“cADPR is a gene dosage-sensitive biomarker of SARM1 activity in healthy, compromised, and degenerating axons” (2020) Experimental Neurology
cADPR is a gene dosage-sensitive biomarker of SARM1 activity in healthy, compromised, and degenerating axons
(2020) Experimental Neurology, 329, art. no. 113252, .
Sasaki, Y.a , Engber, T.M.b , Hughes, R.O.b , Figley, M.D.c , Wu, T.a , Bosanac, T.b , Devraj, R.b , Milbrandt, J.a d , Krauss, R.b , DiAntonio, A.c d
a Washington University in Saint Louis, Genetics, St. Louis, MO, United States
b Disarm Therapeutics, Cambridge, MA, United States
c Washington University in Saint Louis, Developmental Biology, St. Louis, MO, United States
d Needleman Center for Neurometabolism and Axonal Therapeutics, United States
Abstract
SARM1 is the central executioner of pathological axon degeneration, promoting axonal demise in response to axotomy, traumatic brain injury, and neurotoxic chemotherapeutics that induce peripheral neuropathy. SARM1 is an injury-activated NAD+ cleavage enzyme, and this NADase activity is required for the pro-degenerative function of SARM1. At present, SARM1 function is assayed by either analysis of axonal loss, which is far downstream of SARM1 enzymatic activity, or via NAD+ levels, which are regulated by many competing pathways. Here we explored the utility of measuring cADPR, a product of SARM1-dependent cleavage of NAD+, as an in cell and in vivo biomarker of SARM1 enzymatic activity. We find that SARM1 is a major producer of cADPR in cultured dorsal root ganglion (DRG) neurons, sciatic nerve, and brain, demonstrating that SARM1 has basal activity in the absence of injury. Following injury, there is a dramatic SARM1-dependent increase in the levels of axonal cADPR that precedes morphological axon degeneration. In vivo, there is also a rapid and large injury-stimulated increase in cADPR in sciatic and optic nerves. The increase in cADPR after injury is proportional to SARM1 gene dosage, suggesting that SARM1 activity is the prime regulator of cADPR levels. The role of cADPR as an important calcium mobilizing agent prompted exploration of its functional contribution to axon degeneration. We used multiple bacterial and mammalian engineered enzymes to manipulate cADPR levels in neurons but found no changes in the time course of axonal degeneration, suggesting that cADPR is unlikely to be an important contributor to the degenerative mechanism. Using cADPR as a SARM1 biomarker, we find that SARM1 can be partially activated by a diverse array of mitochondrial toxins administered at doses that do not induce axon degeneration. Hence, the subcritical activation of SARM1 induced by mitochondrial dysfunction may contribute to the axonal vulnerability common to many neurodegenerative diseases. Finally, we assay levels of both nerve cADPR and plasma neurofilament light chain (NfL) following nerve injury in vivo, and demonstrate that both biomarkers are excellent readouts of SARM1 activity, with cADPR reporting the early molecular changes in the nerve and NfL reporting subsequent axonal breakdown. The identification and characterization of cADPR as a SARM1 biomarker will help identify neurodegenerative diseases in which SARM1 contributes to axonal loss and expedite target validation studies of SARM1-directed therapeutics. © 2020
Document Type: Article
Publication Stage: Final
Source: Scopus
“The human connectome project for disordered emotional states: Protocol and rationale for a research domain criteria study of brain connectivity in young adult anxiety and depression” (2020) NeuroImage
The human connectome project for disordered emotional states: Protocol and rationale for a research domain criteria study of brain connectivity in young adult anxiety and depression
(2020) NeuroImage, 214, art. no. 116715, .
Tozzi, L.a , Staveland, B.a , Holt-Gosselin, B.a , Chesnut, M.a , Chang, S.E.a , Choi, D.a , Shiner, M.a , Wu, H.b , Lerma-Usabiaga, G.c d , Sporns, O.e , Barch, D.M.f , Gotlib, I.H.c , Hastie, T.J.g , Kerr, A.B.b h , Poldrack, R.A.c , Wandell, B.A.b , Wintermark, M.i , Williams, L.M.a j
a Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, United States
b Center for Cognitive and Neurobiological Imaging, Stanford UniversityCA, United States
c Psychology, Stanford UniversityCA, United States
d BCBL. Basque Center on Cognition, Brain and Language, Donostia – San Sebastián, Gipuzkoa, Spain
e Psychological and Brain Sciences, Indiana UniversityIN, United States
f Psychological and Brain Sciences, Psychiatry & Radiology Washington University in St. LouisMO, United States
g Statistics, Stanford UniversityCA, United States
h Department of Electrical Engineering, Stanford UniversityCA, United States
i Radiology, Stanford UniversityCA, United States
j Sierra-Pacific Mental Illness Research, Education, and Clinical Center (MIRECC) Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, United States
Abstract
Through the Human Connectome Project (HCP) our understanding of the functional connectome of the healthy brain has been dramatically accelerated. Given the pressing public health need, we must increase our understanding of how connectome dysfunctions give rise to disordered mental states. Mental disorders arising from high levels of negative emotion or from the loss of positive emotional experience affect over 400 million people globally. Such states of disordered emotion cut across multiple diagnostic categories of mood and anxiety disorders and are compounded by accompanying disruptions in cognitive function. Not surprisingly, these forms of psychopathology are the leading cause of disability worldwide. The Research Domain Criteria (RDoC) initiative spearheaded by NIMH offers a framework for characterizing the relations among connectome dysfunctions, anchored in neural circuits and phenotypic profiles of behavior and self-reported symptoms. Here, we report on our Connectomes Related to Human Disease protocol for integrating an RDoC framework with HCP protocols to characterize connectome dysfunctions in disordered emotional states, and present quality control data from a representative sample of participants. We focus on three RDoC domains and constructs most relevant to depression and anxiety: 1) loss and acute threat within the Negative Valence System (NVS) domain; 2) reward valuation and responsiveness within the Positive Valence System (PVS) domain; and 3) working memory and cognitive control within the Cognitive System (CS) domain. For 29 healthy controls, we present preliminary imaging data: functional magnetic resonance imaging collected in the resting state and in tasks matching our constructs of interest (“Emotion”, “Gambling” and “Continuous Performance” tasks), as well as diffusion-weighted imaging. All functional scans demonstrated good signal-to-noise ratio. Established neural networks were robustly identified in the resting state condition by independent component analysis. Processing of negative emotional faces significantly activated the bilateral dorsolateral prefrontal and occipital cortices, fusiform gyrus and amygdalae. Reward elicited a response in the bilateral dorsolateral prefrontal, parietal and occipital cortices, and in the striatum. Working memory was associated with activation in the dorsolateral prefrontal, parietal, motor, temporal and insular cortices, in the striatum and cerebellum. Diffusion tractography showed consistent profiles of fractional anisotropy along known white matter tracts. We also show that results are comparable to those in a matched sample from the HCP Healthy Young Adult data release. These preliminary data provide the foundation for acquisition of 250 subjects who are experiencing disordered emotional states. When complete, these data will be used to develop a neurobiological model that maps connectome dysfunctions to specific behaviors and symptoms. © 2020
Author Keywords
Anxiety; Depression; Functional brain imaging; Human connectome project
Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access
“The therapeutic potential of exercise for neuropsychiatric diseases: A review” (2020) Journal of the Neurological Sciences
The therapeutic potential of exercise for neuropsychiatric diseases: A review
(2020) Journal of the Neurological Sciences, 412, art. no. 116763, .
Swenson, S.a , Blum, K.b , McLaughlin, T.c , Gold, M.S.d , Thanos, P.K.a e
a Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biosciences, State University of New York at Buffalo, Buffalo, NY, United States
b Western Univesity Health Sciences, Graduate College, Pomona, CA, United States
c Center for Psychiatric Medicine, Lawrence, MA, United States
d Washington University in St. Louis, School of Medicine, St. Louis, MO, United States
e Department of Psychology, State University of New York at Buffalo, Buffalo, NY, United States
Abstract
Exercise is known to have a myriad of health benefits. There is much to be learned from the effects of exercise and its potential for prevention, attenuation and treatment of multiple neuropsychiatric diseases and behavioral disorders. Furthermore, recent data and research on exercise benefits with respect to major health crises, such as, that of opioid and general substance use disorders, make it very important to better understand and review the mechanisms of exercise and how it could be utilized for effective treatments or adjunct treatments for these diseases. In addition, mechanisms, epigenetics and sex differences are examined and discussed in terms of future research implications. © 2020 Elsevier B.V.
Document Type: Review
Publication Stage: Final
Source: Scopus
“Ketamine and nitrous oxide: The evolution of NMDA receptor antagonists as antidepressant agents” (2020) Journal of the Neurological Sciences
Ketamine and nitrous oxide: The evolution of NMDA receptor antagonists as antidepressant agents
(2020) Journal of the Neurological Sciences, 412, art. no. 116778, .
