Advances in Neurobiology

Volume 4

Series Editor Abel Lajtha

For further volumes: http://www.springer.com/series/8787

In-Young Choi ● Rolf Gruetter Editors

Neural Metabolism In Vivo Editors In-Young Choi, Ph.D. Rolf Gruetter, Ph.D. Department of Laboratory for functional Department of Molecular and metabolic imaging and Integrative Physiology Ecole Polytechnique Federale de Lausanne Hoglund Imaging Center Department of Radiology University of Kansas Medical Center University of Lausanne Kansas City, KS, USA and Geneva Station 6, CH-1015 [email protected] Lausanne, rolf.gruetter@epfl .ch

ISSN 2190-5215 e-ISSN 2190-5223 ISBN 978-1-4614-1787-3 e-ISBN 978-1-4614-1788-0 DOI 10.1007/978-1-4614-1788-0 Springer New York Dordrecht Heidelberg London

Library of Congress Control Number: 2011944816

© Springer Science+Business Media, LLC 2012 All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identifi ed as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights.

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Springer is part of Springer Science+Business Media (www.springer.com) Preface

A greater understanding of the living brain in action has become increasingly feasible through the relentless efforts and devotion of and bioengineers in the past three decades. The development of emerging tools and neuroimag- ing techniques provided us with a new opportunity to integrate real time information regarding the structural organization, function and metabolism of the brain as a whole. The development of this book was truly exciting for us in providing the introduction to the state-of-the-art in vivo tools in the neurobiology of the brain, the least under- stood and most challenging organ. The key advances in neural metabolism in health and disease are indebted to a variety of powerful techniques, namely nuclear magnetic resonance, radiotracer imaging, optical imaging and micro-dialysis. “Neural Metabolism In Vivo ” aims to provide a comprehensive overview of neuro- biology by presenting the basic principles of up-to-date and cutting-edge technology, as well as their application in assessing the functional, morphological and metabolic aspects of the brain. Investigation of neural activity of the living brain via neurovascu- lar coupling using multimodal imaging techniques extended our understanding of fun- damental neurophysiological mechanisms, regulation of cerebral blood fl ow in connection to neural activity and the interplay between neurons, and blood vessels. Constant delivery of glucose and oxygen for energy metabolism is vital for brain function, and the physiological basis of neural activity can be assessed through measurements of cerebral blood fl ow and consumption of glucose and oxygen. Dynamic changes in neural metabolism from the basal resting state to the active state accompany the consumption of the major energy substrates of the brain, glucose, and other alternatives. The complexity of the brain is not only refl ected in its use of various energy sources as described under the “Cerebral energy metabolism and sub- strates in vivo” section, but also the underlying metabolic processes at the cellular and inter-cellular levels. A close interaction between neuron and astrocytes with regard to oxidative metabolism represents still emerging and controversial research areas since the initial observation of glutamate compartmentation by Dr. Lajtha and others in early 1950s. The working hypothesis of the glutamatergic activity coupled to anaero- bic glycolysis is part of the primary neurobiological basis for neural metabolism as

v vi Preface presented under the “In vivo assessment of metabolic compartmentation between neurons and astrocytes” section, yet to be clearly demonstrated in the future. This book presents the complex physiological and neurochemical processes of neural metabolism and function in response to various physiological conditions and pharmacological stimulations. Neurochemical detection technologies and quantita- tive aspects of monitoring cerebral energy substrates and other metabolites in the living brain are described under the “Cerebral metabolism of antioxidants, osmo- lytes and others in vivo ” section. Altogether, the advent of new in vivo tools has transformed neuroscience and neurobiology research, and demands interdisciplinary approaches as each technology could only approximate a very small fraction of the true complexity of the underlying biological processes. However, translational values of the emerging in vivo methods to the application of preclinical to clinical studies cannot be emphasized enough. Thus, it is our hope that advances in our understanding of biochemical, molecular, functional and physiological processes of the brain could eventually help people with neurological problems, which are still dominated by the unknowns.

