Table Of Content©2003 CRC Press LLC
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International Standard Book Number 0-8493-0122-X
Library of Congress Card Number 2002031093
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Library of Congress Cataloging-in-Publication Data
Biomedical imaging in experimenal neuoscience / edited by Nick van Bruggen and
Timothy Roberts.
p. cm. — (Methods & new frontiers in neuroscience)
Includes bibliographical references and index.
ISBN 0-8493-0122-X (alk. paper)
1. Brain—Imaging. 2. Brain—Magnetic resonance imaging. I. van Bruggen, Nick. II.
Roberts, Timothy (Timothy P. L.) III. Methods & new frontiers in neuroscience series
QP376.6 .B55 2002
612.8¢2—dc21
2002031093
©2003 CRC Press LLC
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Series Preface
Our goal in creating the Methods & New Frontiers in Neuroscience series is to
present the insights of experts on emerging experimental techniques and theoretical
concepts that are, or will be, at the vanguard of neuroscience. Books in the series
cover topics ranging from methods to investigate apoptosis to modern techniques
for neural ensemble recordings in behaving animals. The series also covers new and
exciting multidisciplinary areas of brain research, such as computational neuro-
science and neuroengineering, and describes breakthroughs in classical fields like
behavioral neuroscience. We want these books to be the books every neuroscientist
will use in order to get acquainted with new methodologies in brain research. These
books can be given to graduate students and postdoctoral fellows when they are
looking for guidance to start a new line of research.
Each book is edited by an expert and consists of chapters written by the leaders
in a particular field. Books are richly illustrated and contain comprehensive bibli-
ographies. Chapters provide substantial background material relevant to the partic-
ular subject. Hence, they are not only “ methods books,” but they also contain detailed
“tricks of the trade” and information as to where these methods can be safely applied.
In addition, they include information about where to buy equipment and about web
sites helpful in solving both practical and theoretical problems.
We hope that as the volumes become available, the effort put in by us, by the
publisher, by the book editors, and by individual authors will contribute to the further
development of brain research. The extent that we achieve this goal will be deter-
mined by the utility of these books.
Sidney A. Simon, Ph.D.
Miguel A.L. Nicolelis, M.D., Ph.D.
Series Editors
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Preface
The goals of experimental neuroscience research are fundamentally to gain mecha-
nistic understanding of the pathology of disease in order to identify appropriate
targets for potential pharmacological intervention and evaluation of putative thera-
pies. With the advances in gene manipulation and transgene technologies, we have
unprecedented ability to generate animal models of disease that more closely mimic
the clinical conditions.
Noninvasive techniques capable of investigating altered pathophysiologies are
now of paramount importance. Conventional methods that rely on histological and/or
immunohistochemical staining demand the selective sacrifices of large cohorts of
animals and include inherent assumptions of population homogeneity. Noninvasive
imaging offers the obvious attractions of reducing sample sizes, use of individual
data for internal baseline and control purposes, and consequent advantages in sta-
tistical power. It also offers opportunities to investigate behavior in individual ani-
mals that perhaps deviates from population norm expectations, i.e., to identify new
and unanticipated behaviors.
Noninvasive imaging also offers accessibility to specific and dynamic physio-
logical interactions that are amenable only at whole organism or system level, and
cannot be addressed via single-time point, single-mechanism, ex vivo analysis.
Advances in imaging methodologies provide increased physiological specificity at
tissue, vascular, cellular, metabolic, and electrophysiological levels. Experimental
neuroscience seeks to validate these specificities for their ultimate clinical value. On
the other hand, once validated, these specificities can be expanded to characterize
tissue, identify target pharmaceutical approaches, and evaluate novel mode-of-
action-specific therapeutics.
This book is motivated by the rapidly advancing technologies of noninvasive
imaging, the parallel rapid progress in developing genomic and other targeted phar-
maceuticals, and the ongoing demand for greater understanding of diseases and
therapies. Our target audience includes the biologists with interests in how advances
in biomedical imaging may augment their in vivo research endeavors and clinical
practitioners who seek deeper insights into the association between imaging results
and disease pathophysiology.
