Biomagnetics

BIOMAGNETICS
Principles and Applications of

Biomagnetic Stimulation and Imaging
BIOMAGNETICS
Principles and Applications of
Biomagnetic Stimulation and Imaging
Edited by
Shoogo Ueno
Professor Emeritus, The University of Tokyo
Masaki Sekino
Associate Professor, The University of Tokyo
Boca Raton London New York
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Contents
Foreword, vii
Preface, ix
Acknowledgments, xv
Editors, xvii
Contributors, xix
Chapter 1 ◾ Introduction 1
Shoogo Ueno
Chapter 2 ◾ Principles of Biomagnetic Stimulation 23

Shoogo Ueno and Masaki Sekino
Chapter 3 ◾ Applications of Biomagnetic Stimulation

for Medical Treatments and for Brain Research 61
Chapter 4 ◾ Biomagnetic Measurements 89

Sunao Iwaki
Chapter 5 ◾ Principles of Magnetic Resonance Imaging 121

Masaki Sekino, Norio Iriguchi, and Shoogo Ueno
Chapter 6 ◾ Prospects for Magnetic Resonance Imaging

of Impedance and Electric Currents 145
v
vi ◾ Contents
Chapter 7 ◾ Magnetic Control of Biological Cell Growth 185

Shoogo Ueno and Sachiko Yamaguchi-Sekino
Chapter 8 ◾ Effects of Radio Frequency Magnetic Fields

on Iron Release and Uptake from and into
Cage Proteins 219
Oscar Cespedes and Shoogo Ueno
Chapter 9 ◾ Safety Aspects of Magnetic

and Electromagnetic Fields 259
Sachiko Yamaguchi-Sekino, Tsukasa Shigemitsu, and Shoogo Ueno
Chapter 10 ◾ New Horizons in Biomagnetics

and Bioimaging 305
INDEX, 321
Foreword
Biomagnetics covers a vast field in the multidisciplinary world of physics,

chemistry, biology, and medicine, touching many aspects of our lives. To
start with, we ourselves generate some degree of a magnetic field in our
bodies, although not strongly. In biological systems, there are interactions
with magnetism present in the natural environment as well as with those
imposed by modern-age technology where highly developed electromag-
netic devices are part of everyday conversation.
In his long and successful academic career, Professor Shoogo Ueno has
contributed significantly to the scientific and technological development
of the biomagnetics field. He and his associates have worked in many areas
of the biological effects of the magnetism field, some of which, such as the
Moses effect, have been revelatory. Professor Ueno is well known as the
inventor of the “figure-eight” TMS coil, which has been “the device” for
noninvasive stimulation of the human brain because of its capacity for
stimulus localization.
This book, Biomagnetics: Principles and Applications of Biomagnetic
Stimulation and Imaging, covers the whole range of the field and builds
upon the editors’ past work. Many observable phenomena induced by the
interaction of magnetic fields with biological materials are described here
together with the underlying basic physics of magnetism and/or electro-
magnetics so that readers can better understand these phenomena. For
those whose work is highly specialized in the field, this book will be very
useful to widen their scope of understanding biomagnetics. Magnetic
fields can permeate normal biological material, and, therefore, it is pos-
sible to build noninvasive devices to measure magnetic phenomena inside
the body. From the observable interaction of magnetic fields with bio-
logical materials, the in vivo information of physical properties can be
obtained. However, some interaction, especially by time-varying mag-
netic fields, leads to unexpected/unintended phenomena, which could be
vii
viii ◾ Foreword
hazardous to the body under examination. Safety issues of medical nonin-

vasive devices are discussed in this book. There are also many phenomena
in biomagnetics that still need further study to promote their utilization.
In turn, the authors note the possible future trends of the field, which may
encourage young aspiring scholars to work in the field.
Seiji Ogawa, PhD

Professor
Kansei Fukushi University
Aobaku, Sendai, Japan
Preface
Biomagnetics is an interdisciplinary field where magnetics, biology, and

medicine overlap. Recent advances in biomagnetics have enabled us not
only to detect extremely weak magnetic fields from the human brain
but also to control cell orientation and cell growth by extremely high
magnetic fields. Pulsed magnetic fields are used for transcranial mag-
netic stimulation of the human brain, and both high-frequency magnetic
fields and magnetic nanoparticles have promising therapeutic applica-
tions for treatments of cancers and brain diseases such as Parkinson’s and
Alzheimer’s.
On the imaging front, magnetic resonance imaging (MRI) is now a
powerful tool for basic and clinical medicine. New methods of MRI based
on the imaging of impedance of the human body, called impedance MRI,
and the imaging of neuronal current activities in the human brain, called
current MRI, are also being developed.
To understand the most advanced technologies in biomagnetics, basic
sciences such as physics, biology, chemistry, magnetics, electromagnetics,
physiology, and neurophysiology are important to build a foundation and
construct bridges between science and medicine. These basic items are
included in this book.
This book, Biomagnetics: Principles and Applications of Biomagnetic
Stimulation and Imaging, is focused on three important fields: (1) mag-
netic nerve stimulation and transcranial magnetic stimulation (TMS),
(2) biomagnetic measurements and imaging of the human brain by
advanced technologies of magnetoencephalography (MEG) and MRI, and
(3) biomagnetic approaches to potential treatments of cancers, pain, and
other neurological and psychiatric diseases such as Alzheimer’s disease
and depression. Biomagnetic approaches to advanced medicine such as
regenerative medicine and rehabilitation medicine are also included.
ix
x ◾ Preface
The core parts of the book are based on lecture notes that the editors
of the book have used for students in graduate courses at the Department
of Electronic Engineering, Graduate School of Engineering, and the
Department of Biomedical Engineering, Graduate School of Medicine,
University of Tokyo for more than 20 years. Dr. Ueno has been con-
tinuously revising and improving his notes since 1994 when he started
his Laboratory of Biomagnetics and Bioimaging at the Department of
Biomedical Engineering, Faculty of Medicine, at the University of Tokyo,
Tokyo, Japan. Dr. Ueno retired from the University of Tokyo as professor
emeritus. Masaki Sekino is now responsible for a course of biomedical
engineering at the Graduate School of Engineering, University of Tokyo.
In this book, the editors asked five colleagues to join chapter contribu-
tors to further explore and study the field of biomagnetics and bioimaging.
The book is composed of 10 chapters, and a brief outline of each follows.
Chapter 1. Introduction (Shoogo Ueno)
A history of biomagnetic research is described, introducing Gilbert’s

book De Magnete published in 1600. The chapter also includes brief
summaries of studies of biological effects and medical applications
of magnetic and electromagnetic fields, biomagnetic stimulation
and transcranial magnetic stimulation (TMS) of the human brain,
biomagnetic measurements and magnetoencephalography (MEG),
biomagnetic imaging and magnetic resonance imaging (MRI), and
magnetic approaches to cancer therapy and other treatments.
Chapter 2. Principles of Biomagnetic Stimulation (Shoogo Ueno and
Masaki Sekino)
The history and principles of magnetic nerve and muscle stimu-

lation, and TMS of the human brain are introduced. Principles of
electromagnetics, fundamentals for capacitor banks, coil circuits,
and types of coils to stimulate the brain by a transcranial method,
and localization of stimulation areas are introduced. Computational
biomagnetic design for biomagnetic stimulation is also discussed.
Chapter 3. Applications of Biomagnetic Stimulation for Medical

Treatments and for Brain Research (Shoogo Ueno and Masaki Sekino)
Potential medical applications of TMS and repetitive TMS, called

rTMS, are introduced. Reduction of pain sensation by rTMS is
Preface ◾ xi
described first. Studies of treatments of depression by TMS and rTMS

are also reviewed. Potential therapeutic applications of rTMS for neuro
physiological and neuropathological diseases such as Parkinson’s
and Alzheimer’s are also briefly described. For the medical usages
of rTMS, experimental studies using rat hippocampus neurons are
introduced. Both classical and recent studies of cognitive functions
using TMS are discussed.
Chapter 4. Biomagnetic Measurements (Sunao Iwaki)
The history of biomagnetic measurements, called biomagnetism,
is briefly introduced first. Then, the measurements of extremely weak
magnetic fields produced by the brain’s electrical activities, called
magnetoencephalography (MEG), are discussed. The measure-
ment technique for MEG is described, introducing a superconduct-
ing quantum interference device (SQUID) system. Some studies of
functional brain activities and cognitive functions revealed by MEG
measurements are briefly reviewed.
Chapter 5. Principles of Magnetic Resonance Imaging (Masaki Sekino,
Norio Iriguchi, and Shoogo Ueno)
Principles of nuclear magnetic resonance and magnetic reso-
nance imaging are introduced. Hardware and three types of coils
are explained. Pulse sequences related to various imaging techniques
are described. Basic keywords, such as Ramor frequency, T1 and T2
relaxations, and free induction decay to advanced imaging such as
echo planer imaging (EPI), diffusion tensor imaging (DTI), and
functional MRI (fMRI) based on blood oxygenation level dependent
(BOLD) effects are described.
Chapter 6. Prospects of Magnetic Resonance Imaging of Impedance
and Electric Currents (Masaki Sekino, Norio Iriguchi, and Shoogo
Ueno)
Imaging of electrical parameters such as imaging of impedance,
called impedance MRI, and imaging of neuronal electric currents
in the brain, called current MRI, are discussed. First, the history
and the importance of impedance and electric current imaging are
described. Various types of impedance imaging by magnetic reso-
nance techniques are introduced. Then, recent studies on electric
current MRI are introduced and discussed, introducing the images
xii ◾ Preface
obtained by in vitro and in vivo experiments. Recent advances in MR

neuroimaging are also discussed.
Chapter 7. Magnetic Control of Biological Cell Growth (Shoogo Ueno
and Sachiko Yamaguchi-Sekino)
Mechanisms of the biological effects of static and pulsed magnetic
fields are reviewed. The importance of the role of diamagnetic prop-
erties in biological systems is emphasized when they are exposed to
static magnetic fields.
On the basis of the mechanisms of anisotropy of diamagnetic
materials, magnetic control of biological cell orientation and cell
growth are discussed. Biomagnetic approaches to tissue engineering
and regenerative medicine are discussed, introducing new findings
related to bone acceleration by strong static magnetic fields, align-
ment of blood vessel tissues by magnetic fields, and magnetic control
of orientation of nerve axons during sprouting processes obtained by
in vitro and in vivo experiments.
Cancer cell destruction by pulsed magnetic fields is also reviewed,
introducing, for example, physical destruction of leukemia TCC-S
cells combined with magnetizable beads by an antigen–antibody
reaction. Pulsed magnetic stimulation effectively damages only
the cancer cells targeted by an antigen–antibody reaction. Cancer
therapy with repetitive pulsed magnetic stimulation is a promising
method in the near future.
Chapter 8. Effects of Radio Frequency Magnetic Fields on Iron Release
and Uptake from and into Cage Proteins (Oscar Cespedes and
Shoogo Ueno)
An interesting effect of radio frequency magnetic fields on iron
ion release and uptake from and into ferritins, iron cage proteins,
is introduced. The chapter emphasizes that the effects of radio fre-
quency magnetic fields on iron cage proteins may be used in the
medical diagnosis and treatment of brain diseases, for example, for
the imaging and dissolution of the β-amyloid aggregates related to
Alzheimer’s disease.
Preface ◾ xiii
Chapter 9. Safety Aspects of Magnetic and Electromagnetic Fields

(Sachiko Yamaguchi-Sekino, Tsukasa Shigemitsu, and Shoogo Ueno)
Biological effects of magnetic and electromagnetic fields are dis-
cussed. Safety aspects of magnetic fields and electromagnetic fields
used in MRI, TMS, and other medical equipment are important
issues for patients and workers. Safety issues regarding industrial
equipment such as welding machines are also discussed.
Recent guidelines of IEC and EU directives are discussed.
Mechanisms and possible effects of static, low-frequency, and radio
frequency electromagnetic fields are reviewed and discussed.
Chapter 10. New Horizons in Biomagnetics and Bioimaging (Shoogo
Ueno and Masaki Sekino)
Recent advances in biomagnetic imaging and biomagnetic stim-
ulation are discussed. Functional imaging of biological systems by
the combination of low magnetic field MRI and SQUID (supercon-
ducting quantum interference device) systems, molecular bioimag-
ing, and various coil array systems for biomagnetic stimulation are
reviewed and discussed.
This book provides an explanation of physical principles of biomagnetic
stimulation and imaging, as well as applications of these techniques in
neuroscience, clinical medicine, and healthcare. The book aims to edu-
cate graduate students, young scientists, and engineers on how these
techniques are used in hospitals and why they are so promising. A brief
overview of the recent research trend in biomagnetics serves as an infor-
mative guide for researchers and engineers to further study this field.
Acknowledgments
We thank the chapter authors for their intellectual contributions. Further,

we thank the staff of CRC Press/Taylor & Francis, in particular, Francesca
McGowan, editor, physics, for her consistent support and valuable advice
regarding the book proposal and all editing processes; Sarfraz Khan, edi-
torial assistant, for his assistance; Amber Donley, project coordinator, for
her editorial project work; the staff of the editorial project development
team; and John Navas, former senior acquisition editor, who first con-
tacted Shoogo Ueno to discuss a book on biomagnetics in 2012. Without
the enthusiastic and consistent support and help of all the people related
to this project, this book would not have been published.
Finally, but not least, we greatly appreciate Dr. Seiji Ogawa, the inventor
of functional MRI based on the BOLD effect, for kindly agreeing to write
the Foreword for this book. We are honored.
Shoogo Ueno
Masaki Sekino
xv
Editors
Shoogo Ueno, PhD, earned his BS, MS, and PhD (Dr Eng) degrees in
electronic engineering from Kyushu University in 1966, 1968, and 1972,
respectively. Dr. Ueno was an associate professor with the Department
of Electronics, Kyushu University, from 1976 to 1986. From 1979 to 1981,
he spent his sabbatical with the Department of Biomedical Engineering,
Linkoping University, Linkoping, Sweden, as a guest scientist. He served
as a professor in the Department of Electronics, Graduate School of
Engineering, Kyushu University from 1986 to 1994. He subsequently
served as a professor in the Department of Biomedical Engineering,
Graduate School of Medicine, University of Tokyo from 1994 to 2006.
During this time, he also served as a professor in the Department of
Electronic Engineering, Graduate School of Engineering, University of
Tokyo. In 2006 he retired from the University of Tokyo as professor emeri-
tus. Since then, he has been a professor with the Department of Applied
Quantum Physics, Graduate School of Engineering, Kyushu University,
Fukuoka, Japan, and he served as the dean of the faculty of medical tech-
nology, Teikyo University, Fukuoka, Japan from 2009 through 2012.
Dr. Ueno is a fellow of the Institute of Electrical and Electronics Engineers,
IEEE (2001), and a life fellow (2011) and a fellow of the American Institute
for Medical and Biological Engineering, AIMBE (2001). He is a fellow
(2006) and secretary (2012) of the Governing Council of the International
Academy for Medical and Biological Engineering, IAMBE. He was a pres-
ident of the Bioelectromagnetics Society, BEMS (2003–2004), chairman of
the Commission K on Electromagnetics in Biology and Medicine of the
International Union of Radio Science (URSI) (2000–2003). He received
the Doctor Honoris Causa from Linkoping University, Linkoping, Sweden
(1998). He was a 150th Anniversary Jubilee Visiting Professor at Chalmers
University of Technology, Gothenburg, Sweden (2006) and a visiting pro-
fessor at Simon Frasier University, Burnaby, Canada (1994) and Swinburne
xvii
xviii ◾ Editors
University of Technology, Hawthorn, Australia (2008). Dr. Ueno was

awarded the IEEE Magnetics Society Distinguished Lecturer during 2010
and the d’Arsonval Medal from the Bioelectromagnetics Society (2010).
Masaki Sekino, PhD, earned his BS, MS, and PhD (Dr Eng) degrees in
mechanical engineering and electronic engineering from the University
of Tokyo, Tokyo, Japan, in 2000, 2002, and 2005, respectively. Dr. Sekino
was a research associate with the Department of Biomedical Engineering,
Graduate School of Medicine, University of Tokyo, from 2005 to 2006. He
was subsequently a research associate (2006–2010), a lecturer (2010–2011),
and an associate professor (2011–2015) with the Department of Electrical
Engineering and Information Systems, Graduate School of Engineering,
University of Tokyo, Tokyo, Japan.
Dr. Sekino was awarded the International Union of Radio Science
Young Scientist Award (2002), and the International Conference on
Complex Medical Engineering Best Conference Paper Award (2012).
Contributors
Oscar Cespedes Tsukasa Shigemitsu

School of Physics and Astronomy Central Research Institute of
University of Leeds Electric Power Industry
Leeds, United Kingdom Tokyo, Japan
Norio Iriguchi Shoogo Ueno

Center for Multimedia and Department of Biomedical
Information Technology Engineering
Graduate School of Science and Graduate School of Medicine
Technology University of Tokyo
Kumamoto University Tokyo, Japan
Kumamoto, Japan
and
Sunao Iwaki
Automotive Human Factors Department of Applied Quantum
Research Center Physics
National Institute of Advanced Graduate School of Engineering
Industrial Science and Kyushu University
Technology (AIST) Fukuoka, Japan
Tsukuba, Japan
Sachiko Yamaguchi-Sekino
Masaki Sekino
Division of Health Effects Research
Department of Electrical
National Institute of Occupational
Engineering and Information
Safety and Health (JNIOSH)
Systems
Kawasaki, Japan
Graduate School of Engineering
University of Tokyo
Tokyo, Japan
xix
Chapter 1
Introduction
Shoogo Ueno
CONTENTS
1.1 History of Biomagnetics 1
1.1.1 From Gilbert (1600) to d’Arsonval (1896) 1
1.1.2 Modern Biomagnetics in the 1970s and 1980s 4
1.2 Biomagnetic Phenomena and Medical Applications 7
1.2.1 Biomagnetic Phenomena at Different Intensities
and Their Frequencies 7
1.2.2 Biomagnetic Measurements of Magnetic Fields
Produced by Living Systems 8
1.2.3 Biomagnetic Stimulation and Magnetic Treatments 9
1.2.4 Magnetic Resonance Imaging of the Living System 10
1.2.5 Magnetic Control of Cell Manipulation, Cell
Orientation, and Cell Growth 11
1.2.6 Biological Interactions of ELF, Pulsed, and RF
Magnetic Fields 12
1.3 Fundamental Bases for Understanding Biomagnetic Phenomena 12
1.3.1 Electromagnetic Induction in Living Tissues 12
1.3.2 Magnetism of Living Systems and Materials 14
1.4 Summary 16
References 16
1.1 HISTORY OF BIOMAGNETICS
1.1.1 From Gilbert (1600) to d’Arsonval (1896)
Biomagnetics is an interdisciplinary field where magnetics, biology, and
medicine overlap. Biomagnetics is also called biomagnetism, which is
often used in medicine and biology. In this book, however, biomagnetics
1
2 ◾ Biomagnetics
and biomagnetism are used interchangeably. Biomagnetics has a long his-

tory, beginning in 1600 when William Gilbert (1544–1603) published his
groundbreaking book De Magnete.1 In it, he stated that the Earth is itself
a huge magnet (Figure 1.1). Gilbert’s illustration describes that the origin
of Earth’s magnetic fields should exist inside the Earth. He also noted the
relationship between magnetism and human life:
Magnetic force is animate or imitates life; and in many things sur-

passes human life, while this is bound up in the organic body
WILLIAM GILBERT, 1600
William Gilbert, Father of Magnetism

“The Earth is itself a huge magnet”
De Magnete, William Gilbert (1600)
FIGURE 1.1 William Gilbert (1544–1603) and the Earth.

Introduction ◾ 3
The original book was written in Latin, and the above quote is taken
from Busby.2
Gilbert’s hypothesis is very thought-provoking and suggests the study
of interactions between magnetism and human life. It was difficult, how-
ever, to verify Gilbert’s profound hypothesis in 1600 because science and
technology were not well developed at that time. Gilbert was a physicist as
well as a physician for Queen Elizabeth I (1533–1603) in England.
In France in 1896, Jacques-Arsene d’Arsonval (1851–1940) reported a
phenomenon called magnetophosphene, a visual sensation induced in
human subjects when exposed to alternating magnetic fields.3 The magneto
phosphene reported by d’Arsonval was among the first reliable phenomena
related to the interactions of human life with magnetism (Figure 1.2).
The magnetophosphenes were repeated by other groups; for example,
S. P. Thompson in the United Kingdom observed that peripheral areas
in the eye see light more clearly than in the center of the eye.4 C. E.
Magnusson and H. C. Stevens in the United States observed frequency
characteristics in light sensation, changing the frequency of alternating
magnetic fields, and determined that the light is sensitive around 20 Hz.5
P. Lovsund, P. A. Oberg, and S. E. G. Nilsson in Sweden quantitatively
FIGURE 1.2 Jacques-Arsene d’Arsonval (1851–1940). (From Wikipedia, the free

encyclopedia, Jacques-Arsene d’Arsonval.)
4 ◾ Biomagnetics
studied the magnetophosphenes in a dark room and observed that the

threshold for light sensation is 10 mT at 20 Hz.6 Magnetophosphene is a
good model for evaluating biological effects of extremely low frequency
(ELF) magnetic fields, and this phenomenon is often used for safety guide-
lines in international organizations such as the International Commission
on Non-Ionizing Radiation Protection (ICNIRP) and the International
Electrotechnical Commission (IEC).
1.1.2 Modern Biomagnetics in the 1970s and 1980s

In 1970, a special issue on biomagnetics was published in IEEE Transactions
on Magnetics.7 This issue is comprised of selected papers discussed at
an international symposium on the application of magnetism in bio
engineering that was held in Rehovot, Israel, and organized by E. H. Frei
at Weizmann Institute of Science in 1969. It is amazing that most of the
important topics in biomagnetics are discussed in this special issue. These
topics include measurements of magnetic fields produced from the human
heart and brain, theoretical study on magnetocardiography (MCG) and
magnetoencephalography (MEG), the possibility of magnetic stimulation
of peripheral nerves and heart muscles, contrast medium of barium meal
mixed with magnetic materials for enhancing X-ray images, internal mag-
netic capsules driven and guided by external pulsed magnetic fields, and
biological effects of magnetic fields. The fundamental framework of bio-
magnetics for medical applications was introduced in this issue.
In the 1970s, modern biomagnetics accelerated along with develop-
ments of new technologies in quantum physics, superconducting physics,
and electronic engineering; for example, superconducting quantum inter-
ference device (SQUID) systems and magnetic resonance imaging (MRI)
enabled us to accelerate brain research and medical applications.
During the period when SQUID technology was not yet available,
G. Baule and R. McFee8 measured MCG signals by a flux gate magneto
meter with a pair of ferrite cores wound by two millions turns of coils
in 1963. Subsequently, D. Cohen9 measured spontaneous MCG activity
by a SQUID system in magnetically shielded room at the Massachusetts
Institute of Technology in 1970, and his group10 successfully measured the
so-called ST segment shift in MCG direct current signals related to the
injury current produced by coronary artery occlusion. D. Cohen11 also
measured a spontaneous MEG activity related to alpha rhythmic activity
without averaging the signals in 1972.
Introduction ◾ 5
After the success of Cohen’s MEG study, magnetic fields evoked by

visual, somatic, and auditory stimuli were measured by different groups.
For example, D. Brenner and his coworkers12 measured visually evoked
magnetic fields in the human brain in 1975, and they also measured
somatically evoked magnetic fields13 in 1978. M. Reite and his cowork-
ers14 measured auditory evoked magnetic fields in 1978, and G. L. Romani
and his coworkers15 observed the tonotopic organization of the human
auditory cortex by MEG study in 1982. These pioneering studies opened
a new horizon in functional brain research called neuromagnetism in the
1980s.16
Magnetic stimulation of nerves and muscles was studied in the 1970s
to identify ways to avoid undesirable problems in electrical stimulation
through electrodes such as decaying of stimulatory effects due to the
electrochemical reactions at the interface between electrodes and living
tissues, by D. D. Irvin and his group,17 J. A. Maass and M. M. Asa18 in 1970,
and by P. A. Oberg19 in 1973.
In magnetic nerve stimulation, Maass and Asa18 proposed a trans-
former type of stimulation in which a nerve bundle was threaded through
a magnetic core as the secondary winding. These authors showed that the
flux change in the core could be used to excite nerves. Oberg19 proposed
an air gap type of stimulation in which a bundle of nerves was exposed
to alternating magnetic fields. These studies demonstrated experimentally
that induced eddy currents in the membrane tissues could be expected
to stimulate nerves, though the underlying nerve-excitation process from
magnetic stimulation was not understood. S. Ueno and his coworkers20
pointed out that a capacitive stimulatory effect could contribute to mag-
netic nerve stimulation in 1978.
To shed light on the basic excitation mechanisms, studies of a single
nerve axon were carried out by S. Ueno and his coworkers, focusing on
the effects of time-varying magnetic fields on the action potential in lob-
ster giant axon.21,22 The results obtained from the lobster experiments sug-
gested that nerve excitation by magnetic field influence is mediated via
the induction of eddy currents in the tissue surrounding the nerve. The
macroscopic eddy currents that flow along the nerve and in the tissues
surrounding the nerve are important, as they contribute to the depolariza-
tion of the membrane.21,22 After the study of single nerve axons, a new type
of magnetic nerve stimulation without interlinkage between the nerve and
magnetic flux was proposed by S. Ueno and his coworkers23 in 1984.
6 ◾ Biomagnetics
Basic studies of magnetic nerve stimulation have opened a new area of

research for transcranial magnetic stimulation (TMS) of human subjects
in the middle of the 1980s. Stimulation of human brain by TMS with a
round coil was reported by A. T. Barker and his coworkers24 in 1985. The
success of the human brain stimulation by TMS made a strong impact on
the scientific community. By TMS with a round coil, however, it was diffi-
cult to stimulate a localized area of the brain. A method of localized brain
stimulation by TMS with a figure-eight coil was proposed by S. Ueno
and his coworkers25 in 1988, and stimulation of the human motor cortex
within a 5-mm resolution was successfully realized in 1989.26–28 The func-
tional map of the human motor cortex was obtained in a 5-mm resolution
by this method in 1990.29 TMS with a figure-eight coil is now used world-
wide in cognitive brain research and clinical medicine.30
It is also remarkable that a magnetotactic bacteria was discovered by
R. P. Blakemore in 1975.31 Blakemore observed that the magnetotactic
bacteria swim along Earth’s magnetic field. Blakemore and his colleagues
identified a chain of crystals of magnetite (Fe3O4) that exist inside the body
of magnetotactic bacteria.32,33 Magnetotactic bacteria can sense magnetic
torque acting on the angle between the direction of Earth’s magnetic field
and a long chain of magnetites inside the body so as to minimize the mag-
netic torque during swimming. The discovery of magnetotactic bacteria
triggered the studies of biomineralization and biomagnetic sensing mech-
anisms in fish, birds, honeybees, and other animals.34–36 The interactions
of biological systems with a weak magnetic field or the Earth’s magnetic
field with a 30–50 μT order are interesting because all living species on
Earth are exposed to the its magnetic fields.
In contrast, magnetic orientation of fibrin was observed when the
polymerization process from fibrin monomer to fibrin polymer was
exposed to a very strong magnetic field of 11 T by J. Torbet in 1981.37
Through this study, the importance of diamagnetism was recognized in
biological effects of strong magnetic fields.
Effects of magnetic fields on chemical reactions were observed in the
1970s. Magnetic field effects on photochemical reactions were observed
in different groups38–40 in 1976. Photochemical reactions produced by a
radical-pair intermediate in a solution can be expected to show magnetic
field effects that arise from an electron Zeeman interaction, electron-
nuclear hyperfine interaction, or hyperfine interaction mechanism includ-
ing an electron-exchange interaction in a radical-pair intermediate. That
is, a common mechanism of magnetic field effects on chemical processes is
Introduction ◾ 7
that a chemical yield of the cage or escape product shows a magnetic field
dependence when a singlet–triplet intersystem crossing is subject to mag-
netic perturbations.41,42 This area has been well developed as dynamic spin
chemistry in the 1980s and 1990s.41,42 Possible biomagnetic and chemi-
cal effects can be expected when biological systems are exposed to both
magnetic fields and other energy such as light and radiation.43 However,
biological effects of magnetic fields based on dynamic spin chemistry with
a radical-pair model have not yet been clarified.44
Basic studies on biomagnetics and the related fields in the 1970s and
1980s have been explored for further developments in the 1990s and 2000s.
1.2 BIOMAGNETIC PHENOMENA
AND MEDICAL APPLICATIONS
1.2.1 Biomagnetic Phenomena at Different
Intensities and Their Frequencies
Various biomagnetic phenomena for different intensities and their fre-
quencies are shown in Figure 1.3.45,46
Magnetic stimulation of the brain, (i.e., transcranial magnetic stimula-
tion [TMS] of the human brain), requires strong pulsed magnetic fields
106
103 Magnetic stimulation

