.P.^k , Rascovsky, K.^o , Roberson, E.D.^x , Rogalski, E.ⁿ , Shaw, L.^o , Syrjanen, J.^f , Tartaglia, M.C.^y , Tatton, N.^h , Taylor, J.^k , Toga, A.^z , Trojanowski, J.Q.^o , Weintraub, S.ⁿ , Wong, B.^g , Wszolek, Z.^b , Rademakers, R.^b , Boeve, B.F.^f , Rosen, H.J.^k , Boxer, A.L.^k , Coppola, G.^a , ARTFL/LEFFTDS consortium^aa

^a Department of Psychiatry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, Mexico
^b Mayo Clinic, Jacksonville, FL, United States
^c Case Western Reserve University, Cleveland, OH, United States
^d University of California Los Angeles, Los Angeles, CA, Mexico
^e Rainwater Charitable Foundation, Fort Worth, TX, United States
^f Mayo Clinic, Rochester, MN
^g Boston, MA
^h Association for Frontotemporal Degeneration, Radnor, PA, United States
ⁱ University of Washington, Seattle, WA, United States
^j National Centralized Repository for Alzheimer’s Disease and Related Dementia (NCRAD), Indiana University, Indianapolis, IN, United States
^k University of California, San Francisco, CA, Mexico
^l Washington University, St. Louis, MO, United States
^m Columbia UniversityNY
ⁿ Northwestern University, Chicago, IL, Mexico
^o University of Pennsylvania, Philadelphia, PA, United States
^p University of British Columbia, Vancouver, BC, Canada
^q University of North Carolina, Chapel HillNC
^r University of Texas Southwestern Medical Center, Dallas, TX, United States
^s National Alzheimer Coordinating Center (NACC), University of Washington, Seattle, WA, United States
^t University of California, San Diego, CA, Mexico
^u National Institute of Neurological Disorders and Stroke (NINDS), Bethesda, MD, United States
^v Johns Hopkins University, Baltimore, MD, United States
^w Bluefield Project, San Francisco, CA, Mexico
^x University of Alabama at Birmingham, Birmingham, AL
^y University of Toronto, Toronto, ON, Canada
^z Laboratory of Neuroimaging (LONI), USC, Los Angeles, CA, Mexico

Abstract
INTRODUCTION: The Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) consortia are two closely connected studies, involving multiple North American centers that evaluate both sporadic and familial frontotemporal dementia (FTD) participants and study longitudinal changes. METHODS: We screened the major dementia-associated genes in 302 sporadic and 390 familial (symptomatic or at-risk) participants enrolled in these studies. RESULTS: Among the sporadic patients, 16 (5.3%) carried chromosome 9 open reading frame 72 (C9orf72), microtubule-associated protein tau (MAPT), and progranulin (GRN) pathogenic variants, whereas in the familial series we identified 207 carriers from 146 families. Of interest, one patient was found to carry a homozygous C9orf72 expansion, while another carried both a C9orf72 expansion and a GRN pathogenic variant. We also identified likely pathogenic variants in the TAR DNA binding protein (TARDBP), presenilin 1 (PSEN1), and valosin containing protein (VCP) genes, and a subset of variants of unknown significance in other rare FTD genes. DISCUSSION: Our study reports the genetic characterization of a large FTD series and supports an unbiased sequencing screen, irrespective of clinical presentation or family history. © 2020 the Alzheimer’s Association.

Author Keywords
C9orf72;  familial;  frontotemporal dementia;  GRN;  MAPT;  sporadic

Document Type: Article
Publication Stage: Final
Source: Scopus

The Intracerebral Hemorrhage Score: Changing Perspectives on Mortality and Disability
(2020) World Neurosurgery, . 

Garton, A.L.A.^a , Gupta, V.P.^b , Sudesh, S.^c , Zhou, H.^c , Christophe, B.R.^c , Connolly, E.S., Jr.^c

^a Department of Neurosurgery, New York–Presbyterian Hospital/Weill Cornell Medical Center, New York, New, York, United States
^b Department of Neurosurgery, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
^c Department of Neurosurgery, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, United States