We would like to thank the following for their assistance in preparing material
for this book and their patience throughout this project: Evelyn Berry and Alison
Bruce for help with manuscript preparation; and Simon Williams, Annie Ogasawara,
Jed Ross, Joan Greve, Hope Steinmetz, Adrienne Ross, Kai Barck, and Lisa Bern-
stein for their support and patience. We are grateful for all our collaborators that
provided data and illustrations — often at short notice! Finally, we thank our wives
and children for their encouragement and tolerance.
Nick van Bruggen
Tim Roberts
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Editors
Nick van Bruggen is a senior scientist at Genentech Inc. and head of the biomedical
imaging group in the department of physiology. He earned a B.Sc in medicinal
chemistry from University College London and a Ph.D in chemistry from Nottingham
University, U.K. In 1987, while working in the laboratory of Professor David Gadian
at The Royal College of Surgeons of England in London, he helped establish one of
the earliest magnetic resonance imaging (MRI) systems dedicated to experimental
biological research. In 1991, he was appointed to a lectureship position at Hunterian
Institute and focused his research on developing novel MRI techniques for the
investigation and understanding of pathophysiology, including the use of diffusion
MR imaging and functional MRI for stroke research. In 1994, he moved to California
to establish a biomedical imaging facility dedicated to in vivo experimental research
for Genentech Inc., one of the original U.S. biotechnology companies.
Timothy P.L. Roberts is an associate professor in the department of medical
imaging at the University of Toronto. He earned a B.A. and an M.A. in natural
sciences from Cambridge University in England in 1988, and was granted a Ph.D.
in MRI techniques at the Herchel Smith Laboratory for Medicinal Chemistry of
Cambridge University in 1991. His postdoctoral research in the neuroradiology
section of the laboratory of John Kucharczyk and Mike Moseley at the University
of California at San Francisco (UCSF) focused on the quantitative use of high speed
perfusion- and diffusion-sensitive MRI in animal models of cerebral ischemia, met-
abolic encephalopathies, and neonatal development. Dr. Roberts was appointed
assistant professor of radiology at UCSF in 1994 as director of the biomagnetic
imaging laboratory. He investigated electrophysiologic aspects of brain function
using magnetoencephalography (MEG) and cellular and vascular responses using
diffusion-weighted, perfusion-sensitive, and BOLD MRI. In 2002 Dr. Roberts moved
to Canada where he holds the Canada Research Chair in Imaging Research.
He is a member of the International Society for Magnetic Resonance in Medi-
cine, the American Society of Neuroradiology, the Cognitive Neuroscience Society,
the Organization for Human Brain Mapping, the International Society of Cerebral
Blood Flow and Metabolism, and the Institute of Physics. He has authored or co-
authored over 150 journal articles and book chapters in the fields of physiological
and functional MRI, magnetoencephalography, and magnetic source imaging.
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Contributors
Helene Benveniste
Department of Anesthesiology
SUNY at Stony Brook
Stony Brook, NY
Stephen J. Blackband
University of Florida
Department of Biochemistry
Gainesville, FL
Fernando Calamante
Institute of Child Health
Unit of Biophysics
London, England
Richard Carano
Genentech Inc.
Department of Physiology
South San Francisco, CA
Yin-Ching I. Chen
Massachusetts General Hospital
MGH-NMR Center
Charlestown, MA
Simon Cherry
University of California
Department of Biomedical Engineering
Davis, CA
Alexander J. de Crespigny
Massachusetts General Hospital
MGH-NMR Center
Charlestown, MA
Elizabeth Disbrow
University of California at Davis
Center for Neuroscience
Davis, CA
Mathias Hoehn
Max Planck Institut
Neurologische Forschung
Köln, Germany
Bruce G. Jenkins
Massachusetts General Hospital
MGH-NMR Center
Charlestown, MA
Harley Kornblum
University of California
School of Medicine
Los Angeles, CA
Mark Francis Lythgoe
Institute of Child Health
Unit of Biophysics
London, England
Thomas M. Mareci
University of Florida
Department of Biochemistry
Gainesville, FL
Joseph B. Mendeville
Massachusetts General Hosp.