Kalmoe, M.C.a , Janski, A.M.a , Zorumski, C.F.a , Nagele, P.b , Palanca, B.J.c , Conway, C.R.a
a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
b Department of Anesthesia and Critical Care, The University of Chicago Medical Center, Chicago, IL, United States
c Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
N-methyl-D-aspartate receptor (NMDAR) antagonists, including ketamine and nitrous oxide, are currently intensely studied as rapid-acting antidepressant agents. Interestingly, both of these compounds are also drugs of abuse. Intravenous ketamine, a dissociative anesthetic that induces complex downstream effects via NMDARs, rapidly reduces depressive and suicidal symptoms in treatment-resistant depression (TRD), as demonstrated by several trials. Recently, the United States Food and Drug Administration (FDA) approved an intranasal version of ketamine (esketamine) for TRD. The United States Drug Enforcement Agency (DEA) lists ketamine as a Class III scheduled drug (moderate-low potential for physical and psychological abuse). The FDA has established a Risk Evaluation and Management Strategy (REMS) program to ensure proper drug storage, handling, dispensing, and monitoring intranasal esketamine to minimize misuse/abuse opportunities. Nitrous Oxide is a colorless, odorless, gas that has been in medical use for over 150 years. The mechanisms of action of nitrous oxide are not fully understood; however, it is known to act as a non-competitive inhibitor of NMDA-type glutamate receptors. Currently, nitrous oxide is used for inhalational general anesthesia and analgesia for short procedures. Inhaled nitrous oxide is also used recreationally, primarily by teens and young adults, but is not believed to have strong addiction potential. In contrast to ketamine, nitrous oxide is not a controlled substance and can be legally purchased without a prescription. A recent double-blind, prospective, cross-over study demonstrated that nitrous oxide reduced depressive symptoms in a group of severely ill TRD patients. Though this is a promising initial study, further investigation is needed. © 2020 Elsevier B.V.
Author Keywords
Esketamine; Ketamine; Major depressive disorder; Nitrous oxide; NMDAR; Treatment resistant depression
Document Type: Review
Publication Stage: Final
Source: Scopus
“Overcontrol and neural response to errors in pediatric anxiety disorders” (2020) Journal of Anxiety Disorders
Overcontrol and neural response to errors in pediatric anxiety disorders
(2020) Journal of Anxiety Disorders, 72, art. no. 102224, .
Gilbert, K., Perino, M.T., Myers, M.J., Sylvester, C.M.
Department of Psychiatry, Washington University in St. Louis, 4444 Forest Park, Suite 2100, St. Louis, MO 63108, United States
Abstract
Multiple risk factors that may contribute to the development and severity of pediatric anxiety disorders, one of which is dimensional overcontrol. Overcontrol is a constellation of characteristics including heightened performance monitoring, inflexibility, perfectionism and aversion to making mistakes. In this study, we examined overcontrol in children with anxiety disorders and tested whether the underlying dimension of overcontrol specifically explains altered brain response to errors in pediatric anxiety disorders. Parent-reported scores of child overcontrol were collected in a sample of children (ages 8–12 years) with (n = 35) and without (n = 34) anxiety disorders and the relationship of overcontrol and anxiety symptoms to neural responding to errors during functional magnetic resonance imaging (fMRI) was examined. Results indicated childhood overcontrol was elevated in pediatric anxiety disorders and was significantly associated with anxiety severity, even when controlling for comorbid depression and ADHD. Additionally, overcontrol was associated with reduced neural response to errors versus correct responses in the bilateral dorsal anterior cingulate cortex (dACC) and insula, even when controlling for anxiety symptoms. Overcontrol may serve as an underlying mechanism associated with clinical pediatric anxiety that demonstrates significant associations with aberrant neural error responding. Overcontrol may be an underlying mechanism contributing to pediatric anxiety that could be targeted for early intervention. © 2020 Elsevier Ltd
Author Keywords
dACC; Errors; Overcontrol; Pediatric anxiety; Performance monitoring
Document Type: Article
Publication Stage: Final
Source: Scopus
“Effects of Dopaminergic Drugs on Cognitive Control Processes Vary by Genotype” (2020) Journal of Cognitive Neuroscience
Effects of Dopaminergic Drugs on Cognitive Control Processes Vary by Genotype
(2020) Journal of Cognitive Neuroscience, 32 (5), pp. 804-821.
Furman, D.J.a , White, R.L., 3rda b , Naskolnakorn, J.a , Ye, J.a , Kayser, A.c , D’Esposito, M.a
a University of California, Berkeley
b Washington University School of Medicine
c University of California, San Francisco, Mexico
Abstract
Dopamine (DA) has been implicated in modulating multiple cognitive control processes, including the robust maintenance of task sets and memoranda in the face of distractors (cognitive stability) and, conversely, the ability to switch task sets or update the contents of working memory when it is advantageous to do so (cognitive flexibility). In humans, the limited specificity of available pharmacological probes has posed a challenge for understanding the mechanisms by which DA, acting on multiple receptor families across the PFC and striatum, differentially influences these cognitive processes. Using a within-subject, placebo-controlled design, we contrasted the impact of two mechanistically distinct DA drugs, tolcapone (an inhibitor of catechol-O-methyltransferase [COMT], a catecholamine inactivator) and bromocriptine (a DA agonist with preferential affinity for the D2 receptor), on the maintenance and switching of task rules. Given previous work demonstrating that drug effects on behavior are dependent on baseline DA tone, participants were stratified according to genetic polymorphisms associated with cortical (COMT Val158Met) and striatal (Taq1A) DA system function. Our results were partially consistent with an inverted-U-shaped relationship between tolcapone and robust rule maintenance (interaction with COMT genotype) and between bromocriptine and cued rule switching (interaction with Taq1A genotype). However, when task instructions were ambiguous, a third relationship emerged to explain drug effects on spontaneous task switching (interaction of COMT genotype and bromocriptine). Together, this pattern of results suggests that the effects of DA drugs vary not only as a function of the DA system component upon which they act but also on subtle differences in task demands and context.
Document Type: Article
Publication Stage: Final
Source: Scopus
“Roadmap for the Emerging Field of Cancer Neuroscience” (2020) Cell
Roadmap for the Emerging Field of Cancer Neuroscience
(2020) Cell, 181 (2), pp. 219-222.
Monje, M.a , Borniger, J.C.b , D’Silva, N.J.c , Deneen, B.d , Dirks, P.B.e , Fattahi, F.f , Frenette, P.S.g , Garzia, L.h , Gutmann, D.H.i , Hanahan, D.j , Hervey-Jumper, S.L.k , Hondermarck, H.l , Hurov, J.B.m , Kepecs, A.b , Knox, S.M.n , Lloyd, A.C.o , Magnon, C.p , Saloman, J.L.q , Segal, R.A.r , Sloan, E.K.s , Sun, X.t , Taylor, M.D.u , Tracey, K.J.v , Trotman, L.C.b , Tuveson, D.A.b , Wang, T.C.w , White, R.A.x , Winkler, F.y
a Departments of Neurology & Neurological Sciences, Pediatrics, Pathology, Neurosurgery, and Psychiatry & Behavioral Sciences, Stanford University, Stanford, CA 94305, United States
b Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, United States
c Department of Periodontics and Oral Medicine, School of Dentistry, Department of Pathology, School of Medicine, University of Michigan, Ann Arbor, MI 48109, United States
d Center for Cell and Gene Therapy, Department of Neurosurgery, Baylor College of Medicine, Houston, TX 77030, United States
e Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumor Research Center, Departments of Surgery and Molecular Genetics, Hospital for Sick Children, Toronto, ON M5G1X8, Canada
f Department of Biochemistry and Biophysics, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94115, United States
g Departments of Medicine and Cell Biology, Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY 10461, United States
h Cancer Research Program, Research Institute of the McGill University Health Center and Department of Surgery, McGill University, Montreal, QC, Canada
i Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
j Swiss Institute for Experimental Cancer Research, Swiss Federal Institute of Technology Lausanne, Ludwig Institute for Cancer Research, Swiss Cancer Center Leman, Lausanne, Switzerland
k Department of Neurosurgery, University of California, San Francisco, San Francisco, CA 94115, United States
l School of Biomedical Sciences and Pharmacy, Hunter Medical Research Institute, University of Newcastle, Callaghan, NSW 2308, Australia
m Cygnal Therapeutics, Cambridge, MA 02139, United States
n Program in Craniofacial Biology, Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA 94143, United States
o MRC Laboratory for Molecular Cell Biology, University College London, London, WC1E 6BT, United Kingdom
p UMR1274 (Equipe Cancer et Microenvironnement-INSERM-CEA), Institut de Radiobiologie Cellulaire et Moléculaire, Institut de Biologie François Jacob, Direction de la Recherche Fondamentale, Paris, France
q Departments of Medicine and Neurobiology, University of Pittsburgh, Pittsburgh, PA 15260, United States
r Department of Neurobiology, Harvard Medical School and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, United States
s Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC 3052, Australia
t Departments of Pediatrics and Biological Sciences, University of California at San Diego, La Jolla, CA 92093, United States
u Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumor Research Center, Developmental and Stem Cell Biology Program, Departments of Surgery, Laboratory Medicine & Pathology and Medical Biophysics, Hospital for Sick Children, Toronto, ON M5G1X8, Canada
v The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY 11030, United States
w Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, United States
x Division of Hematology and Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, United States
y Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, DKTK & Clinical Cooperation Unit Neurooncology, German Cancer Research Center, Heidelberg, Germany
Abstract
Mounting evidence indicates that the nervous system plays a central role in cancer pathogenesis. In turn, cancers and cancer therapies can alter nervous system form and function. This Commentary seeks to describe the burgeoning field of “cancer neuroscience” and encourage multidisciplinary collaboration for the study of cancer-nervous system interactions. © 2020 Elsevier Inc.