Kansas City, KS, USA In-Young Choi, Ph.D. Lausanne, Switzerland Rolf Gruetter, Ph.D. Acknowledgements

First and foremost, our sincere thanks and appreciation go to all of the authors who put their considerable ruminations and efforts as well as their talents, time and energy to make this work possible. Under one coherent theme of the neural metabo- lism in vivo, 99 contributors provided outstanding overviews of this vast and chal- lenging area, and bore with us with great patience for the past 4 years during the long editing process of this book. We offer our sincere thanks to over 150 reviewers who devoted their time in providing valuable suggestions and constructive com- ments. Our interaction with prominent scientists from all related disciplines has been a great privilege and an invaluable experience during this endeavor. We are also eternally thankful to Dr. Abel Lajtha who has been our champion by supporting, encouraging and inspiring us from the start of this project. We express our deep respect to his extraordinary insights, knowledge and contribution to the fi eld of neurochemistry. Our pronounced gratitude goes to Joel Tanzi who helped us through his talent with the editing process. Our gratitude is owed to Drs. Sebastián Cerdán and Phil Lee for their patient and thorough review of many pages of this book. Last but not least, we thank Springer Science for providing us with this unique opportunity and the Springer editors who have worked with us throughout the editing process.

Kansas City, KS, USA In-Young Choi, Ph.D. Lausanne, Switzerland Rolf Gruetter, Ph.D.

vii

Contents

Part I Non-invasive Methods for Neural Metabolism

1 Introduction to Nuclear Magnetic Resonance (NMR) Methods ...... 3 Allen W. Song 2 Hardware Requirements for In Vivo Nuclear Magnetic Resonance Studies of Neural Metabolism ...... 33 Hellmut Merkle, Phil Lee, and In-Young Choi 3 Diffusion Sensitive Magnetic Resonance Imaging of the Central Nervous System ...... 65 Jeffrey J. Neil and Joseph J.H. Ackerman 4 Tools to Enhance the Contrast in MR Images: From Lanthanide Complexes and Iron Oxide Particles to MEMRI ...... 79 Annemie Van der Linden, Vincent Van Meir, Dario Longo, and Silvio Aime 5 Principles of 1H NMR In Vivo ...... 133 Robin A. de Graaf 6 In Vivo Cerebral 31P Magnetic Resonance Spectroscopy ...... 149 Ernest B. Cady 7 In Vivo 13C Magnetic Resonance Spectroscopy and Metabolic Modeling: Methodology ...... 181 Pierre-Gilles Henry, Dinesh K. Deelchand, Isabelle Iltis, Malgorzata Marjanska, Gülin Öz, Alexander A. Shestov, and Julien Valette 8 13C NMR Spectroscopy as a Tool in Neurobiology ...... 221 Asta Haberg, Ursula Sonnewald, Janniche Hammer, Torun Melø, and Haytham Eloqayli

ix x Contents

9 Overview of Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) Methodologies ...... 255 Paul Cumming and Guido Böning 10 Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) ...... 271 Andrei G. Vlassenko and Mark A. Mintun 11 Neuroreceptor Imaging ...... 305 Habib Zaidi and Miho Shidahara 12 Optical Approaches to Study Metabolic Consequences of Spreading Depression In Vivo ...... 331 C. William Shuttleworth 13 Microdialysis and Microfi ltration: Technology and Cerebral Applications for Energy Substrates...... 371 Kirsten Huinink, Jakob Korf, and Jan Bert Gramsbergen