Parting of water of the heart (τ = 1 msec)
Magnetic orientation Magnetic stimulation
1 MRI magnet of the brain (τ = 0.1 msec)
Magnetic flux density (T)
Blood flow change via

Magnetophosphene magnetic stimulation
10–3 of sensory nerves
Ca2+ release
Earth ELF
consumer electronics
10–6 Magnetic storm
Urban magnetic fields Hyperthermia
10–9 Lung (MPG)
Heart (MCG) Mobile telephone

10–12 Brain (MEG)
Evoked fields
SQUID
sensitivity Brain stem
10–15
DC 1 103 106 109
Frequency of magnetic field (Hz)
FIGURE 1.3 Various biomagnetic phenomena observed or used at different fre-

quencies (Hz) and magnetic field intensities (T).
8 ◾ Biomagnetics
of 1–2 T for a short period of time (0.1–0.2 msec) to get sufficient induced
electric fields for the stimulation of neurons in the brain. Magnetic stimu-
lation of the heart requires more strong pulsed magnetic fields (1–5 T) with
a 1–2 msec pulse width to excite the cardiac muscles. In Figure 1.3, the
frequencies of the pulsed magnetic fields are converted from pulse width.
Rapid changes in blood flow in the hands of human subjects are
observed when the hand is exposed to alternating magnetic fields of 32 mT
at 3.8 kHz.47 The explanation for the blood flow changes following mag-
netic field exposure is that nerve system information from the skin sensory
receptors is sent via the spinal cord to the central nervous system, which
modulates the efferent nerve activity and affects the blood flow of the skin.
The magnetophosphene shows a V-shaped curve for light sensation
with a minimum threshold of 10 mT at 20 Hz.6
Effects of magnetic fields on biological systems are observed mostly in the
range of magnetic fields higher than the Earth’s magnetic field of 30–50 μT.
Health effects of extremely low frequency (ELF) electromagnetic fields
are discussed, introducing possible mechanisms including a model of
calcium release from living cells exposed to ELF fields. Amplitudes and
frequencies of ELF electromagnetic fields related to consumer electronics
and power lines are in the oval area marked in Figure 1.1.
Magnetic fields used in clinical MRI systems today are 0.3 T for per-
manent magnets and 1.5–3.0 T for superconducting magnet systems. For
research purposes, 4–7 T MRI systems are used. Magnetic orientation
of biological materials is observed in 4–8 T magnetic fields. “Parting of
water” or the “Moses effect” is observed in 8-T magnetic fields.
In contrast, biomagnetic fields or magnetic fields produced from the
living systems are extremely weak, 10–15 to 10–11 T or 1 fT to 10 pT order of
magnetic fields, buried with urban noise. These biomagnetic fields are usu-
ally measured by superconducting quantum interference device (SQUID)
systems in a magnetically shielded room.
1.2.2 Biomagnetic Measurements of Magnetic

Fields Produced by Living Systems
Magnetoencephalography (MEG) is a most promising tool for study-
ing functional organization of the brain noninvasively with a high spatial
(millimeter) and high temporal (millisecond) resolution. The magnetic sig-
nals are 10–14 to 10–12 T or 10 f T to 1 pT order of magnetic fields for evoked and
spontaneous brain electrical activities. The magnetic fields produced from
the human brain stem evoked by auditory stimuli, called auditory evoked
Introduction ◾ 9
brain stem magnetic fields, are extremely weak, 5 × 10–15 T or 5 f T magnetic
fields, and these magnetic fields are detected by SQUID systems by averaging
several thousand times above signal-to-noise ratio. Spontaneous brain mag-
netic activities such as alpha MEG activities of 10–12 T or pT order of magnetic
fields are detected by SQUID systems without averaging the signals.
Magnetocardiography (MCG) is a noninvasive modality for detecting
electrical activities of the heart, and the biomagnetic signals are 10–12 to
10–10 T or 1–100 pT order of magnetic fields.
Magnetopneumography (MPG) is a technique to measure magnetic
fields from the lung.48,49 The MPG measures remnant magnetic fields
produced by magnetic contaminants in the lung or deposition of inhaled
magnetic nanoparticle dusts in the lung. The lung is magnetized by exter-
nal magnetic fields and a relaxation process from a peak of the magnetized
vector of MPG signals to a low level of signals due to randomization of
the magnetized vector. The relaxation process is reflected by the ability of
phagocytosis of alveolar macrophages.
Origins or sources of magnetic fields of MEG and MCG are electrical
currents generated by electrical activities of neurons and muscles, whereas
the magnetic fields of MPG come from magnetic dust in and around alve-
olar macrophages in the lungs.
In biomagnetic measurements, spatiotemporal distributions of magnetic
fields over the surface of the body are obtained by multichannel SQUID
systems, and the sources of biomagnetic fields are estimated by solving
inverse problems. From a mathematical point of view, there are no unique
solutions in inverse problems, and localizations of sources are estimated by
adding some assumptions and boundary or constraint conditions.
1.2.3 Biomagnetic Stimulation and Magnetic Treatments

Magnetic stimulation of the brain requires around 1–2 T of pulsed mag-
netic fields with 0.1–0.2 msec pulse width. Magnetic stimulation of the
heart requires around 2–4 T of pulsed magnetic fields with 1–2 msec dura-
tion.50,51 The pulse width of stimulation is determined by the chronaxie in
the strength-duration curve, which is roughly equal to the time constant
of the excitation of electrical characteristics of membrane tissues. The
optimal pulse duration for membrane excitation is around 0.1–0.2 msec
for nerve tissues and is around 1–2 msec for cardiac muscles. The rapid
changes in these pulsed magnetic fields induce electric fields in the living
body, and the nervous and muscular systems are stimulated by the mag-
netically induced electric fields.
10 ◾ Biomagnetics
For therapeutic applications of magnetic brain stimulation, rapid-rate

transcranial magnetic stimulation or repetitive TMS (rTMS) with a series
of repetitive pulses at several or several tens of hertz is used, for example,
as an alternative approach to induce seizure for the treatment of depres-
sion in place of electroconvulsive therapy (ECT).52,53 This approach could
allow selective stimulation of brain sites that are involved in depression,
thus reducing side effects (e.g., memory deficits) due to electrical disrup-
tion of function in unrelated sites.52,53 The technique of rTMS has promis-
ing potential applications not only for the treatment of depression but also
for Parkinson’s disease, dementia, and other brain diseases, as well as for
reduction of intractable pain and rehabilitation or recovery process of an
injured brain after a stroke.
From the viewpoint of a therapeutic application of rTMS for neurologi-
cal disorders, a number of animal studies testing the basic mechanisms
of rTMS-induced alternations of neurotrophic factors, gene expression,
and changes in plasticity have been conducted. The experimental results
obtained by M. Fujiki and O. Stewart54 and by other groups55–58 suggest
that there is strong evidence that the expression of certain genes such as
the immediate early gene, astrocyte-specific glial fibrillary acidic protein
(GFAP) messenger ribonucleic acid (mRNA)54 and brain-derived neuro-
tropic factor (BDNF)55 are altered in response to rTMS. This indicates that
the measurable effects of rTMS reach the cellular and molecular levels.54,58
The effects of rTMS on neuronal electric activities in the rat hippocam-
pus were studied, focusing on long-term potentiation (LTP) by M. Ogiue-
Ikeda and her colleagues.56,57
Risk and safety aspects of rTMS with pulse trains of high frequencies
need to be investigated.59,60
1.2.4 Magnetic Resonance Imaging of the Living System

Magnetic resonance imaging (MRI) is an indispensable tool in medicine.
The Nobel Prize in Physiology and Medicine in 2003 was awarded to Paul
Christian Lauterbur (1929–2007) of the United States and Peter Mansfield
(1933–) of the United Kingdom, for the discovery of principles of nuclear
magnetic resonance imaging. P. C. Lauterbur proposed a principle of imag-
ing by induced local interactions in magnetic resonant frequencies with
linear gradient magnetic fields in addition to the main static magnetic field
in 1973.61 P. Mansfield developed pulse sequences for imaging such as echo
planar imaging in 1977.62 MRI is a noninvasive imaging tool, and because
of its variety of potential modality, MRI has evolved and is still evolving.
Introduction ◾ 11
Seiji Ogawa (1934–)63 of Japan proposed a functional MRI (fMRI) based

on blood oxygenation level dependent (BOLD) effects to visualize func-
tional organizations in the brain in 1990. This BOLD-fMRI is a powerful
tool for functional brain research and clinical medicine because it requires
no injection of contract agents into human subjects.
A method of diffusion weighted imaging (DWI) was studied in the 1990s
by different groups including D. Le Bihan and coworkers,64 and through
a theoretical study of estimation of the effective self-diffusion tensor from
NMR spin echo by P. J. Basser and his coworkers,65 the DWI has developed
a new imaging tool called the diffusion tensor imaging (DTI) to visualize
structural networks of neural fibers in the brain in the 2000s.
In 1998, S. Ueno and N. Iriguchi66 proposed a method to visualize elec-
trical impedance distributions in the living body called impedance MRI.
H. Kamei and his coworkers67 proposed a method to image neuronal cur-
rents in the brain called current MRI in 1999. The imaging of electrical
currents and impedance distributions in the head based on new principles
of MRI will be very important for studying brain functions of humans.68
The signal-to-noise ratio is essentially low in current MRI, and the issues
of fundamental factors such as a sensitivity limit, RF inhomogeneity, the
dielectric resonance effect, and so on need to be investigated. M. Sekino
and his coworkers estimated a theoretical limit of sensitivity of 10–8 to
10–9 T for current MRI and obtained a transient decrease in signal inten-
sity in the rat brain using a 4.7-T MRI system.69
Recent advances in superconducting technology have enabled us to use
high-field MRI systems. The 1.5-T and 3-T MRI systems are used in clini-
cal diagnoses, and 4- and 7-T MRI systems are used for human research.
Ultrahigh 11-T MRI systems for human subjects are also being devel-
oped. Safety aspects of potential health effects of these ultrahigh field MRI
systems need to be clarified.
1.2.5 Magnetic Control of Cell Manipulation,

Cell Orientation, and Cell Growth
A phenomenon, called parting of water or Moses effect, where water is
divided into two parts by magnetic fields of up to 8 T, was observed by
S. Ueno and M. Iwasaka70,71 in 1994. When a horizontally positioned half-
filled water chamber is exposed to 8-T magnetic field with a field gradient
of 50 T/m, water is parted in two making two water walls, and the bottom
of the water chamber appears in between water walls.70,71 This effect will
be useful in manipulating biological cells magnetically.
12 ◾ Biomagnetics
Magnetic alignment or magnetic orientation of biological materials is

observed when the materials are exposed to strong static magnetic fields of
a 5–10 T order.37 Fibrin,37 collagen, and other adherent cells such as osteo-
blasts, vascular endothelial cells, smooth muscle cells, and Schwann cells
orient either parallel or perpendicular to magnetic fields, depending on
the anisotropy of magnetic susceptibility of biological materials. Using this
effect, for example, bone growth acceleration is observed when samples
of mixture of bone morphogenetic protein 2 (BMP-2) and collagen are
exposed to 8-T magnetic fields for 60 hours in the beginning period in bone
formation.72 The magnetic orientation of biological materials has promis-
ing potential applications for tissue engineering and regenerative medicine
where the cells or tissues should be aligned in preferred directions.73,74
1.2.6 Biological Interactions of ELF, Pulsed, and RF Magnetic Fields

There are many studies on the interactions of extremely low frequency
(ELF) magnetic and electromagnetic fields with biological systems. The
low-energy level ELF magnetic and electromagnetic fields are produced by
consumer electronics and power lines.
Hyperthermia is a medical method for cancer therapy where cancer
cells are heated by electromagnetic induction. Magnetic nanoparticles are
often used for hyperthermia to increase heat effectively around the tar-
geted lesions. New biomagnetic approaches to cancer therapy by pulsed
magnetic fields, without cell heating, are also studied.75,76
Studies of possible health effects of radio frequency (RF) electromag-
netic fields have become important because of the rapid increase in mobile
telephones and the rapid increase in high-field MRIs. Different approaches
to the relationship between human health and mobile telephony are
needed, from biological cellular level study (i.e., in vitro study and animal
study, in vivo study and human study, or epidemiological study). In paral-
lel to these animal and human studies, physical and numerical studies or
dosimetry studies are essential to determine the level and distributions of
energy absorbed in the living body exposed to the RF fields.
1.3 FUNDAMENTAL BASES FOR UNDERSTANDING

BIOMAGNETIC PHENOMENA
1.3.1 Electromagnetic Induction in Living Tissues
Biological effects of magnetic and electromagnetic fields are classified into
three categories:43 (1) effects of time-varying magnetic fields, (2) effects of
Introduction ◾ 13
static magnetic fields, and (3) effects of multiplications of both static mag-
netic fields and other energy such as light and radiation.
When we discuss the effects of time-varying magnetic fields, the rela-
tionship between magnetism and electricity is important. Hans C. Oersted
(1777–1851) discovered a phenomenon that electric currents produce mag-
netic fields in 1820 in Denmark. Michael Faraday (1791–1867) discovered
a phenomenon called electromagnetic induction in 1831 in England.
Electric currents are induced in the secondary coil when the currents in
the primary coil change rapidly. In other words, electric fields are induced
by time-varying magnetic fields. James C. Maxwell (1831–1879) derived
the fundamental four equations, called Maxwell’s equations, to describe
the relationship between magnetism and electricity mathematically in
1864. That is, electromagnetic phenomena consist of electric and magnetic
fields that change with time and space. Maxwell’s equations are laws that
define the relationship between temporally and spatially averaged electric
and magnetic fields.
Because the living body is composed of conductive tissues and mate-
rials, electric fields are induced in it when it is exposed to time-varying
magnetic fields. In the case of low-frequency magnetic fields lower than
several 100 kHz or pulsed magnetic fields, stimulatory effects of excitable
membranes such as nervous system and muscular system are dominant.
Transcranial magnetic brain stimulation is realized by this principle.
In contrast, in the case of high-frequency magnetic and electromagnetic
fields higher than several 100 kHz and in the range of RF fields, thermal
effects of living systems are dominant. Health effects of RF electromag-
netic fields used in mobile telephony and MRI systems are discussed
mainly on the basis of the thermal effects. The specific absorption rate
(SAR) (W/kg) is used for the evaluation of biological effects of RF fields.
When an electric field E (V/m) is induced in a tissue exposed to RF elec-
tromagnetic fields, SAR (W/kg) in the tissue is determined by
SAR = σE2/ρm
where σ is electrical conductivity (S/m) and ρm is the mass density (kg/m3)

of tissue. The induced electric field E (V/m) is dependent on external RF
fields and electromagnetic properties of tissues represented by permittiv-
ity (dielectric constant and electrical conductivity).
Mechanisms of biological effects of magnetic and electromagnetic fields
are summarized in Table 1.1.46
14 ◾ Biomagnetics
TABLE 1.1 Mechanisms of Biological Effects of Electromagnetic Fields

Type of Field Formulae Examples
1. Time-varying magnetic field
∂B
a. Low frequencies J = −σ Nerve stimulation
Eddy currents ∂t
b. High frequencies E2 Thermal effects
Heat SAR = σ
ρ
2. Static magnetic field
1 2
a. Homogeneous magnetic field T=− B ∆χsin2θ Magnetic orientation of
Magnetic torque 2µ 0 biological cells
b. Inhomogeneous magnetic Parting of water by
χ
field F= (gradB)B magnetic fields
Magnetic force µ0 (Moses effect)
3. Multiplication of magnetic fields
and other energy
a. Photochemical reactions with Yield effect of cage product
radical pairs and escape product
b. Singlet–triplet intersystem
crossing
1.3.2 Magnetism of Living Systems and Materials

When we discuss biological effects of static magnetic fields, magnetic
properties of living systems and materials are important to understand
the biomagnetic effects. From the magnetism viewpoint, all materials are
classified into three categories: diamagnetic, paramagnetic, and ferro-
magnetic materials. The origins of magnetic properties of these materials
are explained by behaviors of magnetic moments and spins of nuclei and
electrons where interactions between neighboring spins are characterized
by an exchange interaction in quantum physics. In this section, however,
we discuss the magnetic properties by phenomenological classification as
follows.
Diamagnetic materials are magnetized in the opposite direction of
applied magnetic fields when the materials are exposed to the external
magnetic fields. The magnetization is extremely weak, and the magneti-
zation disappears reversibly when the external magnetic fields disappear.
Diamagnetic materials are almost nonmagnetic materials and “transpar-
ent” for magnetic fields in usual daily life. Most of the human body is
composed of diamagnetic materials. Water is a typical example of dia-
magnetism. Oxyhemoglobin is also a diamagnetic material. Diamagnetic
Introduction ◾ 15
materials are only slightly subject to the opposed direction of magnetic

force. However, if magnetic force is very strong with a strong magnetic
field of Tesla order and a high gradient magnetic field of several 10 T/m
order, we can observe a visible phenomenon such as parting of water or
the Moses effect.70,71 The magnetic force acting on materials is propor-
tional to the product value of the magnetic susceptibility of the materials
and magnetic field and the spatial gradient of magnetic field. Although
the magnetic susceptibility of water is very small, magnetic force acting on
water is strong enough to push back water when the product values of the
magnetic field and the spatial gradient of magnetic field are very strong.
One of the important characteristics of diamagnetic materials is anisot-
ropy of magnetic susceptibility of materials. When diamagnetic materi-
als are exposed to external magnetic fields, the materials act to rotate to
a preferred direction so as to minimize magnetic torque induced by the
anisotropy of magnetic susceptibility of the materials. Magnetic orienta-
tion of biological materials is observed by this principle.
Paramagnetic materials are magnetized in the same direction of applied
magnetic fields when the materials are exposed to the external magnetic
fields. The magnetization is not strong, and the magnetization disappears
reversibly when the external magnetic fields disappear. Paramagnetic
materials are attracted to magnetic force, but the attractive force is not
strong compared with the force in the case of ferromagnetic materials.
Oxygen is a paramagnetic molecule. Deoxyhemoglobin is a paramagnetic
material. Free radicals that are produced transiently and dynamically on
the processes of chemical reactions are paramagnetic species.
Using the paramagnetic property of oxygen, extinguishing a candle
flame by magnetic fields was demonstrated by S. Ueno in 1989.77 Candle
flames are extinguished by a closed curtain of paramagnetic oxygen gas
called the “magnetic curtain.” When candle flames are captured by the
magnetic curtain, they produce magnetic fields of 1.0–1.5 T with a high
gradient magnetic field of 100–300 T/m.
The BOLD-fMRI by S. Ogawa63 visualizes the changes in MRI signals
based on the changes in magnetic property of paramagnetic deoxyhemo-
globin and diamagnetic oxyhemoglobin in blood in capillaries and veins
in the brain.
Ferromagnetic materials are magnetized strongly in the same direction
of applied magnetic fields when the materials are exposed to the exter-
nal magnetic fields. The magnetization is strong, and magnetization does
not disappear irreversibly when the external magnetic fields disappear.
16 ◾ Biomagnetics
Ferromagnetic materials are attracted by magnetic force strongly. Magnets

and iron nails are ferromagnetic materials. Iron, nickel, and cobalt are
typical ferromagnetic metallic elements.
Ferrimagnetic materials are in the category of ferromagnetic materials
and are strongly attracted by magnetic force. Magnetites (Fe3O4), ferrites,
and many other iron oxides are ferrimagnetic materials.
When the magnetic materials are nanostructured below the single
domain size, the materials behave as superparamagnetic particles. The
superparamagnetic particles have a large magnetic susceptibility well
above that of conventional paramagnetic materials. The superparamag-
netic materials act as important roles in magnetic nanobioscience and bio-
magnetics. The effects of RF magnetic fields on iron ion release and uptake
from and into iron cage proteins are investigated, focusing on the role of
superparamagnetic ferrihydrate nanoparticles inside ferritins.78
1.4 SUMMARY
In this biomagnetics overview, we study biomagnetics, an interdisciplin-
ary field. We focus on basic principles and medical applications of bio-
magnetic stimulation and imaging in the following chapters. We hope the
readers enjoy the essence of recent advances in biomagnetics in this book.
We recommend that readers refer to other bibliographies related to bio-
magnetics, bioelectromagnetics, brain science, neuroimaging, and regen-
erative medicine, as well as basic sciences to expand their exposure to and
knowledge of the world of biomagnetics. We provide some other review
articles, book chapters, and books.79–89
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22 ◾ Biomagnetics
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Marcel Dekker, New York.
Chapter 2
Principles of
Biomagnetic Stimulation
CONTENTS
2.1 Introduction 24
2.1.1 Basic Principles 24
2.1.2 Advantages of Magnetic Stimulation 26
2.2 Magnetic Stimulator 28
2.2.1 Stimulator Coils 28
2.2.1.1 Circular Coil 28
2.2.1.2 Figure-Eight Coil 30
2.2.1.3 Coil Array 31
2.2.1.4 Emerging Coil Designs 32
2.2.1.5 Cooling Systems 34
2.2.1.6 Measurement of Magnetic Field and Coil Current 35
2.2.2 Driving Circuit 36
2.2.2.1 Hardware 36
2.2.2.2 Analysis of Driving Circuit 38
2.2.3 Coil Navigation System 40
2.2.4 Multimodal Imaging Using Magnetic Stimulation 41
2.3 Mechanisms of Magnetic Stimulation 43
2.3.1 Fundamentals of Electrophysiology 43
2.3.1.1 Resting Membrane Potential 43
2.3.1.2 Action Potential 44
2.3.2 Transcranial Magnetic Stimulation 46
2.3.2.1 Resting Motor Threshold 46
2.3.2.2 Stimulation Site 46
2.3.3 Peripheral Nerve Stimulation 47
23
24 ◾ Biomagnetics
2.3.3.1 Activating Function 47

2.3.3.2 Stimulation Site 48
2.4 Numerical Analyses of Magnetic Field and Eddy Current 48
2.4.1 Numerical Methods 48
2.4.1.1 Finite Element Method 48
2.4.1.2 Scalar Potential Finite Difference Method 49
2.4.2 Numerical Model of the Brain 50
2.4.3 Analyses of Transcranial Magnetic Stimulation 51
2.4.3.1 Comparison of Electroconvulsive Therapy
and Magnetic Stimulation 51
2.4.3.2 Magnetic Stimulation to the Cerebellum 53
2.4.4 Use of Numerical Methods in Coil Design 53
2.5 Summary and Future Prospects 55
References 56
2.1 INTRODUCTION
2.1.1 Basic Principles
Electromagnetic induction, which provides the fundamental principle
of biomagnetic stimulation, was discovered by Michael Faraday in 1831.
When a pair of coils is situated close to one another and the current
flowing in one coil varies, an electromotive force arises in the other coil.
The current flowing in the primary coil generates a magnetic field, and a
rapid switching of the current causes a steep variation in the magnetic flux
linkage. The magnitude of electromotive force in the circuit is proportional
to the time rate of change in this flux linkage. The electromotive force is
directed so that the magnetic field arising from the secondary coil current
inhibits the variation of flux linkage. Because biological tissues and fluids
are electrically conductive, the electromagnetic induction occurs also in
the body to induce electric fields and resulting currents. When a rapidly
varying current is applied to a coil located on the surface of the body,
electric fields are induced in nearby tissues owing to the varying magnetic
fields. The magnetic stimulation is understood as an electric stimulation
mediated by magnetic fields because the resulting biological effects
originate from the induced electric fields. Considering that the magnetic
permeabilities of biological tissues are nearly equal to that of free space,
electric properties of biological tissues play important roles in biological
effects of alternating and pulsed magnetic fields. At low frequencies below
Principles of Biomagnetic Stimulation ◾ 25
tens of kilohertz, depolarization of excitable membrane is the dominant

mechanism of biological effects, and thermal effects are negligible in
many cases.
In 1896, d’Arsonval reported magnetophosphene in which an exposure
of the head to an alternating magnetic field evokes a visual perception.1
This phenomenon has been investigated in many studies afterward and
treated as a valuable experimental model for assessing the effects of mag-
netic fields on the human body. The magnetophosphene exhibits a signifi-
cant dependence on the frequency of magnetic field, and the most clearly
perceptible magnetophosphene occurs in the vicinity of 20 Hz.2 At this
frequency, magnetic fields above 10 mT applied to the eyes evoke magneto
phosphene. Several mechanisms have been assumed for the magnetophos-
phene. It is generally believed that induced electric fields stimulate the
retinas and optic nerves.
Subsequently, biomagnetic stimulation of nerves and muscles by
means of applying pulsed magnetic fields has attracted attention. Several
pioneering studies on the methodology of magnetic stimulation have
been carried out since 1965.3–5 These studies did not reach clinical appli-
cations because of technical problems like difficulty measuring evoked
electromyograms. Barker et al.6 succeeded in magnetically stimulat-
ing the brain in 1985 by applying magnetic fields transcranially to the
brain. They used a circular coil producing pulsed magnetic fields with
the intensity of around 1 T. Ueno et al.7,8 proposed a method for locally
stimulating the brain using a figure-eight coil and succeeded in stimu-
lating the human motor cortex with a 5-mm resolution. These achieve-
ments led to the subsequent progress of methodological and clinical
studies of transcranial magnetic stimulation (TMS).9–12 Inducing electric
fields specifically in the target region of the brain enables us to activate
neurons in this region. Figure 2.1a shows a TMS of the primary motor
cortex. Stimulation causes a contraction of the corresponding muscles.
Figure 2.1b and c show spatial patterns of electric fields induced in the
brain by stimulations using a circular coil and a figure-eight coil. The
TMS is now widely used for diagnostics, therapies, and basic studies of
brain function.
Magnetic field is generated as a pulse with durations usually shorter
than 1 msec. Figure 2.2a and b show the waveforms of monophasic and
biphasic pulses. Intensity of the magnetic field generated from the coil is
proportional to the coil current.
26 ◾ Biomagnetics
Coil current
(b) Electric field
Coil current
(a) (c) Electric field
FIGURE 2.1 (a) Transcranial magnetic stimulation. (b) Electric fields induced by
a circular coil. (c) Electric fields induced by a figure-eight coil.
In addition to the brain, the spinal root, diaphragm, and heart can also
be magnetically stimulated. Applications of magnetic stimulations to arti-
ficial respiration and defibrillation have been explored.
2.1.2 Advantages of Magnetic Stimulation

Because limited techniques are available for directly stimulating the
human brain, TMS is expected to be developed by continuously taking
advantage of its unique feature. The brain is surrounded by the skull,
which has a high electric resistivity. When electric stimulations are
delivered through electrodes attached to the surface of the scalp, electric
fields hardly penetrate into the brain. Though the brain stimulations
through the electrode are possible using a quite strong electric field,
the resulting intense pain has put restrictions on clinical applications
of such stimulations. Biological tissues such as the brain, skull, and
scalp are nonmagnetic. Magnetic fields penetrate into the brain without
any hindrance by intermediate tissues and efficiently induce electric
fields in the brain. Unlike the electric stimulation, TMS does not give
strong stimulations to pain receptors in the scalp. Owing to this major
advantage of reduced pain, TMS obtained a wide field of applications.
By comparing these two methods for delivering electric stimulations
to the body, applying electric field through the electrodes, and inducing
Coil current (A)