Mounting evidence indicates that the nervous system plays a central role in cancer pathogenesis. In turn, cancers and cancer therapies can alter nervous system form and function. This Commentary seeks to describe the burgeoning field of “cancer neuroscience” and encourage multidisciplinary collaboration for the study of cancer-nervous system interactions. © 2020 Elsevier Inc.
Document Type: Article
Publication Stage: Final
Source: Scopus
“RNA-Induced Conformational Switching and Clustering of G3BP Drive Stress Granule Assembly by Condensation” (2020) Cell
RNA-Induced Conformational Switching and Clustering of G3BP Drive Stress Granule Assembly by Condensation
(2020) Cell, 181 (2), pp. 346-361.e17. Cited 3 times.
Guillén-Boixet, J.a , Kopach, A.c , Holehouse, A.S.b g , Wittmann, S.c , Jahnel, M.a c , Schlüßler, R.a , Kim, K.a , Trussina, I.R.E.A.a , Wang, J.c , Mateju, D.c , Poser, I.c , Maharana, S.a , Ruer-Gruß, M.c , Richter, D.a , Zhang, X.f , Chang, Y.-T.d e , Guck, J.a , Honigmann, A.c , Mahamid, J.f , Hyman, A.A.c , Pappu, R.V.b , Alberti, S.a c , Franzmann, T.M.a
a Center for Molecular and Cellular Bioengineering, Biotechnology Center, Technische Universität Dresden, Tatzberg 47/49, Dresden, 01307, Germany
b Department of Biomedical Engineering and Center for Science and Engineering of Living Systems, Washington University in St. Louis, St. Louis, MO 63130, United States
c Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, 01307, Germany
d Center for Self-Assembly and Complexity, Institute for Basic Science, Pohang, 37673, South Korea
e Department of Chemistry, Pohang University of Science and Technology, Pohang, 37673, South Korea
f Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
g Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, United States
Abstract
Reconstitution of stress granule assembly reveals an autoinhibitory conformation of G3BP that is alleviated by RNA binding, demonstrating how this central node of the stress granule network phase-separates in response to rising cellular RNA concentrations. © 2020 The Author(s)
Stressed cells shut down translation, release mRNA molecules from polysomes, and form stress granules (SGs) via a network of interactions that involve G3BP. Here we focus on the mechanistic underpinnings of SG assembly. We show that, under non-stress conditions, G3BP adopts a compact auto-inhibited state stabilized by electrostatic intramolecular interactions between the intrinsically disordered acidic tracts and the positively charged arginine-rich region. Upon release from polysomes, unfolded mRNAs outcompete G3BP auto-inhibitory interactions, engendering a conformational transition that facilitates clustering of G3BP through protein-RNA interactions. Subsequent physical crosslinking of G3BP clusters drives RNA molecules into networked RNA/protein condensates. We show that G3BP condensates impede RNA entanglement and recruit additional client proteins that promote SG maturation or induce a liquid-to-solid transition that may underlie disease. We propose that condensation coupled to conformational rearrangements and heterotypic multivalent interactions may be a general principle underlying RNP granule assembly. © 2020 The Author(s)
Author Keywords
G3BP; liquid-to-solid transition; Neurodegenerative disease; phase separation; RNP granules; stress granules; stress response
Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access
“Genomics of MPNST (GeM) Consortium: Rationale and Study Design for Multi-Omic Characterization of NF1-Associated and Sporadic MPNSTs” (2020) Genes
Genomics of MPNST (GeM) Consortium: Rationale and Study Design for Multi-Omic Characterization of NF1-Associated and Sporadic MPNSTs
(2020) Genes, 11 (4), .
Miller, D.T.a , Cortés-Ciriano, I.b , Pillay, N.c d , Hirbe, A.C.e , Snuderl, M.f , Bui, M.M.g , Piculell, K.a , Al-Ibraheemi, A.h , Dickson, B.C.i , Hart, J.j , Jones, K.k , Jordan, J.T.l , Kim, R.H.m , Lindsay, D.d , Nishida, Y.n , Ullrich, N.J.o , Wang, X.p , Park, P.J.q , Flanagan, A.M.c d
a Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA 02115, United States
b European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, Cambridge, CB10 1SD, United Kingdom
c Department of Pathology, University College London Cancer Institute, Bloomsbury, London WC1E 6BT, UK
d Royal National Orthopaedic Hospital, Brockley Hill, Stanmore, Middlesex HA7 4LP, UK
e Oncology Division, Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA
f Department of Pathology, New York University Langone Health, New York City, NY 10016, USA
g Department of Pathology, Moffitt Cancer Center, Tampa, FL 33612, United States
h Department of Pathology, Boston Children’s Hospital, Boston, MA 02115, United States
i Department of Pathology and Laboratory Medicine, Mt. Sinai Hospital, Toronto, Canada
j Department of Pathology, Lifespan Laboratories, Rhode Island Hospital, Providence, RI 02903, USA
k Departments of Orthopaedics and Oncological Sciences; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
l Pappas Center for Neuro-Oncology, Massachusetts General Hospital, Boston, MA 02114, United States
m Department of Medical Oncology, Princess Margaret Cancer Center, University Health Network, Toronto, Canada
n Department of Rehabilitation, Nagoya University Hospital, Nagoya, Aichi 466-8550, Japan
o Department of Neurology, Boston Children’s Hospital, Boston, MA 02115, United States
p Moffitt Cancer Center, Tampa, FL 33612, United States
q Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, United States
Abstract
The Genomics of Malignant Peripheral Nerve Sheath Tumor (GeM) Consortium is an international collaboration focusing on multi-omic analysis of malignant peripheral nerve sheath tumors (MPNSTs), the most aggressive tumor associated with neurofibromatosis type 1 (NF1). Here we present a summary of current knowledge gaps, a description of our consortium and the cohort we have assembled, and an overview of our plans for multi-omic analysis of these tumors. We propose that our analysis will lead to a better understanding of the order and timing of genetic events related to MPNST initiation and progression. Our ten institutions have assembled 96 fresh frozen NF1-related (63%) and sporadic MPNST specimens from 86 subjects with corresponding clinical and pathological data. Clinical data have been collected as part of the International MPNST Registry. We will characterize these tumors with bulk whole genome sequencing, RNAseq, and DNA methylation profiling. In addition, we will perform multiregional analysis and temporal sampling, with the same methodologies, on a subset of nine subjects with NF1-related MPNSTs to assess tumor heterogeneity and cancer evolution. Subsequent multi-omic analyses of additional archival specimens will include deep exome sequencing (500×) and high density copy number arrays for both validation of results based on fresh frozen tumors, and to assess further tumor heterogeneity and evolution. Digital pathology images are being collected in a cloud-based platform for consensus review. The result of these efforts will be the largest MPNST multi-omic dataset with correlated clinical and pathological information ever assembled.
Author Keywords
clinical genetics; genomics; MPNST; neurofibromatosis; next generation sequencing; pathology; tumor evolution
Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access
“Treatable Movement Disorders of Infancy and Early Childhood” (2020) Seminars in Neurology
Treatable Movement Disorders of Infancy and Early Childhood
(2020) Seminars in Neurology, 40 (2), pp. 177-191.
Aravamuthan, B.R., Pearson, T.S.
Division of Pediatric Neurology, Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
Abstract
Movement disorders in childhood can be difficult to diagnose early. Disease processes present variably and can mimic each other. It is particularly important to remain vigilant for the subset of these movement disorders that are treatable. These disorders can be managed with (1) treatments specific to the disease that substantially reduce symptoms; (2) treatments that can prevent progression; (3) treatments that can hasten recovery; or (4) surveillance and management of the associated, sometimes life-threatening, comorbidities. Here, we present a practical and phenomenology-oriented framework for diagnosing and managing these treatable movement disorders of infancy and early childhood. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.
Document Type: Article
Publication Stage: Final
Source: Scopus
“Rindopepimut with bevacizumab for patients with relapsed EGFRvIII-expressing glioblastoma (REACT): Results of a double-blind randomized phase II trial” (2020) Clinical Cancer Research
Rindopepimut with bevacizumab for patients with relapsed EGFRvIII-expressing glioblastoma (REACT): Results of a double-blind randomized phase II trial
(2020) Clinical Cancer Research, 26 (7), pp. 1586-1594. Cited 1 time.