Part II In Vivo Assessment of Neural Activity Via Neurovascular Coupling

14 The Coupling of Cerebral Metabolic Rate of Glucose and Cerebral Blood Flow In Vivo ...... 417 Steen G. Hasselbalch and Olaf B. Paulson 15 Neuronal Basis of Non-Invasive Functional Imaging: From Microscopic Neurovascular Dynamics to BOLD fMRI ...... 433 Anna Devor, David A. Boas, Gaute T. Einevoll, Richard B. Buxton, and Anders M. Dale 16 Imaging of Brain Function Using Deoxyhemoglobin and Magnetic Fields ...... 501 Kâmil Uğurbil 17 FMRI Using Exogenous Agents and Cerebral Blood Volume Contrast ...... 547 Joseph B. Mandeville 18 FMRI in Mice: Functional Phenotyping of Transgenic Mouse Lines Based on Hemodynamic Readouts...... 593 Thomas Mueggler, Christof Baltes, Simone C. Bosshard, Felicitas L. Princz-Kranz, David Ratering, Florence Razoux, Esther Sydekum, and Markus Rudin 19 In Vivo Studies of Brain Oxygen Metabolism and Oxidative Phosphorylation ...... 623 Xiao-Hong Zhu and Wei Chen Contents xi

Part III Cerebral Energy Metabolism and Substrates In Vivo

20 Cerebral Glucose Transport and Homeostasis ...... 655 João M.N. Duarte and Rolf Gruetter 21 Glucose Metabolism During Neural Activation ...... 675 Marianne Fillenz 22 Measurements of Metabolism in the Living Brain ...... 699 Rolf Gruetter 23 Functions of Glycogen in the Central Nervous System ...... 707 Richard D. Evans, Angus M. Brown, and Bruce R. Ransom 24 Pyruvate Transport and Metabolism in the Central Nervous System ...... 715 Tiago B. Rodrigues, Alejandra Sierra, Paloma Ballesteros, and Sebastián Cerdán 25 Blood-Brain Barrier Transport of Lactate ...... 755 Gitte Moos Knudsen 26 Cerebral Acetate Metabolism: Towards Its In Vivo Assessment ...... 763 Basil Künnecke 27 Brain Fatty Acid Uptake ...... 793 James A. Hamilton, Kellen Brunaldi, Richard P. Bazinet, and Paul A. Watkins 28 The Ketogenic Diet and Brain Metabolism ...... 819 Marc Yudkoff, Yevgeny Daikhin, Oksana Horyn, Ilana Nissim, and Itzhak Nissim 29 Redox Shuttles in the Brain ...... 841 Beatriz Pardo and Laura Contreras 30 Mitochondria in Neurodegeneration ...... 885 Russell H. Swerdlow

Part IV In Vivo Assessment of Metabolic Compartmentation Between Neurons and Astrocytes

31 Studies of Brain Metabolism: A Historical Perspective ...... 909 Arne Schousboe 32 Glutamate- Cycle and Anaplerosis ...... 921 Gülin Öz, David A. Okar, and Pierre-Gilles Henry 33 Brain Metabolic Compartmentalization, Metabolism Modeling, and Cerebral Activity-Metabolism Relationship ...... 947 Michel Merle and Jean-Michel Franconi xii Contents

34 Radiotracer Perspective on Cerebral Compartmentation ...... 993 Bruno Weber, Renaud Jolivet, Matthias T. Wyss, and Alfred Buck 35 Nitrogen Metabolism In Vivo ...... 1005 Keiko Kanamori and Brian D. Ross

Part V Cerebral Metabolism of Antioxidants, Osmolytes and Others In Vivo

36 (GSH) Synthesis and Metabolism ...... 1029 Maike M. Schmidt and Ralf Dringen 37 Brain Ascorbate: Protective, Yet Permissive for Redox Signaling ...... 1051 Margaret E. Rice 38 N-Acetyl-Aspartate (NAA) Metabolism ...... 1075 Kishore K. Bhakoo 39 In Vivo GABA Metabolism ...... 1095 In-Young Choi and Jun Shen 40 1H-Magnetic Resonance Spectroscopy of Cerebral Phenylalanine Content and its Transport at the Blood-Brain Barrier ...... 1117 Roland Kreis 41 Measurement of Brain Creatine Metabolism In Vivo: Magnetic Resonance Spectroscopy Studies of Transgenic Animals ...... 1135 Arend Heerschap, Christine I.H.C. Nabuurs, Hermien E. Kan, Bé Wieringa, and Dirk Isbrandt