4000
3000
2000
1000
0
−500 0 500 1000 1500
Time (μsec)
(a) −1000
Coil current (A)
4000
2000
0
−200 0 200 400 600
Time (μsec)
−2000
(b) −4000
FIGURE 2.2 (a) Monophasic and (b) biphasic waveforms of current flowing in
the coil. Magnetic field intensity is proportional to the current.
the electric field by pulsed magnetic field, one can find a difference in the
resulting electric field distributions. In the case of using electrodes, the
streamline of electric field flows out from the positive electrode, diffuses
in the body, and flows into the negative electrode. In the case of TMS, the
induced fields flow along closed-loop pathways in the body, as shown in
Figure 2.1b and c.
Recent clinical studies have shown that TMS improves various symp-
toms of neurological and psychiatric diseases. It should be noted that the
TMS exhibits therapeutic effects even for a percentage of drug-resistant
patients. TMS is advantageous also in terms of rarely causing side effects,
which are sometimes problematic in drug treatment. As discussed pri-
marily in Chapter 3, TMS is a promising technique for a variety of fields
such as brain research, diagnosis of the nervous system, treatment of dis-
eases, and recovery of brain function.
28 ◾ Biomagnetics
2.2 MAGNETIC STIMULATOR
2.2.1 Stimulator Coils
2.2.1.1 Circular Coil
Circular coils have been used since TMS was invented.6 Owing to the simplest
structure among various types of coils, the circular coils are still widely used
today. As shown in Figure 2.1b, the coil conductors are wound up circularly.
Figure 2.3a shows a circular coil for basic studies. The generated magnetic
fields are perpendicular to the surface of the head below the coil center and are
tangential to the surface below the coil conductor. The electric fields generated
in the brain form circular pathways along the surface of the head and in the
direction opposite the coil current. The magnitude of electric field is zero
below the center of the coil and is highest below the coil conductors. As a
result, the electric fields distribute in an area whose dimension is comparable
to the coil diameter. Because the magnitude of magnetic field decreases with
the distance from the coil, the electric fields are highest at the surface of the
head and attenuate at deep regions in the brain. Coils with smaller diameters
(a)
(b)
(c)
FIGURE 2.3 (a) Circular coil, (b) figure-eight coil, and (c) double-cone coil.
These coils are widely used for magnetic stimulation.
exhibit steeper attenuations of fields. In order for electric fields to reach

deeper regions in the brain, using a coil with large diameter is desirable.
The spatial distribution of magnetic field generated from a circular coil
can be analytically formulated. For simplicity, a circular coil with a radius
of a lies in the x–y plane with its center coinciding with the origin. A cur-
rent I is applied to the coil. The following formulas give the magnetic field
vector generated from the circular coil in a spherical coordinate:
1 ∂
Br = (Aϕ sinθ) (2.1)
r sinθ ∂θ
1 ∂
Bθ = − (rAϕ ) (2.2)
r ∂r
Bφ = 0 (2.3)
where μ0 = 4π × 10−7 H/m is the permeability of free space. The transform

between the Cartesian coordinate and the spherical coordinate is given by
x = r sin θ cos φ, y = r sin θ sin φ, and z = r cos θ. Aφ is the magnetic vector
potential:
2π
µ Ia cos ϕ ′dϕ ′
Aϕ = 0
4π ∫
0
(a + r − 2ar sinθcos ϕ ′)1/2
2 2

µ0 4Ia ⎡ (2 − k 2 )K(k)− 2E(k) ⎤ (2.4)
=
4π a 2 + r 2 + 2ar sinθ ⎢⎣ k2 ⎥⎦
4ar sinθ
k2 =
a + r 2 + 2ar sinθ (2.5)
2
where K(k) and E(k) are elliptic integrals of the first and second kinds,
respectively.
π/2
∫
1
K(k) = dθ (2.6)
0
1− k 2 sin 2 θ
π/2

E(k) =
∫
0
1− k 2 sin 2 θ dθ
(2.7)
30 ◾ Biomagnetics
Various coils introduced below can be modeled as a set of circular coils

for analyzing the magnetic field distributions. The above equations can be
applied to such analyses.
The current flowing in the coil is subject to Lorentz force owing to the
magnetic field generated from the coil itself. The generation of pulsed force
causes a vibration of coil conductors. Acoustic noise produced from the
coil at the moment of delivering stimulation originates from the Lorentz
force. In a circular coil, force is generated outwardly so that the coil gets
slightly distended.
2.2.1.2 Figure-Eight Coil
The figure-eight coil was originally developed by Ueno et al.7,8 This coil
is now in widespread clinical use along with the single circular coil. The
figure-eight coil consists of a pair of circular coils adjacent to one another,
and the current is applied in the opposite directions to these circular coils.
Magnetic fields are produced from the two circular coils in the opposite
directions, and the magnetic fields induce electric fields in the brain. As
shown in Figure 2.1c, the electric field flows in the brain in the reversed
direction, forming two loop pathways. The electric fields converge in the
target region in the brain below the intersection of the figure-eight coil,
resulting in an electric field intensity approximately 3× higher than those
around the target.11 In the single circular coil, however, the electric fields
form a circular pathway. The resulting fields get the maximum intensity
below the coil conductors, and the intensity becomes zero below the center
of the circle.
The figure-eight coil enables one to stimulate a target area in the human
cerebral cortex with a spatial resolution as high as 5 mm.7 Thus, this coil
is extremely effective when stimuli should be delivered to a specific target
area. Another advantage of this coil is the ability to provide a vectorial
stimulation because the electric fields in the target area are induced in a
specific direction along the surface of the head. The attitude of the coil
defines the direction of electric field.
Figure 2.3b and c show two major figure-eight coils: planar coil and
double-cone coil. In the double-cone coil, the outer conductors come close
to the surface of the head, which intensify the electric field at the target
area. The electric fields in the brain generally attenuate with the distance
from the coil conductors. An increase in the diameter of the coil leads to
stronger electric fields in deep parts of the brain.
2.2.1.3 Coil Array
Researchers have investigated potential benefits of composing an array of
small coils distributed over the surface of the head for TMS. A variety of
stimulations can be delivered according to spatial and temporal patterns
of currents applied to the coil elements. The magnetic field arising from
the coil array is the superposition of magnetic fields from each coil
element. In principle, the circular and figure-eight coils can be imitated
with correspondingly designed current patterns. Various coils including
these two could be replaced with one coil array. Mathematical methods
such as lead field and minimum-norm estimation can be used to obtain
the pattern of coil currents for a given distribution of stimulating electric
fields in the brain. A unique advantage of the coil array is the ability to
deliver a train of stimulating pulses for different target areas with a short
pulse interval.
Advantages of a coil array have been evaluated based on numerical sim-
ulations.13,14 Figure 2.4 shows coil elements distributed over the surface of
a numerical human head model. This simulation showed that the focality
and depth of stimulation can be improved by properly selecting the coil
current direction and current phases in the neighboring coils.
240
210
180
150
z (mm)
120
90
60
30 240
180
0 120
50 100 60 y (mm)
150 200 0
x (mm)
FIGURE 2.4 Coil array designed on a numerical model of human head. The array
consisted of 40 elements. (From Lu, M. et al., IEEE Transactions on Magnetics 45:
1662–1665, 2009.)
32 ◾ Biomagnetics
While these advantages have been reported, development of a proto-

type coil is not technically easy. Thickness of the coil conductor is a few
millimeters in many cases, allowing pulsed currents of kiloamperes to
flow through the conductor. Because the conductor should be wound mul-
tiple turns, miniaturization of the element coil is limited. When driving
currents are applied to multiple coils for imitating a large coil, adjacent
coils may have currents in the opposite directions. Such currents do not
contribute to the generation of magnetic fields but cause ohmic loss and
decreased efficiency. In addition, the coil array requires much larger driv-
ing circuits and cables compared with the single coils. The research and
development of coil array will be carried out considering the balance of its
unique advantages and technical challenges.
2.2.1.4 Emerging Coil Designs

Various coil designs have been explored for achieving high performances
such as higher focality, deeper penetration, and improved efficiency of
stimulations. By using four or more coil elements over the head, high
flexibility in the design of the spatiotemporal pattern of magnetic field
pulses becomes possible.15 Model simulations showed that a good control
of the excited area was achieved by proper positioning of the coil. The use
of three-dimensional configurations of multiple coil elements (such as a
slinky coil or a differential coil) can produce more focused stimulation
than is possible with planar coils.16,17 In the H-coils, coil conductors were
distributed along the surface of the brain to deliver electric fields to deeper
parts of the brain.18 Deeper distribution of the electric fields would lead to
improved efficacy of TMS especially in therapeutic applications.
Sekino et al.19–21 proposed an eccentric figure-eight coil that induces
strong electric fields in the target brain tissue with a given coil current.
This coil is a modification of the figure-eight coil. The center of the outer
circumference in the ordinary figure-eight coil coincides with the cen-
ter of the inner circumference, as shown in Figure 2.5a. In the eccentric
figure-eight coil, the inner circumferences are shifted closer together, as
shown in Figure 2.5b. The dense conductors at the middle of the coil lead
to intensified stimulating currents. Numerical analyses were carried out
to obtain magnetic field distribution of the eccentric figure-eight coil and
electric fields in the brain. The eccentric coil required a driving current
intensity of approximately 18 percent less than that required by the con-
centric coil to cause comparable electric field intensities within the brain.
The electric field localization of the eccentric coil was slightly higher than
Magnetic field
Coil current
Eddy current
(a)
Magnetic field
Coil current
Eddy current
(c)
(b)
FIGURE 2.5 (a) Eddy currents induced by an ordinary figure-eight coil. (b) Eddy
currents induced by an eccentric figure-eight coil. (c) Schematic of a bowl-shaped
coil.
that of the concentric coil. A prototype eccentric coil was designed and
fabricated. Instead of winding a wire around a bobbin, eccentric spiral
slits were formed on the insulator cases, and a wire was woven through the
slits. The coils were used to deliver TMS to healthy subjects. The current
slew rate corresponding to motor threshold values for the concentric and
eccentric coils were 86 and 78 A/μsec, respectively. Results indicated that
the eccentric coil consistently requires a lower driving current to reach the
motor threshold than the concentric coil does.
As discussed in Section 3.4.4, the installation of a TMS system at a patient’s
home has been proposed for providing the continuous therapeutic effects
of daily sessions. Because the figure-eight coil induces a highly localized
electric field, it is challenging to achieve accurate coil positioning above the
targeted brain area without help by a medical expert. A bowl-shaped coil
for stimulating a localized but wider area of the brain was proposed.22,23
The bowl-shaped coil consists of the conductors aligned tangentially to the
surface of the head and the counter conductors running over the tangen-
tial conductors, as shown in Figure 2.5c. Electric fields are induced along
the aligned tangential conductors. The length and width of the arrayed
tangential conductors determine the localization of stimulation. Thus, the
bowl-shaped coil exhibits a moderate and tunable localization of electric
34 ◾ Biomagnetics
field distribution. In order to design a compact stimulator coil, the coun-

ter conductor elements were arrayed above the field-inducing conductor.
The coil’s electromagnetic characteristics were analyzed using numerical
simulations, and the analysis showed that the bowl-shaped coil induced
electric fields in a wider area of the brain model compared with the figure-
eight coil. The expanded distribution of the electric field led to greater
robustness to the positioning error.
Efficacy of introducing iron cores into stimulator coils has been evalu-
ated in many studies.24,25 The iron core leads to a reduction of magnetic
reluctance of the coil, enabling us to drive the coil with smaller currents.
This produces the benefit of a miniaturized driving circuit. In addition,
the magnetic field distribution of the coil can be modified by placing iron
cores that have a high magnetic permeability close to the coil. Technical
challenges associated with the use of iron core are increased weight of the
coil and heat generation due to iron loss.
When a metal plate is introduced between the coil and the head, eddy
currents induced in the metal plate provide a shielding effect on the mag-
netic field.26 Focality of electric field in the brain can be improved using
this effect.
2.2.1.5 Cooling Systems
Electric currents in the coil cause heat generation due to the resistance
of the coil.27,28 The amount of heat is proportional to the square of coil
current and to the repetition rate of pulses. Heat generation is prominent
when stimulating with high currents and high repetition rates. This issue
is particularly important in therapeutic applications of TMS because
stimulations are delivered at a repetition rate higher than five pulses per
second. Guidelines are provided in each country that define the maximum
temperature on the coil surface attached to the human body. Coils should
be designed and tested following those guidelines.
One approach for addressing heat generation is to introduce a heat
insulator between the coil conductor and the human head. The heat insu-
lator suppresses the rising temperature on the side attached to the head,
while radiating heat from the opposite side.
Coils should be actively cooled when heat generation is relatively high.
Two major methods are air cooling and liquid cooling. Air-cooling is
provided from a fan installed above the coil or from an external blower
through a tube. Air cooling can be implemented with simple machinery. For
liquid cooling, the coolant is circulated between the coil and an external
heat exchanger. It has higher capacity: however, the circulation system

with sealed fluid channel and pump complicates the design.
2.2.1.6 Measurement of Magnetic Field and Coil Current

Magnetic fields for stimulation are generated typically with intensities of
approximately 1 T and pulse widths of hundreds of microseconds. A search
coil is suitable for measuring such magnetic fields. The search coil is
fabricated by winding a lead wire several times with a diameter of a few
millimeters. When the magnetic field at the search location coil varies with
time, a voltage is induced in the search coil because of electromagnetic
induction. Instantaneous induced voltage is proportional to the time rate
of change in magnetic field intensity. The induced voltage of search coil
reflects the magnetic field component parallel to the winding axis of search
coil. Figure 2.6a shows a measurement of magnetic field using a search
coil. This search coil consists of five 6.3-mm diameter inner loop turns
and four 7.1-mm diameter outer loop turns. The search coil is attached
(a)
6 Magnetic flux 800

density
Magnetic flux density (mT)
4
Search coil voltage (V)
400
2
0 0
–2
–400
–4 Search coil
voltage
–6 –800
–100 0 100 200 300 400
(b) Time (μsec)
FIGURE 2.6 (a) Homemade search coil for measuring magnetic fields generated
from the stimulating coil. (b) Measured search coil voltage and estimation of
magnetic field intensity.
36 ◾ Biomagnetics
to the stimulator coil with its axis perpendicular to the winding plane
of the stimulator coil, and the search coil measures the magnetic field
component of this axis. Induced voltage is recorded using an oscilloscope.
The following formula gives the induced voltage V:
dB
V = πa 2 N (2.8)
dt
where B is the generated magnetic field and a and N are the respective
radius and number of turns of the search coil. The integral of voltage with
respect to time gives the estimation of magnetic field intensity.
t
∫
1
B= 2 V(τ)dτ (2.9)
πa N
0
Figure 2.6b shows the waveforms of measured voltage and estimated

magnetic field intensity.
The magnetic field generated from the coil is proportional to the cur-
rent flowing in the stimulator coil. The current of the stimulator coil can
be measured using a commercial current transformer, as shown in Figure
2.2. The current transformer should be selected considering current mag-
nitudes of kiloamperes. The output of the current transformer is recorded
using the oscilloscope.
2.2.2 Driving Circuit
2.2.2.1 Hardware
The driving circuit for magnetic stimulation supplies pulsed electric
currents to the stimulator coil. Figure 2.7 shows a simplified circuit
diagram for generating biphasic pulses.29 The circuit is composed of a
power supply, a high voltage generator, and a semiconductor switch. The
power supply circuit generates DC voltages from the AC input. The high
voltage generator outputs voltages of kilovolts for charging the capacitor.
Resistance limits the current for charging the capacitor. The mechanism of
storing electric charges in the capacitor and then discharging for providing
currents to the coil enables the generation of strong current from relatively
small equipment. When the thyristor is turned on after the positive charging
of the capacitor, electric current begins to flow in the coil. Here, the circuit
is equivalent to the coil L and capacitor C connected serially. Sinusoidal
current flows in these elements with the pulse width T given by
Semiconductor switch
Resistance
Power supply
High voltage
AC
generator
Coil
Capacitor
FIGURE 2.7 Diagram of driving circuit for magnetic stimulator. The circuit
provides pulsed currents to the coil. (From Sekino, M. et al., Proceedings of the
ICME International Conference on Complex Medical Engineering 728–733, 2012.)
T = 2π LC (2.10)
After turning on the thyristor, the current gradually increases and

reaches the maximum at the moment of the charge in capacitor reducing
to zero. The current subsequently begins to decrease, and the capacitor is
negatively charged. When the current reduces to zero, the negative capaci-
tor voltage reaches the minimum. Then, the current takes the same time
course with the reversed polarity. The diode that is connected parallel to
the thyristor in the opposite direction allows the reverse current to flow.
When the coil current reduces to zero again, the capacitor is positively
charged. The circuit is deactivated at that moment because the thyristor is
turned off. The capacitor voltage ideally recovers to the level it had before
the pulse generation. In actual circuits, however, voltage drop occurs
because of resistance in the coil and capacitor. The capacitor is charged
again before subsequent pulse generation so that the voltage recovers to
the initial value. The repetition rate of pulse generation is controlled by
the internal unit, allowing the circuit to generate single pulse and repeated
pulses with rates ranging typically from 1 to 20 Hz.
Circuit elements such as the capacitor and thyristor have maximum
rated powers. The circuit can be substantially downsized if one uses single
pulse only.30,31 Pulse generations with high repetition rates require rela-
tively large elements. Some of the repetitive pulse generator is equipped
with multiple capacitors. As described in the next section, a generation of
monophasic pulse leads to significant discharge of the capacitor. In this
38 ◾ Biomagnetics
case, preparation for the subsequent pulse generation takes a longer time
in comparison with the case of biphasic pulse. Generation of the mono-
phase pulse train usually requires multiple capacitors.
2.2.2.2 Analysis of Driving Circuit

This section shows an analysis of pulse waveform for the case of monophasic
pulse. As shown in Figure 2.8, the major elements in the circuit consists
of the inductance L of the stimulator coil, DC voltage source V0, capacitor
C, resistance R, diode D, and switches S1 and S2. First, the capacitor C is
charged by opening the switch S2 and closing the switch S1. No current
flows in the diode D and resistance R at this moment because the diode
allows the current to flow in only one direction downward. After sufficient
charging of capacitor C, switch S1 is opened and switch S2 was closed.
Current begins to flow in the coil L, and the capacitor C begins to be
discharged. The voltage v of capacitor is equal to that of coil. The following
equations give the relations among coil current iL , capacitor current iC ,
and voltage v:
diL
v=L (2.11)
dt
dv
iC = C (2.12)
dt
S1 S2
D v
L
V0 C
R
iC iR iL
FIGURE 2.8 Simplified circuit for analyzing a monophasic pulse current. (From
Mano, Y., and Tsuji, S., Magnetic Stimulation—Basic Principles and Applications.
Ishiyaku Publishers, Tokyo, 2005.)
The relation iL + iC = 0 holds when no current flows in the capacitor R.

The following equation holds for the time course of iL:
d 2i L i L
L + =0 (2.13)
dt 2 C
where the moment of closing switch S2 is defined as t = 0. The above

equation gives a well-known simple harmonic oscillation. The following
is one solution satisfying the initial condition of iL = 0 at t = 0:
C t (2.14)
iL = V0 sin
L LC
The coil current initially exhibits a sinusoidal increase. Coil voltage is

given by
diL t
v=L = V0 cos (2.15)
dt LC
After the closing of switch S2, voltage v decreases and becomes zero at
the time t1 = (π/2)(LC)1/2. The voltage v then turns to be negative, and the
diode allows the current to flow also in the resistance R. The Ohm’s low
holds between the voltage v and current iR in the resistance.
v = RiR (2.16)
The continuity of currents iR + iL + iC = 0 leads to
d 2v 1 dv v
C + + = 0 (2.17)
dt 2 R dt L
When the relation L > 4R2C holds, among the solution of the above
equation the following one is connected to Equation 2.15 at t1 = (π/2)(LC)1/2:
t − t1 ⎞ ⎛ ⎞
exp ⎛ −
C 1 1
v = −2V0 R ⎝ ⎠
sinh ⎜ 2 − ⋅(t − t1 )⎟ (2.18)
L − 4R C
2
2RC ⎝ (2RC) LC ⎠

40 ◾ Biomagnetics
t − t1 ⎞
exp ⎛ −
dv v C
iL = −C − = V0
dt R L − 4R C
2 ⎝ 2RC ⎠
⎡ 4R 2C ⎛ 1 1 ⎞
× ⎢ 1− cosh ⎜ 2 − ⋅(t − t1 )⎟
⎢⎣ L ⎝ (2RC) LC ⎠
⎛ 1 1 ⎞⎤
+ sinh ⎜ 2 − ⋅(t − t1 )⎟ ⎥ (2.19)
⎝ (2RC) LC ⎠⎦

Both voltage v and current iL attenuate toward zero over time. The com-
bination of Equations 2.14 and 2.15 gives the monophasic waveform shown
in Figure 2.2. The magnetic field generated from the coil is proportional to
the current iL , and the electric field induced in the body is proportional to
the time derivative of current diL/dt.
2.2.3 Coil Navigation System

Figure 2.9 shows a typical coil navigation system for transcranial magnetic
stimulation. A dedicated marker is equipped with three reflective spheres.
Markers are fixed on the stimulator coil and on the bed for patient. An infrared
binocular camera observes the three reflective spheres, which enable the
system to estimate the position and orientation of the markers. The position
of the center of the coil relative to the marker is measured beforehand
using a dedicated probe. In addition, the positions of several landmarks
Reflective marker
Binocular camera
Stimulator coil
FIGURE 2.9 Coil navigation system using a near-infrared binocular camera and
reflective markers.
on the head, such as the nasion and preauricular points, are measured.
Placing the patient supine leads to stabilized positioning between the head
and marker. The system enables us to see the position of the stimulator coil
relative to the head in real time. The system reads the patient’s magnetic
resonance images for graphically showing the location of the coil and the
target position on the brain. The binocular camera achieves submillimeter
accuracy in estimating the position of markers. Introducing such a
navigation system enables us to precisely and quickly place the stimulator
coil above the target position. This is particularly valuable for highly
localized stimulations using figure-eight coils.
2.2.4 Multimodal Imaging Using Magnetic Stimulation

A combination of magnetic stimulation and other modalities such as
electroencephalography (EEG) and magnetic resonance imaging (MRI)
is effective for measuring the evoked brain activities. The combinations
give rise to technical challenges for preventing influences of magnetic field
pulses on measuring methods. The EEG is sensitive to external noise due
to the requirement of recording small evoked potentials. Magnetic field of
MRI causes strong electromagnetic forces on the stimulator coil.
Iramina et al.32 reported the measurement of evoked potentials induced
by magnetic stimulation for observing the neuronal connectivity in the
brain. Figure 2.10a shows an EEG measurement system to eliminate the
electromagnetic interaction caused by the stimulation. Using this artifact
free amplifier, TMS-evoked EEG responses were successfully measured,
as shown in Figure 2.10b. Several components of the evoked potential
appeared at 9, 20, and 50 msec after a cerebellar stimulation. During
motor area stimulation, there was no clear peak of the waveforms within
10 msec latency. Occipital stimulation caused more evoked responses to
spread to the center of the brain than at other areas of stimulation. The
evoked signal by TMS was possibly conducted posteriorly to anteriorly
along the pathways of the neuronal fiber exiting the cerebellum into the
cerebral cortex.
Reaction maps of the stimulation at the occipital area were then
obtained using the 9-msec evoked potential component.33 From the reac-
tion map, it was possible to consider that the fast component of evoked
signal by stimulation to the cerebellum was conducted posteriorly to ante-
riorly along the pathways of the neuronal fiber exiting the cerebellum to
the cerebral cortex. The response at the right brain was large when the left
42 ◾ Biomagnetics
20
Amplitude (uV)
10
SW F3
0 F4
Vin C Fz
G1 G2 –10
Vref
–20
–50 0 50 100 150 200
Active Time (ms)
GND
Control
20
Inion
10
Amplitude (uV)
F3
0 F4
Anti-alias filter Multiplexer Fz
–10
S/H Isolator Computer
–20
A/D –50 0 50 100 150 200
Time (ms)
20
Amplitude (uV)
10
TMS F3
0 F4
SW Fz
–10
Attenuator
–20
–50 0 50 100 150 200
(a) (b) Time (ms)
FIGURE 2.10 (a) Block diagram of TMS-compatible EEG amplifier and timing
chart of the circuit. (b) Measurement points of EEG and stimulated point on
the head. The stimulus point, which is located on the cerebellum, was 20 mm
superior to the inion. (From Iramina, K. et al., Journal of Applied Physics 93:
6718–6720, 2003.)
cerebellum was stimulated. The response at the left brain was large when
the right cerebellum was stimulated. The response map gave information
of the neuronal connectivity. Magnetic stimulation will become a useful
tool for the study of cortical reactivity and neuronal connectivity of the
brain.
An MRI is useful for observing spatial distribution of brain activities.
For demonstrating a magnetic stimulation in the MRI system, the head
and coil are placed in a static magnetic field. Applying a pulsed electric
current to the stimulator coil under the magnetic field causes an impul-
sive Lorentz force. The coil and supporting structure should be durable
against the force. In addition, the magnetic field generated in the MRI
system affects acquisition of images. The timings of pulse generation and
MRI acquisition should be staggered with each other. The cable between
the coil and driving circuit should be long enough so that the driving
circuit is placed distant from the MRI magnet. A lot of studies have been
carried out using simultaneous operation of magnetic stimulation and
MRI.34,35
2.3 MECHANISMS OF MAGNETIC STIMULATION

2.3.1 Fundamentals of Electrophysiology
2.3.1.1 Resting Membrane Potential
Intracellular space has a lower electric potential compared with that of
extracellular space. The difference in potential is caused by cations accu-
mulating on the outer surface of the cell membrane and anions on the
inner surface. The potential of intracellular space normally ranges from
−40 to −80 mV with respect to the extracellular space, which is called
the resting membrane potential. Many biological macromolecules exist as
organic anions that have negative net charges. When large organic anions
remain in intracellular space because of the impermeability through the
membrane, the membrane-transportable cations and anions are affected
by these organic anions and distribute with different concentrations in
both sides of the membrane. This phenomenon is called Donnan’s effect.
Intracellular inorganic ions are composed mainly of potassium (K+) and
small amounts of sodium (Na+) and chloride (Cl−). On the other hand, Na+
and Cl− compose the greater part of extracellular inorganic ions.
When the difference in concentration occurred between the internal
and external side of the membrane only owning to Donnan’s effect, the
resting membrane potential is expressed by Nernst’s formula as follows:
RT Co
E= ln (2.20)
zF Ci
where E is an intracellular electric voltage on the basis of the extracellular

voltage, Co is an extracellular ion concentration, Ci is an intracellular ion
concentration, R is gas constant, T is a temperature, F is Faraday constant,
and z is a valence of ion. Because the potassium channels are opening while
the sodium ones are closing at the resting state, the resting potential mostly
corresponds with the difference in potassium concentration between the
intra-extra cellular spaces. Additionally, the cellular membrane has an
active ion-exchanging mechanism (Na+–K+ exchange pump) that selectively
intake K+ to intracellular space and outflows intracellular Na+ to extra
cellular space. This active pump system is driven by proteins on cellular
membrane selectively transporting ions. Some of the ion-channel proteins
have a voltage-dependent gating system, and it contributes to generating
the action potential (details are described at the next section). Ion concen-
tration differences between the intra-extracellular cellular spaces represent
a complex result of this active pump system and Donnan’s effect.
44 ◾ Biomagnetics
2.3.1.2 Action Potential
When a local depolarization occurred at the cellular membrane by the
excitation stimuli, a voltage-dependent Na+ channel on the membrane
opens. Subsequently, Na+ flows into intracellular space due to the gradi-
ent of concentration and electrical potential between intra-extra cellular
spaces. Corresponding to the decrease in net negative potential of the
membrane owing to the Na+ inflow, large numbers of the Na+ channels
open and the greater Na+ influx occurs. According to the Na+ gate open-
ing, an electric current caused by Na+ inflow exceeds those of K+ from K+
leak channels, and finally the membrane potential shows a positive charge
at the intracellular side, which means the resting potential is reversed.
This phenomenon is known as action potential. The depolarization and
subsequent Na+ channels opening spread to surrounding area, and the
propagation of action potential occurs.
The basic properties of the action potential propagation are analyzable
using the electric circuit model of the cellular membrane. As shown in
Figure 2.11a, a cellular membrane has electric properties rm and cm. The rm
represents penetration resistance per unit length at an ion transition, and
cm is an electric capacity of the membrane. Additionally, a nerve cell also
cm
rm
ri
im (x)
V(x) V(x + Δx)
Ii (x) Ii (x + Δx)
(a) Δx
EL EK ENa c
m
gL gK gNa
ri
im (x)
(b) Ii (x) Ii (x + Δx)
FIGURE 2.11 (a) A passive cable model for analyzing propagation of action
potential. (b) An equivalent circuit of nerve fiber with the Hodgkin-Huxley
model of voltage-gated channels.
has a resistance per unit length ri along to the direction of nerve fibers.
Extracellular cellular resistance is negligible compared with rm; thus, it is
considered as zero in this case. On the basis of these conditions, a mem-
brane electric current im per unit length is represented as
∂V V
im = cm + (2.21)
∂t rm
where V is a membrane potential in this formula. An intracellular electric

current, along with the direction of the nerve fiber, follows Ohm’s law.
∂V
ri I i = − (2.22)
∂x
where x represents the position at the direction of the fiber. A membrane

electric current im satisfy a current continuity equation:
∂I i
im = − (2.23)
∂x
With the combination of these three formulae, the cable properties of

the cellular membrane are represented as
∂2V ∂V
λ2 −V = τ
∂x 2 ∂t
where the constants λ and τ are given by
rm
λ=
ri (2.24)
τ = cmrm (2.25)
This passive cable model is quite useful to examine the propagation

characteristic of the action potential.
Actual membrane resistance depends on the voltage due to the actions
of voltage-dependent ion channels. To express this characteristic, rm for
46 ◾ Biomagnetics
each type of ion is treated as separately and voltage dependent. Moreover,