Abstract
Background: Intracerebral hemorrhage (ICH) remains a devastating diagnosis. While the ICH Score continues to be used in the clinical setting to prognosticate outcomes, contemporary improvements in management have reduced mortality rates for each scoring tier. The aims of this study were to examine mortality rates within ICH Score strata and examine if these findings are stable when major disability is included in categorizing poor outcomes. Methods: From a single-institution cohort built between 2009 and 2016, 582 patients were extracted based on the criteria for complete ICH Score, discharge mortality, and functional status for survivors. Mortality rates were stratified by ICH Score and compared with both historical and similar contemporary cohorts. Poor outcome was defined as severe disability (modified Rankin Scale score 5) in addition to death, stratified by ICH Score, and compared. A secondary analysis of patients with ICH Score of 2 was performed in light of the primary results. Results: Mortality rates stratified by ICH Score were notably lower than expected for low- and moderate-grade ICH compared with the original cohort. However, when defining a poor outcome as including severe disability (modified Rankin Scale score 5) in addition to death, the rates for poor outcomes were higher for patients with ICH Score of 2 (51.16% vs. 26%, P = 0.017) and no different for any other score group compared with the original cohort. Conclusions: Though the original ICH Score overestimates mortality for low-grade and moderate-grade hemorrhages, it may underpredict severe disability. © 2019 Elsevier Inc.

Author Keywords
Disability;  Functional outcomes;  ICH Score;  Intracerebral hemorrhage;  Mortality;  Surgery;  Withdrawal of care

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

Clock regulation of protein secretion
(2020) Nature Cell Biology, 22 (1), . 

Burris, T.P.

Center for Clinical Pharmacology, Washington University and St. Louis College of Pharmacy, St. Louis, MO, United States

Document Type: Article
Publication Stage: Final
Source: Scopus

Personality in Combination with Alcohol and Drug Use and Psychiatric Disorders to Predict Psychosocial Characteristics and Behaviors of Hepatitis C Patients
(2020) Journal of Clinical Psychology in Medical Settings, . 

Sims, O.T.^{a b c d e} , Oh, H.^f , Pollio, D.E.^{a b c} , Hong, B.A.^g , Pollio, E.W.^h , North, C.S.^{i j}

^a Department of Social Work, College of Arts and Sciences, University of Alabama at Birmingham, 3137 University Hall, 1720 2nd AVE S, Birmingham, AL 35294-1260, United States
^b Department of Health Behavior, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, United States
^c Center for AIDS Research, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
^d Integrative Center for Healthy Aging, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
^e Center for AIDS Prevention Studies, Division of Prevention Science, Department of Medicine, University of California San Francisco, San Francisco, CA, United States
^f Department of Social Work, School of Social Sciences & Education, California State University Bakersfield, Bakersfield, CA, United States
^g Department of Psychiatry, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
^h School of Nursing, University of Alabama at Birmingham, Birmingham, AL, United States
ⁱ The Altshuler Center for Education & Research Metrocare Services, Dallas, TX, United States
^j Department of Psychiatry, School of Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States

Abstract
The objectives of this study were to assess the prevalence of personality disorders and to examine personality as a predictor of psychosocial characteristics and behaviors of HCV patients. HCV patients (n = 259) from three infectious disease and liver clinics who completed Cloninger’s Temperament and Character Inventory (TCI), an inventory for personality traits, were included in the study. Patients with low scale scores in the character dimension of both cooperativeness and self-directedness (low CO/SD) were defined as having a personality disorder. Using low CO/SD in combination with demographic, psychiatric/substance use, and HCV-related variables, linear regression was used to construct separate models of risky behaviors, quality of life, functioning, burden of illness, and social support. The prevalence of low CO/SD was high in this sample of HCV patients. Low CO/SD was an independent predictor of risky behaviors, quality of life, functioning, and social support. © 2020, Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Alcohol use;  Drug use;  Hepatitis C;  Personality;  Prevalence;  Psychosocial

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

Combining the lack of chromogranins with chronic L-DOPA treatment affects motor activity in mice
(2020) Cell and Tissue Research, . 

Castañeyra-Ruiz, L.^{a b} , Castañeyra, A.^c , González-Santana, A.^{a b c} , Machado, J.D.^b , Borges, R.^b

^a Department of Neurosurgery, School of Medicine, Washington University in Saint Louis, St. Louis, MO, United States
^b Unidad de Farmacología, Facultad de Medicina, Universidad de La Laguna, La Laguna, Tenerife E-38200, Spain
^c Dept. Ciencias Médicas Basicas, Facultad de Medicina, Universidad de La Laguna, Tenerife, Spain

Abstract
We have tested whether the lack of chromogranins (Cgs) A and B could provoke CNS disorders when combined with an excess of dopamine. We chronically treated (over 6 months) mice lacking both chromogranins A and B (Cgs-KO) with a low oral dosage of L-DOPA/benserazide (10/2.5 mg/kg). Motor performance in the rota-rod test, open field activity, and metabolic cages indicated a progressive impairment in motor coordination in these mice, and an increase in rearing behavior, which was accompanied by an increase in DA within the substantia nigra. We conclude that mild chronic L-DOPA treatment does not produce nigro-striatal toxicity that could be associated with parkinsonism, neither in control nor Cgs-KO mice. Rather, Cgs-KO mice exhibit behaviors compatible with an amphetamine-like effect, probably caused by the excess of catecholamines in the CNS. © 2020, Springer-Verlag GmbH Germany, part of Springer Nature.