Index ...... 1149 Contributors

Joseph J. H. Ackerman Departments of Chemistry, Radiology and Internal Medicine , Washington University , St. Louis , MO , USA [email protected] Silvio Aime Department of Chemistry IFM/Molecular Imaging Center , University of Turin , Turin , Italy [email protected] Paloma Ballesteros Laboratory of Organic Synthesis and Molecular Imaging , University at a Distance UNED , Madrid , Spain [email protected] Christof Baltes Philips Healthcare , Best , The Netherlands [email protected] Richard P. Bazinet Department of Nutritional Sciences , University of Toronto , Toronto , ON , Canada [email protected] Kishore K. Bhakoo Translation Molecular Imaging, Singapore Bioimaging Consortium , Agency for Science, Technology and Research , Biopolis Way , Singapore [email protected] David A. Boas Martinos Center for Biomedical Imaging , Massachusetts General Hospital (MGH), Harvard Medical School , Charlestown , MA , USA [email protected] Guido Böning Department of Nuclear Medicine , Ludwig Maximilian University of Munich , Munich , Germany [email protected] Simone C. Bosshard Institute for Biomedical Engineering , University and Eidgenössische Technische Hochschule (ETH) Zurich , Zurich , Switzerland [email protected]

xiii xiv Contributors

Angus M. Brown University of Nottingham, Queens Medical Centre , Nottingham , UK [email protected] Kellen Brunaldi Department of Physiology and Biophysics , Boston University School of Medicine , Boston , MA , USA [email protected] Alfred Buck Department of Nuclear Medicine , University Hospital Zurich , Zurich , Switzerland [email protected] Richard B. Buxton Department of Radiology, Radiology - Center for Functional MRI , University of California San Diego , La Jolla , CA , USA [email protected] Ernest B. Cady Department of Medical and Bioengineering, University College London Hospitals Foundation NHS Trust, London, UK [email protected] Sebastián Cerdán Laboratory for Imaging and Spectroscopy by Magnetic Resonance , Institute of Biomedical Research “Alberto Sols” CSIC/UAM , Madrid , Spain [email protected] Wei Chen Center for Magnetic Resonance Research, Department of Radiology , University of Minnesota , School of Medicine, Minneapolis , MN , USA [email protected] In-Young Choi Department of Neurology, Department of Molecular & Integrative Physiology , Hoglund Brain Imaging Center, University of Kansas Medical Center , Kansas City , KS , USA [email protected] Laura Contreras Departamento de Biología Molecular , Centro de Biología Molecular “Severo Ochoa”, UAM-CSIC, Universidad Autónoma, Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), ISCIII, Cantoblanco, Madrid , Spain [email protected] Paul Cumming Department of Nuclear Medicine , Ludwig Maximilian’s University of Munich , Munich , Germany [email protected] Yevgeny Daikhin Children’s Hospital of Philadelphia and Department of Pediatrics , University of Pennsylvania School of Medicine , Philadelphia , PA , USA Anders M. Dale Department of , Department of Radiology, University of California San Diego , San Diego , CA , USA [email protected] Contributors xv