Reardon, D.A.a , Desjardins, A.b , Vredenburgh, J.J.c , O’Rourke, D.M.d , Tran, D.D.e , Fink, K.L.f , Nabors, L.B.g , Li, G.h , Bota, D.A.i , Lukas, R.V.j , Ashby, L.S.k , Paul Duic, J.l , Mrugala, M.M.m , Cruickshank, S.n , Vitale, L.o , He, Y.o , Green, J.A.o , Yellin, M.J.o , Turner, C.D.o , Keler, T.o , Davis, T.A.o , Sampson, J.H.b , for the ReACT trial investigatorsp
a Dana-Farber Cancer Institute, Boston, MA, United States
b Duke University Medical Center, Durham, NC, United States
c Saint Francis Hospital and Medical Center, Hartford, CT, United States
d University of Pennsylvania, Philadelphia, PA, United States
e Washington University, St. Louis, MO, United States
f Baylor Research Institute, Dallas, TX, United States
g University of Alabama at Birmingham, Birmingham, AL, United States
h Stanford University School of Medicine, Stanford, CA, United States
i UC Irvine Medical Center, Irvine, CA, United States
j University of Chicago, Chicago, IL, United States
k Barrow Neurological Institute, Phoenix, AZ, United States
l Department of Neurosciences, Winthrop University Hospital, Mineola, NY, United States
m University of Washington School of Medicine, Seattle, WA, United States
n Scott Cruickshank and Associates, Santa Barbara, CA, United States
o Celldex Therapeutics, Inc., Hampton, NJ, United States
Abstract
Purpose: Rindopepimut is a vaccine targeting the tumor-specific EGF driver mutation, EGFRvIII. The ReACT study investigated whether the addition of rindopepimut to standard bevacizumab improved outcome for patients with relapsed, EGFRvIII-positive glioblastoma. Patients and Methods: In this double-blind, randomized, phase II study (NCT01498328) conducted at 26 hospitals in the United States, bevacizumab-native patients with recurrent EGFRvIII-positive glioblastoma were randomized to receive rindopepimut or a control injection of keyhole limpet hemocyanin, each concurrent with bevacizumab. The primary endpoint was 6-month progression-free survival (PFS6) by central review with a one-sided significance of 0.2. Results: Between May 2012 and 2014, 73 patients were randomized (36 rindopepimut, 37 control). Rindopepimut toxicity included transient, low-grade local reactions. As primary endpoint, PFS6 was 28% (10/36) for rindopepimut compared with 16% (6/37) for control (P ¼ 0.12, one-sided). Secondary and exploratory endpoints also favored the rindopepimut group including a statistically significant survival advantage [HR, 0.53; 95% confidence interval (CI), 0.32-0.88; two-sided log-rank P ¼ 0.01], a higher ORR [30% (9/30) vs. 18% (6/34; P ¼ 0.38)], median duration of response [7.8 months (95% CI, 3.5-22.2) vs. 5.6 (95% CI, 3.7-7.4)], and ability to discontinue steroids for ≥6 months [33% (6/18) vs. 0% (0/19)]. Eighty percent of rindopepimut-treated patients achieved robust anti-EGFRvIII titers (≥1:12,800), which were associated with prolonged survival (HR ¼ 0.17; 95% CI, 0.07-0.45; P < 0.0001). Conclusions: Our randomized trial supports the potential for targeted immunotherapy among patients with GBM, but the therapeutic benefit requires validation due to the small sample size and potential heterogeneity of bevacizumab response among recurrent patients with GBM. © 2020 American Association for Cancer Research Inc.. All rights reserved.
Document Type: Article
Publication Stage: Final
Source: Scopus
“Incomplete vesicular docking limits synaptic strength under high release probability conditions” (2020) eLife
Incomplete vesicular docking limits synaptic strength under high release probability conditions
(2020) eLife, 9, .
Malagon, G.a b , Miki, T.a c , Tran, V.a , Gomez, L.C.a , Marty, A.a
a Université de Paris, SPPIN-Saints Pères Paris Institute for the Neurosciences, CNRS, Paris, France
b Department of Cell Biology and Physiology, Washington University, St. Louis, United States
c Graduate School of Brain Science, Doshisha UniversityKyoto, Japan
Abstract
Central mammalian synapses release synaptic vesicles in dedicated structures called docking/release sites. It has been assumed that when voltage-dependent calcium entry is sufficiently large, synaptic output attains a maximum value of one synaptic vesicle per action potential and per site. Here we use deconvolution to count synaptic vesicle output at single sites (mean site number per synapse: 3.6). When increasing calcium entry with tetraethylammonium in 1.5 mM external calcium concentration, we find that synaptic output saturates at 0.22 vesicle per site, not at 1 vesicle per site. Fitting the results with current models of calcium-dependent exocytosis indicates that the 0.22 vesicle limit reflects the probability of docking sites to be occupied by synaptic vesicles at rest, as only docked vesicles can be released. With 3 mM external calcium, the maximum output per site increases to 0.47, indicating an increase in docking site occupancy as a function of external calcium concentration. © 2020, Malagon et al.
Author Keywords
calcium concentration; neuroscience; rat; release site; synapse
Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access
“Organization of Propagated Intrinsic Brain Activity in Individual Humans” (2020) Cerebral Cortex (New York, N.Y. : 1991)
Organization of Propagated Intrinsic Brain Activity in Individual Humans
(2020) Cerebral Cortex (New York, N.Y. : 1991), 30 (3), pp. 1716-1734. Cited 1 time.
Raut, R.V.a , Mitra, A.a , Marek, S.b , Ortega, M.c , Snyder, A.Z.a c , Tanenbaum, A.c , Laumann, T.O.b , Dosenbach, N.U.F.a c d e f , Raichle, M.E.a c
a Department of Radiology, Washington University, St. Louis, MO 63110, USA
b Department of Psychiatry, Washington University, St. Louis, MO 63110, USA
c Department of Neurology, Washington University, St. Louis, MO 63110, USA
d Department of Pediatrics, Washington University, St. Louis, MO 63110, USA
e Department of Biomedical Engineering, Washington University, St. Louis, MO 63110, USA
f Department of Occupational Therapy, Washington University, St. Louis, MO 63110, USA
Abstract
Spontaneous infra-slow (<0.1 Hz) fluctuations in functional magnetic resonance imaging (fMRI) signals are temporally correlated within large-scale functional brain networks, motivating their use for mapping systems-level brain organization. However, recent electrophysiological and hemodynamic evidence suggest state-dependent propagation of infra-slow fluctuations, implying a functional role for ongoing infra-slow activity. Crucially, the study of infra-slow temporal lag structure has thus far been limited to large groups, as analyzing propagation delays requires extensive data averaging to overcome sampling variability. Here, we use resting-state fMRI data from 11 extensively-sampled individuals to characterize lag structure at the individual level. In addition to stable individual-specific features, we find spatiotemporal topographies in each subject similar to the group average. Notably, we find a set of early regions that are common to all individuals, are preferentially positioned proximal to multiple functional networks, and overlap with brain regions known to respond to diverse behavioral tasks-altogether consistent with a hypothesized ability to broadly influence cortical excitability. Our findings suggest that, like correlation structure, temporal lag structure is a fundamental organizational property of resting-state infra-slow activity. © The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.
Author Keywords
functional connectivity; hubs; infra-slow; networks; resting-state fMRI
Document Type: Article
Publication Stage: Final
Source: Scopus
“Neurological Monitoring and Complications of Pediatric Extracorporeal Membrane Oxygenation Support” (2020) Pediatric Neurology
Neurological Monitoring and Complications of Pediatric Extracorporeal Membrane Oxygenation Support
(2020) Pediatric Neurology, .
Said, A.S.a , Guilliams, K.P.a b , Bembea, M.M.c
a Division of Pediatric Critical Care, Department of Pediatrics, Washington University in St. Louis, St. Louis, MO, United States
b Division of Pediatric Neurology, Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
c Division of Pediatric Anesthesiology and Critical Care, Department of Pediatrics, Johns Hopkins University, Baltimore, MD, United States
Abstract
Extracorporeal membrane oxygenation is extracorporeal life support for life-threatening cardiopulmonary failure. Since its introduction, the use of extracorporeal membrane oxygenation has expanded to patients with more complex comorbidities without change in patient mortality rates. Although many patients survive, significant neurological complications like seizures, ischemic strokes, and intracranial hemorrhage can occur during extracorporeal membrane oxygenation care. The risks of these complications often add to the complexity of decision-making surrounding extracorporeal membrane oxygenation support. In this review, we discuss the pathophysiology and incidence of neurological complications in children supported on extracorporeal membrane oxygenation, factors influencing the incidence of these complications, commonly used neurological monitoring modalities, and outcomes for this complex patient population. We discuss the current literature on the use of electroencephalography for both seizure detection and monitoring of background electroencephalographic changes, in addition to the use of less commonly used imaging modalities like transcranial Doppler. We summarize the knowledge gaps and the lack of clinical consensus guidelines for managing these potentially life-changing neurological complications. Finally, we discuss future work to further understand the pathophysiology of extracorporeal membrane oxygenation-related neurological complications. © 2020 Elsevier Inc.