MGH-NMR Center
Charlestown, MA
Michel Modo
University of London
Institute of Psychiatry
Department of Psychology
London, England
Timothy P.L. Roberts
University of Toronto
Department of Medical Imaging
Toronto, Ontario
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Nicola R. Sibson
University of Oxford
Department of Biochemistry
Oxford, England
David L. Thomas
University College London
Wellcome Trust High Field Laboratory
London, England
Nick van Bruggen
Genentech Inc.
Department of Physiology
South San Francisco, CA
Steven C.R. Williams
University of London
Institute of Psychiatry
Department of Clinical Neuroscience
London, England
Stephen R. Williams
University of Manchester
Imaging Science and Biomedical
Engineering
Manchester, England
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Table of Contents
Chapter 1
Principles of MRI Contrast
Timothy P.L. Roberts and Nick van Bruggen
Chapter 2
MRI Measurement of Cerebral Perfusion and Application to Experimental
Neuroscience
Mark F. Lythgoe, David L. Thomas, and Fernando Calamante
Chapter 3
MRI Measurement of Cerebral Water Diffusion and Its Application
to Experimental Research
Richard A.D. Carano, Nick van Bruggen, and Alex J. de Crespigny
Chapter 4
Functional Magnetic Resonance Imaging
Mathias Hoehn
Chapter 5
Functional Imaging in Nonhuman Primates
Elizabeth Disbrow
Chapter 6
Pharmacologic Magnetic Resonance Imaging (phMRI)
Bruce G. Jenkins, Yin-Ching I. Chen, and Joseph B. Mandeville
Chapter 7
Anatomical Studies in the Rodent Brain and Spinal Cord:
Applications of Magnetic Resonance Microscopy
Helene Benveniste, Tom Mareci, and Steve Blackband
Chapter 8
Magnetic Resonance Spectroscopy: Principles and Applications
Stephen R. Williams and Nicola R. Sibson
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Chapter 9
Small Animal Imaging with Positron Emission Tomography
Simon R. Cherry and Harley I. Kornblum
Chapter 10
MRI and Novel Contrast Agents for Molecular Imaging
Michel M. Modo and Steven C.R. Williams
Chapter 11
The Future for Biomedical Imaging: Emerging and Alternative Technologies
Nick van Bruggen and Timothy P.L. Roberts
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Principles of MRI
Contrast
Timothy P.L. Roberts and Nick van Bruggen
CONTENTS
1.1
Introduction
1.2
Origins of Signals and Sensitivity to Physical Factors: Making
a Physiological Inference from a Physical Truth
1.2.1
Sources of Intrinsic Contrast: T1, T2, and T2* Relaxation Times
1.2.1.1
Generation of Contrast Exploiting T2*
1.2.1.2
Generation of Contrast Exploiting T2
1.2.1.3
Generation of Contrast Exploiting T1
1.2.2
Spin Gymnastics: Tagging, Labeling, and Saturation
1.2.2.1
Generation of Contrast Exploiting Diffusion
1.2.2.2
Spin Labeling
1.2.2.3
Magnetization Transfer
1.2.3
When Intrinsic Contrast Is InsufÞcient: Contrast Media
1.2.3.1
Low Molecular Weight Gadolinium-Based
Contrast Agents
1.2.3.2
Other Elements: Dysprosium and Iron
1.2.3.3
Macromolecular Contrast Agents
1.2.3.4
Targeted Contrast Agents
1.3
Conclusion
Acknowledgment
1.1 INTRODUCTION
Magnetic resonance imaging (MRI) has become the mainstay of radiological tech-
niques in diagnostic imaging and the technique of choice for assessing diseases of
the central nervous system. Its utility in experimental research using laboratory
animals has inevitably lagged behind its clinical counterpart due, in part, to equip-
ment costs and requirements for qualiÞed operators. However with technological
advances, increased availability, and deeper understanding of its physiological spec-
iÞcity and capabilities, the utility of MRI in experimental research is assured. Its
success in clinical practice and now in experimental research — an impressive
achievement considering MRI was introduced into clinical medicine a little over two
1
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