Dinesh K. Deelchand Center for Magnetic Resonance Research, Department of Radiology , University of Minnesota Medical School , Minneapolis , MN , USA [email protected] Anna Devor Departments of Neurosciences and Radiology , University of California San Diego , La Jolla , CA , USA Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA [email protected] Ralf Dringen Center for Biomolecular Interactions Bremen , University of Bremen , Bremen , Germany Center for Environmental Research and Sustainable Technologies, Leobener Strasse, Bremen, Germany School of Psychology and Psychiatry, Monash University, Clayton, VIC, Australia [email protected] João M. N. Duarte Laboratory for functional and metabolic imaging , Ecole Polytechnique Federale de Lausanne , Lausanne , Switzerland joao.duarte@epfl .ch Gaute T. Einevoll Department of Mathematical Sciences and Technology , Norwegian University of Life Sciences , Aas , Norway [email protected] Haytham M. Eloqayli Department of Neuroscience , Jordan university of Science and Technology (JUST) , Irbid , Jordan [email protected] Richard D. Evans School of Biomedical Sciences , Queens Medical Centre, University of Nottingham , Nottingham , UK Marianne Fillenz Department of Physiology, Anatomy and Genetics , Oxford University , Oxford , UK marianne.fi [email protected] Jean-Michel Franconi Unité de Résonance Magnétique des Systèmes Biologiques, Université Victor Segalen , Bordeaux cedex , France [email protected] Robin A. de Graaf Departments of Diagnostic Radiology and Biomedical Engineering , MRRC, , New Haven , CT , USA [email protected] Jan Bert Gramsbergen Molecular Neurosciences, South University, Odense , Denmark [email protected] xvi Contributors

Rolf Gruetter Laboratory for functional and metabolic imaging, Ecole Polytechnique Federale de Lausanne , Department of Radiology, University of Lausanne and Geneva, Station 6, CH-1015, Lausanne , Switzerland rolf.gruetter@epfl .ch Asta Haberg Department of Neuroscience , Norwegian University of Science & Technology , Trondheim , Norway [email protected] James A. Hamilton Department of Physiology and Biophysics , Boston University School of Medicine , Boston , MA , USA [email protected] Janniche Hammer Department of Neuroscience , Norwegian University of Science & Technology , Trondheim , Norway [email protected] Steen G. Hasselbalch Neurobiology Research Unit , University Hospital, Rigshospitalet , Copenhagen , Denmark [email protected] Arend Heerschap Department of Radiology , Radboud University Nijmegen Medical Centre , Nijmegen , The Netherlands [email protected] Pierre-Gilles Henry Center for Magnetic Resonance Research, Department of Radiology , University of Minnesota Medical School , Minneapolis , MN , USA [email protected] Oksana Horyn Children’s Hospital of Philadelphia and Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA Kirsten Huinink Department of Psychiatry , University Medical Center of Groningen , Groningen , The Netherlands Isabelle Iltis Center for Magnetic Resonance Research, Department of Radiology , University of Minnesota Medical School , Minneapolis , MN , USA [email protected] Dirk Isbrandt Zentrum für Molekulare Neurobiologie , University Medical Center Hamburg-Eppendorf, ENP/ZMNH , Hamburg , Germany [email protected] Renaud Jolivet Institute of Pharmacology and Toxicology , University of Zurich , Zurich , Switzerland [email protected]fl .ch Hermien Kan Department of Radiology , Radboud University Nijmegen Medical Centre , Nijmegen , The Netherlands [email protected] Contributors xvii

Keiko Kanamori Magnetic Resonance Spectroscopy Laboratory , Huntington Medical Research Institutes , Pasadena , CA , USA [email protected] Gitte Moos Knudsen Neurobiology Research Unit, section 9201 , Copenhagen University Hospital - Rigshospitalet , Copenhagen , Denmark [email protected]; [email protected] Jakob Korf Department of Psychiatry , University Medical Center of Groningen , Groningen , The Netherlands [email protected] Roland Kreis Department of Clinical Research , University Bern, AMSM, DRNN/DKF , Bern , Switzerland [email protected] Basil Künnecke Magnetic Resonance Imaging and Spectroscopy, CNS Discovery and Translational Area , F. HoffmannLa Roche Ltd , Basel , Switzerland [email protected] Phil Lee Department of Molecular & Integrative Physiology , Hoglund Brain Imaging Center, University of Kansas Medical Center , Kansas City, KS , USA [email protected] Annemie Van der Linden Bio-Imaging Lab, Campus Drie Eiken, Building Uc, Department of Biomedical Sciences , University of Antwerp , Antwerp (Wilrijk) , Belgium [email protected] Dario Longo Department of Chemistry IFM , Molecular Imaging Center, University of Torino , Turin , Italy [email protected] Joseph B. Mandeville Athinoula A. Martinos Center for Biomedical Imaging , Massachusetts General Hospital , Charlestown , MA , USA [email protected] Malgorzata Marjanska Center for Magnetic Resonance Research, Department of Radiology , University of Minnesota Medical School , Minneapolis , MN , USA [email protected] Vincent Van Meir Bio-Imaging Lab, Campus Drie Eiken, Building Uc, Department of Biomedical Sciences , University of Antwerp , Antwerp (Wilrijk) , Belgium [email protected] xviii Contributors