Author Keywords
Electroencephalography; Extracorporeal membrane oxygenation; Intracranial hemorrhage; Seizures; Stroke
Document Type: Review
Publication Stage: Article in Press
Source: Scopus
“Post-Intensive-Care Syndrome for the Pediatric Neurologist” (2020) Pediatric Neurology
Post-Intensive-Care Syndrome for the Pediatric Neurologist
(2020) Pediatric Neurology, .
Hartman, M.E.a , Williams, C.N.b c , Hall, T.A.d , Bosworth, C.C.e , Piantino, J.A.b f
a Division of Pediatric Critical Care Medicine, Department of Pediatrics, Washington University in St. Louis, St. Louis, MO, United States
b Pediatric Critical Care and Neurotrauma Recovery Program, Oregon Health & Science University, Portland, OR, United States
c Division of Pediatric Critical Care, Department of Pediatrics, Oregon Health & Science University, Portland, OR, United States
d Division of Pediatric Psychology, Department of Pediatrics, Oregon Health & Science University, Portland, OR, United States
e Department of Psychology, Washington University School of Medicine, St. Louis Children’s Hospital, St. Louis, MO, United States
f Division of Pediatric Neurology, Department of Pediatrics, Oregon Health & Science University, Portland, OR, United States
Abstract
The number of children who survive critical illness has steadily increased. However, lower mortality rates have resulted in a proportional increase in post-intensive-care morbidity. Critical illness in childhood affects a child’s development, cognition, and family functioning. The constellation of physical, emotional, cognitive, and psychosocial symptoms that begin in the intensive care unit and continue after discharge has recently been termed post-intensive-care syndrome. A conceptual model of the post-intensive-care syndrome experienced by children who survive critical illness, their siblings, and parents has been coined post-intensive-care syndrome in pediatrics. Owing to their prolonged hospitalizations, the use of sedative medications, and the nature of their illness, children with primary neurological injury are among those at the highest risk for post-intensive-care syndrome in pediatrics. The pediatric neurologist participates in the care of children with acute brain injury throughout their hospitalization and remains involved after the patient leaves the hospital. Hence it is important for pediatric neurologists to become versed in the early recognition and management of post-intensive-care syndrome in pediatrics. In this review, we discuss the current knowledge regarding post-intensive-care syndrome in pediatrics and its risk factors. We also discuss our experience establishing Pediatric Neurocritical Care Recovery Programs at two large academic centers. Last, we provide a battery of validated tests to identify and manage the different aspects of post-intensive-care syndrome in pediatrics, which have been successfully implemented at our institutions. Dissemination of this “road map” may assist others interested in establishing recovery programs, therefore mitigating the burden of post-intensive-care morbidity in children. © 2020
Author Keywords
Critical Care; Educational intervention; Pediatrics; PICS; Post-intensive-care syndrome
Document Type: Review
Publication Stage: Article in Press
Source: Scopus
“Early developmental electroencephalography abnormalities, neonatal seizures, and induced spasms in a mouse model of tuberous sclerosis complex” (2020) Epilepsia
Early developmental electroencephalography abnormalities, neonatal seizures, and induced spasms in a mouse model of tuberous sclerosis complex
(2020) Epilepsia, .
Rensing, N., Johnson, K.J., Foutz, T.J., Friedman, J.L., Galindo, R., Wong, M.
Department of Neurology and Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, MO, United States
Abstract
Objective: Tuberous sclerosis complex (TSC) is one of the most common genetic causes of epilepsy. Seizures in TSC typically first present in infancy or early childhood, including focal seizures and infantile spasms. Infantile spasms in TSC are particularly characteristic in its strong responsiveness to vigabatrin. Although a number of mouse models of epilepsy in TSC have been described, there are very limited electroencephalographic (EEG) or seizure data during the preweanling neonatal and infantile-equivalent mouse periods. Tsc1GFAPCKO mice are a well-characterized mouse model of epilepsy in TSC, but whether these mice have seizures during early development has not been documented. The objective of this study was to determine whether preweanling Tsc1GFAPCKO mice have developmental EEG abnormalities or seizures, including spasms. Methods: Longitudinal video-EEG and electromyographic recordings were performed serially on Tsc1GFAPCKO and control mice from postnatal days 9-21 and analyzed for EEG background abnormalities, sleep-wake vigilance states, and spontaneous seizures. Spasms were also induced with varying doses of N-methyl-D-aspartate (NMDA). Results: The interictal EEG of Tsc1GFAPCKO mice had excessive discontinuity and slowing, suggesting a delayed developmental progression compared with control mice. Tsc1GFAPCKO mice also had increased vigilance state transitions and fragmentation. Tsc1GFAPCKO mice had spontaneous focal seizures in the early neonatal period and a reduced threshold for NMDA-induced spasms, but no spontaneous spasms were observed. Significance: Neonatal Tsc1GFAPCKO mice recapitulate early developmental aspects of EEG abnormalities, focal seizures, and an increased propensity for spasms. This mouse model may be useful for early mechanistic and therapeutic studies of epileptogenesis in TSC. © 2020 International League Against Epilepsy
Author Keywords
EEG; electroencephalography; epilepsy; infantile spasms; seizure; tuberous sclerosis
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Cryo-EM structures of the ATP release channel pannexin 1” (2020) Nature Structural and Molecular Biology
Cryo-EM structures of the ATP release channel pannexin 1
(2020) Nature Structural and Molecular Biology, .
Deng, Z.a b , He, Z.a b , Maksaev, G.a b , Bitter, R.M.a b , Rau, M.c , Fitzpatrick, J.A.J.a c d e , Yuan, P.a b
a Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, United States
b Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, MO, United States
c Washington University Center for Cellular Imaging, Washington University School of Medicine, St. Louis, MO, United States
d Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
e Department of Biomedical Engineering, Washington University in Saint Louis, St. Louis, MO, United States
Abstract
The plasma membrane adenosine triphosphate (ATP) release channel pannexin 1 (PANX1) has been implicated in many physiological and pathophysiological processes associated with purinergic signaling, including cancer progression, apoptotic cell clearance, inflammation, blood pressure regulation, oocyte development, epilepsy and neuropathic pain. Here we present near-atomic-resolution structures of human and frog PANX1 determined by cryo-electron microscopy that revealed a heptameric channel architecture. Compatible with ATP permeation, the transmembrane pore and cytoplasmic vestibule were exceptionally wide. An extracellular tryptophan ring located at the outer pore created a constriction site, potentially functioning as a molecular sieve that restricts the size of permeable substrates. The amino and carboxyl termini, not resolved in the density map, appeared to be structurally dynamic and might contribute to narrowing of the pore during channel gating. In combination with functional characterization, this work elucidates the previously unknown architecture of pannexin channels and establishes a foundation for understanding their unique channel properties. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Well Water and Parkinson’s Disease in Medicare Beneficiaries: A Nationwide Case-Control Study” (2020) Journal of Parkinson’s Disease
Well Water and Parkinson’s Disease in Medicare Beneficiaries: A Nationwide Case-Control Study
(2020) Journal of Parkinson’s Disease, 10 (2), pp. 693-705.
Silver, M.R.a , Racette, B.A.a b , Dube, U.a , Faust, I.M.a , Searles Nielsen, S.a
a Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
b School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
Abstract
BACKGROUND: Well water frequently is considered a risk factor for Parkinson’s disease (PD), but few studies were designed appropriately to test whether geographic factors affect PD risk. OBJECTIVE: To determine the risk of PD in relation to residential use of private well water. METHODS: In a nationwide, population-based case-control study, we identified all incident PD cases (N = 89,790) and all comparable controls (N = 21,549,400) age 66-90 who solely relied on Medicare coverage in the U.S. in 2009. We estimated the probability of use of private well water using zip code of residence at diagnosis/reference and U.S. Census data on household water source. We modeled this exposure linearly in logistic regression to calculate the odds ratio (OR) and 95% confidence interval (CI) of PD risk in relation to well water use. We adjusted for age, sex and race/ethnicity, and verified that smoking and use of medical care did not confound results. We repeated analyses with a 2-year exposure lag and separately within each U.S. state. RESULTS: Use of well water was inversely associated with PD risk (OR = 0.87, 95% CI 0.85-0.89). We confirmed this association in a Cox survival analysis in which we followed controls for 5 years, death or PD diagnosis. There was little evidence that well water use increased risk of PD in any individual state. CONCLUSIONS: Although it remains possible that exposures in well water in more narrow geographic regions increase PD risk, in general these results suggest that exposures more common in urban/suburban areas might also be relevant.