Nernst’s potential of each ion is put into the model as a resource of electric
voltage. This model is named the Hodgkin-Huxley model, and the electric
property of an action potential propagation is well described by Hodgkin-
Huxley equations.
2.3.2 Transcranial Magnetic Stimulation

2.3.2.1 Resting Motor Threshold
Cortial motor threshold (CMT) is an index of the stimulation intensity for
TMS. The CMT is defined as the intensity of motor cortex stimulation that
induces the motor evoked potential (MEP) higher than 50 μV with the
probability greater than 50 percent. The CMT is indicated as the relative
intensity to the maximum (approximately 2–3 T, defined as 100 percent).
The CMT measured at the resting state is called the resting motor thresh-
old (RMT). The RMT is distinguished from the active motor threshold
(AMT) whose value is often lower than the RMT. These definitions are
based on the guideline released from the International Federation of
Clinical Neurophysiology (IFCN). Generally, the CMT is determined by
stimulating the motor cortex approximately 10 times by changing the
intensity and the stimulus intensity, which induces MEPs larger than
50 μV, where a probability of greater than 50 percent is assessed. In the
formal procedure defined by IFCN, the initial intensity is set at 35 percent
and the operator tries to look for the coil strength that shows MEP 5 times
or more out of 10 stimulations with increasing intensity by a 5 percent
step. Then, the same procedure is repeated by lowering the coil intensity
by a 1 percent step to find the index, which indicates MEP less than
5 times in 10 trials. Finally, CMT is determined by adding 1 percent
to this index.36 On the other hand, the simplified manner has reported
that the observation of muscle twitches more than 50 percent instead of
CMT, and evaluated the interindividual variability.37 RMT is known to
have a large variation among subjects and shows approximately 20 per-
cent change of the value owing to the coil position even in the subject. The
numerical calculation by finite element method reported that the eddy
current density in the brain was 6 A/m2 when the human head model was
stimulated by the pulsed magnetic field strength, which is equal to RMT.38
2.3.2.2 Stimulation Site
Neurons are sensitive to externally applied electric fields generated parallel
to dendrites and axons. In transcranial electric stimulation, as shown in
Stimulator coil
Anode
Electric field
Axon
Pyramidal
hillock Electric field
neuron
Interneuron
(a) (b)
FIGURE 2.12 (a) Electric stimulation of neurons in the brain. (b) Magnetic
stimulation of neurons in the brain. Interneurons are susceptible to the induced
currents.
Figure 2.12, excitation occurs at the axon hillock where the axon runs out
from the cell body of pyramidal neurons oriented perpendicular to the sur-
face of the brain. In TMS, on the other hand, the electric field parallel to
the brain surface mainly excites interneurons running in this direction.
This leads to an excitation of connecting pyramidal neurons, and muscle
contraction finally occurs. A stimulation of the primary motor cortex evokes
a twitch. A shift of coil position from the maximally sensitive position causes
a delay of 0.7–0.8 msec in the latency of motor evoked potentials. This delay
corresponds to the time passing one synapse.39 The distribution of induced
electric field strongly depends on the structure of gyrus and sulcus.40
2.3.3 Peripheral Nerve Stimulation

2.3.3.1 Activating Function
In the peripheral nervous system, nerve fibers form bundles. Assuming a
straight running nerve fiber, the mechanism of nerve excitation by magnetic
stimulation can be investigated. Roth and Basser 41 proposed a physical
model of stimulating a peripheral nerve fiber and introduced a term of
electric field induced by time-varying magnetic field into the cable equation
of nerve fiber. On the basis of this model, the cable equation is revised as
∂2V ∂V ∂ε
λ2 2 −V = τ + λ 2 x (2.26)
∂x ∂t ∂x
48 ◾ Biomagnetics
where the second term in the right side expresses the influence of magnetic
stimulation. This equation shows an interesting point that the influence
of magnetic stimulation is not proportional to the electric field strength
itself but proportional to the spatial gradient of electric field ∂εx/∂x. This
term is referred to as the activating function. When an inhomogeneous
magnetic field is induced depending on the geometry of stimulator coil,
peripheral nerve stimulation is likely to occur at the location exhibiting
high activating function.
2.3.3.2 Stimulation Site
The conductivity of biological tissue differs between tissue types. At the
boundary between bone and muscle, for example, there is a discontinuous
change in conductivity. Liu and Ueno42 calculated the activating function
to study the influence of the interface between tissues with different con-
ductivities on nerve excitation. A Neumann-type boundary condition is
derived for applying the finite element method to calculate the induced elec-
tric field. The spatial distributions of electric fields and activating functions
in homogeneous and inhomogeneous volume conductors are calculated
for comparison. The results show that the interface between conductors of
different conductivities exhibits a large magnitude of activating function.
Such locations are susceptible to magnetic nerve excitations. In addition,
the point where a nerve fiber bends is susceptible to magnetic stimulation
because of a high activating function.
2.4 NUMERICAL ANALYSES OF MAGNETIC

FIELD AND EDDY CURRENT
2.4.1 Numerical Methods
2.4.1.1 Finite Element Method
The finite element method (FEM) is a numerical framework for solving
partial differential equations. The method originally evolved in the field of
structural mechanics. The basic principle is based on the variation method
that has been known through the ages. First, a functional is derived so that
a first-order minute error in the field distribution gives a resulting influence
in only second order. Then, the volume for analysis is divided into meshes.
Tetrahedral or hexahedral elements are usually used for a simple generation
of meshes and flexible modeling of curving surfaces. The use of tetrahedral
elements enables extremely flexible generation of meshes according to
the target of calculation. Because of this characteristic, the mesh density
can be increased locally at locations where the field steeply varies or the
target object has complex geometry. Various algorithms for automatically
generating meshes have been investigated. After the generation of meshes,
the nodes are assigned on the sides or on the vertexes of each element, and
an expansion of field equation is derived in terms of unknown parameters
on the nodes. Substitution of this equation into the functional gives an
expansion of functional with the unknown parameters. Because of the
variation principle, this expression takes an extremal value with respect
to a minimal variation of the unknown parameters. The differential of
the expression by the unknown parameters is equal to zero. Doing this
calculation for the all unknown parameters gives a simultaneous linear
equation for the unknown parameters. Numerical analyses lead to the
solution for the unknown parameters.
Because the FEM allows the use of the tetrahedral element, which is
applicable to complicated geometries, this method is appropriate for the
analyses of objects with complicated geometries. However, many numeri-
cal models of the human body consist of cubic voxels originating from
voxels of cross-sectional images. In this case, the boundaries between tis-
sues should be reconstructed to fit the tetrahedral meshes. In the case of
the brain, methods for segmenting tissues from image pixels are devel-
oped. Software for generating tetrahedral mesh is available.
2.4.1.2 Scalar Potential Finite Difference Method

The scalar potential finite difference (SPFD) method is widely used for
calculating induced electric fields in biological bodies.43 The target body
is modeled with voxels, and the equation of the electromagnetic field is
solved with electric scalar potentials at the nodes contained as unknown
parameters. For using this method, the skin depth should be much larger
than the dimension of the calculated body, and the secondary magnetic
field arising from induced current should be much smaller than the pri-
mary current. These conditions are satisfied in typical electromagnetic
fields in TMS. The following equation is obtained by combining Faraday’s
law, current continuity equation, and Ohm’s law and by discretizing the
equation about the node 0:
6
⎛ 6
⎞ 6
∑n=1
snφn − ⎜
⎝
∑
n=1
sn ⎟ φ0 = jω
⎠
∑(−1) s l A
n=1
n
nn 0n (2.27)
50 ◾ Biomagnetics
where ϕn is the electric scalar potential at the node n, A0n is the external
magnetic vector potential parallel to the side n of the voxel connecting the
nodes 0 and n, ln is the length of side n, and sn is the conductance of side
n given by
sn = σ nan/ln (2.28)
Here, an is the area of face perpendicular to the side n and σn is the mean
conductivity of four voxels sharing the node n.
For calculating the electric field in the voxel, first, a system of equations
is constructed from Equation 2.27 with the electric scalar potentials ϕn
included as unknown parameters and for all nodes having finite conduc-
tivities. The electric scalar potential is obtained by solving the system of
equations using sparse matrix methods such as successive overrelaxation.
Then, the electric fields on the sides of voxel are calculated from magnetic
vector potentials and electric scalar potentials. The electric field of voxel is
obtained for x, y, and z components as the average of electric fields on the
four sides.
2.4.2 Numerical Model of the Brain

Analyses of induced electric field distributions have been carried out using
simplified models consisting of concentric spheres or standard human
head models.44 The use of a simplified spherical model is effective because
of a lower amount of calculation, especially for theoretically evaluating
the coil performance depending on coil design. The standard human
head model providing precise anatomy of the brain, on the other hand,
is valuable for estimating the electric field that is not able to be measured
experimentally. Examples of analyses using the standard model will be
introduced below. The results of these analyses reveal the influence of
complex brain geometries such as gyrus and sulcus on the induced electric
fields.45
In TMS, the resting motor threshold and therapeutic effect have indi-
vidual variations. Differences in the electric field according to the shape
of the brain may underlie this individual variation. The geometry of the
standard head model is different from that of individual subjects, and it
has been difficult to investigate the individual variation using the stan-
dard model. To understand the origin of individual variation, the brain
model should be generated individually and perform analyses of electric
fields.
(a) (b)
FIGURE 2.13 (a) A numerical model of the brain consisting of gray matter, white
matter, and cerebrospinal fluid. (b) Numerical simulation of induced current in
the brain using the scalar-potential finite difference method.
In some recent studies, numerical models based on individual brain

shapes have been generated and used for analyses.46 The aim was to show
the individual variation in electric fields and to investigate the correla-
tion with motor evoked potentials. The individual numerical models are
generated from the MRI of subjects. Figure 2.13 shows an example of
an individual head model consisting of gray matter, white matter, and
cerebrospinal fluid and the result of electric field analysis using the SPFD
method.
2.4.3 Analyses of Transcranial Magnetic Stimulation

2.4.3.1 Comparison of Electroconvulsive Therapy
and Magnetic Stimulation
Electroconvulsive therapy (ECT) is a psychiatric treatment in which electric
currents applied to the brain generate a cerebral seizure. The efficacy of
ECT has been reported for the treatment of some symptoms of mental ill-
nesses and neurological disorders that are not medicinally curable, includ-
ing depression, schizophrenia, and Parkinson’s disease. Safer methods of
ECT administration have been introduced including the use of anesthet-
ics. However, ECT is still an invasive treatment because the applied cur-
rents flow not only in the target region but throughout the brain as well.
There are many side effects associated with ECT such as severe headaches
and partial loss of memory after treatment. Because the localized stimu-
lation reduces the risk of side effects, TMS is a more desirable method of
treatment than ECT. To induce a comparable neural activation to ECT, it
is important to evaluate current distributions generated inside the brain
in TMS.
52 ◾ Biomagnetics
Sekino and Ueno47 compared current density distributions in ECT and

TMS by numerical simulations, as shown in Figure 2.14.48 In the ECT
model, electric currents were applied through electrodes with a voltage
of 100 V. In the TMS model, a figure-eight coil was placed on the vertex.
TMS generated comparable current densities to ECT. While the skull sig-
nificantly affected current distributions in ECT, TMS efficiently induced
eddy currents in the brain. In addition, the dependences of the current
distribution in TMS on stimulus conditions were investigated.49 Magnetic
stimulations were performed using figure-eight coils with diameters of 50,
75, and 100 mm, and coil positions varied from the vertex to the forehead.
The difference in current distributions in ECT and TMS decreased with
(a) (b)
(c) (d)
18
(e) (f ) 0
A/m2
FIGURE 2.14 (a, b) Current distributions in electroconvulsive therapy (ECT).

(c, d) Current distributions in magnetic stimulation using a 100-mm circular coil.
(e, f) Current distributions in magnetic stimulation using a 75-mm figure-eight
coil. (From Sekino, M., and Ueno, S., Neurology and Clinical Neurophysiology 88:
1–5, 2004.)
the coil position approaching the forehead. The difference decreased with
an increase in the coil diameter.
2.4.3.2 Magnetic Stimulation to the Cerebellum

The cerebellum is responsible for maintaining the body’s posture and bal-
ance, as the antigravity muscles of the lower limbs are under the direction
of the cerebellum to maintain standing posture. In addition, the cerebellum
controls timings of muscular contractions for smooth motions. The cerebel-
lum is connected to the motor cortex via neuronal fiber tracts, and activities
in these areas are influenced by each other. TMS to the cerebellum enhances
or depresses activities in the motor cortex, which reveals functional relations
between these areas. Contractions of skeletal muscles evoked by cerebellar
TMS reflect neuronal pathways from the cerebellum to peripheral nerves.
While the distance between the cerebrum and the stimulating coil is
smaller than 2 cm, the distance between the cerebellum and the stimulator
coil is 3 or 4 cm. It is important to clarify whether the increase in the distance
affects the localization of eddy current. Sekino et al.50 performed numerical
simulations of the eddy current induced by TMS to the cerebellum.
Solutions were obtained on a three-dimensional human head model
with inhomogeneous conductivity, as shown in Figure 2.15. The figure-
eight coil had a diameter of 110 mm. Electric current applied to the coil
had an intensity of 44.2 kA turns, which resulted in a magnetic field inten-
sity of 0.56 T at the center of the coil element. The maximum current den-
sity in the cerebellum was 2.9 A/m2. Distribution of the eddy current in
the cerebellum was limited to approximately 1 cm beneath the surface of
the cerebellum. The eddy current had a localized distribution in the cer-
ebellum, while the magnetic field had a broad distribution.
2.4.4 Use of Numerical Methods in Coil Design

The electromagnetic characteristics of the coil depend on the design
parameters such as shape, diameter, and number of turns. As described
above, electric field distributions can be estimated for a given coil design
using numerical methods. In addition, spatial integration of the magnetic
fields generated around the coil gives the estimation of coil inductance as
follows:
∫ B dV (2.29)
1
L= 2
µ0I 2
54 ◾ Biomagnetics
0.56
(a) 0(T) (b)
0.32 4.0
(c) 0(T) (d) 0(A/m2)
FIGURE 2.15 (a) Distribution of magnetic field on the surface of the head model
in magnetic stimulation to cerebellum. (b) Three-dimensional view of the brain.
(c) Distribution of magnetic field on the surface of the brain. (d) Distribution
of eddy current on the surface of the brain. (From Sekino, M. et al., IEEE
Transactions on Magnetics 42: 3575–3577, 2006.)
Figure 2.16 shows the electromagnetic characteristics of eccentric figure-

eight coils introduced in Section 2.2.1.4. Here, three parameters of inner
diameter, outer diameter, and number of turns were varied. The resulting
coil inductance, pulse width, maximum eddy current density, working
voltage, and coil resistance were estimated.
The increases in inner diameter, outer diameter, and number of turns
caused increases in the eddy current density, inductance, and working
voltage. The working voltage should not be very high for ensuring safety.
The pulse width of around 200 μsec is close to the values of clinically
used stimulators. Resistance increases with the winding length. The heat
generation increases in proportion to the resistance. When eddy current
increases given a constant coil current, stimulation can be performed with
smaller coil currents to obtain the required current density in the brain.
Taking this point into consideration, enlarging the diameters or increas-
ing the number of turns enables us to reduce the heat generation.
12
10
8
6
4
2
0
80 90 100 110
(a) Outer diameter (mm)
14
12
10
8
6
4
2
0
0 10 20 30 40
(b) Inner diameter (mm)
14
12
10
8
6
4
2
0
6 7 8 9 10 11 12
(c) Number of turns
Inductance (µH) Voltage (× 100 V)
Pulse width (× 100 µsec) Resistance (mΩ)
Maximum eddy current density (A/m2)
FIGURE 2.16 Influences of (a) outer diameter, (b) inner diameter, and (c) num-
ber of turns on the characteristics of eccentric figure-eight coil. (From Kato, T.
et al., Journal of Applied Physics 111: 07B322, 2012.)
2.5 SUMMARY AND FUTURE PROSPECTS

As discussed in this chapter, the unique feature of TMS is its noninvasiveness
for stimulating the brain. Using a figure-eight coil, the brain can be stimulated
with a resolution as high as 5 mm. Design of stimulator coil has a high degree
56 ◾ Biomagnetics
of freedom, and focality and efficiency of stimulation strongly depend on the

design parameters. Novel coil designs are still explored in many recent studies.
Research and development of the driving circuit is actively progressing for
achieving high output power, downsized equipment, and high efficiency.
One of the technical issues in TMS is stimulation of a deep part of the
brain. Coil designs for deeper penetration of induced fields have been
investigated. The ultimate goal is to achieve a three-dimensional localiza-
tion of induced fields at a deep part of the brain. Though no method has
been proposed for achieving such stimulation so far, further research is
needed on this challenging but interesting physical problem. For prevent-
ing unexpected side effects, brain areas outside the target should not be
strongly stimulated. Development of a systematic method for designing
the coil windings from the given electric field distribution in the brain
would be quite valuable.
Methods for making numerical brain models of individual subjects are
now becoming available. This technique has medical significance if the
effect of TMS can be predicted for each patient beforehand. More TMS
therapeutic applications are be performed. The prediction of individual
TMS therapeutic effect will enable one to provide more effective and more
efficient therapy.
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Chapter 3
Applications of
Biomagnetic Stimulation
for Medical Treatments
and for Brain Research
CONTENTS
3.1 Introduction 62
3.1.1 Applications in Brain Research 62
3.1.2 Applications in Medicine 63
3.2 Functional Mapping of the Brain 63
3.2.1 Principles 63
3.2.1.1 Characteristics of Figure-Eight Coils 63
3.2.1.2 Spatial Resolution of Brain Mapping 64
3.2.1.3 Electroencephalography Responses Evoked
by Magnetic Stimulation 66
3.2.2 Medical Applications 68
3.3 Applications in Brain Research 69
3.3.1 Virtual Lesion 69
3.3.2 Applications in Cognitive Neuroscience 69
3.3.2.1 Episodic Memory 69
3.3.2.2 Influence on P300 Evoked Potentials 70
3.3.3 Paired-Pulse Stimulation 71
3.3.4 Repetitive Magnetic Stimulation 72
3.3.4.1 Changes in Long-Term Potentiation 72
61
62 ◾ Biomagnetics
3.3.4.2 Ischemic Tolerance of Hippocampus 73

3.3.4.3 Neuronal Plasticity 75
3.4 Applications in Medicine 76
3.4.1 Diagnosis of Nervous System 76
3.4.2 Treatment of Neurological Diseases 77
3.4.2.1 Parkinson’s Disease 77
3.4.2.2 Neuropathic Pain 79
3.4.3 Treatment of Psychiatric Diseases 80
3.4.4 Development of Magnetic Stimulator for Home
Treatment 81
3.4.5 Safety of Magnetic Stimulation 82
References 83
3.1 INTRODUCTION
3.1.1 Applications in Brain Research
It is well known that each part of the brain has a different function. In the
early days of neuroscience, knowledge about localization of brain function
was accumulated through observations of patients suffering brain
disorders. Cerebrovascular disorders or injuries occurring in a specific
part of the brain often cause a particular brain function abnormality.
This reveals that a specific part of the brain is necessary for fulfilling the
function. Broca and Welnicke identified the speech center based on such an
approach. Observations of patients with brain disorders played important
roles in understanding the localization of brain function. However, a
methodological limitation existed owing to the uncontrollability of the
location of the disorders. Penfield performed direct electric stimulations
to a patient’s brain during a surgical treatment of epilepsy and recorded
the evoked responses. Various mental activities arose according to the
positions of stimulation, which provided a brief map of the localized brain
function. Because transcranial electric stimulations of the brain cause
pain, mapping of brain function using electric stimulation could not be
performed practically except for patients under craniotomy.
As discussed in Chapter 2, transcranial magnetic stimulation (TMS)
enables noninvasive and localized stimulation of the brain. Such local-
ized stimulation, resembling Penfield’s work, makes it possible to depict a
functional map of the brain even for normal subjects. Moreover, magnetic
stimulation exerted on a region where spontaneous brain activities occur
Biomagnetic Stimulation for Medical Treatments and Brain Research ◾ 63
transiently interferes with these activities. This TMS ability represents the
feasibility of producing a virtual lesion that imitates the above disorders.
Such interference of brain function, once controlled, owns superiority in
terms of reproducibility and safety, and this approach affirmatively facili-
tates systematic investigation of functional localization of the brain.
3.1.2 Applications in Medicine
TMS is used for clinical examinations of neuronal pathways that connect
the primary motor cortex and peripheral muscles. To be specific, TMS
applied to the primary motor cortex evokes contraction of muscles, for
example, in a finger, and the motor evoked potential (MEP) measured
through electrodes provides a criterion. It has been well studied that
amplitudes and latencies of MEP are affected by neurological diseases
such as cerebral infarction and spinal cord injury. These examinations
using TMS are now widely used in clinical practice.
Therapeutic applications of TMS for neurological diseases and mental
illnesses have also been significantly developed in recent years. Repetitive
TMS (rTMS) that leads to functional changes in the central nervous system
is reported to be effective for relieving symptoms of a variety of diseases,
including depression, Parkinson’s disease, and neuropathic pain. TMS
treatment is effective even for some patients who failed in drug treatment,
and TMS hardly causes side effects. The Food and Drug Administration
(FDA) gave clearance for TMS treatment on depression. In addition, ani-
mal experiments showed that preconditioning of the hippocampus using
rTMS induced ischemic tolerance of the hippocampus. With the succes-
sive clinical results of TMS treatment on other diseases, therapeutic appli-
cations of rTMS will continue to progress in the future.
In addition to the brain, magnetic stimulation is applied to nerves in
the pelvic floor to treat urinary incontinence and to relieve muscle fatigue.
The rTMS is a novel treatment complementary to drugs, and it will is
expected to improve through further studies and clinical trials.
3.2 FUNCTIONAL MAPPING OF THE BRAIN

3.2.1 Principles
3.2.1.1 Characteristics of Figure-Eight Coils
TMS is capable of stimulating targeted areas in the brain. Among various
coils that have been developed, the figure-eight coil is one of the most widely
used.1,2 The figure-eight coils are advantageous in stimulating localized
64 ◾ Biomagnetics
1.9 3.4
0.0 0.0
Coil diameter: 40 mm A/m2 Coil diameter: 80 mm A/m2
2.8 3.8
0.0 0.0
Coil diameter: 60 mm A/m2 Coil diameter: 100 mm A/m2
FIGURE 3.1 Distributions of eddy currents in a conductive cuboid induced by

figure-eight coils with different diameters. Large diameter leads to broad and
deep distributions of eddy currents.
targets compared with other types of coils. When an electric current flows
through the figure-eight coil, the current generates time-varying magnetic
fields from the two circular coils in the opposite directions. Eddy currents
are induced in the target in the direction opposite the coils’ currents so that
the magnetic fields arising from the eddy currents attenuate the primary
magnetic fields generated from the figure-eight coil. Eddy currents in the
two loops flow in the same direction below the middle of the coil. This
convergence of eddy currents leads to the locally increased current density.
Furthermore, the figure-eight coil induces eddy current in a specific direc-
tion at this location. Figure 3.1 shows that the intensity of the eddy current
density in the target increases as the diameter of figure-eight coils becomes
larger. The maximum eddy current density induced by the 100-mm coil was
twice as high as that of the 40-mm coil. The maximum eddy current den-
sity was observed on the surface of the target for all the coils. The magnetic
fields attenuate with the distance from the coil. The above mentioned two
characteristics of figure-eight coils, i.e., the intensity of eddy current density
and the penetration depth, can be adjusted by varying the diameters.
3.2.1.2 Spatial Resolution of Brain Mapping

The brain is divided into small areas according to their specific functions.
When the motor cortex in the right hemisphere relevant to the thumb is
Y Cz
B´
X
C A B
C´
T4
B´
C´
0.5 mV
Onset of magnetic stimulation
5 ms
FIGURE 3.2 EMG responses to TMS. A: Thenar point stimulation. B: Stimulation

at a point 5 mm posterior to the thenar point. C: Stimulation at a point 5 mm
anterior to the thenar point. B′: Stimulation at a point 5 mm above the thenar
point. C′: Stimulation at a point 5 mm lower from the thenar point.2
stimulated, the left thumb twitches. Figure 3.2 shows the recorded MEPs
with varied locations of stimulation. A clear MEP was observed when the
motor cortex corresponding to the left thumb, point A, was stimulated. No
specific waveform was acquired at points B, B′, C, and C′, whose distances
from A were all 5 mm. This result indicates that the localized stimula-
tion of the human motor cortex was achieved with a spatial resolution of
5 mm. Figure 3.3 shows the functional mapping of the regions relevant
to the hand and foot. The arrows show the directions of eddy currents
66 ◾ Biomagnetics
Cz
T4
Abductor pollicis brevis muscle

Abductor digiti minimi muscle
Bracioradial muscles
Abductor hallucis muscle of the foot
Abductor digiti minimi muscle of the foot
FIGURE 3.3 Functional distribution of the human motor cortex related to the
hand and foot areas. The arrows show current directions for neural excitation.
The distance between grid points is 5 mm.2
exhibiting the maximum excitability. For example, when the stimulation

was applied at point A with the opposite direction, the thumb did not
respond. The regional and directional dependences of excitability reflect
the structures of gyri and sulci of the brain.
3.2.1.3 Electroencephalography Responses Evoked
by Magnetic Stimulation
The combination of TMS with functional brain imaging such as functional
MRI (fMRI), positron emission tomography (PET), and electroencephalog-
raphy (EEG) is an effective approach for investigating the functional con-
nectivity in the brain. EEG is a useful tool for functional mapping because
of its high temporal resolution. The combination of TMS with simultaneous
EEG provides us the possibility to noninvasively probe the brain’s excitabil-
ity, time-resolved activity, and functional connectivity.3 The experimental
setup for recording EEG evoked by TMS is shown in Figure 3.4. The electri-
cal brain activities are recorded through the electrodes on the surface of the
head. The example of recorded EEG is shown in Figure 3.5.
However, combining TMS and EEG is not simple work owing to the
heat and artifact induced by the interference between TMS and elec-
trodes. Dhuna et al.4 reported the possibility of burn injury by heating the
FIGURE 3.4 Experimental setup for recording electroencephalograms evoked

by TMS.
2 3
1
6
4 5
7 12 13
Stimulated 8 11
9 10
24
14 15 18 19 23
17 20 21 22
28 29 30
27 31 32
25 26 33
39 40
38 41
37
42
36 49 50
35 48 43
51
55 44
34 56 52
46 54
58 59
57 53
2 uV
45
60 0.1 s
FIGURE 3.5 Recorded electroencephalogram. Because of the dedicated amplifier

and electrode for combination with TMS, the electroencephalograms were not
affected by the artifact of TMS.
68 ◾ Biomagnetics
electrode (Ag-AgCl). Eddy current induced by time-varying magnetic field

generates the heat. In order to reduce the eddy current in the electrode,
an electrode with slits was developed. With this electrode, heating was
reduced by 32 percent.4 In order to suppress the artifact, TMS-compatible
EEG systems also have been developed. EEG activities evoked by TMS
were measured successfully with a sample-and-hold circuit controlled
by the trigger signal from the magnetic stimulator. In addition to these
techniques, the independent component analysis was also introduced to
remove the stimulus artifact in off-line analysis.5
3.2.2 Medical Applications
Functional mapping of the brain is applied also for neurosurgery.6 Iden
tifying motor and language areas before surgery is important for prevent-
ing damage to these areas. Identification using TMS is shown in Figure 3.6.
R L
(c)
Both legs
Left leg
(a)
Shoulder
Arm/elbow
Fingers
Central sulcus Thumb
(b) (d)
FIGURE 3.6 Representative demonstration of navigated brain stimulation for

human brain mapping.6 (a, b) Stimulation area is reached by utilizing on-line, inter-
active interface that guides the stimulation coil to the target. The maximum electric
field induced in the brain is visualized, and the strength of the field in the target is
determined. (c) The system allows precise determination of a stimulation target from
other imaging modalities or according to anatomical landmarks. (d) Reliable map of
motor areas can be reached by recording the muscle responses to stimulation.
The functional map that Penfield obtained using electric stimulations can

now be noninvasively reproduced using TMS with a figure-eight coil.
There are several techniques available for functional mapping of the
brain. For example, motor area identification can be conducted using
fMRI, and language area identification can be conducted with the Wada
test. However, the accuracy of the identification using fMRI has not
yet been established, and the Wada test has a problem of invasiveness.
Identification using TMS is totally noninvasive, and TMS can be per-
formed even in an operating room. For these reasons, TMS is useful for
surgical planning.
3.3 APPLICATIONS IN BRAIN RESEARCH