Author Keywords
Adrenal;  Behavior;  Catecholamines;  Striatum;  Substantia nigra

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

The neural basis of predictive pursuit
(2020) Nature Neuroscience, . 

Yoo, S.B.M.^a , Tu, J.C.^{a d} , Piantadosi, S.T.^b , Hayden, B.Y.^{a c}

^a Department of Neuroscience, Center for Magnetic Resonance Research, Minneapolis, MN, United States
^b Department of Psychology, University of California Berkeley, Berkeley, CA, United States
^c Center for Neuroengineering, University of Minnesota, Minneapolis, MN, United States
^d Department of Neuroscience, Washington University in St Louis, St Louis, MO, United States

Abstract
It remains unclear whether and, if so, how nonhuman animals make on-the-fly predictions during pursuit. Here we used a novel laboratory pursuit task that incentivizes the prediction of future prey positions. We trained three macaques to perform a joystick-controlled pursuit task in which prey follow intelligent escape algorithms. Subjects aimed toward the likely future positions of the prey, which indicated that they generate internal predictions and use these to guide behavior. We then developed a generative model that explains real-time pursuit trajectories and showed that our subjects use prey position, velocity and acceleration to make predictions. We identified neurons in the dorsal anterior cingulate cortex whose responses track these three variables. These neurons multiplexed prediction-related variables with a distinct and explicit representation of the future position of the prey. Our results provide a clear demonstration that the brain can explicitly represent future predictions and highlight the critical role of anterior cingulate cortex for future-oriented cognition. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.

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

Defining Individual-Specific Functional Neuroanatomy for Precision Psychiatry
(2020) Biological Psychiatry, . 

Gratton, C.^{a b} , Kraus, B.T.^a , Greene, D.J.^{c d} , Gordon, E.M.^{j k l} , Laumann, T.O.^c , Nelson, S.M.^{j k l m} , Dosenbach, N.U.F.^{d e h i} , Petersen, S.E.^{c d e f g}

^a Department of Psychology, Northwestern University, Evanston, IL, United States
^b Department of Neurology, Northwestern University, Evanston, IL, United States
^c Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
^d Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States
^e Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
^f Department of Neuroscience, Washington University in St. Louis, St. Louis, MO, United States
^g Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
^h Department of Pediatrics, Washington University in St. Louis, St. Louis, MO, United States
ⁱ Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
^j VISN Center of Excellence for Research on Returning War Veterans, Waco, TX, United States
^k Department of Psychology and Neuroscience, Baylor University, Waco, TX, United States
^l Center for Vital Longevity, School of Behavioral and Brain Sciences, University of Texas at Dallas, Dallas, TX, United States
^m Department of Psychiatry and Behavioral Science, Texas A&M Health Science Center, College of Medicine, Bryan, TX, United States

Abstract
Studies comparing diverse groups have shown that many psychiatric diseases involve disruptions across distributed large-scale networks of the brain. There is hope that functional magnetic resonance imaging (fMRI) functional connectivity techniques will shed light on these disruptions, providing prognostic and diagnostic biomarkers as well as targets for therapeutic interventions. However, to date, progress on clinical translation of fMRI methods has been limited. Here, we argue that this limited translation is driven by a combination of intersubject heterogeneity and the relatively low reliability of standard fMRI techniques at the individual level. We review a potential solution to these limitations: the use of new “precision” fMRI approaches that shift the focus of analysis from groups to single individuals through the use of extended data acquisition strategies. We begin by discussing the potential advantages of fMRI functional connectivity methods for improving our understanding of functional neuroanatomy and disruptions in psychiatric disorders. We then discuss the budding field of precision fMRI and findings garnered from this work. We demonstrate that precision fMRI can improve the reliability of functional connectivity measures, while showing high stability and sensitivity to individual differences. We close by discussing the application of these approaches to clinical settings. © 2019 Society of Biological Psychiatry

Author Keywords
Brain networks;  fMRI;  Functional connectivity;  Individual differences;  Precision imaging;  Reliability

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

JAMA Psychiatry: Best of 2019
(2019) JAMA Psychiatry, . 

Zorumski, C.F.

Taylor Family Institute for Innovative Psychiatric Research, Center for Brain Research in Mood Disorders, Department of Psychiatry, Washington University School of Medicine in St Louis, 660 S Euclid Ave, St Louis, MO 63110, United States

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