Torun Mel¿ Department of Neuroscience , Norwegian University of Science & Technology , Trondheim , Norway [email protected] Hellmut Merkle Laboratory of Functional and Molecular Imaging , National Institute of Neurological Disorders and Stroke, National Institutes of Health , Bethesda , MD , USA [email protected] Michel Merle Unité de Résonance Magnétique des Systèmes Biologiques, Université Victor Segalen , Bordeaux cedex , France [email protected] Mark A. Mintun Department of Radiology , Avid Radiopharmaceuticals , Philadelphia, PA , USA [email protected] Thomas Mueggler Pharmaceuticals Division , Preclinical Translational Neuroscience , Basel , Switzerland [email protected] Christine I. H. C. Nabuurs Department of Radiology , Radboud University Nijmegen Medical Centre , Nijmegen , The Netherlands [email protected] Jeffrey J. Neil Departments of Pediatric Neurology, Pediatrics and Radiology , Washington University School of Medicine , St. Louis , MO , USA [email protected] Ilana Nissim Children’s Hospital of Philadelphia and Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA Itzhak Nissim Children’s Hospital of Philadelphia and Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA [email protected] David A. Okar Department of Veterans Affairs Medical Center, Department of Biochemistry, Molecular Biology and Biophysics , University of Minnesota , Minneapolis , MN , USA [email protected] Gülin Öz Center for Magnetic Resonance Research, Department of Radiology , University of Minnesota Medical School , Minneapolis , MN , USA [email protected] Beatriz Pardo Departamento de Biología Molecular, Centro de Biología Molecular “Severo Ochoa” UAM-CSIC, Universidad Autónoma, Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), ISCIII, Cantoblanco, Madrid, Spain [email protected] Contributors xix

Olaf B. Paulson Memory Disorders Research Unit and Neurobiology Research Unit, Rigshospitalet, and Danish Research Centre for Magnetic Resonance, Hvidovre Hospital, Faculty of Health Sciences, Copenhagen University, Denmark [email protected] Felicitas L. Princz-Kranz Institute for Biomedical Engineering , University and Eidgenössische Technische Hochschule (ETH) Zurich , Zurich , Switzerland [email protected] Bruce R. Ransom Department of Neurology , University of Washington School of medicine , Seattle , WA , USA [email protected] David Ratering Institute for Biomedical Engineering , University and Eidgenössische Technische Hochschule (ETH) Zurich , Zurich , Switzerland [email protected] Florence Razoux Institute for Biomedical Engineering, University and Eidgenössische Technische Hochschule (ETH) Zurich, Zurich, Switzerland [email protected] Margaret E. Rice Department of Neurosurgery, Department of Physiology and Neuroscience , New York University School of Medicine , New York , NY , USA [email protected] Tiago B. Rodrigues Laboratory for Imaging and Spectroscopy by Magnetic Resonance (LISMAR), Institute of Biomedical Research “Alberto Sols” CSIC/UAM, Madrid, Spain [email protected]; [email protected] Brian D. Ross Magnetic Resonance Spectroscopy Laboratory , Huntington Medical Research Institutes , Pasadena , CA , USA [email protected] Markus Rudin Institute for Biomedical Engineering, Institute of Pharmacology and Toxicology , University and Eidgenössische Technische Hochschule (ETH) Zurich, University of Zurich , Zurich , Switzerland [email protected] Jorgina Satrústegui Department of Molecular Biology , Center for Molecular Biology Severo Ochoa CSIC-UAM, Center for Biomedical Research on Rare Diseases, Universidad Autónoma Madrid Campus of Cantoblanco , Madrid , Spain [email protected] xx Contributors