3.3.1 Virtual Lesion
TMS enables spatiotemporal controls of brain activities, with both
excitation and disturbance, with varied pulse intensities and frequencies.
By virtue of this feature, neuroscientists use the virtual lesion approach
in which TMS causes a transient disturbance in the brain function. Brain
function is generally realized through interactions in multiple regions of
the brain. For instance, in visual perception processes such as visual search,
letter recognition, and face recognition, giving TMS to a specific part of
the brain causes a reduction in the performance of visual perception in
some cases. These findings indicate that the stimulated area is necessary
for the realization of visual perception. The influences of TMS on visual
perception have been investigated with precisely controlled locations
and timing for administering virtual lesions. This methodology provides
a powerful tool for investigating the mechanism of spatiotemporal
information processing in the brain related to visual perception. Virtual
lesion facilitates the accumulation of knowledge on the localization of
brain function.
3.3.2 Applications in Cognitive Neuroscience

3.3.2.1 Episodic Memory
Episodic memory is a sequential memory related to memorable things
that contain time, place, and emotion of the memories. It is a kind of long-
term memory and is sometimes related to personal experiences or social
occurrences. It is generally recognized that the prefrontal area has a role
in generation of episodic memories, but there are still different hypotheses
about the localization of the detailed function in the prefrontal area.
70 ◾ Biomagnetics
Word
Pattern
TM
S
0.5
sec
FIGURE 3.7 Timeline (left to right) for presentation of Kanji words and abstract
patterns in one trial of 9-sec duration.7 Pulses of TMS are indicated by paired
vertical arrows. Shaded areas beneath the baseline indicate when cognitive stim-
uli are visible.
Epstein et al.7 carried out a study to reveal this localization. As shown

in Figure 3.7, ten Japanese subjects underwent sequential visual stimuli,
which contained 18 sets of Kanji words and abstract patterns, and TMS
pulses were delivered between the visual stimulations. The TMS coil was
placed at the left dorsolateral prefrontal cortex (DLPFC), the right DLPFC,
the cranial vertex, and off the head. After the set of stimuli, subjects took
a test to check the memory correctness of the pair of Kanji and abstract
patterns. As shown in Figure 3.8, the subjects had fewer correct responses
with the right DLPFC stimulation when compared with the stimulations
on other areas. This result indicates that the right DLPFC has a role in
generating the episodic memory. As in this example, TMS can elucidate
the mechanisms of higher brain function.
3.3.2.2 Influence on P300 Evoked Potentials

P300 is a kind of EEG response that appears when subjects undergo some
stimulation or task and pay attention or memorize something. The memo-
rable stimulations have a lot of variety. When the subjects notice some-
thing, P300 is observed after 300 msec of the stimulation.
The study by Iwahashi et al.8 using TMS revealed the detailed brain
function related to P300 generation. According to this study, when a TMS
was applied on the left supramarginal gyrus after 200 and 250 msec of
the auditory stimulation, the latency of P300 was delayed about 50 msec.
However, in the case of applying TMS after 100 and 150 msec of the
%
Correct recall
70
60
50
40
30
20
10
0
Left Vertex Right Off
DLPFC DLPFC head
Magnetic stimulation site
FIGURE 3.8 Overall percent correct for subsequent recall of paired associates
according to site of TMS.7 The comparison of interest is between the left and right
DLPFC, with an active TMS control at the vertex. In a second control, the mag-
netic coil is off the head. The asterisk indicates P < 0.05 for right versus left DLPFC.
auditory stimulation, the delay was not observed. Because the TMS inhib-
its the function of the stimulated area, these results suggest that the cortex
around the left supramarginal gyrus contributes to the generation of P300
at around 200 msec after the auditory stimulation.
3.3.3 Paired-Pulse Stimulation
Paired-pulse stimulation is a protocol that has a short time interval
between the first and second stimulation. The first stimulation is applied
with a low intensity that does not evoke MEP, and the second stimula-
tion is applied with a high intensity that evokes MEP. The influence of the
first stimulation on MEP is evaluated, and using this methodology, one
can reveal the synaptic function in the motor cortex or discuss the related
physiological mechanisms.
In the study by Kobayashi et al.9 the stimulation intensity was fixed at
70–80 percent for the first one, and 120–140 percent for the second one,
and the interval was changed from 1 to 15 msec to investigate the effects
on MEP. Observed MEP had two peaks, N1 and N2, and the increase in
the interval resulted in the higher N2 amplitude, while the N1 ampli-
tude was not affected. The authors concluded that the N1 was the direct
wave (D wave) resulting from the directly stimulated pyramidal neurons,
and the N2 was the indirect wave (I wave) resulting from the pyramidal
72 ◾ Biomagnetics
neurons indirectly stimulated through interneurons. This study is impor-

tant as evidence that there are two types of responses evoked by TMS.
3.3.4 Repetitive Magnetic Stimulation

3.3.4.1 Changes in Long-Term Potentiation
Long-term potentiation (LTP) is a long-lasting increase in the efficacy of
synaptic transmission resulting from a high-frequency stimulation.10 LTP
in the hippocampus is thought to be a typical model of synaptic plasticity
related to learning and memory.
The most commonly used protocol for LTP induction is an electric
stimulation to hippocampus slices. Electric stimulation to the hippo-
campus slices, typically to the Schaffer collaterals, generates excitatory
postsynaptic potentials (EPSPs) in the postsynaptic CA1 cells. If the
Schaffer collaterals are stimulated only two or three times per minute,
the magnitude of the evoked EPSP in the CA1 neurons remains constant.
However, a brief, high-frequency train of stimuli to the same neurons
causes LTP, which is evident as a long-lasting increase in EPSP magni-
tude (Figure 3.9). This high-frequency electric stimulation of a neuron is
called tetanus stimulation.
Recently, rTMS has become an increasingly important tool for the
potential treatment of neurological and psychiatric disorders. Depression
and Parkinson’s disease are major targets of the rTMS treatment.11,12
Many animal studies have reported rTMS-induced changes in cellular
functions.13 Gene expressions, such as c-fos, glial fibrillary acidic protein
(GFAP), and brain-derived neurotrophic factor (BDNF), were enhanced in
the rat brain by rTMS.14–17 And rTMS-related effects in the hippocampus
Pre-tetanus fEPSP
Post-tetanus fEPSP
Max left slope

0.1 mV
5 msec
FIGURE 3.9 Basic mechanisms of LTP.13,20 The plots show the changes in field
EPSP (fEPSP) after LTP induction stimuli (tetanus stimulation).
have been investigated on, e.g., monoamine release, neurogenesis, and

memory function.17–19
Ogiue-Ikeda et al.13,20 investigated the effects of rTMS on rat hippocam-
pus, focusing on changes in LTP after rTMS. The authors firstly inves-
tigated the influence of rTMS on field excitatory postsynaptic potentials
(fEPSP) after applying tetanus stimulation to the rat hippocampus.20 The
rats were magnetically stimulated by a round coil positioned over the
head. The stimulator delivered biphasic cosine current pulses 238 μsec in
duration. The peak magnetic fields were set to 0.50 T (lower than motor
threshold) and 1.25 T (above motor threshold) at the center of the coil.
The motor threshold was defined as the intensity with which the hind
limbs moved as a result of the magnetic stimulation. Rats received 10 sec
trains of 25 pulses/sec with a 1-sec intertrain interval four times per day
for 7 days. After magnetic stimulation of 7 days, hippocampus slices were
prepared and fEPSPs were recorded from the dendrites of CA1 pyramidal
cells by stimulating Schaffer collaterals. There was no significant differ-
ence between the LTP of the 0.50-T stimulated and sham control groups.
The LTP of the 1.25-T stimulated group, however, was inhibited compared
with the LTP of the sham control group, suggesting that the synaptic
plasticity in the hippocampus was impaired by strong TMS, as shown in
Figure 3.10b. The calculation of eddy current distribution showed that the
estimated eddy currents around the hippocampus were approximately
4 A/m2 (0.5 T) and 10 A/m2 (1.25 T), respectively.
The authors also demonstrated the same rTMS experiment to examine
the dependency on the field intensity.13 Rats were magnetically stimulated
for 7 days with the condition described above, but the peak magnetic fields
at the center of the coil were modified as 0.75 and 1.00 T. LTP enhance-
ment was observed only in the 0.75-T rTMS group, as shown in Figure
3.10a, while no change was observed in the 1.00-T rTMS group. These
results suggest that the effect of rTMS on LTP depends on the stimulus
intensity.
3.3.4.2 Ischemic Tolerance of Hippocampus

A mild exposure to cerebral ischemia confers transient tolerance to a sub-
sequent ischemic challenge in the brain. This phenomenon of ischemic
tolerance has been confirmed in various animal models of forebrain
ischemia and focal cerebral ischemia. On the contrary, CA1 pyramidal
neurons in the hippocampus are highly vulnerable to cerebral ischemia.21
Brief periods (minutes) of severe ischemia cause neuronal degeneration
74 ◾ Biomagnetics
500
= 0.75 T TMS (rat n = 10)
450 = Sham (rat n = 10)
400 Error bar = ± 1SE
% of basal EPSP slope

350
300
250
200
150
100
50
–20 –10 0 10 20 30 40 50 60
(a) Time (min)
500
= 1.25 T TMS (rat n = 8)
450 = Sham (rat n = 8)
Error bar = ± 1SE
400
% of basal EPSP slope
350
300
250
200
150
100
50
–20 –10 0 10 20 30 40 50 60
(b) Time (min)
FIGURE 3.10 Changes in LTP at rat hippocampus slices after rTMS13,20: (a) LTPs
of 0.75-T stimulated and sham control groups and (b) LTPs of 1.25-T stimulated
and sham control groups.
in the CA1 region 3 to 7 days after the ischemia by apoptosis.22 Recent

studies have focused on applying electric stimulation to the brain via elec-
trodes to potentially reduce ischemic symptoms.23 However, the invasive-
ness of electric stimulation (e.g., surgery and anesthetization) reduces its
feasibility as a therapeutic treatment.
Instead of invasive electric stimulation, Ogiue-Ikeda et al.21 investigated
the acquisition of ischemic tolerance in the rat hippocampus using rTMS.
On the basis of the authors’ previous studies about rTMS effects on hip-
pocampus LTP,13,20 the stimulus intensity was set at 0.75 T (the estimated
maximum eddy current was approximately 9 A/m2 in the brain). The rats
received 0.75-T rTMS of 1000 pulses/day for 7 days. The fEPSPs were mea-
sured in the hippocampal CA1. After rTMS treatment, the hippocampus
Non-ischemia, 5 min ischemia, 10 min ischemia, 30 min ischemia,

sham sham sham sham Pre-tetanus fEPSP
Post-tetanus fEPSP
100 µV
10 msec
Non-ischemia, 5 min ischemia, 10 min ischemia, 30 min ischemia,
stimulated stimulated stimulated stimulated
(a)
400
Non-ischemia, sham
Non-ischemia, stimulated
5 min ischemia, sham
350 5 min ischemia, stimulated
300
**
10 min ischemia, sham
10 min ischemia, stimulated *
% of basal fEPSP slope

30 min ischemia, sham 280
% of basal fEPSP slope
30 min ischemia, stimulated

300 260
240
250 220
200
180 * *
200 160
140
120 *
150 **
100
Non- 5 min 10 min 30 min
100 ischemia
(c) Ischemic time
50
–20 0 20 40 60
(b) Time (min)
FIGURE 3.11 Effects of rTMS on ischemic tolerance of hippocampus.21

(a) Examples of pre-tetanus and post-tetanus fEPSPs after each ischemic condi-
tion. (b) LTP in the stimulated and sham control groups in each ischemic condi-
tion. (c) Average value of the maintenance phases of LTP (ranging from 10 min
after tetanus stimulation to 60 min). Open circle: LTPs in the nonischemia group.
Open circle, square, triangle, and diamond represent LTPs in the nonischemia
group, postischemia 5, 10, and 30 min after ischemia in the sham control group,
respectively. Closed circle, square, triangle, and diamond represent LTPs in the
nonischemia group, postischemia 5, 10, and 30 min after ischemia in the sham
control group, respectively.
slices were exposed to ischemic conditions to examine the influence of rTMS

on ischemic tolerance. LTP was induced by the same protocol as described
in the previous section. The LTP of the stimulated group was enhanced
compared with the LTP of the sham control group in each ischemic condi-
tion (Figure 3.11), suggesting that rTMS has the potential to protect hippo-
campal function from ischemia.
3.3.4.3 Neuronal Plasticity
Studies on neuronal plasticity attract attention in association with learning,
memory, and recovery of brain function through rehabilitation. Recent
neuroimaging studies using functional MRI and magnetoencephalography
76 ◾ Biomagnetics
have revealed that cerebral infarction and limb amputation cause partial
changes in the localization of brain function.
The primary somatosensory cortex and primary motor cortex are
located posteriorly and anteriorly, respectively, in the central sulcus.
Assume, for example, that one has had the right-hand amputated. The
brain is intact, and the neurons in the motor and somatosensory areas
corresponding to the right hand suddenly lose their roles. In the following
days and weeks, the localization of brain function changes so that adjacent
brain areas, corresponding to the lip, for example, expand their areas to
irrupt into the right-hand area. Similar changes occur also in the motor
cortex. TMS may be used to interpose these processes for the patient to
obtain better quality of life afterward. TMS may enable such rehabilitation
after a cerebral infarction by stimulating the primary motor area, supple-
mentary motor area, and prefrontal area with prospectively programmed
patterns for appropriate stimulations.
3.4 APPLICATIONS IN MEDICINE
3.4.1 Diagnosis of Nervous System
The most popular method of the magnetic stimulation to examine the
nervous system is the measurement of central motor conduction time
(CMCT).24 The CMCT is the time taken for neural impulses to travel
through the central nervous system on their way to the target muscles.
In this method, the primary motor cortex (M1) is stimulated by TMS
and MEP is recorded. Subsequently, the nerve root on the neck or lumbar
is stimulated with recording MEP. Finally, the CMCTs with these MEP
latencies (cortex latency–spinal cord latency) are calculated. The delay of
CMCT reflects the disturbance of pyramidal tract.
A great number of TMS (or magnetic stimulation) studies for the
inspection of nerve disorders have been reported.25–32 Guillain–Barré syn-
drome (GBS) and chronic inflammatory demyelinating polyneuropathy
(CIDP) are the representative inflammatory demyelinating peripheral
nerve diseases. In several reports, TMS has been applied to these diseases
to inspect a conduction disturbance.25–27 Oshima et al.28 reported the use
of magnetic simulation as a tool to determine the involvement of the cor-
ticospinal tract in GBS patients with hyperreflexia. The authors examined
the central motor conduction, and the results revealed axonal motor neu-
ropathy and normal F-wave conduction in these patients. In this case, the
inspection of nerve conduction by the magnetic stimulation indicated the
functional corticospinal tract involvement in patients with a GBS variant.

Charcot-Marie-Tooth (CMT) disease is the representative inherited disor-
ders of the peripheral nervous system, and CMT has four variants. Clays
et al.29 reported the differences in CMCT in CMT variants using magnetic
stimulation. The CMCT in CMT1 showed a remarkable delay while that of
CMT2 delayed slightly. Diabetes leads to peripheral neuropathy. Tchen30
reported that TMS for diabetes showed a delay of CMCT. Maetzu et al.31
used TMS for diabetes and measured the CMCT based on the calcula-
tion using F-wave latency. The authors showed that motor transmissions
were not damaged in diabetic patients. Öge reported that CMCT extended
in n-hexane polyneuropathy,32 and Chokroverty stimulated the phrenic
nerve at the neck and root and showed that magnetic stimulation is poten-
tially useful for clinical application.33
3.4.2 Treatment of Neurological Diseases

3.4.2.1 Parkinson’s Disease
Parkinson’s disease (PD) is a neurodegenerative brain disorder that occurs
when neurons in the substantia nigra die or become impaired. Normally,
these cells produce dopamine, which allows smooth, coordinated func-
tion of the body’s muscles; therefore, less dopamine leads the patient with
less ability to regulate their movements and emotions.
In recent years, some clinical trials of single or rTMS for PD have been
performed. A pioneering study has been published by Pascual-Leone et
al.34 In the report, effects of 5-Hz rTMS on several neurological param-
eters such as choice reaction time (cRT), movement time (MT), and error
rate (ER) in a serial reaction-time task were investigated in six medicated
patients with PD and 10 age-matched normal controls. In normal subjects,
subthreshold 5-Hz rTMS did not significantly change cRT, slightly short-
ened MT, but increased ER. In the patients, rTMS significantly shortened
cRT and MT without affecting ER. The authors mentioned that the repeti-
tive, subthreshold motor cortex stimulation can improve performance in
patients with PD and could be useful therapeutically.
In animal experiments, Funamizu et al.35 demonstrated that rTMS
showed protecting effects on the lesioned rats by administering a neu-
rotoxin MPTP (l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine). Forty-
eight hours before rTMS treatment, MPTP was injected into the rats to
induce specific damages in dopaminergic neurons. Subsequently, the rats
received 1.25-T rTMS (10 trains of 25 pulses/sec for 8 sec) from the round
coil that is described in Section 3.3.4.1. The rTMS effects were examined
78 ◾ Biomagnetics
by histological studies at substantia nigra, which contains a high popu-

lation of dopaminergic neurons and checking the behavioral parameters
(functional observational battery-hunched posture score). The functional
observational battery-hunched posture score for the MPTP-rTMS group
was significantly lower and the number of rearing events was higher com-
pared with the MPTP-sham group. These behavioral parameters revert
to control levels (Figure 3.12a). The double-labeling immunofluoresence
experiments using tyrosine hydroxylase as the dopaminergic marker and
NeuN as the specific neuronal marker showed that the number of surviv-
ing dopamine neurons in the MPTP-sham rats were significantly reduced
compared with that of the substantia nigra pars compacta in the undam-
aged rats, while the number of those neurons in the MPTP-rTMS group
was significantly larger than the MPTP-sham group (Figure 3.12b). These
***
3.5
*** *
FOB-hunched posture score
2.5
1.5
0.5
0
(a) Control MPTP-sham MPTP-rTMS
### ***
90
80
TH positive neurons (%)
70
60
50
40
30
20
10
0
(b) Saline-sham MPTP-sham MPTP-rTMS
FIGURE 3.12 Effects of rTMS on MPTP-treated rats.35 (a) Functional observa-

tional battery (FOB) of hunched posture score during a 3-min observation period
in the home cage 3 days after administration of MPTP. (b) The percentage of TH
positive neurons.
results suggested that rTMS treatment reactivates the dopaminergic sys-

tem in lesion rats.
3.4.2.2 Neuropathic Pain
Neuropathic pain is caused by a lesion or dysfunction in the nerve systems.
The nerves affected by some abnormalities (e.g., stroke, cancer, diabetes,
and amputation) send wrong pain signals to the brain even without ade-
quate sensory input. Induced pain like burning, aching, stabbing, shoot-
ing, or shocking electrically is often described.36
As a treatment for the patients suffering neuropathic pain, the efficacy
of brain stimulation has been established. Tsubokawa et al.37 first applied
brain stimulation to patients with thalamic pain with implanting elec-
trodes into the cerebral cortex. In this clinical trial, the direct stimu-
lation of the motor cortex was effective for pain relief. Saitoh et al.38
reported that six out of eight patients experienced pain reduction as a
result of motor cortex stimulation, and this kind of stimulation might be
effective for treating peripheral as well as central deafferentation pain.
The direct stimulation of the motor cortex was effective for relieving
neuropathic pain, and the therapeutic effect was considered strongly
related to the stimulated area. The acquired pain relief supposed that
transmission of the pain signal was modulated by the stimulation of the
ascending nerve tracts.
In order to understand the mechanism of pain perception and the
therapeutic effect of brain stimulation, studies using PET and fMRI have
been performed in both animals and humans.39,40 The results of these
studies showed that brain stimulation of the motor cortex induced brain
activations at the areas of thalamus, cognitive cingulate, and insula. Pain-
relieving effect by brain stimulation is supposed to have a relationship
with brain activations of these areas.
As a noninvasive treatment method of brain stimulation for reliev-
ing neuropathic pain, rTMS has been introduced. Recent clinical studies
showed that stimulation of the motor cortex by rTMS is also effective in
relieving neuropathic pain. Saitoh et al.41,42 reported that the rTMS of the
precentral gyrus at frequencies of 10 Hz reduced pain significantly, com-
pared with lower stimulation of 1 or 5 Hz. The effect of rTMS at higher fre-
quency was greater in patients with a noncerebral lesion than those with
a cerebral lesion. These results indicate that patients with a noncerebral
lesion are more suitable candidates for high-frequency rTMS of the pre-
central gyrus.
80 ◾ Biomagnetics
The therapeutic effect of rTMS for pain relief also depends on the stim-
ulated area. Hirayama et al.41 examined several cortical areas of motor
cortex (M1), the postcentral gyrus (S1), premotor area (preM), and sup-
plementary motor area (SMA) as stimulation targets using a navigation-
guided rTMS. The authors reported 10 of the 20 patients (50 percent)
indicated that stimulation of M1, but not other areas, provided significant
and beneficial pain relief. That group’s result indicated that a significant
effect was lasting for 3 hours after the stimulation of M1 and stimulation
of other targets was not effective. Interestingly, this indicates the M1 is the
sole target for treating intractable pain with rTMS, whereas M1, S1, preM,
and SMA are located adjacently.
In the future, the motor cortex stimulation using rTMS will be recog-
nized as a treatment complementary to drug therapy.
3.4.3 Treatment of Psychiatric Diseases

A variety of clinical trials toward treatment of psychiatric diseases
using TMS have been performed in this decade. So far, treatments by
TMS for depression, schizophrenia, obsessive-compulsive disorder, and
attention-deficit hyperactivity disorder have been reported. Clinical use
of TMS for depression is the most widely investigated. Depression is a
disorder of the brain and is caused by a combination of genetic, bio-
logical, environmental, and psychological factors. Imbalance of neu-
rotransmitters, in particular, lack of serotonin, leads to depressive
illness. Administration of depression medications (antidepressants, e.g.,
selective serotonin reuptake inhibitors) is the prime choice for depres-
sion treatment. However, treatment-resistant depression still remains in
approximately 20 percent of the patients, and some of them show severe
clinical conditions. Electroconvulsive therapy (ECT) is a technique used
to treat patients with depression by injecting currents into the brain
through electrodes positioned on the surface of the head.43 To avoid
side effects such as the loss of memory function, TMS is considered as
a promising method for the treatment of depression in place of ECT
or as an alternative to ECT. In early times of the clinical trial, applica-
tion of single-pulse TMS to depression has been investigated. And then,
George et al.11 demonstrated rTMS treatment for six medication-resistant
depressed inpatients and two patients showed remarkable improvement
of clinical status. A number of studies have been performed for clini-
cal trials for depression treatments afterward. Important parameters
for treatment are stimulation sites and conditions. A prefrontal cortex
(left dorsolateral prefrontal cortex) is well known to exhibit therapeutic

effects by TMS in depression treatment.11 Fast (5–20 Hz) or slow (1 Hz)
rTMS with the intensity of 80–110 percent of the motor threshold are
commonly used for the treatment. However, fixed parameters have not
been reported and the prevention of seizures by rTMS is the most con-
cerning problem.
3.4.4 Development of Magnetic Stimulator for Home Treatment

Current magnetic stimulators are only operated by doctors and are avail-
able only at large hospitals. Therefore, only a limited number of patients
are able to be treated by rTMS. Moreover, the effect of rTMS is temporary,
and the brain must be treated at fixed intervals—everyday, if possible. The
development of inexpensive, compact, and energy efficient magnetic stim-
ulators that can be installed at a patient’s home is necessary to generalize
magnetic stimulation treatment.
Researchers have sought to find a method to increase the efficiency
of electromagnetic coils to induce magnetic stimulators operated at low
powers. Though a variety of coils have been proposed previously, these
coil designs have mainly aimed at controlling the region and depth of
stimulation rather than the application of magnetic fields at low driving
currents. To attain this objective, several papers have been published on
how to increase efficiency of the coil by changing its shape. Sekino et
al.44–46 made the center of the inner peripheral circle of each coil shifted
to the middle of the figure-eight coil to enhance the concentration of
electric field directly under the center of the figure-eight coil, as shown
in Figure 3.13. This coil design had an increased efficiency of 22 per-
cent and decreased heat generation in proportion of the square of the
current.
On the other hand, researchers have aimed to compensate the loss of
robustness to locational error arising from the high locality of the induced
electric field by adequately increasing the range where the electric field
deploys. In one approach, Yamamoto et al. 47 proposed a bowl-shaped coil.
They increased the uniformity of the induced electric field in the brain
by arranging the conductor along the surface of head. Additionally, the
intensity and range of induced electric coil is adjustable by changing the
density and coverage of the conductor.
To make magnetic stimulators inexpensive, researchers have focused
on improving the coil navigation system. In the conventional method, the
stimulator coil is placed above the target point using an infrared binocular
82 ◾ Biomagnetics
(a)
(b) (c)
FIGURE 3.13 (a) Formation of an eccentric spiral coil on a plastic insulator

case.47 (b) Finished eccentric coil equipped with a grip and a lead cable. Coil con-
ductors are observed through a 1-mm-thick insulator. (c) A prototype magnetic
stimulator system for home treatment.
camera. Unfortunately, this system is not suited to home treatment because

of its large size and cost. Accordingly, a compact and inexpensive position-
ing system has been developed.48 In this new system, glass that is attached
to the magnetic sensor has been developed. This system made it possible
not only to decide the position of the coil with higher accuracy by 5 mm
but also to decrease the size of the whole positioning system.
3.4.5 Safety of Magnetic Stimulation

Though it is generally recognized that TMS hardly causes adverse side
effects, there are several potential side effects to be avoided.49 The stimula-
tor coil produces acoustic noise that may exceed 140 dB. This is louder than
the maximum of the recommended safety level for the auditory system.
The patient and operator should use ear protectors. The rTMS may induce
a seizure; this is the most severe side effect. To be prepared in case of acci-
dental side effects, the operator should record the patient’s physiological
signals during stimulations. If the patient has metallic implants near the
stimulated region or has taken drugs that lower the threshold of seizure,
the rTMS should be avoided.