Author Keywords
Case-control studies; drinking water; epidemiology; geographic factors; ground water; Medicare; Parkinson’s disease
Document Type: Article
Publication Stage: Final
Source: Scopus
“Transdiagnostic and Illness-Specific Functional Dysconnectivity Across Schizophrenia, Bipolar Disorder, and Major Depressive Disorder” (2020) Biological Psychiatry: Cognitive Neuroscience and Neuroimaging
Transdiagnostic and Illness-Specific Functional Dysconnectivity Across Schizophrenia, Bipolar Disorder, and Major Depressive Disorder
(2020) Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, .
Huang, C.-C.a b k , Luo, Q.a b c , Palaniyappan, L.d e f g , Yang, A.C.h i , Hung, C.-C.i n , Chou, K.-H.j k , Zac Lo, C.-Y.a b , Liu, M.-N.i l m , Tsai, S.-J.j l m , Barch, D.M.o p q , Feng, J.a b r , Lin, C.-P.a b j k , Robbins, T.W.a b s t
a The Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, China
b Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, (Fudan University), Ministry of Education, Shanghai, China
c Ministry of Education Frontiers Center for Brain Science, Institutes of Brain Science and Human Phenome Institute, Fudan University, Shanghai, China
d Department of Psychiatry, University of Western Ontario, London, Ontario, Canada
e Department of Medical Biophysics, University of Western Ontario, London, Ontario, Canada
f Robarts Research Institute, University of Western Ontario, London, Ontario, Canada
g Lawson Health Research Institute, London Health Sciences Centre and St Joseph’s Health Care London, London, Ontario, Canada
h Division of Interdisciplinary Medicine and Biotechnology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
i Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan, Taiwan
j Brain Research Center, National Yang-Ming University, Taipei, Taiwan, Taiwan
k Institute of Neuroscience, National Yang-Ming University, Taipei, Taiwan, Taiwan
l Division of Psychiatry, School of Medicine, National Yang-Ming University, Taipei, Taiwan, Taiwan
m Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan, Taiwan
n Bali Psychiatric Center, Ministry of Health and Welfare, Taipei, Taiwan, Taiwan
o Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
p Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
q Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States
r Department of Computer Science, University of Warwick, Coventry, United Kingdom
s Department of Psychology, University of Cambridge, Cambridge, United Kingdom
t Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, United Kingdom
Abstract
Background: Mental disorders are typically defined as distinct diagnostic entities, but similar patterns of clinical and cognitive impairments are frequently found across diagnostic groups. We investigated whether these transdiagnostic deficits result from common neural substrates across disorders or various illness-specific mechanisms, or a combination of both. Methods: Functional magnetic resonance imaging data were collected from clinically stable patients with major depressive disorder (n = 53), bipolar disorder (n = 78), or schizophrenia (n = 100) and matched healthy control subjects (n = 109) using a single scanner. Group comparisons were conducted to identify transdiagnostic and illness-specific features, and possible confounding effects of medication were considered. A multivariate approach with cross-validation was used to associate dysconnectivity features with shared cognitive deficits. Results: Transdiagnostic dysconnectivities were identified within somatomotor (Cohen’s d = 0.50–0.58) and salience (Cohen’s d = 0.52–0.58) networks and between subcortical-limbic (Cohen’s d = 0.55–0.69) and subcortical-dorsal attention (Cohen’s d = 0.56–0.61) networks. The executive control network was found to be illness-specifically disconnected from the prefrontal-limbic-pallidal circuit in major depressive disorder (Cohen’s d = 0.57–0.58), prefronto-striato-parietal circuit in bipolar disorder (Cohen’s d = 0.48–0.53), and default mode network in schizophrenia (Cohen’s d = 0.47–0.56). Working memory deficits were associated with a linear combination of 11 transdiagnostic and 5 illness-specific dysconnectivities (r = .322, p = 9.7 × 10−4, n = 340). The associations of the identified dysconnectivities with medication dosage were nonsignificant. Conclusions: Disconnectivity in the somatomotor network was a common transdiagnostic profile, while there were illness-specific patterns in different parts of the prefrontal cortex for different disorders. These findings suggest that prominent psychiatric disorders share common impairments, possibly linked to perception and motor output, as well as unique dysconnectivity profiles that hypothetically mediate the more distinctive features of the disorder-specific psychopathology. © 2020 Society of Biological Psychiatry
Author Keywords
Bipolar disorder; Depression; Dysconnectivity; Functional magnetic resonance imaging; Schizophrenia; Transdiagnostic
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“BRAINSTORM: A Multi-Institutional Phase 1/2 Study of RRx-001 in Combination With Whole Brain Radiation Therapy for Patients With Brain Metastases” (2020) International Journal of Radiation Oncology Biology Physics
BRAINSTORM: A Multi-Institutional Phase 1/2 Study of RRx-001 in Combination With Whole Brain Radiation Therapy for Patients With Brain Metastases
(2020) International Journal of Radiation Oncology Biology Physics, .
Kim, M.M.a , Parmar, H.A.b , Schipper, M.c , Devasia, T.c , Aryal, M.P.a , Kesari, S.d , O’Day, S.d , Morikawa, A.e , Spratt, D.E.a , Junck, L.f , Mammoser, A.g , Hayman, J.A.a , Lawrence, T.S.a , Tsien, C.I.h , Aiken, R.i , Goyal, S.j , Abrouk, N.k , Trimble, M.l , Cao, Y.a , Lao, C.D.e
a Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, United States
b Department of Radiology, University of Michigan, Ann Arbor, MI, United States
c Department of Biostatistics, University of Michigan, Ann Arbor, MI, United States
d Providence Saint John’s Health Center, John Wayne Cancer Institute, Santa Monica, CA, United States
e Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States
f Department of Neurology, University of Michigan, Ann Arbor, MI, United States
g Department of Neurosurgery, Louisiana State University, New Orleans, LA, United States
h Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, United States
i The Cancer Institute of New Jersey/Rutgers University, New Brunswick, NJ, United States
j Department of Radiation Oncology, George Washington University, Washington, DC, United States
k Clinical Trials Innovations, Mountain View, CA, United States
l Henry Ford Allegiance Health, Jackson, MI, United States
Abstract
Purpose: To determine the recommended phase 2 dose of RRx-001, a radiosensitizer with vascular normalizing properties, when used with whole-brain radiation therapy (WBRT) for brain metastases and to assess whether quantitative changes in perfusion magnetic resonance imaging (MRI) after RRx-001 correlate with response. Methods and Materials: Five centers participated in this phase 1/2 trial of RRx-001 given once pre-WBRT and then twice weekly during WBRT. Four dose levels were planned (5 mg/m2, 8.4 mg/m2, 16.5 mg/m2, 27.5 mg/m2). Dose escalation was managed by the time-to-event continual reassessment method algorithm. Linear mixed models were used to correlate change in 24-hour T1, Ktrans (capillary permeability), and fractional plasma volume with change in tumor volume. Results: Between 2015 and 2017, 31 patients were enrolled. Two patients dropped out before any therapy. Median age was 60 years (range, 30-76), and 12 were male. The most common tumor types were melanoma (59%) and non-small cell lung cancer (18%). No dose limiting toxicities were observed. The most common severe adverse event was grade 3 asthenia (6.9%, 2 of 29). The median intracranial response rate was 46% (95% confidence interval, 24-68) and median overall survival was 5.2 months (95% confidence interval, 4.5-9.4). No neurologic deaths occurred. Among 10 patients undergoing dynamic contrast-enhanced MRI, a reduction in Vp 24 hours after RRx-001 was associated with reduced tumor volume at 1 and 4 months (P ≤ .01). Conclusions: The addition of RRx-001 to WBRT is well tolerated with favorable intracranial response rates. Because activity was observed across all dose levels, the recommended phase 2 dose is 10 mg twice weekly. A reduction in fractional plasma volume on dynamic contrast-enhanced MRI 24 hours after RRx-001 suggests antiangiogenic activity associated with longer-term tumor response. © 2020 The Author(s)
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Access Type: Open Access
“MYT1L: A systematic review of genetic variation encompassing schizophrenia and autism” (2020) American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
MYT1L: A systematic review of genetic variation encompassing schizophrenia and autism
(2020) American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics, .
Mansfield, P.a , Constantino, J.N.b c , Baldridge, D.c
a Saint Louis University, Saint Louis, MO, United States
b Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, United States
c Department of Pediatrics, Washington University School of Medicine, Saint Louis, MO, United States
Abstract
Variations in MYT1L, a gene encoding a transcription factor expressed in the brain, have been associated with autism, intellectual disability, and schizophrenia. Here we provide an updated review of published reports of neuropsychiatric correlates of loss of function and duplication of MYT1L. Of 27 duplications all were partial; 33% were associated exclusively with schizophrenia, and the chromosomal locations of schizophrenia-associated duplications exhibited a distinct difference in pattern-of-location from those associated with autism and/or intellectual disability. Of 51 published heterozygous loss of function variants, all but one were associated with intellectual disability, autism, or both, and one resulted in no neuropsychiatric diagnosis. There were no reports of schizophrenia associated with loss of function variants of MYT1L (Fisher’s exact p <.00001, for contrast with all reported duplications). Although the precise function of the various mutations remains unspecified, these data collectively establish the candidacy of MYT1L as a reciprocal mutation, in which schizophrenia may be engendered by partial duplications, typically involving the 3′ end of the gene, while developmental disability—notably autism—is associated with both loss of function and partial duplication. Future research on the specific effects of contrasting mutations in MYT1L may provide insight into the causal origins of autism and schizophrenia. © 2020 Wiley Periodicals, Inc.