Maike M. Schmidt Center for Biomolecular Interactions, Center for Environmental Research and Sustainable Technologies , University of Bremen , Bremen , Germany [email protected] Arne Schousboe Department of Pharmacology and Pharmacotherapy, Faculty of Pharmaceutical Sciences , , Copenhagen , Denmark [email protected] Jun Shen Section on Magnetic Resonance Spectroscopy, National Institute of Mental Health, National Institutes of Health, Molecular Imaging Branch, Mood & Anxiety Disorders Program, Bethesda, MD, USA [email protected] Alexander A. Shestov Department of Radiology , Center for Magnetic Resonance Research, University of Minnesota Medical School , Minneapolis , MN , USA [email protected] Miho Shidahara Division of Medical Physics , Tohoku University Graduate School of Medicine , Sendai, Miyagi , Japan [email protected] C. William Shuttleworth Department of Neurosciences , University of New Mexico School of Medicine , Albuquerque , NM , USA [email protected] Alejandra Sierra Laboratory for Imaging and Spectroscopy by Magnetic Resonance (LISMAR) , Institute of Biomedical Research “Alberto Sols” , Madrid , Spain Allen W. Song Duke University Medical Center, Brain Imaging and Analysis Center , Durham , NC , USA [email protected] Ursula Sonnewald Department of Neuroscience , Norwegian University of Science & Technology , Trondheim , Norway [email protected] Russell H. Swerdlow Departments of Neurology, Molecular & Integrative Physiology , University of Kansas School of Medicine , Kansas City , KS , USA [email protected] Esther Sydekum Institute for Biomedical Engineering , University and ETH Zurich , Zurich , Switzerland [email protected] Contributors xxi

Kâmil Uğurbil Department of Radiology, Neurosciences, and Medicine Center for Magnetic Resonance Research , University of Minnesota, Medical School , Minneapolis , MN , USA [email protected] Julien Valette Center for Magnetic Resonance Research, Department of Radiology , University of Minnesota Medical School , Minneapolis , MN , USA Andrei G. Vlassenko Department of Radiology , Washington University School of Medicine , St. Louis , MO , USA [email protected] Paul A. Watkins Kennedy Krieger Institute and Department of Neurology, Johns Hopkins University School of Medicine , Baltimore , MD , USA [email protected] Bruno Weber Institute of Pharmacology and Toxicology , University of Zurich , Zurich , Switzerland [email protected] Bé Wieringa Department of Cell Biology , Radboud University Nijmegen Medical Centre , Nijmegen , The Netherlands [email protected] Matthias T. Wyss Department of Nuclear Medicine , University Hospital Zurich , Zurich , Switzerland [email protected] Marc Yudkoff Children’s Hospital of Philadelphia and Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA Division of Child Development, Rehabilitation and Metabolic Disease, Children’s Hospital of Philadelphia, Philadelphia, PA, USA [email protected] Habib Zaidi Division of Nuclear Medicine and Molecular Imaging , Geneva University Hospital , Geneva , Switzerland Geneva Neuroscience Center, Geneva University, Geneva, Switzerland Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, Netherlands [email protected] Xiao-Hong Zhu Center for Magnetic Resonance Research, Department of Radiology , University of Minnesota , School of Medicine, Minneapolis , MN , USA [email protected]