The focal and vectorial TMS is suitable for noninvasive and precise
investigation of brain function, and this technique has opened a new field
in neuroscience. TMS is a unique technique enabling external stimulations
to the brain of healthy subjects. The concept of a virtual lesion, combined
with a variety of tasks, is utilized as a powerful tool for elucidating
functional connectivity in the brain. If coils enabling stimulations to
deeper parts of the brain such as the hippocampus are developed, further
understanding of the brain function will be realized.
Clinical studies on therapeutic applications of rTMS are actively carried
out in the world. Trials for applying rTMS for neurological and psychiatric
diseases are carried out as a treatment complementary to drug admin-
istrations. Compact and low cost magnetic stimulators are in demand
because the treatments using rTMS require daily continuous stimulations
in many cases. Further evolution may occur if the control of gene expres-
sion using rTMS becomes possible, with facilitation or inhibition of syn-
apse formation or with expression of neuronal cell function around the
lesion. Treatment of osteoporosis and other orthopedic diseases will also
be explored. In parallel to the studies on the therapeutic effects of TMS
through accumulating results of clinical studies and animal experiments,
it is important to understand the mechanism of therapeutic effects using
EEG and MRI. Deep understandings of the mechanism will lead to a sys-
tematic investigation of stimulus conditions for achieving a high efficacy
and will realize a prior prediction of the efficacies for individual patients.
TMS involves various parameters such as coil geometry, target region,
repetition rate, intensity, and number of pulses. The optimal parameters
should be established for each disease. Safety of TMS needs to be discussed
further, incorporating up-to-date results of basic and clinical studies.
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Chapter 4
Biomagnetic
Measurements
Sunao Iwaki
CONTENTS
4.1 Introduction 90
4.1.1 History of Magnetoencephalography 90
4.1.2 Clinical Applications 91
4.2 Hardware 92
4.2.1 SQUID 92
4.2.2 Multichannel MEG System 93
4.3 Physiological Background of Biomagnetic Signals 94
4.3.1 Cortical Neural Activity 94
4.3.2 Current Dipole Modeling of Synaptic Activities 95
4.4 Formulation of MEG Signal Generation 96
4.4.1 Maxwell’s Equation and Primary Current 96
4.4.2 Dipolar Current in Volume Conductor 97
4.4.3 Boundary Element Method 98
4.4.4 Lead Field 99
4.5 Neural Source Reconstruction from MEG Signals 100
4.5.1 MEG Inverse Problem 100
4.5.2 Equivalent Current Dipole 101
4.5.2.1 Single ECD Model 101
4.5.2.2 Multidipole Model 101
4.5.2.3 Multiple Signal Classification 104
4.5.3 Distributed Source Imaging 105
4.5.3.1 Minimum-Norm Estimates 106
4.5.3.2 Beamformer 107
89
90 ◾ Biomagnetics
4.6 Examples of MEG Measurements 109

4.6.1 Visual Evoked Responses 109
4.6.2 Auditory Evoked Responses 110
4.6.3 Multimodal Neuroimaging 112
References 114
4.1 INTRODUCTION
4.1.1 History of Magnetoencephalography
By the end of the twentieth century, there were several methods developed
to measure human brain activities noninvasively. Magnetoencephalogra
phy (MEG) is one of the completely noninvasive techniques that records
distribution of magnetic fields generated by the neuroelectrical activities
of the human brain by using an array of ultrasensitive magnetic sensors
located around the scalp (Hämäläinen et al., 1993). Since the first recording
in 1929 (Berger, 1929), electroencephalography or EEG, which measures
distributions and temporal changes in the electric potential generated by
cerebral neural activities, was widely used both in clinical applications and
in research on the working human brain. MEG is the magnetic counter-
part of EEG that carries information complementary to that of EEG. More
specifically, MEG mainly records neuroelectrical activity whose dipolar
generator orients tangentially to the scalp, whereas EEG is sensitive to both
tangentially and radially oriented sources. Also, MEG is thought to be use-
ful to localize generators of the neural activities that lie in the cortical area.
In EEG, accurate estimation of source location is often difficult because
the distribution of electrical potentials on the scalp is severely affected by
complex inhomogeneity of conductivity in the head and the poor electri-
cal conductivity of the skull. On the other hand, spatial distribution of
the magnetic field mainly reflects neural currents that flow in the macro-
scopically relatively homogeneous intracranial space (Hämäläinen et al.,
1993). Under such favorable conditions where brain activity is modeled as
a single current dipole, the location of the neural source in the brain can
be determined within a few millimeters spatial accuracy.
Although the first MEG recordings were carried out by using an induction-
coil magnetometer (Cohen, 1968), measurements of MEG signals typi-
cally require more sensitive magnetic sensors such as the superconducting
quantum interference device (SQUID) (Jaklevic et al., 1964) because the
magnetic fields generated by the human brain activity are very weak, on
Biomagnetic Measurements ◾ 91
T (Tesla)
10–4 Geomagnetic field
10–6 Urban magnetic noise
10–8 Sensitivity of flux-gate magnetometer

10–10 MCG (magnetocardiography)
10–12 Spontaneous MEG (alpha-rhythm)

Event-related MEG
10–14 Sensitivity of SQUID magnetometer
FIGURE 4.1 Amplitudes of magnetic fields generated from typical biomagnetic

and environmental sources.
the order of 10–100 fT (femto-Tesla) (Figure 4.1). After the invention of

the SQUID magnetometer (Zimmermann et al., 1970), which is based
on the principle of superconductive tunneling (Josephson, 1972), and the
first measurements of MEG signals corresponding to human alpha-band
spontaneous brain activities (Cohen, 1972), SQUID systems have been
widely used for practical MEG signal recordings. First, recordings of the
event-related brain responses, which have smaller field strength compared
to the spontaneous activities, were conducted a few years later by using
SQUID magnetometers with signal averaging techniques (Brenner et al.,
1975; Teyler et al., 1975).
The history of the development of SQUID systems is described in detail
in Section 4.2.2.
4.1.2 Clinical Applications
Identifying the epileptic foci is the most prevalent use of MEG measure-
ments in the clinical applications that had been studied since the early
1980s (Barth et al., 1982; Hari et al., 1993; Nakasato et al., 1994). Patients
with recurrent and pharmacotherapy-resistant epilepsy could benefit from
epilepsy surgery in which resection of epileptic foci is involved (Choi et al.,
2008). In epileptic surgery, it is crucial to remove only the abnormal tissue
and preserve normal functional tissue especially in the cortical regions.
On the other hand, it is difficult to locate the epileptic foci even when the
abnormal structure such as vascular malformation is detected by using
other imaging modalities. Also, the abnormal tissues including epileptic
foci are often surrounded by eloquent brain areas responsible for essen-
tial functions such as language. For these reasons, it is important to pre-
cisely locate the epileptic foci and dissociate the abnormal area from the
92 ◾ Biomagnetics
surrounding intact tissues before surgery. MEG is one of the techniques

used for the pre-surgical evaluation. Especially after the helmet-shaped
SQUID magnetometer with whole-scalp coverage became commercially
available, MEG has been routinely used as a tool to localize the epilep-
tic foci (Stefan et al., 2003) and to optimize placement of intracranial
electrodes to map brain functions around the foci for surgical planning
(Knowlton et al., 2009).
Although pre-surgical evaluation for epileptic patients is the most com-
mon clinical application of MEG, there are several other clinical fields
where MEG shows promise (Hari and Salmelin, 2012). There are accumu-
lating evidences suggesting that MEG could be used for monitoring stroke
recovery (Rossini et al., 2004; Forss et al., 2011) and objective evaluation
of chronic pain (Ploner et al., 2002; Kakigi et al., 2003; Raij et al., 2004).
Research on MEG application to human language functions are also being
conducted. Some examples show possible use of MEG in determining lan-
guage lateralization (Papanicolaou et al., 2004; Pirmoradi et al., 2010),
which is originally performed by using an invasive method (Wada test)
(Wada, 1949) before brain surgery, or in diagnosing language disabilities
such as dyslexia (Salmelin et al., 1996; Helenius et al., 1999).
4.2 HARDWARE
4.2.1 SQUID
Although the first MEG recordings were carried out by using an induction-
coil magnetometer (Cohen, 1968), measurements of MEG signals typically
require more sensitive magnetic sensors such as a superconducting quan-
tum interference device (SQUID) (Jaklevic et al., 1964). The SQUID is a
superconducting ring with one (dc SQUID) or two (RF SQUID) insulating
layers to form Josephson junction (Josephson, 1972). In the current instru-
mentation of MEG system, dc SQUID, which has more sensitivity to tiny
changes in the magnetic field compared to RF SQUID (Clarke et al., 1976),
is usually used. The dc SQUID has a couple of Josephson junctions in par-
allel in the superconducting ring (Figure 4.2). Without external magnetic
flux passing through the SQUID ring, the input bias current Ib is split
equally between both junctions. When a small external magnetic field
is applied to the SQUID ring, Josephson junctions, which are character-
ized by the maximum critical current, limit the flow of induced currents
without losing the superconductivity and magnetic flux quantization that
occurs in the superconducting ring where magnetic flux through the ring
Ib
V
I0 Φ I0
FIGURE 4.2 Schematic diagram of dc SQUID where Ib is the bias current, I0

is the critical SQUID current, Φ is magnetic flux passing through the SQUID
superconducting ring, and V is the output voltage to the flux Φ.
must be an integral multiple of the so-called flux quantum (Φ0 = h/(2e) =

2.07 × 10−15 Wb). Under a constant biasing current Ib, measured voltage
oscillates with the changes in phase at the two junctions, depending on
the change in the magnetic flux, where one period of voltage variation
corresponds to an increase of one flux quantum. Thus, the change in the
magnetic flux is evaluated by counting the oscillations (Clarke, 1994). By
attaching a flat coil of superconducting wire called flux transformer, the
current induced in the SQUID ring can be increased, which results in the
increased sensitivity to detect the magnetic fields smaller than 10−15 T,
thus enabling measurements of brain magnetic fields.
4.2.2 Multichannel MEG System

Until the early 1980s, most of the MEG systems had single-channel SQUID
coupled with gradiometric pickup coils to compensate for large changes in
ambient magnetic fields or external magnetic noise (Figure 4.1). After the
mid-1980s, there had been an extensive effort to build multichannel MEG
systems. First, multichannel SQUID magnetometers, which have four to
seven sensor channels covering an area of a few centimeters in diameter,
were built between the mid- and late 1980s (Ilmoniemi et al., 1984; Romani
et al., 1985; Williamson et al., 1985; Knuutila et al., 1987; Ohta et al., 1989).
From the late 1980s to the early 1990s, several private companies as
well as academic institutes developed multichannel SQUID systems hav-
ing larger spatial coverage of 10 cm in diameter or more, which usually
covers most of the human hemisphere, with more than 20 SQUID mag-
netometers (Kajola et al., 1989; Hoenig et al., 1991; Pantev et al., 1991). In
these systems, either axial or planar gradiometers were used, where pairs
of oppositely wound coil is connected in series so that the sensor becomes
94 ◾ Biomagnetics
Axial gradiometer Planar gradiometer
FIGURE 4.3 Gradiometric pickup coils to reduce disturbance from the external
magnetic noise.
insensitive to uniform magnetic field generated far away from the sensor
(Vrba et al., 1982; Duret and Karp, 1984) (Figure 4.3).
The first helmet-shaped MEG system with whole-scalp coverage using
122-channel planar-gradiometer SQUID sensor array was built in 1992
(Ahonen et al., 1993); it enabled users to monitor the entire cortical neu-
ral activities simultaneously. Since the early 1990s, several manufactur-
ers made the helmet-shaped MEG systems commercially available (Vrba
et al., 1993; Kado et al., 1999). Currently, systems with more than 300
SQUID sensors are available and are being used in many academic and
clinical institutes.
4.3 PHYSIOLOGICAL BACKGROUND
OF BIOMAGNETIC SIGNALS
4.3.1 Cortical Neural Activity
The human brain is composed of neurons and glial cells. The glial cells
work primarily for the structural support for neurons and for regulating
the internal environment by maintaining the concentration of cerebro-
spinal fluid and transporting substances between blood vessels and neu-
rons to keep them working. Neurons are the electrically excitable cells that
process and transmit information in the brain. The neuron is composed
of a cell body (soma), dendrites, and an axon. The soma and dendrites are
mostly located in the gray matter, which is distributed on the surface of
the cerebral cortex. Inside the gray matter is a tissue called white mat-
ter that mostly consists of the glial cells and the myelinated axons, which
connects between different brain structures. The distal terminal of the
axon is connected to the dendrites of another neuron through synapse
and transmits impulses by sending the neurotransmitters to postsynaptic

receptors of the next neuron. When the neurotransmitters reach the post-
synaptic neuron, electrochemical reaction changes the permeability of the
postsynaptic membrane to specific ion, which causes a current along the
interior of the postsynaptic neuron and results in the depolarization of
the postsynaptic neuron and an excitatory postsynaptic potential (EPSP).
4.3.2 Current Dipole Modeling of Synaptic Activities

Because the cortical pyramidal neurons, which are major generators of
EPSP, are spatially aligned parallel to each other and oriented perpendicu-
lar to the cortical surface, the resultant direction of the electrical current
flow in the dendrite becomes also perpendicular to the cortical surface.
Observed from a distance, the local postsynaptic activity is well mod-
eled by a current dipole oriented perpendicular to the cortical surface.
Hämäläinen et al. discussed how the equivalent current dipole amplitude
for a single PSP is comparable to approximately 20 fA m, and they con-
clude that the estimated dimension of the “active” area required to gener-
ate typical magnetic field strength outside of the head is tens of square
millimeters or on the order of 10 nA m in terms of a local equivalent cur-
rent dipole strength (Hämäläinen et al., 1993; Chapman et al., 1984) (see
Figure 4.4).
Another major electrical activity of the neuron is the action poten-
tial, which travels along the axon and is characterized by a wave of depo-
larization followed by a repolarization and typically modeled by a pair
of oppositely oriented dipoles in proximity whose magnitude is about
100 fA m. Because the two dipoles have opposite direction, they form a
current quadrupole, whose magnetic field strength rapidly diminishes
with distance as 1/r3 compared to the 1/r2-dependent dipolar field of
Dendrites Soma
Axon
Brain magnetic field

Neural current
FIGURE 4.4 Equivalent current dipole model of the cortical neural activity.
96 ◾ Biomagnetics
synaptic activity. Further, temporal summation for action potentials that

lasts only about 1 msec is less effective than the synaptic potentials that
have a duration of tens of milliseconds. Thus, MEG signals are mostly
generated by the synaptic activities (Hämäläinen et al., 1993).
4.4 FORMULATION OF MEG SIGNAL GENERATION

4.4.1 Maxwell’s Equation and Primary Current
Section 4.3.2 described that the local cortical activities are modeled as
an equivalent current dipole. Suppose that the macroscopic conductivity
distribution σ(r) and the spatial configurations of the source dipoles are
known. Then MEG field distributions as they are measured outside of the
head can be calculated from Maxwell’s equation.
In the macroscopic point of view, the current density distribution J(r)
generated by the electrical activities of the cortical neurons can be divided
into two components, namely, the primary current Jp(r) and the volume
current Jv(r). The volume current is a component that is produced by the
electric field, which is formed by the primary electrical activities of the
neurons, in the volume conductor.
J(r) = Jp(r) + Jv(r) = Jp(r) + σ(r)E(r) = Jp(r) − σ(r)∇V(r) (4.1)
where E(r) is the distribution of the electric field, which is to be replaced

by the gradient of the electric scalar potential V(r). It is the distribution
of primary current Jp(r) that should be estimated from the MEG data to
locate the brain activity.
We can assume that the magnetic permeability is homogeneous through-
out the biological tissues under consideration including scalp, skull, cere-
brospinal fluid, and brain, and is the same as that of free space μ(r) = μ0. We
can further assume that the quasi-static approximation on the Maxwell’s
equation in our frequencies of interest, which is typically less than 1 kHz,
i.e., temporal derivatives of E and B, can be ignored (∂E/∂t = 0, ∂B/∂t = 0).
As we discussed in Section 4.3.2, the local synaptic activity is modeled
as an equivalent current dipole. Suppose there is local activity at rQ; then,
the primary current distribution can be described as
Jp(r) = Q · δ(r − rQ) (4.2)
where δ(r) is the Dirac delta function and Q is the amplitude of the equiva-
lent current dipole.
4.4.2 Dipolar Current in Volume Conductor

From Maxwell’s equation and Biot-Savart’s law, the magnetic field out-
side of the head B(r) for given primary current distribution Jp(r′) is calcu-
lated. This is called the biomagnetic forward problem. Under quasi-static
approximation, the magnetic field distribution is written as
µ0 J(r ′)× R
B(r) =
4π ∫ R3
d v ′ (4.3)
where r is the point where the magnetic field is calculated (outside of

the head), r′ is the primary current source location, and R = r – r′ (see
Figure 4.5).
Suppose the volume conductor, in which the primary and the volume
currents are distributed, consists of several compartments Gi, i = 1, …, m,
each of them has homogeneous conductivity σi. The boundary between
compartments Gi and Gj is defined by a surface Sij. Then, the biomagnetic
forward problem can be formulated as (Hämäläinen et al., 1993)
(σ i + σ j )V(r) = 2σ 0V0 (r)+

1
2π ∑(σ − σ )∫ V(r ′)dΩ (r ′) (4.4)
ij
i j r
Sij
B(r) = B 0 (r)+
µ0
4π ∑(σ − σ )∫ V(r ′) RR × dS′ (4.5)
ij
i j 3 ij
Sij
Measured magnetic field
J(r´) B(r) B(r)·n

V
R
r´ n
r Pickup coil
B: Magnetic field produced by

neuroelectric current
n: A normal vector of the pickup
coil surface
FIGURE 4.5 Configuration of the neural source and the magnetic field
measurement.
98 ◾ Biomagnetics
where V0 and B0 are the distributions of the electric potential and the mag-
netic field produced by Jp and are calculated as (Geselowitz, 1967)
∇′ ⋅ J p
∫ ∫
1 1 1
V0 (r) = − J p (r ′)⋅ ∇′ d v ′ = d v ′ (4.6)
4πσ 0 R 4πσ 0 R
G G
µ0 p
∫
R
B 0 (r) = J (r ′)× 3 d v ′ (4.7)
4π R
G
If the volume conductor is assumed to be spherically symmetric, where

the distribution of the conductivity can be described as σ(r) = σ(r), the dis-
tribution of the magnetic field B outside of the conductor can be calculated
analytically without solving partial differential equations (Ilmoniemi et
al., 1985; Sarvas, 1987).
µ 0 FQ × rQ − (Q × rQ ⋅r)∇F(r,rQ )
B(r) = (4.8)
4π F(r,rQ )2
where
F(r, rQ) = a(ra + r2 − rQ · r) (4.9)
∇F(r, rQ) = (r−1a2 + a−1a · r + 2a + 2r)r − (a + 2r + a−1a · r)rQ (4.10)
a = (r − rQ), a = |a|, r = |r| (4.11)
The notable characteristics of the spherical volume conductor are that

radially directed primary current does not generate any magnetic field
and that a primary current located at the center of the sphere also does not
produce any magnetic field outside of the conductor.
4.4.3 Boundary Element Method

Chapter 3 describes the calculation of the MEG distribution under the
assumption that the human brain is modeled as a spherical volume con-
ductor. When computing the MEG distribution for a volume conductor
with arbitrary shape, we have to employ numerical techniques to solve
Equation 4.4. One of the techniques to numerically solve the partial
differential equation is to use the boundary element methods (BEM). In

using BEM, we first need to create triangle mesh by segmenting the bound-
ary surface Si surrounding the compartments with different conductivi-
ties Gi (triangulation). Suppose the surface Si is divided into ni triangles
∆ ik (k = 1, …,ni ), the continuous equation (Equation 4.4) can be discretized
as follows (Barnard et al., 1967; Oostendorp and van Oosterom, 1989).
ni
V =
i
∑ H V + g (4.12)
j=1
ij j i
where vector gi and matrix Hij are described as
∫
1 2
g ki = V0 (r ′)d S ′i (4.13)
µ k σ i + σ i+
i −
∆ ik
1 σ −j − σ +j 1
H klij =
2π σ i− + σ i+ µ ik ∫ ∆ ik
Ω lj (r ′)d S ′l (4.14)
σ i− and σ i+ are conductivities of inside and outside of the surface Si, µ ik is

the area of the kth triangle on the surface Si, and Ω l (r) is a solid angle of
j
the triangle ∆ k from the point r (van Oosterom and Strackee, 1983).
i
In solving the linear system Equation 4.12, the inverting matrix becomes
singular reflecting the arbitrariness in determining the reference point to
define the potential distribution. The mathematical technique called defla-
tion can be used to avoid this singularity issue (Lynn and Timlake, 1968).
After obtaining the distribution of the potential distribution V on each
surface, the magnetic field distribution can be calculated by directly inte-
grating Equation 4.5 on the discretized surfaces.
4.4.4 Lead Field
Section 4.4.3 describes the numerical methods to calculate spatial dis-
tribution of the electrical potential on the scalp (i.e., EEG) and the mag-
netic field outside of the head (i.e., MEG) for given primary neural current
distribution Jp. As shown in the equations, there is a linear relationship
between MEG distribution B and amplitudes of the primary current dis-
tribution Jp. Suppose bi is the amplitude of the magnetic field measured by
100 ◾ Biomagnetics
the ith sensor. Then, bi is written as a weighted integration of the sensitiv-

ity of the sensor in the volume conductor where the primary current is
distributed.

∫
bi = Λ i (r)⋅ J p (r)dv (4.15)
where vector field Λi is usually called the “lead field.” The lead field is
uniquely defined by the conductivity distribution σ(r) and the configura-
tion of the magnetic field sensor (i.e., location of the sensor and the direc-
tion of the pickup coil).
When employing a set of equivalent current dipoles shown in Equation
4.2 as a model of primary current distribution, the MEG signal generated
by the n current dipoles with dipole moments Q j located at rQ j (j = 1, …, n)
and measured by ith sensor is described as
bi = ∑ Λ (r
j=1
i Qj ) ⋅Q j (4.16)
4.5 NEURAL SOURCE RECONSTRUCTION

FROM MEG SIGNALS
4.5.1 MEG Inverse Problem
The problem to estimate the neural current distribution from the spatio-
temporal characteristics of measured MEG data is called the biomagnetic
inverse problem (Figure 4.6).
In general, the problem to reconstruct the internal current distribu-
tion from the measurements of the electric potential or the magnetic field
conducted outside of the conduction medium does not have a unique
solution (an ill-posed problem). This is obvious from the fact that there
are certain configurations of the primary current distribution that do not
generate any magnetic fields outside the conducting medium (a magneti-
cally “silent” source). One example of those magnetically silent sources
is the radial dipolar current source in the spherically symmetric con-
ductor. In solving the ill-posed inverse problem, we must impose addi-
tional mathematical and/or physiological constraints to obtain a unique
solution.
J Forward problem
B = f(J) + n
Source current Measured

distribution magnetic field
Noise
Bm = fˆ(x)
Inverse problem
Source current Measured
distribution magnetic field
FIGURE 4.6 Forward and inverse problems in biomagnetism.
4.5.2 Equivalent Current Dipole

Modeling the primary current distribution by using a small number of
equivalent current dipoles is a common technique to impose additional
constraints to the ill-posed biomagnetic inverse problem. The dipole
model was first introduced to biomagnetism to localize the primary cur-
rent source of somatosensory evoked magnetic field (Brenner et al., 1978)
and has been used until today to locate neural sources with relatively sim-
ple spatial configuration.
4.5.2.1 Single ECD Model

Single ECD is the simplest form of an equivalent dipole model to describe
an internal neural generator. In the early days, the dipole parameters, i.e.,
location, amplitude, and orientation, had been estimated from the geomet-
ric characteristics of the field pattern, where the dipole lies directly below
the midpoint between the two field extrema with its direction normal to
the plane passing through the extrema. The depth of the dipole can be
estimated from the distance between the extrema d as d 2 . The standard
procedure to estimate the dipole parameters is to use the iterative nonlin-
ear parameter optimization algorithm such as the Levenberg-Marquardt
method (Levenberg, 1944; Marquardt, 1963). Details of the parameter esti-
mation are described in a more general form in the next section.
4.5.2.2 Multidipole Model
In the multiple dipole model of the primary current distribution, we
assume that the distribution of the measured magnetic field is generated
by a set of n dipoles with their moments Q j (j = 1, …, n) and located at rj.

Suppose the predicted magnetic field distribution generated by n ECDs
as bmodel and the measured field as bmeas. Then, bmodel is calculated by the
forward equation (Equation 4.16). The nonlinear least squares parameter
fitting technique (Marquardt, 1963) is applied to obtain a set of dipole
parameters, which minimizes the difference between the predicted and
the measured field distributions (Figure 4.7),
2
E = b meas − b model (4.17)
One way to evaluate the validity of the obtained model is to calculate

the goodness-of-fit index,
2
b − b model (4.18)
g = 1− meas 2
b meas
which indicates how well the field pattern predicted by the equivalent
dipoles agrees with that measured in the experiment.
Another important point in using the multidipole model is how to
determine the number of dipoles to explain the current field distribution.
Typically, multiple sources with their distance larger than a few centi-
meters show field patterns that have only minor overlap if their orienta-
tions are favorable. In these cases, location, amplitude, and orientation of
each primary source may be estimated successfully by applying the single
a a´
Source Sink
d
a a´
d/√2
FIGURE 4.7 Simple geometric method to estimate location of the single ECD
from magnetic field distribution.
dipole model separately. On the other hand, if the field pattern does not
show obvious separation between sources, spatiotemporal characteristics
of the measured MEG data may be used to estimate the number of active
source dipoles (Scherg, 1990 for review) to be assumed in the multidipole
model. The standard method to estimate the number of active sources in
the measured spatiotemporal MEG data is to use singular value decompo-
sition (SVD) (de Munck, 1990).
Bmeas = USV (4.19)
where Bmeas is a m × L spatiotemporal MEG data measured by m sensors at

L time points Bmeas = [b1, b2, …, bL], S is a diagonal matrix of the singular
values, and U and V are the unitary matrices containing left and right
singular vectors, respectively. Suppose si (i = 1, …, m) are the singular val-
ues set in descending order. Then the square error between measured and
predicted fields as expressed in Equation 4.17, where we assume r equiva-
lent current dipoles to explain the spatiotemporal characteristics of the
measured magnetic fields, can be calculated from the sum of squares of
the least m − r significant singular values,
Emin ≥ ∑s
i=r+1
2
i (4.20)
and the resulting goodness-of-fit index is estimated by
∑s 2
i
g≤ i=1
m (4.21)
∑s
i=r+1
2
i
The adequate number of equivalent current dipole r may be determined

from the behavior of square error as shown in Equation 4.20 when r is
changed. Some criteria in choosing a reasonable number of singular val-
ues r are reported in reference to the noise level of the measurements (Wax
and Kailath, 1985) (see Figure 4.8).
Dipole ∆pi+1 = pi – ∆d ∂E
parameters ∂pi
Nonlinear
parameter bmeas – bmodel
GOF = 1 – 100 [%]
optimization bmeas
Calculated E Measured
Forward data Error data MEG
model calculation system
bmodel bmeas
FIGURE 4.8 Schematic diagram of the standard technique to estimate dipole

parameters by using the iterative nonlinear parameter optimization algorithm.
4.5.2.3 Multiple Signal Classification

In optimizing ECD parameters in the multidipole model, the global minimi-
zation of Emin sometimes cannot be achieved because the optimization step
may get caught in a local minimum especially when the measured field pat-
terns are relatively complex. To avoid the convergence to the local minimum,
several optimization techniques such as the simulated annealing (Kirkpatrick
et al., 1983) and the genetic algorithm (McNay et al., 1996) had been employed.
Also, in these cases, it is usually difficult to determine the initial dipole loca-
tions where the optimization algorithm starts and is frequently dependent on
heuristic or empirical methods. One approach to search optimal locations of
multiple source dipoles is to use an algorithm called the multiple signal clas-
sification (MUSIC) (Mosher et al., 1992), which is originally developed to pro-
cess signals from antenna array (Schmidt, 1986). Application of the MUSIC
algorithm to the biomagnetic inverse problem is based on a separation of spa-
tiotemporal measured data into signal and noise subspaces and on the three-
dimensional search of the suboptimal estimates for multiple dipole locations.
First, eigendecomposition is applied to the covariance matrix of the
spatiotemporal measured data, which is obtained by R meas = B meas B meas to
T
determine the separation between signal and noise subspaces.
⎡ Ds ⎤ ⎡ Vs ⎤
R meas = VDV T = [ Vs Vn ] ⎢ ⎥⎢ ⎥ (4.22)
⎢⎣ Dn ⎥⎦ ⎢⎣ Vn ⎥⎦
where Ds is a diagonal matrix containing r most significant eigenvalues

of the signal subspace, Vs is corresponding eigenvectors that span a signal
subspace, Dn is a diagonal matrix of eigenvalues of the noise subspace, and
Vn is corresponding eigenvectors for noise subspace.
Next, MUSIC cost function, which has multiple maxima at the loca-
tions of the active sources, are calculated on the grid points covering the
entire source space. Because the noise subspace is orthogonal to the lead
field at the correct source location, the possible distribution of the active
sources can be obtained by scanning the orthogonality Si between lead
field Λi and the noise subspace projector P⊥ = Vn Vn at each grid point i.
T
2
Si = P⊥ ⋅ Λ̂ i (4.23)
F
where Λ̂ i is the normalized lead field at grid point i and is written as

Λ̂ i = Λ i Λ i . Under ideal conditions where we can ignore noise, Si ap
proaches 0 at the exact dipolar source location. Contour plot of 1/Si, which
is also called the MUSIC localizer (Sekihara et al., 1998), illustrates the
distribution of possible source dipoles in the three-dimensional space.
Because the scanning of the MUSIC localizer does not require an itera-
tive optimization procedure, the search for the location of active source
dipoles should not be time-consuming.
The basic assumption of the MUSIC algorithm is that the correlations
between the active sources located in different positions are negligible.
Under such conditions where this assumption does not hold, it is impos-
sible to appropriately separate the signal and noise subspaces from the
spatiotemporal measured data that may severely distort spatial distribu-
tion of the MUSIC localizer (see Figure 4.9).
4.5.3 Distributed Source Imaging

In the previous section, ECD models to solve biomagnetic inverse problems
were discussed. The explicit assumption in using the ECD model is that the
relevant neural activities are approximated by the set of small number of
focal neural sources. There is an alternative approach to solve the biomag-
netic inverse problem by using a more general form of the neural source
configuration in which a large number of local ECDs are distributed in the
entire brain volume or on the cortical surface (the distributed source model).
Suppose Q = [q1, q2, …, qN] as N local current dipoles to describe primary
current distribution and bmeas = [b1, b2, …, bM] as the MEG field distribution
Scanning grids
Measured data matrix: Bmeas
(a) Separate signal/noise subspaces

T T
Rmeas = BmeasB meas = VDV
D
= [Vs Vn] s [VsVn]T
SQUID sensors Dn
(b) Evaluate cost function
Svi = ||VnVnTΛi|F2
Λi
Svi ≠ 0
Svi → 0
(c) Locate current dipoles
Source location
FIGURE 4.9 Schematic diagram of the multiple signal classification (MUSIC)

algorithm applied to the biomagnetic inverse problem.
measured at M sensors, and Λ = [Λ1, Λ2, …, ΛM] as the lead field matrix, the
MEG forward model for distributed source model is written as
bmeans = Λ · Q + n (4.24)
where n is the noise in the measured data.
4.5.3.1 Minimum-Norm Estimates
The linear equation (Equation 4.24) does not generally have a unique solu-
tion because of the underdetermined nature of the system. The number of
parameters to be estimated (N) is on the order of thousands, whereas the typi-
cal number of equations, which corresponds to the number of sensors (M),
is on the order of hundreds at most. In the traditional inverse formulation, a
“minimum-norm constraint” is commonly employed in which the least norm
solution is selected from among the possible set of solutions (Hämäläinen and
Ilmoniemi, 1984). The solution under minimum-norm constraint is given by
ˆ = Λ − b meas (4.25)
Q
where Λ− is the generalized inverse (Menke, 1984) of the lead field matrix
and is written as
( )
−1 −1 −1
Λ − = ( Wc WCT ) ΛT Λ ( Wc WCT ) ΛT + γ 2 I (4.26)

The diagonal matrix Wc contains the weighting factors for “depth nor-
malization” to avoid minimum-norm solution bias toward superficial
locations (Jeffs et al., 1987), and γ is a regularization parameter that con-
trols the degree of regularization and is determined in accordance with
the signal-to-noise ratio of measured signal. Using this method, the solu-
tion Q̂ that minimizes the objective function,
2 2
Ec = b meas − b model + γ 2 Wc Q̂ (4.27)
is selected for the reconstructed current distribution (Menke, 1984). Here,

bmodel is the field distribution predicted by the reconstructed neural cur-
rent distribution Q̂ . Selecting the appropriate weighting factors Wc in
Equations 4.26 and 4.27 (i.e., small weighting values for deep current loca-
tions and large values for shallow locations), the bias in the solution toward
superficial sources can be equalized. However, in general, the optimal set
of regularization parameters and weighting factors is difficult to derive
theoretically and is highly dependent on detailed measurement geometry
(Jeffs et al., 1987). Some methods that handle this difficulty with iterative
algorithms have been proposed (Gorodnitsky et al., 1995; Srebro, 1996).
The simplest form of obtaining the depth weighting factor Wc is derived
directly from the lead field matrix for each possible source location i as
Wc = diag{||Λi2||} (4.28)
where ||a2|| indicates the L2 norm of vector a.