Author Keywords
autism; MYT1L; reciprocal mutation; schizophrenia
Document Type: Review
Publication Stage: Article in Press
Source: Scopus
“Action at a Distance: Geriatric Research during a Pandemic” (2020) Journal of the American Geriatrics Society
Action at a Distance: Geriatric Research during a Pandemic
(2020) Journal of the American Geriatrics Society, .
Nicol, G.E.a , Piccirillo, J.F.b , Mulsant, B.H.c , Lenze, E.J.a
a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
b Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO, United States
c Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto, ON, Canada
Abstract
BACKGROUND: “Action at a distance” may be the new norm for clinical researchers in the context of the COVID-19 pandemic that may require social distancing for the next 18 months. We must minimize face-to-face contact with vulnerable populations. But we must also persist, adapt, and help our older patients and study participants during the pandemic. METHODS: Clinical researchers have an obligation to help, and we can. Recommendations for clinical researchers working with older adults during the COVID-19 pandemic are discussed. RESULTS: Implement technology now: Minimize face-to-face contact with participants by utilizing digital tools, such as shifting to electronic informed consent and digital HIPAA-compliant tools such as e-mailed surveys or telehealth assessments. Assess the psychological and social impact of COVID-19: How are participants coping? What health or social behaviors have changed? How are they keeping up with current events? What are they doing to stay connected to their families, friends, and communities? Are their healthcare needs being met? Current studies should be adapted immediately to these ends. Mobilize research platforms for patient needs: Leverage our relationships with participants and rapidly deploy novel clinical engagement techniques such as digital tools to intervene remotely and reduce the negative effects of social isolation on our participants. Equip research staff with tangible resources, and provide timely population-specific health information to support patients and healthcare providers. CONCLUSIONS: We have an opportunity to make an impact on our older adult patients now as this pandemic continues to unfold. Above all, clinical researchers need to continue working, to help as many people as possible through the crisis. © 2020 The American Geriatrics Society
Author Keywords
clinical research; mobile health; social isolation
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Access Type: Open Access
“Correlates of Physical Activity and Cardiorespiratory Fitness in Racially and Ethnically Diverse People with Serious Mental Illness in Supportive Housing” (2020) Community Mental Health Journal
Correlates of Physical Activity and Cardiorespiratory Fitness in Racially and Ethnically Diverse People with Serious Mental Illness in Supportive Housing
(2020) Community Mental Health Journal, .
Cabassa, L.J.a , Stefancic, A.b , Wang, X.a , Guo, S.a , Lu, N.Y.b , Weatherly, C.a
a George Warren Brown School of Social Work, Washington University in St. Louis, Campus Box 1196, One Brookings Drive, St. Louis, MO 63130, United States
b Department of Psychiatry, Columbia University, 1051 Riverside Dr., Rm 3506, New York, NY 10031, United States
Abstract
We examined demographic, health, and mental health correlates of physical activity and cardiorespiratory fitness (CRF) in racially and ethnically diverse people with serious mental illness (SMI) living in supportive housing. We used baseline data from 314 people with SMI enrolled in a randomized effectiveness trial of a peer-led healthy lifestyle intervention. Sedentary behavior and physical activity were measured with the International Physical Activity Questionnaire. CRF was measured with the 6-min walking test (6MWT). Correlates were identified via ordinary least squares and logistic regressions. Participants were mostly male and racial/ethnic minorities. Thirty-four percent engaged in at least 150-min-per-week of at least moderate-intensity physical activity. On average, participants walked 316.8 m in the 6MWT. Our models show that physical activity and CRF were not evenly distributed in racially and ethnically diverse people with SMI and are associated with multiple demographic, mental health, and health factors. Our findings suggest subgroups and factors that can be targeted to develop health interventions to improve the physical health of people with SMI. © 2020, Springer Science+Business Media, LLC, part of Springer Nature.
Author Keywords
Cardiorespiratory fitness; Physical activity; Sedentary behaviors; Serious mental illness
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Identifying the guilty word: Simultaneous versus sequential lineups for DRM word lists” (2020) Memory and Cognition
Identifying the guilty word: Simultaneous versus sequential lineups for DRM word lists
(2020) Memory and Cognition, .
Finley, J.R.a , Wixted, J.T.b , Roediger, H.L., IIIc
a Department of Biological and Behavioral Sciences, Fontbonne University, 6800 Wydown Blvd, St. Louis, MO 63105, United States
b Department of Psychology, University of California, San Diego, CA, United States
c Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
Abstract
Recent research in the eyewitness identification literature has investigated whether simultaneous or sequential lineups yield better discriminability. In standard eyewitness identification experiments, subjects view a mock-crime video and then are tested only once, requiring large samples for adequate power. However, there is no reason why theories of simultaneous versus sequential lineup performance cannot be tested using more traditional recognition memory tasks. In two experiments, subjects studied DRM (Deese-Roediger-McDermott) word lists (e.g., bed, rest, tired,..) and were tested using “lineups” in which six words were presented either simultaneously or sequentially. A studied word (e.g., tired) served as the guilty suspect in target-present lineups, unstudied related words (e.g., nap) served as fillers in target-present and target-absent lineups, and critical lures (e.g., sleep) were included in some target-present and target-absent lineups as well, to serve as attractive alternatives to the target word (or suspect). ROC analyses showed that the simultaneous test format generally yielded superior discriminability performance compared to the sequential test format, whether or not the critical lure was present in the lineup. © 2020, The Psychonomic Society, Inc.
Author Keywords
DRM; Eyewitness memory; Methodology; ROC; Word recognition
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Reduced neurosteroid potentiation of GABAA receptors in epilepsy and depolarized hippocampal neurons” (2020) Annals of Clinical and Translational Neurology
Reduced neurosteroid potentiation of GABAA receptors in epilepsy and depolarized hippocampal neurons
(2020) Annals of Clinical and Translational Neurology, .
Joshi, S.a , Roden, W.H.b , Kapur, J.a c d , Jansen, L.A.a b e
a Department of Neurology, University of Virginia, Charlottesville, VA, United States
b Seattle Children’s Research Institute, Seattle, WA, United States
c Department of Neuroscience, University of Virginia, Charlottesville, VA, United States
d UVA Brain Institute, University of Virginia, Charlottesville, VA, United States
e Department of Neurology, Washington University School of Medicine, St. Louis, WA, United States
Abstract
Objective: Neurosteroids regulate neuronal excitability by potentiating γ-aminobutyric acid type-A receptors (GABARs). In animal models of temporal lobe epilepsy, the neurosteroid sensitivity of GABARs is diminished and GABAR subunit composition is altered. We tested whether similar changes occur in patients with epilepsy and if depolarization-induced increases in neuronal activity can replicate this effect. Methods: We determined GABAR α4 subunit expression in cortical tissue resected from pediatric epilepsy patients. Modulation of human GABARs by allopregnanolone and Ro15-4513 was measured in Xenopus oocytes using whole-cell patch clamp. To extend the findings obtained using tissue from epilepsy patients, we evaluated GABAR expression and modulation by allopregnanolone and Ro15-4513 in cultured rat hippocampal neurons exposed to high extracellular potassium (HK) to increase neuronal activity. Results: Expression of α4 subunits was increased in pediatric cortical epilepsy specimens encompassing multiple pathologies. The potentiation of GABA-evoked currents by the neurosteroid allopregnanolone was decreased in Xenopus oocytes expressing GABARs isolated from epilepsy patients. Furthermore, receptors isolated from epilepsy but not control tissue were sensitive to potentiation by Ro15-4513, indicating higher expression of α4βxγ2 subunit-containing receptors. Correspondingly, increasing the activity of cultured rat hippocampal neurons reduced allopregnanolone potentiation of miniature inhibitory postsynaptic currents (mIPSCs), increased modulation of tonic GABAR current by Ro15-4513, upregulated the surface expression of α4 and γ2 subunits, and increased the colocalization of α4 and γ2 subunit immunoreactivity. Interpretation: These findings suggest that seizure activity-induced upregulation of α4βxγ2 subunit-containing GABARs could affect the anticonvulsant actions of neurosteroids. © 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Access Type: Open Access
“Does patient expectancy account for the cognitive and clinical benefits of mindfulness training in older adults?” (2020) International Journal of Geriatric Psychiatry
Does patient expectancy account for the cognitive and clinical benefits of mindfulness training in older adults?
(2020) International Journal of Geriatric Psychiatry, .
Haddad, R.a , Lenze, E.J.a , Nicol, G.a , Miller, J.P.b , Yingling, M.a , Wetherell, J.L.c
a Department of Psychiatry, Healthy Mind Lab, Washington University School of Medicine, St. Louis, MO, United States
b Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
c Department of Psychiatry, University of California San Diego, San Diego, CA, United States
Abstract
Objectives: Patient expectations of treatment effects could influence neuropsychological and clinical outcomes in clinical trials of behavioral and lifestyle interventions, which could potentially confound the interpretation of findings. Our aim was to examine whether patient expectancy mediated effectiveness of Mindfulness-Based Stress Reduction (MBSR) for improving cognitive function and clinical outcome. Methods: The present study uses data from a single-blind, multi-site, randomized controlled trial comparing MBSR to a health education attention control in older adults with anxiety and/or depressive disorders and subjective cognitive concerns. Using the Credibility and Expectations Questionnaire, we measured expectancy and perceived credibility of the interventions assigned to patients. Using mediational analysis, we examined the influence of expectancy and credibility on two key outcomes: memory performance and clinical global improvement. Results: Neither expectancy nor perceived credibility of intervention accounted significantly for MBSR’s effectiveness for memory test performance or clinical global improvement. Conclusion: In this clinical trial, expectancy for improvement did not account for the effectiveness of MBSR on memory performance or clinical outcomes in depressed and anxious older adults. We advise that clinical trials of behavioral and lifestyle interventions for brain health in older adults should measure and test the role of expectancy. © 2020 John Wiley & Sons Ltd
Author Keywords
anxiety; clinical improvement; credibility; depression; expectancy; Mindfulness-Based Stress Reduction; older adults memory improvement
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Delineation of phenotypes and genotypes related to cohesin structural protein RAD21” (2020) Human Genetics
Delineation of phenotypes and genotypes related to cohesin structural protein RAD21
(2020) Human Genetics, .
Krab, L.C.a b c , Marcos-Alcalde, I.d e , Assaf, M.f , Balasubramanian, M.g , Andersen, J.B.h , Bisgaard, A.-M.i , Fitzpatrick, D.R.j , Gudmundsson, S.k , Huisman, S.A.a l , Kalayci, T.m , Maas, S.M.a n , Martinez, F.o , McKee, S.p , Menke, L.A.a , Mulder, P.A.q , Murch, O.D.r , Parker, M.s , Pie, J.t , Ramos, F.J.u , Rieubland, C.v , Rosenfeld Mokry, J.A.w , Scarano, E.x , Shinawi, M.y , Gómez-Puertas, P.d , Tümer, Z.h z , Hennekam, R.C.a
a Department of Pediatrics, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, 1105AZ, Netherlands
b Cordaan, Outpatient Clinic for ID Medicine, Klinkerweg 75, Amsterdam, 1033 PK, Netherlands
c Odion, Outpatient Clinic for ID Medicine, Purmerend, Netherlands
d Molecular Modelling Group, Centro de Biología Molecular Severo Ochoa, CBMSO (CSIC-UAM), Madrid, Spain
e School of Experimental Sciences-IIB, Universidad Francisco de Vitoria, UFV, Pozuelo de Alarcón, Spain
f Banner Childrens Specialists Neurology Clinic, Glendale, AZ, United States
g Clinical Genetics Service, Sheffield Children’s Hospital, Academic Unit for Child Health, University of Sheffield, Sheffield, United Kingdom
h Department of Clinical Genetics, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Gl. Landevej 7, Glostrup, 2600, Denmark
i Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark
j MRC Human Genetics Unit, University of Edinburgh, Edinburgh, United Kingdom
k Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
l Prinsenstichting, Purmerend, Netherlands
m Division of Medical Genetics, Department of Internal Medicine, Istanbul University, Istanbul, Turkey
n Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
o Unidad de Genética, Hospital Universitario y Politécnico La Fe, Valencia, Spain
p Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, United Kingdom
q Autism Team Northern-Netherlands, Jonx Department of Youth Mental Health and Autism, Lentis Psychiatric Institute, Groningen, Netherlands
r Institute of Medical Genetics, University Hospital of Wales, Cardiff, United Kingdom
s Clinical Genetic Service, Northern General Hospital, Sheffield, United Kingdom
t Unit of Clinical Genetics Unit, Service of Pediatrics, University Hospital “Lozano Blesa”, University of Zaragoza School of Medicine, Saragossa, Spain
u Unit of Clinical Genetics Unit and Functional Genomics, Department of Pharmacology and Physiology, University of Zaragoza School of Medicine, Saragossa, Spain
v Department of Pediatrics, Division of Human Genetics, Inselspital, University of Bern, Bern, Switzerland
w Department of Molecular and Human Genetics, Baylor College of Medicine, Baylor Genetics Laboratories, Houston, TX, United States
x Rare Disease Unit, Department of Pediatrics, St. Orsola Hospital, Bologna, Italy
y Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, United States
z Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
Abstract
RAD21 encodes a key component of the cohesin complex, and variants in RAD21 have been associated with Cornelia de Lange Syndrome (CdLS). Limited information on phenotypes attributable to RAD21 variants and genotype–phenotype relationships is currently published. We gathered a series of 49 individuals from 33 families with RAD21 alterations [24 different intragenic sequence variants (2 recurrent), 7 unique microdeletions], including 24 hitherto unpublished cases. We evaluated consequences of 12 intragenic variants by protein modelling and molecular dynamic studies. Full clinical information was available for 29 individuals. Their phenotype is an attenuated CdLS phenotype compared to that caused by variants in NIPBL or SMC1A for facial morphology, limb anomalies, and especially for cognition and behavior. In the 20 individuals with limited clinical information, additional phenotypes include Mungan syndrome (in patients with biallelic variants) and holoprosencephaly, with or without CdLS characteristics. We describe several additional cases with phenotypes including sclerocornea, in which involvement of the RAD21 variant is uncertain. Variants were frequently familial, and genotype–phenotype analyses demonstrated striking interfamilial and intrafamilial variability. Careful phenotyping is essential in interpreting consequences of RAD21 variants, and protein modeling and dynamics can be helpful in determining pathogenicity. The current study should be helpful when counseling families with a RAD21 variation. © 2020, The Author(s).
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Access Type: Open Access
“Model-based whole-brain effective connectivity to study distributed cognition in health and disease” (2019) Network Neuroscience
Model-based whole-brain effective connectivity to study distributed cognition in health and disease
(2019) Network Neuroscience, 4 (2), pp. 338-373.
Gilson, M.a , Zamora-López, G.a , Pallarés, V.a , Adhikari, M.H.a , Senden, M.b , Campo, A.T.c , Mantini, D.d e , Corbetta, M.f g , Deco, G.a h , Insabato, A.i
a Center for Brain and Cognition, Department of Information and Communication Technologies, Universitat Pompeu Fabra, Barcelona, Spain
b Department of Cognitive Neuroscience, University of Maastricht, Maastricht, Netherlands
c BarcelonaBeta, Barcelona, Spain
d Neuroplasticity and Motor Control Research Group, KU Leuven, Leuven, Belgium
e Brain Imaging and Neural Dynamics Research Group, IRCCS San Camillo Hospital, Venice, Italy
f Department of Neuroscience, Venetian Institute of Molecular Medicine (VIMM), Padova Neuroscience Center (PNC), University of Padua, Italy
g Department of Neurology, Radiology, and Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
h Institució Catalana de la Recerca i Estudis Avançats (ICREA), Barcelona, Spain
i Institut de Neurosciences de la Timone, CNRS, Marseille, France
Abstract
Neuroimaging techniques are now widely used to study human cognition. The functional associations between brain areas have become a standard proxy to describe how cognitive processes are distributed across the brain network. Among the many analysis tools available, dynamic models of brain activity have been developed to overcome the limitations of original connectivity measures such as functional connectivity. This goes in line with the many efforts devoted to the assessment of directional interactions between brain areas from the observed neuroimaging activity. This opinion article provides an overview of our model-based whole-brain effective connectivity to analyze fMRI data, while discussing the pros and cons of our approach with respect to other established approaches. Our framework relies on the multivariate Ornstein-Uhlenbeck (MOU) process and is thus referred to as MOU-EC. Once tuned, the model provides a directed connectivity estimate that reflects the dynamical state of BOLD activity, which can be used to explore cognition. We illustrate this approach using two applications on task-evoked fMRI data. First, as a connectivity measure, MOU-EC can be used to extract biomarkers for task-specific brain coordination, understood as the patterns of areas exchanging information. The multivariate nature of connectivity measures raises several challenges for whole-brain analysis, for which machine-learning tools present some advantages over statistical testing. Second, we show how to interpret changes in MOU-EC connections in a collective and model-based manner, bridging with network analysis. Our framework provides a comprehensive set of tools that open exciting perspectives to study distributed cognition, as well as neuropathologies. © 2019 Massachusetts Institute of Technology.
Author Keywords
Biomarker; Classification; Cognition; Community analysis; Connectivity estimation; Dynamic communicability and flow; Effective connectivity; FMRI; Machine learning; Network theory; Recurrent network; Whole-brain dynamic model
Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access