The diagonal weighting matrix Wc can be also used to introduce prior
information obtained by other neuroimaging modalities such as struc-
tural magnetic resonance imaging (MRI) and functional MRI (fMRI) into
the source space when solving the biomagnetic inverse problem (Dale and
Sereno, 1993; Dale et al., 2000; Iwaki et al., 2013).
4.5.3.2 Beamformer
Beamformer is an adaptive array signal processing technique originally
developed for radar and seismic research (van Veen and Buckley, 1988).
Beamforming techniques can be successfully applied to form an adaptive
spatial filter to extract time series that arise from the neural activity at a
specific brain location and block the signal from other parts of the brain
with linear weighted sum of the MEG signals measured by the sensor
Beamforming
FIGURE 4.10 Beamforming technique to extract neural activity at a specific

location by adaptive spatial filtering.
array. In this section, we discuss the technique to design linearly con-

strained minimum variance (LCMV) beamformer (van Veen et al., 1997)
to be used to map the neural activities from MEG data (see Figure 4.10).
For the LCMV beamformer, we design a spatial filter for each point cov-
ering the whole cortical region by selecting the filter weights that minimize
total signal power but at the same time do not suppress the MEG signal
arising from the neural activity at the specific point. This is accomplished
by solving the minimization problem below (van Veen et al., 1997).
{ } {
min trace ⎡⎣ C ( y(r0 )) ⎤⎦ = min ⎡⎣ FT (r0 )C(B)F(r0 )⎤⎦
F( r0 ) F( r0 )
}

subject to FT(r0) · Λ(r0) = I (4.29)
where F(r0) is the filter weights for the cortical point of interest r0, C(y(r0))
is a covariance matrix of the neural activity at r0, which is not observable,
C(B) is a covariance matrix of the spatiotemporal measure data B, and
Λ(r0) is a lead field vector at r0. By using the methods of Lagrange multipli-
ers, the solution for the minimization problem is obtained as
F(r0) = [ΛT(r0)C−1(B)Λ(r0)]−1ΛT(r0)C−1(B) (4.30)
Applying linear filter F(r0) to the measured spatiotemporal MEG data

B, the time series of the neural activity at r0 are estimated as
ŷ(r0 ) = F(r0 )B (4.31)

4.6 EXAMPLES OF MEG MEASUREMENTS

This section describes some examples of MEG application on the cogni-
tive neuroscience research.
4.6.1 Visual Evoked Responses

Here we present an example of visualizing human brain activity while
performing a three-dimensional (3D) mental image manipulation task in
which subjects were required to mentally rotate 3D objects (mental rota-
tion) (Shepard and Metzler, 1971; Cooper, 1973). The mental rotation pro-
cessing includes rotating and matching of a pair of 3D mental objects,
which is known to activate both extrastriate visual areas and the parietal
area as demonstrated by previous studies employing either positron emis-
sion tomography (PET) (Parsons et al., 1985) or functional MRI (Tagaris
et al., 1996). Some studies have used EEG or MEG measures to investigate
temporal characteristics of brain activity during mental rotation process-
ing; however, owing to the difficulty in estimating the distribution of neu-
ral sources associated with higher-order visual functions, most of these
studies could shed light only on the waveforms at the recording sites or on
the single ECD modeling of the possible generators (Peronnet and Farah,
1989; Kaufman et al., 1990). To overcome this difficulty, the weighted
minimum-norm approach as described in Equations 4.25 and 4.26 was
used to map brain activities in the visual area and parietal areas with high
temporal resolution from MEG data acquired during the mental rotation
processing (see Figure 4.11).
Figure 4.12 shows the results of neural source imaging obtained by the
weighted minimum-norm method (Iwaki et al., 2002). The neural activ-
ity in the primary visual area was followed by the activation in the lateral
posterior temporal regions (Brodmann’s area [BA] 19, 37) in the latency
range between 190 and 220 msec after the onset of mental rotation stimuli.
Activity in the intraparietal and inferior parietal areas (BA 7, 40) around
Rotation angle
(a) (b)
FIGURE 4.11 Examples of the visual stimuli used in the mental rotation task.
(a) Rotationally-symmetric pair. (b) Minor-reversed pair.
t = 180 msec
t = 210 msec
t = 240 msec
(a)
t = 180 msec
(b)
FIGURE 4.12 Results of the neural source imaging during the performance of
the mental rotation task obtained by the weighted minimum-norm method.
(a) Mental rotation. (b) Control.
240 msec was also observed. On the other hand, activity in the primary
visual area was detected in the control condition in which subjects were
not required to rotate the 3D objects (Iwaki et al., 1999).
This example suggests that the distributed source imaging techniques
such as weighted minimum-norm estimates are capable of visualizing
brain activities without a priori knowledge of the number of active sources
when they are located a few centimeters apart from each other.
4.6.2 Auditory Evoked Responses

The most prominent evoked response to the auditory stimuli is called the
N100 or N1 component that has a peak at about 100 msec after the onset
of the stimuli. Its magnetic counterpart N100m or N1m is also recorded
quite robustly by the MEG sensor covering the temporal cortex. Within
each hemisphere, the MEG field pattern shows that the source of N1m can
be well explained by a single ECD. The results of the single ECD estima-
tion in each hemisphere show that the neural sources of N1m located in
the primary auditory are in the Heschl’s gyrus on the superior temporal
gyrus (Figure 4.13).
The N1m component is evoked in response not only to the onset of the
auditory stimuli but also to the offset of the stimuli. This offset response
N1moff is also measured for the auditory language stream while the sub-
jects listened to (1) a series of spoken sentences and (2) white noise whose
amplitude was modulated by the envelope of the spoken sentences as con-
trol stimuli, and both included sudden and brief interruptions (Figure
4.14a). Auditory evoked magnetic fields corresponding to the interrup-
tion and resumption of the speech were measured. Statistically significant
enhancement was observed only in the N1m component of the auditory
evoked offset response (N1moff ) to the interruptions of the verbal stream
compared to the onset response (N1mon) to the resumptions of the stream
(Figure 4.14b) (Iwaki et al., 2012). These results suggest that the human
auditory cortex plays an important role in perceiving interruptions of ver-
bal streams.
Stimuli
(a)
(b)
FIGURE 4.13 (a) Waveforms and the spatial distribution of the N1m auditory
evoked magnetic fields. (b) Results of the neural source estimation from N1m
MEG distribution. The dipoles are located in the bilateral primary auditory
cortex.
Sound intensity (dB)

0 dB Interruption Resumption
–4 dB
–9 dB
–15 dB 500 msec
100 msec
2.90 3.00 3.10 3.20 3.30 3.40 3.50
(a) Elapsed time from the beginning of the recorded speech (sec)
Stimuli to the left ear Stimuli to the right ear Stimuli to the left ear Stimuli to the right ear
mean (+–SE) peak RMS amplitude (fT/cm)
mean (+–SE) peak RMS amplitude (fT/cm)

SPEECH NOISE SPEECH NOISE SPEECH NOISE SPEECH NOISE
200 200 200 200
Right hemisphere response

Left hemisphere response
150 150 150 150
100 100 100 100
50 50 50 50
N1moff
N1mon
N1moff
N1mon
N1moff
N1mon
N1moff
N1mon
N1moff
N1mon
N1moff
N1mon
N1moff
N1mon
N1moff
N1mon
(b)
FIGURE 4.14 (a) Typical acoustic waveforms of the sudden interruptions with
500 msec duration embedded in the natural spoken language stream. (b) Mean
and standard error of the N1moff and N1mon peak amplitudes elicited by the inter-
ruption of speech stream (SPEECH) and corresponding white noise (NOISE).
4.6.3 Multimodal Neuroimaging
Although MEG can record temporal changes of post-synaptic neural activity
with good temporal resolution (on the order of milliseconds), the principal
difficulty in interpreting MEG data is in reconstructing the spatial distribu-
tion of the neural activity in the brain from MEG spatiotemporal distribu-
tions measured at sensors located at a distance from the brain area from
which activity is being assessed. On the other hand, fMRI makes it pos-
sible to precisely visualize the spatial distribution of human brain activity
with a resolution that is typically approximately a few millimeters; however,
fMRI measures hemodynamic changes (blood oxygenation level dependent
[BOLD] signals) (Ogawa et al., 1990; Belliveau et al., 1991), which are an
indirect measure of neural activity. These changes peak a few seconds after
the onset of neural firing in an area; therefore, this technique has limited
temporal resolution. On the basis of these inherent limitations in each of the
measurement modalities, it is natural to combine data from both techniques
to enhance both the spatial and temporal resolutions. As stated in Section
4.5.3.1, the weighted minimum-norm technique can be used to impose
physiologically plausible constraints on the biomagnetic inverse problem by

introducing structural and functional MRI priors into the weighting matrix
when solving the underdetermined linear system (Equations 4.25 and 4.26).
The example shown here uses a combination of MEG and fMRI data as
well as a brain structure obtained from high-resolution structural MRI to
visualize human brain activity while perceiving 3D objects in 2D random-
dot motion images, which is usually called 3D structure perception from
motion or 3D-SFM (Wallach and O’Connell, 1953). Perception of a three-
dimensional object shape from visually presented moving dots requires
integration of the embedded movement and spatial information that acti-
vates both dorsal (i.e., the parieto-occipital [PO] and the intraparietal [IP]
regions) and ventral (i.e., the posterior inferior temporal [IT] region) visual
systems (Orban et al., 1999; Paradis et al., 2000; Beers et al., 2009); however,
the neural dynamics underlying the reconstruction of a 3D object from a 2D
optic flow is not known. The results of the fMRI statistical parametric map-
ping (SPM) analysis (Friston, 1998) were used to introduce plausible weights
in the weighted minimum-norm estimates (Liu et al., 1998) to obtain time-
resolved images of the brain activity during 3D-SFM (Figure 4.15).
150 msec Occipital visual area (V1/V2)
Parieto-occipital
junction
280 msec
(a)
Intra-parietal
area
340 msec
Inferior-
380 msec temporal area
(b)
FIGURE 4.15 (a) Example of the visual stimuli used in the 3D-SFM experiment.
(b) Results of the fMRI-weighted MEG inverse analysis in the typical subject
performing the 3D-SFM task. The blue circles denote the sites where we observed
the major neural activity during 3D-SFM processing.
The results show that the neural activity in the parieto-occipital, the
intraparietal, and the inferior-temporal regions as well as primary visual
area were increased during the 3D SFM at the latencies between 200
and 450 msec after the onset of visual motion (Iwaki et al., 2013). These
results demonstrate that the noninvasive multimodal neuroimaging, in
which structural and functional MRI data are incorporated into the MEG
inverse problem, is capable of visualizing neural dynamics of the human
brain with spatial accuracy comparable to fMRI without compromising
the excellent temporal accuracy of MEG (Iwaki, 2012).
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Chapter 5
Principles of Magnetic
Resonance Imaging
CONTENTS
5.1 Introduction 121
5.2 Magnetic Resonance Signal and Relaxation Times 123
5.2.1 Electromotive Force 123
5.3 Overview of the Spin-Warp Imaging Technique 127
5.3.1 Recognition of Nuclei Distributed in the First Direction 128
5.3.2 Recognition of Nuclei Distributed in the Second Direction 129
5.3.3 Recognition of Nuclei Distributed in the Third Direction 131
5.3.4 k Space 133
5.3.5 Image Contrast 135
5.4 Diversification of MRI Application Techniques 137
5.4.1 Magnetic Resonance Angiography 137
5.4.2 Perfusion and Diffusion Imaging 138
5.4.3 Functional Neuroimaging 140
5.4.4 Magnetic Resonance Spectroscopy 140
5.4.5 MRI of Other Nuclei than Protons 141
5.5 Concluding Remarks 142
References 142
5.1 INTRODUCTION
Magnetic resonance imaging (MRI) is a way of producing cross-sectional
images of the human body noninvasively. A proton (or hydrogen nucleus)
is spinning with a positive charge, and it is generating a magnetic flux in
the direction of the Ampere’s law. Therefore, protons can be regarded as
121
small, spinning magnets with north poles and south poles in Newtonian
physics. When a part of the body is exposed to a static magnetic field, each
spinning magnet makes a precession around the axis of the static mag-
netic field. If a radiofrequency (rf) wave is then transmitted, some of the
magnets begin to make a precession with the same phase of the transmit-
ted rf wave. This is the magnetic resonance (MR). In the resonating state,
a large number of magnets establish a large magnetic flux rotating around
the axis of the static magnetic field at the frequency of the transmitted rf
wave. The rf wave is then turned off, and subsequently an electrical coil
tuned at the proper rf frequency picks up the electromotive force (EMF)
before the rotating magnetic flux decays in amplitude. Resonance fre-
quency is proportional to the external magnetic field. Hence, modifying
the static magnetic field by using a gradient magnetic field, the position
of each proton can be distinguished, and a computer can reconstruct an
image from the EMF signal.
The first successful nuclear magnetic resonance (NMR) experiments
were reported by two independent groups in the United States (Bloch
et al., 1946; Purcell et al., 1946). In 1952, Purcell and Bloch received the
Nobel Prize for their observations. Since chemical shift phenomena were
discovered in the 1950s, NMR techniques were developed as important
tools for chemical analyses. The early experiments were limited in scope
by the relatively poor instrumentation available at that time. In the late
1960s, superconducting magnets were introduced to NMR experiments
and revolutionized the scope of NMR together with the emergence of
Fourier transform NMR (Ernst and Anderson, 1966). Lauterbur (1973)
published the first NMR image of two small tubes of water. By 1980, the
clinical evaluation of MRI had begun, and since that time, there have been
continuing developments in instrumentation and applications that have
led to where we are today. MRI is now established as an important modal-
ity in medical practice. The application techniques of MRI have diversified
in recent years. Those techniques are, for example, magnetic resonance
angiography (MRA), perfusion and diffusion imaging, and functional
neuroimaging (fMRI). Scanning time has been dramatically shortened.
Because there are clear attractions in using noninvasive methods for the
study of living systems, those MRI techniques that investigate the brain
and tissue characteristics appear to have a very bright future. Therefore,
in this chapter, we give an overview of the principles of MRI techniques.
Principles of Magnetic Resonance Imaging ◾ 123
5.2 MAGNETIC RESONANCE SIGNAL

AND RELAXATION TIMES
5.2.1 Electromotive Force
When protons are placed in a static magnetic field B0, the spinning nuclei
begin to make a precession. The phase of the precession is primarily gov-
erned by uncertainty, and the phases of each precession are at random.
Therefore, the direction of the net macroscopic vector of magnetization
M0 is expected to be that of the z axis, the axis of the external static mag-
netic field B0. When the radiofrequency (rf) field of the magnetic flux den-
sity B1 and the Larmor angular frequency ω 0, which is equal to γB0, is
applied to the nuclei for a duration Δt and in the direction of the x axis
perpendicular to the z axis, the spinning nuclei make a precession around
the x axis by the angle θ = γB1Δt, where γ is the gyromagnetic ratio of the
nuclei. This occurs because the B1 field is the only apparent field experi-
enced by the nuclei in the rotation frame (Figure 5.1). Thus, the vector of
magnetization M0 makes precession around the x axis, and the flip angle θ
is the phase of the macroscopic precession of the magnetization M0.
The sample is generally conductive. When a magnetic flux tries to pass
through the sample, eddy currents are generated in the sample to produce
Magnetization M0
Flip angle θ
= γB1Δt
FIGURE 5.1 Precession of the magnetization M0 around the x axis.

a counter magnetic flux, and this is experienced by the rf coil as the resis-
tance of the coil itself. When the electrical rf coil and the sample are sup-
plied with the rf power P, the current i* of the coil is i* = (P/R)1/2, where
R is the equivalent, gross resistance of the rf coil and the sample. If B1 is
defined as the magnetic flux density produced by a coil carrying unit cur-
rent, the magnetic flux density B1* = B1 ( P /R )1/2. The B1 value of the rf coil
can be determined also by the geometrical configuration of the rf coil.
Figure 5.2 shows the magnetization M 0* of a volume of interest (VOI) of
a sample at the time when the lip angle θ has been made 90 degree by the
rf field (B1 cos ω 0t) generated by the coil, carrying unit current i = cos ω 0t.
Magnetic resonance signals can be acquired with the same coil, and the
electromotive force (EMF) ξs induced by the magnetization M 0* is given by
( )
ξ s = −d B1* M 0* /dt

Because the rf field is B1 cos ω 0t, the EMF is exhibited by
ξ s = ω 0 B1 M 0* sinω 0t

The number N* of nuclei in the VOI is N* = 103 cvA, where A is Avogadro’s

number (6.02 ×1023), v is the volume of the VOI in m3, and c is the concen-
tration of nuclei in M. Then, M 0* = 103 cvAγ 2 (h/2π) 2 B0 I (I + 1)/3kT, where
z Main static field B0
Unit current i
= cos ω0t
Magnetization M0*
Main static field B0 = B1 cos ω0t
FIGURE 5.2 Magnetization M 0* just after the application of a 90° pulse.

h is Planck’s constant, I is the spin quantum number, k is Boltzmann’s

constant, and T is the temperature in Kelvin. If the concentration c, the rf
field B1 and the volume v of VOI are determined, then the EMF ξs can be
numerically calculated, because all other constants are known.
Proton density is an important source of the NMR signal that conveys
much information about the subject tissue. But the total NMR signal has
more information than the number of nuclei reflected in the amplitude of
the signal. Relaxation is the term given to a process of transition from an
unstable, high-energy state to a stable, low-energy state.
When proton nuclei are exposed to a static magnetic field B0, the indi-
vidual magnetic moments align parallel or antiparallel with the static
magnetic field B0. Spinning nuclei whose expected axes of precessions are
parallel with the static magnetic field B0 are called α nuclei and are in a
low-energy, stable state. Spinning nuclei whose expected axes of preces-
sions are antiparallel with the static magnetic field B0 are called β nuclei
and are in a high-energy, unstable state. In the state of thermal equilib-
rium, nuclei are in only one of those two states, and the number of α nuclei
is slightly greater than the number of β nuclei. As small as this slight excess
is, it accounts for the small macroscopic net magnetization M0 directing
parallel with the static magnetic field B0, and it is this differential that
accounts for the on which MRI is based.
When a 90 degree rf pulse is applied, α nuclei are excited and elevated
to the high-energy state, and the number of α nuclei becomes the same as
that of β nuclei. When a 180 degree rf pulse is applied, the number of β
nuclei becomes greater than that of α nuclei. If excited nuclei are left in the
thermal equilibrium, they will be allowed to lose energy to become low-
energy, stable α state. This is the process of T1 or longitudinal relaxation.
T1 relaxation is an exponential process, and T1 is the time constant of the
exponential process. T1 relaxation can be expressed as a macroscopic phe-
nomenon, dMz/dt = (M0 – Mz)/T1, where Mz is the z axis component of
the transitional magnetization. T1 relaxation is also the macroscopic phe-
nomenon where the magnetization is allowed to return to the initial state
of the thermal equilibrium. For example, the proton T1 value of the white
matter of the human brain is typically 690 msec at 20 MHz. When mol-
ecules are restricted in movement as in solids, T1 relaxation hardly occurs,
and T1 values are even as long as several hours. The nuclei are often the
elements of large molecules, and T1 values reflect the molecular structures.
Spinning nuclei, small magnets with north poles and south poles, affect
each other. Here, the magnetic flux density of the static magnetic field B0
actually experienced by a spinning nucleus is altered by other spinning

nuclei. For this reason, spinning nuclei placed in the same static magnetic
field B0 make precessions with slightly different frequencies, and phases of
precessions become incoherent. Thus, T2 relaxation takes place. T2 relax-
ation is also an exponential process, and T2 is the time constant of the
exponential process. T2 relaxation can be expressed as a macroscopic phe-
nomenon, dMxy/dt = −Mxy/T2, where Mxy is the component of transitional
magnetization perpendicular to the direction of the static magnetic field
B0. T2 relaxation is also the macroscopic phenomenon where the magneti-
zation decays in amplitude in the xy plane. By T2 relaxation, the amplitude
of EMF ξs becomes smaller and exhibits free induction decay (FID). The
FID signal ξs can be expressed as
ξs = ξs0 exp (iω 0t) exp (−t/T2)
and the initial value of the amplitude ξ s0 = ω 0 B1 M 0* . In contrast to T1 relax-

ation, the exchange of energy in T2 relaxation does not take place between
spinning nuclei and lattices but only among nuclei. For example, the pro-
ton T2 value of the white matter of the human brain is typically 110 msec.
T2 relaxation is accelerated in large molecules, and T2 values of the
nuclei of large molecules are generally short. T2 values of nuclei of small
molecules are also short when small molecules are combined to large mol-
ecules. For example, an anticancer drug fluorourasil solution exhibits a
sharp 19F resonance peak and has a longer T2 value than 200 msec, but
once it is incorporated into the liver cells, the T2 value becomes shorter
than 10 msec.
When the static magnetic field B0 is inhomogeneous, phases of nuclei
precessions become incoherent. This process appears like a relaxation and
( )
is called T2 star T2* relaxation.
By shimming, or improving the homogeneity of the static magnetic
ratio B0, the T2* value is made long. The FID signal ξs from nuclei in an
inhomogeneous static magnetic field can be expressed as
(
ξ s = ξ s0 exp(iω 0t)exp −t/T2* )
After nuclei are excited by a 90 degree pulse, the vector of magnetiza-
tion M0 on the xy plane begins to decay exponentially in amplitude by T2*
relaxation. However, if a 180 degree pulse follows immediately, the phases
90 degree pulse 180 degree pulse
T2/2 T2/2
ξs0
ξSE
T2* T2* t
T2
Echo time Te
FIGURE 5.3 Spin echo (SE) signal.
are refocused to be coherent and the nuclei generate an echo (Hahn, 1950).
This is the spin echo (SE) signal, and the 180 degree pulse is often called a
time-reversing pulse, because it refocuses the phases of nuclear precessions
as if time were reversed (Figure 5.3). The spin echo signal amplitude ξSE is
affected by T1 relaxation as a matter of course during the repetition time
Tr and the T2 relaxation during the echo time Te. ξSE is expressed as ξSE =
ξs0{1 − exp (−Tr/T1)}exp (−Te/T2). The SE signal ξs can be hence expressed as
(
ξ s = ξ s0 {1− exp(−Tr /T1 )}exp(−Te /T2 )exp(iω 0t)exp − t − Te /T2* )
The SE signal ξs has a feature where the amplitude is symmetrical in
regard to the echo time Te. Therefore, if the excitation pulse and refocus-
ing pulse are θ1 and 2θ2 instead of 90 and 180 degree, respectively, then the
signal ξs can be expressed as
( )
ξ s =ξ s0 {1− exp(−Tr /T1 )}exp(−Te /T2 )exp(iω 0t)exp − t − Te /T2* sinθ1sin 2 θ 2
5.3 OVERVIEW OF THE SPIN-WARP IMAGING TECHNIQUE

In MRI scanners, the scanning space inside the magnet has three inter-
secting planes corresponding to three anatomical planes of the body (axial,
coronal, and sagittal). The three planes are indicated by three intersecting
axes, with the z axis of the static magnetic field B0.
A gradient magnetic field can be used to assign nuclei to a position in
space within the body. The gradient field is generated by a gradient coil
(Turner, 1993). The gradient coils create opposing magnetic fields by
carrying currents in opposite directions. The field from one coil opposes
the field from the other, creating a net field that serves as a gradient field.
Gradient field can be applied in each of the three orthogonal directions
(x, y, and z). A gradient coil of any direction changes the magnetic flux
density of the z direction. When a gradient coil of z direction is applied,
the magnetic flux density in the z direction is the static magnetic field B0
itself at the center of the magnet, but it is higher at a position apart from
the center in the positive z direction. When a gradient coil of x direction is
applied, the magnetic flux density in the z direction is higher than B0 at a
position apart from the center in the positive x direction.
Slice selection is performed by applying a gradient magnetic field and an
excitation rf pulse simultaneously. Also, the recognition of nuclear distribu-
tion in the second and third directions is performed by employing gradient
coils. The spin-warp imaging technique is the traditional term for such popu-
lar methods of MRI as field echo (FE) imaging, spin echo (SE) imaging, and
echo-planar imaging (EPI). The main feature of spin-warp imaging technique
is the process of detecting the location of a spinning nucleus in the phase of
precession by varying a linear, gradient magnetic field (Edelstein et al., 1980).
5.3.1 Recognition of Nuclei Distributed in the First Direction

When a sample is placed in a static magnetic field B0 and a linear gradient
magnetic field Gz is superimposed to the static magnetic field B0, nuclei in
the sample are excited by an rf field only in the region where the magnetic
flux density is specific to the nuclear magnetic resonance frequency ω 0.
This process is the slice-selective excitation of nuclei, and the selection is
in the z axis direction of the applied gradient field Gz. By modulating the
excitation power, the profile of the slice selection can be determined. An
excitation power with a sinc, or (sin t)/t, envelope function gives an excita-
tion of a square profile. Because a Fourier-transformed sinc function in
time is a square function in frequency, the slice profile resulted from a sinc
excitation is square. An excitation power with a Gaussian envelope func-
tion gives a Gaussian excitation. The effective frequency bandwidth of an
excitation is the reciprocal of the effective duration of the applied rf pulse.
When an excitation pulse has a sinc envelope function with a main lobe
of 1 msec in duration at half maximum, the resulting slice has a square
profile of about 1 kHz in bandwidth. The longer the excitation duration is,
the thinner the resulting slice thickness is.
As shown in Figure 5.4, when the gradient field is 1 mT/m, the pro-
ton resonance frequency is made distributed in 42.6 Hz/mm, because the
Excitation frequency f0 = 42,600,000 + 1280 Hz
4.7 msec at the half maximum
Gradient field in z direction

Slice sift from the center Gz = 1 mT/m
30 mm
0
z
Slice thickness 5 mm
FIGURE 5.4 Slice selection with a gradient field.
resonance frequency of protons is about 42,600,000 Hz/T. When a pulse

is applied with a sinc envelope of the main lobe of 4.7 msec in duration at
half maximum, the Fourier-transformed bandwidth is 213 Hz. Hence, a
slice is excited with a thickness of 5 mm. If the frequency f0 of the of the rf
pulse is f0 = 42,600,000 + 1280 Hz, then the position of the slice selection
will be shifted by 30 mm in the +z axis direction.
5.3.2 Recognition of Nuclei Distributed in the Second Direction

The recognition of nuclei distributed in the second, or x axis direction,
can be performed by acquiring signals simultaneously applying a linear,
gradient magnetic field Gx in the x axis direction. With the gradient field
Gx, the resonance frequency of nuclei distributed in the x axis is linearly
distributed in the direction of x axis from lower frequencies to higher fre-
quencies than that of nuclei without the gradient field. For example, if the
gradient field Gx is 1 mT/m, then in the region of −0.1 m to +0.1 m inclu-
sively in the x axis direction, the frequency deviation of resonance will
be linearly distributed −4260 Hz to +4260 Hz inclusively. This frequency
bandwidth is small enough to be processed by an ordinary computer.
The signal acquired by an rf coil has various frequencies specific to
the locations of nuclei distributed in the x axis direction, and the spe-
cial distribution of nuclei is restored by Fourier transformation. This is
the process of encoding the locations of nuclei in the x axis direction and
simply called reading-out of the signal. By the Fourier transformation, a
projection curve of the sample in the x axis direction can be obtained.
Projection data are often exhibited in an absolute value ( Re + I m ) with

2 2 1/2
the real amplitude Re and imaginary Im both detected by quadrature

demodulation.For example, if the number of acquired data points is 512
and half of those points are real and the rest are imaginary, then the pro-
jection can be exhibited in a 256-point line graph.
With the application of a reading-out gradient field Gx, the signal
intensity rapidly diminishes because frequencies of nuclear precessions
are made distributed in the x axis direction and the phases of precessions
rapidly become incoherent. This decay can be recovered by applying a
negative, dephasing gradient field −Gxd and then reversing the gradient
field to the positive gradient field +Gx. By this, a field echo (FE) signal is
generated. As shown in Figure 5.5, the FE is generated at the time when
the gray areas are the same. When the gradient field Gx is 1 mT/m, proton
frequency deviation occurring because of the gradient field Gx is 42,600
Hz/m in the x axis direction. If the field of view (FOV) of the MR image is,
for example, 30 cm in the x axis direction, then the frequency bandwidth
covering the FOV range of 30 cm will be 12,800 Hz, and according to the
Sampling theorem, the sampling rate of the AD converter must be greater
than 25,600 Hz.
In spin echo (SE) imaging, most of acquired signals are the combined
echoes of the SE signal generated by a 180 degree pulse and the FE sig-
nal generated by reversing the reading-out gradient field Gx. Usually, the
moment of SE refocusing and the moment of FE refocusing are made
coincident. The acquired data contain various frequencies of precessions
of nuclei, and the frequencies are restored to the original state of locations
of nuclei by the Fourier transformation.
Figure 5.6 is an example of an echo signal acquired during the time ts.
The axis is time in second. Figures 5.7 and 5.8 show the real part Re and
SE
FE
Gx
–Gxd ts
FIGURE 5.5 Reversing the gradient magnetic field and a field echo (FE) signal.
FIGURE 5.6 Echo signal acquired with the reading-out gradient field G x.
FIGURE 5.7 Fourier-transformed real part Re of the echo.
(
FIGURE 5.8 Fourier-transformed absolute value Av = Re + I m
2 2
)1/2 of the echo.
absolute value Av = ( Re2 + I m2 ) of the signal data, respectively. The axes

1/2
are frequency in hertz. The curve of the absolute value Av is similar to the
envelope shape of the real part Re curve.
5.3.3 Recognition of Nuclei Distributed in the Third Direction

Recognition of nuclei distributed in the third direction is performed
by a technique called phase encoding. It begins after the slice-selective
excitation. First, a small gradient field G y in the third, y axis direction is
applied for a certain period Δt. By the application of the gradient G y, a
nucleus located far in the +y direction from the original, central point is
exposed to a higher static magnetic field than that of the nucleus located
at the original, central point. In the period Δt, the phase of precession of
the nucleus far from the center becomes larger than that of the nucleus
at the center. On the other hand, a nucleus located far in the −y direction
from the original, central point is exposed to a lower static magnetic field
than that of the nucleus located at the original, central point. In the period
Δt, the phase of precession of the nucleus far from the center becomes
smaller than that of the nucleus at the center. Second, a gradient field G y
which is 2 times larger in amplitude is applied in the same y axis direction
for the same period Δt and also after the second slice-selective excitation.
Thus, the gradient field is successively changed stepwise in amplitude and
applied, for example, in 256 steps. By this, the farther nuclei are located
from the original point, the greater change of the gradient field G y in
amplitude is experienced by the nuclei, and hence the greater change of
the precession phase is experienced by the nuclei during the period Δt. By
Fourier transformation of the acquired 256 data set, it is recognized how
far the nuclei are located from the original point.
When the gradient field G y is varied in amplitude 256 times, for

example, from −2.54 mT/m to +2.56 mT/m by step of 0.02 mT/m, a nucleus
at the position 10 cm apart from the original point in the y axis direc-
tion, experiences a deviation of the static magnetic field in amplitude by
0.002 mT each time, and the proton resonance frequency changes 256
times by 85.2 Hz each time. If the duration Δt is 3 msec, for example, at the
position 10 cm apart from the original point, the phase of the precession
changes 256 times by 2π × 85.2 × 0.003 = 1.6 rad every time. By Fourier
transformation, the nuclear distribution in the y axis direction is restored.
A typical FE imaging sequence is, as shown in Figure 5.9, a combination
of a slice-selective excitation in the z axis direction, a frequency encoding
in the x axis direction, and a phase encoding in the y axis direction. By
two-dimensional Fourier transformation of a set of acquired signal data,
the two-dimensional distribution of nuclei is restored. Hence, the result-
ing image is on the plane of one axis in frequency in Hz and another axis
in θ in rad per encoding step, as shown in Figure 5.10.
RF α degree excitation FE signal
Gz
Gx
Gy
FIGURE 5.9 FE imaging sequence.
Phase θ [rad/encoding step]

y
Frequency f [Hz]
FIGURE 5.10 Frequency-phase plane.

RF 90 degree 180 degree SE signal
Te/2 Te/2
Gz
Gx
Gy
FIGURE 5.11 SE imaging sequence.
A SE imaging sequence employs a 180 degree pulse, as shown in

Figure 5.11. The 180 degree pulse is applied in the period Te/2 after the 90
degree selective excitation. By this, SE signal is detected in the echo time
Te after the slice-selective excitation.
5.3.4 k Space
By varying the amplitude of the gradient field in the phase-encoding
direction, nuclei are labeled according to their phases of precessions. The
acquired data are then put in successive order on a plane traditionally
called k space (Ljunggren, 1983). The echo signals put on the k space are
those demodulated and subtracted by the primary frequency ω 0 = 2πν0.
Obviously, each signal data appear to have waves containing different fre-
quencies. Those waves are specific to the horizontal x axis distribution of
nuclei and generated by the reading-out gradient field Gx.
The waves in the vertical direction of the k space are also specific to the
vertical y axis distribution of nuclei and generated by varying the ampli-
tude of the phase-encoding gradient field G y. When a quadrature demod-
ulation is employed, each data has a real part and imaginary part. For
example, if the number of data points of a signal is 512, then 256 are real
data points and the remaining 256 are imaginary data points. Hence, when
the number of phase-encoding steps is 256, the vertical phase-encoded
data have 256 real data points and imaginary data points. Therefore, on
the k space, there are a real data set of 256 × 256 points and an imaginary
data set of 256 × 256 points. Figure 5.12 shows an example of a real data
set of 256 × 256.
FIGURE 5.12 Acquired real part data on the k space.
Figure 5.13 shows 256 one-dimensional Fourier-transformed real data

on the k space. Each horizontal line is a line graph consisting of 256 points.
The vertical array is not Fourier transformed yet. Figure 5.14 shows one-
dimensional Fourier-transformed absolute value Av = ( Re2 + I m2 ) data on
1/2
the k space. Each horizontal line is a line graph consisting of 256 points,
while the vertical array is not Fourier transformed yet.
A two-dimensional nuclear distribution of an orange is shown in
Figure 5.15. This was restored by a two-dimensional Fourier transforma-
tion of the horizontal and vertical wave lines on the k space. The nuclear
distribution is displayed in absolute values. The matrix size is 256 × 256.
The unit of the horizontal axis is frequency f in hertz and corresponds
linearly to the distance l in meters from the central point. The unit of the
vertical axis is phase θ in rad/step and also corresponds linearly to the
FIGURE 5.13 One-dimensional Fourier-transformed real part data on the k space.

FIGURE 5.14 One-dimensional Fourier-transformed absolute value data on the

k space.
FIGURE 5.15 Two-dimensional Fourier-transformed absolute value data on the

k space.
distance l in meters from the point. If the intensity diagram is gray scaled
and displayed on a CRT, then we obtain an ordinary MR image.
5.3.5 Image Contrast
By applying an excitation rf pulse, the magnetization vector is given
a component perpendicular to the z axis and the component decays in
amplitude by T2* relaxation. When a FE image sequence is used, and if
both the repetition time Tr and echo time Te are long, then the resulting FE
image is a T2* -weighted image affected by T2* relaxation. The T2* relaxation
of the brain tissue often reflects the brain activity, and T2* -weighted images
are important in the field of fMRI.
With a SE imaging sequence, the magnetization vector is given a com-

ponent perpendicular to the z axis and the component decays in ampli-
tude by T2 relaxation. If the repetition time Tr is longer than T1 and the
echo time Te is shorter than T2, then the resulting SE image reflects the
nuclear density distribution.
If the echo time Te remains short and the repletion time Tr is short-
ened, the sample of long T1 undergoes successive excitations before the
magnetization recovery by T1 relaxation and generates small signal. The
resulting image is a T1-weighted image and has a constant reflecting the T1
distribution. If both the repetition time Tr and echo time Te are long, then
the resulting SE image is a T2-weighted image affected by T2 relaxation.
Compared with FE images, the influence of inhomogeneity of the static
magnetic field is reduced in SE imaging.
T1-weighted images give higher-intensity signals from the white mat-
ter than the gray matter. T2-weighted images give higher-intensity signals
from the gray matter than the white matter. The contrast arises because
the water protons of white matter have shorter T1 and T2 values than those
of gray matter. The shorter T1 value causes the white matter protons to
undergo less saturation, and hence, to generate higher signal intensity
in the T1-weighted image. On the other hand, because of their shorter T2
value, the white matter protons undergo a greater degree of signal loss
during the echo time Te of the T2-weighted image.
Figure 5.16 shows a coronal T1-weighted SE image (Figure 5.16a)
and T2-weighted SE image (Figure 5.16b) of a 46-year-old male patient
(a) (b)
FIGURE 5.16 (a) T1-weighted and (b) T2-weighted images.

FIGURE 5.17 T2-weighted image of the same patient of Figure 5.16.
with multiple tumor lesions. Those images were obtained at IKR-TRIC

University Hospital, Muenster in Germany and offered by Siemens
Japan K.K. The MRI scanner was a Siemens Prisma 3Tesla machine. The
T1-weighted image (Figure 5.16a) is a TSE image with a slice thickness of
4 mm and matrix size of 320. TSE is a technique to obtain an SE image very
fast. The total acquisition time was 84 sec. The T2-weighted image (Figure
5.16b) is a TIRM image with a slice thickness of 4 mm and matrix size of
640. TIRM is a technique to obtain an inversion-recovery (IR) image very
fast. The total acquisition time was 180 sec. Both images were obtained by
a Siemens-specific implementation called iPAT2 (standing for integrated
parallel acquisition techniques square), which allows iPAT in two direc-
tions simultaneously (phase-encoding direction and three-dimensional
direction for three-dimensional sequences).
Figure 5.17 shows an axial T2-weighted SE image of the same patient of
Figure 5.16. The image was obtained also at IKR-TRIC University Hospital,
Muenster in Germany and offered by Siemens Japan K.K. The MRI scan-
ner was a Siemens Prisma 3Tesla machine. The T2-weighted image (left) is a
TSE image with a slice thickness of 4 mm and matrix size of 512. The total
acquisition time was 132 sec. The image was obtained also by the iPAT2.
5.4 DIVERSIFICATION OF MRI APPLICATION TECHNIQUES

5.4.1 Magnetic Resonance Angiography
Magnetic resonance angiography (MRA) is developing a powerful tech-
nique to obtain flow images. It does not necessarily require the injection
of a contrast agent and permits the measurement of flow velocities. It is
becoming increasingly used for the assessment of abnormalities in the

cerebrovascular system and peripheral vasculature.
There are two important methods for MRA. Those are the time-of-flight
(TOF) method and the phased-contrast (PC) method. In a TOF method,
the water protons in a slice of a certain thickness are first labeled. The
labeling is performed by applying an excitation rf pulse. Because satura-
tion makes the numbers of α and β nuclei equal, few signals are generated
from the saturated region. In a time t after the saturation, fresh and unsat-
urated nuclei flow into the saturated region. As a result, contrast is gener-
ated between stationary and flowing water protons. Three-dimensional,
TOF MRA is used in clinical practices. If consecutive excitation pulses are
applied at intervals that are much shorter than T1, there is an increase in
signal intensity, because the inflowing spins generate more signals than
the stationary nuclei, which undergo the saturation. FE, FLASH (fast low-
angle shot) sequences are commonly used for the three-dimensional, TOF
MRA. The three-dimensional data sets contain information about both
stationary and flowing nuclei. Vascular structures can be extracted out of
the full data set by virtue of their increased intensity via a post-processing
routine called maximum intensity projection (MIP).
Flow can induce phase change in MR signals. As water protons move
along a gradient magnetic field, they accumulate a phase shift that is pro-
portional to their velocity. In the PC method, a gradient field is applied
in a certain direction. The faster the nuclei flow in the gradient direction,
the more the transverse magnetization changes phase. By subtraction of
data sets with and without the gradient magnetic field, an angiogram is
obtained. Three-dimensional, PC MRA is also used in clinical practices.
Compared to the TOF method, the PC method takes a longer time for
signal acquisition, but the background tissue signals are small.
5.4.2 Perfusion and Diffusion Imaging

Once nuclei in the neck region are excited, arterial flow will carry the
labeled nuclei into the brain tissue and influence the observed signal from
brain water. Subtractions of images with and without the labeling per-
mit measurements of regional perfusion (Edelstein et al., 1980; Ljunggren,
1983). A technique of signal targeting with alternating radiofrequency
(EPISTER) is also used (Williams et al., 1992; Zhang et al., 1993). This is
an echo-planar imaging (EPI) technique combined with TOF technique,
and generates a perfusion image by subtraction of images with and with-
out saturation pulses (Edelman et al., 1994). The EPI is a rapid imaging
technique to obtain a two-dimensional data set by filling the k space with

signals generated by one excitation pulse.
Diffusion measurements by NMR were introduced in the 1960s
(Stejskal, 1965; Stejskal and Tanner, 1965). In water, all molecules move
randomly. It is often referred to as Brownian motion and involves dis-
placement distances that are small and comparable to the cell sizes. Hence,
the water diffusion can be affected by the cell structure and diffusion-
weighted images can reflect the changes of the cell structure. In the tis-
sue of cerebral infarction, diffusion of water is restricted and the apparent
diffusion coefficient (ADC) of water becomes small. This is allegedly
caused by the water shift from the extracellular spaces into the intracel-
lular spaces (Kohno et al., 1995; Mosley et al., 1990). Nuclei moving ran-
domly under a gradient magnetic field lose signals, and the diffusion can
be detected by MRI. Neither a T1-weighted nor T2-weighted image reveals
the lesions of cerebral infarction obtained in a few hours after the onset,
but a diffusion-weighted image often reveals the lesions in the early stage
of infarction (Mintrovich et al., 1991; Pennock et al., 1994; Warach et al.,
1992). Diffusion-weighted images are often linked to the anisotropy of the
tissue structure. The anisotropy can be detected by the relations between
the direction of the gradient field and the extent of signal loss by the water
movement (LeBihan and Turner, 1992).
Figure 5.18 shows axial diffusion-weighted images (left and center) and
an ADC image (right) of the same patient of Figures 5.16 and 5.17. The
attenuation b factors were b = 0 (left) and 1000 (center). The images were
obtained also at IKR-TRIC University Hospital, Muenster in Germany
FIGURE 5.18 Diffusion-weighted and apparent diffusion coefficient images of

the same patient in Figure 5.16.
and offered by Siemens Japan K.K. The MRI scanner was a Siemens
Prisma 3Tesla machine. The images are with a slice thickness of 4 mm. The
total acquisition time was 63 sec. The images were obtained by GRAPPA,
standing for generalized autocalibrating partially parallel acquisition, a
Siemens-specific technique.
5.4.3 Functional Neuroimaging
Functional neuroimaging (fMRI) is one of the most important MRI tech-
niques developed recent years and visualizes the active regions of the brain
noninvasively. Functional imaging uses FE imaging sequences of long echo
time Te as 50 msec and reflects T2* characteristics of the tissues. Electrons of
Fe2+ of deoxy-hemoglobin (Deoxy-Hb) have much greater magnetic momen-
tum than those of proton nuclei, and proton resonance spectra of deoxy-
hemoglobin (Deoxy-Hb) solution exhibit broad peaks caused by the effects
of paramagnetic features of Deoxy-Hb. Also, the water resonance frequency
is broadened by the effects of the gradient magnetic field due to the Fe2+ elec-
trons. Therefore, T2*-weighted images of water around Deoxy-Hb generate
few signals. In the living brain, the gradient magnetic fields caused by the Fe2+
electrons strongly influence not only the water in the blood vessels but also,
to a much greater extent, the outer neural tissues of the water volume of the
blood vessels (Ogawa and Lee, 1990; Ogawa et al., 1990; Turner et al., 1991).
When a region in the brain is active, the blood flow increases in the
region, oxy-hemoglobin (Oxy-Hb) increases, and Deoxy-Hb decreases in
relative quantity. By the blood oxygenation level dependent effects, the sig-
nal intensities from the active region in the obtained T2* -weighted images
increases (Bandettini et al., 1992; Frahm et al., 1992). Also, fMRI reflects
internal verbal generations and recalling of sensory or motor stimulation.
(LeBihan et al., 1993; McCauthy et al., 1993; Rueckert et al., 1994).
Figure 5.19 shows a functional neuroimaging routine. A simultaneous
time-course analysis for multiple regions of interest (ROIs) is carried out
in routine. The image was also offered by Siemens Japan K.K.
5.4.4 Magnetic Resonance Spectroscopy

The ability to obtain localized spectra offers great potential for detecting
human disease at the early stage of biochemical alteration. The proton sig-
nal from water is much greater than signals from metabolites. However,
the suppression of water is expanding the use of MRI in metabolite evalu-
ation. In the field of magnetic resonance spectroscopy, metabolite maps of
specific chemicals or chemical shift images are also obtained.
FIGURE 5.19 Functional neuroimaging routine.
5.4.5 MRI of Other Nuclei than Protons

There are important nuclei other than protons for MRI. Figure 5.20 shows
a natural abundance carbon-13 MRI of a human arm reflects the distri-
bution of –CH2– chain of the subcutaneous fatty tissues and bone mar-
row (Iriguchi and Hasegawa, 1993). Phosphorus-31 chemical shift images,
FIGURE 5.20 Natural abundance carbon-13 MRI of a human upper arm.

which are images of adenosine triphosphate (ATP), phosphocreatine (PCr),

and inorganic phosphate (Pi) of a human brain, are obtained. Those images
reflect the energy metabolism of the brain. Deuterium MRI and fluorine
MRI are carried out in experiments with those nuclei as contrast media.
5.5 CONCLUDING REMARKS
In the last century, MRI scanners were classified simply by their field
strength, namely, low-field (0.5 T and below), mid-field (1.0 T), and high-
field (1.5 T and higher) scanners. Continued progress in high-performance
gradient coil technologies have made high-quality and fast imaging a
reality. Techniques have been diversified dramatically. MRI scanners are
classified in a more sophisticated way, i.e., productivity in scanning real-
ity and real-time post-processing procedures and friendliness in design
concepts for clinical use. In the field of basic technology, it is apparent that
MRI is not simply a method of obtaining radiological images, but it can
also provide a great deal of physiological information. Some MRI tech-
niques will be developed for noninvasive mapping of physical, chemical,
and physiological properties such as temperature, mechanical elasticity,
pressure, electrical conductivity, permittivity, and metabolite concentra-
tion. Development will be continued in this century.
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Chapter 6
Prospects for Magnetic

Resonance Imaging
of Impedance
and Electric Currents
CONTENTS
6.1.1 Advantages of Magnetic Resonance Imaging
in Impedance Imaging 146
6.1.2 Advantages of MRI in Electric Current Imaging 147
6.2 Influence of Sample Impedance on MRI 148
6.2.1 Electric Properties of Biological Tissues 148
6.2.1.1 Permittivity and Conductivity 148
6.2.1.2 Frequency Characteristics and Anisotropy 150
6.2.1.3 Human Models for Numerical Simulations
of Electromagnetic Fields 153
6.2.2 RF Distribution in a Cylindrical Sample 154
6.2.3 RF Distribution in the Human Head 155
6.2.3.1 Finite Difference Time Domain Method 155
6.2.3.2 RF Distribution in the Human Head
at Varied Frequencies 157
6.3 Magnetic Resonance Imaging of Impedance 159
6.3.1 Large Flip Angle Method 159
6.3.2 Use of an External AC Field 159
6.3.3 Conductivity Imaging Using Diffusion MRI 161
145
6.3.3.1 Principles 161

6.3.3.2 Experimental Results 162
6.3.4 Impedance Imaging Using RF Current 165
6.3.4.1 Principles 165
6.3.4.2 Experimental Results 167
6.3.5 Magnetic Resonance Electrical Impedance Tomography 167
6.4 Magnetic Resonance Imaging of Electric Currents 169
6.4.1 Changes in Magnetic Resonance Signals Resulting
from the Magnetic Field 169
6.4.2 Sensitivity to a Weak Electric Current 170
6.4.2.1 Neuronal Current Dipole 170
6.4.2.2 Theoretical Evaluation of Sensitivity 171
6.4.2.3 Experimental Evaluation of Sensitivity 174
6.4.3 Animal Studies 174
6.4.3.1 Brain Slices 174
6.4.3.2 In Vivo Experiments 176
6.4.4 Human Studies 178
References 181
6.1 INTRODUCTION
6.1.1 Advantages of Magnetic Resonance Imaging
in Impedance Imaging
Analyses of electromagnetic fields play an important role in understanding
electromagnetic phenomena in living bodies. Worldwide, several groups
develop and distribute standard models of the human body,1,2 and these
models benefit research into electromagnetic fields. However, the present
methodology for developing these standard models imposes certain limi-
tations on the scope and accuracy of these analyses. The models consist
of multiple tissues or organs segmented from cross-sectional images of
the body. Each tissue has specific permittivity and conductivity values.
Each organ, such as the brain, is modeled as a uniform medium. The elec-
tric properties of actual organs and tissues, however, are not necessarily
uniform because of a variety of substructures. Moreover, these standard
models do not replicate the anatomy of an individual subject and are not
applicable to subject-specific analyses. One solution to the aforemen-
tioned issues will be the development of new methodology for impedance
Prospects for MRI of Impedance and Electric Currents ◾ 147
imaging of living bodies. Imaging of electric impedance will enable us

to determine both the local distribution of electric properties within an
organ and the detailed anatomy of an individual subject.
Electrical impedance tomography (EIT), in which multiple electrodes
are attached to the subject’s skin, has widely been used to obtain the three-
dimensional impedance distribution in a body.3 The basic principle of
EIT is to apply electric currents between a pair of selected electrodes and
to simultaneously measure the resulting potentials at other electrodes.
Another technique for impedance imaging is to apply microwaves, instead
of currents, from surrounding antennas to the body.4 The spatial resolu-
tion of these techniques is limited, in principle, by the number of elec-
trodes or antennas. In addition, it is difficult to obtain EIT of the brain,
which is surrounded by a resistive skull.
To improve spatial resolution, studies have been conducted to investi-
gate the use of magnetic resonance imaging (MRI) to obtain impedance
distributions. MRI is inherently sensitive to the magnetic fields generated
in the body during measurement. When an electric current is externally
applied to the body, the magnetic field generated by the current affects the
amplitude and phase angle of the MRI signal. The distribution of conduc-
tivity and permittivity inside the body can be estimated from this effect.
Compared with EIT, the use of MRI in impedance imaging significantly
improves spatial resolution. The use of MRI can also improve the accuracy
of estimates for the electric properties of organs surrounded by bones or
other resistive tissues. The first half of this chapter provides an overview
of several major techniques for estimating the distribution of conductivity
and permittivity using MRI.
6.1.2 Advantages of MRI in Electric Current Imaging

Electric currents flowing in a body can be detected by observing surface
potentials or surrounding magnetic fields. This idea forms the foundation
for principal measurement techniques in biomagnetics. Although the cur-
rent distribution inside a body can be estimated by inversely analyzing
the measured fields, such analysis contains a mathematical ill-posedness.
Because MRI is sensitive to magnetic fields, MRI can be a potent tool for
mapping electric currents flowing in the body. The second half of this
chapter provides an overview of MRI-based imaging of electric currents
and discusses techniques that are especially applicable to neuronal electric
activities.
As explained in Chapter 5, the frequency of the MRI signal is pro-

portional to the strength of the magnetic field. The magnetic field pro-
duced by current in the body is added to the main static magnetic field,
which results in a slight local shift in the signal frequency and phase
angle in and around the current pathway. When the current is externally
controllable, a typical method for electric current imaging is to obtain
a pair of phase angle maps with the current switched on and off and to
then subtract the two phase angle maps to estimate the current distri-
bution. Another effect of electric current is a local decrease in the MRI
signal intensity. Because the magnetic fields resulting from an internal
current are usually inhomogeneous, the magnetic fields cause dephasing
of nuclear magnetization, which leads to the decreased signal intensity.
One can select either the phase angle or signal intensity to obtain current
distributions.
One of the ultimate goals of MRI-based electric current imaging is
to detect extremely weak magnetic fields arising from neuronal electric
activities. Visualization of the spatiotemporal dynamics of the brain’s
neuronal activities is essential for understanding functional networks of
neurons. Detailed spatial distributions of neuronal activities have been
investigated using functional MRI (fMRI), in which a local change in
blood flow resulting from neuronal activities affects the MRI signal inten-
sity. However, using fMRI, detailed measurements of the temporal evolu-
tion of neuronal activities are difficult to obtain because the change in
blood flow lags a second behind the electrical activity. During the last 15
years, there have been attempts to detect both weak magnetic fields gen-
erated in phantoms and neuronal magnetic fields produced in cultured
cells or animals. This methodology has a potential temporal resolution of
tens of milliseconds and a spatial resolution below 1 mm. Neuronal mag-
netic fields are very weak, as low as 1 pT or smaller in the human brain.
Evaluating the sensitivity to magnetic fields is crucial for discussing this
methodology’s feasibility.
6.2 INFLUENCE OF SAMPLE IMPEDANCE ON MRI

6.2.1 Electric Properties of Biological Tissues
6.2.1.1 Permittivity and Conductivity
An MRI signal is emitted from the body as a radiofrequency (RF) elec-
tromagnetic wave, and propagating through space, this wave is received
by an RF coil. As the Larmor equation in Chapter 5 indicates, frequency
f of the RF wave is proportional to strength B of the applied magnetic

field. The frequencies for 1.5- and 3-T field strengths are 64 and 128 MHz,
respectively.
The propagation velocity of RF waves is 3.0 × 108 m/sec in a vacuum.
The velocity in biological tissue depends on electric permittivity ε and
magnetic permeability μ of the tissue, as expressed by
1
v= (6.1)
εµ
The ratio of tissue permittivity ε to vacuum permittivity ε0 = 8.9 × 10−12

F/m is denoted by the relative permittivity: εr = ε/ε0. Because the relative
permittivities of biological tissues are higher than 1, propagation velocities
in tissues are smaller than velocities in vacuum.
A traveling wave generally satisfies the relation
v
λ= (6.2)
f
where λ is the wavelength, v is the velocity, and f is the frequency. Combining

Equations 6.1 and 6.2 with the Larmor equation demonstrates the follow-
ing important behavior: the wavelength of the RF wave decreases when
the strength of the magnetic field increases or when the permittivity is
high.
In many molecules contained in biological tissues, the centers of
positive and negative electric charges are not in the same position. Such
molecules are called polar molecules. One of the major components of
biological tissues, a water molecule has two O-H bonds at an angle of 104°.
The distribution of electrons within a water molecule shifts toward the
oxygen atom, and consequently, water is a polar molecule. The relative
permittivity of water is as high as 80. Permittivity becomes high when the
material contains a considerable amount of polar molecules. On the basis
of Equation 6.1, the velocity of an RF wave traveling in water is estimated
to be as low as 1/9 of the velocity in vacuum.
Conductivity is another important electric property for understand-
ing MRI physics. Conductivity is a measure of a material’s ability to con-
duct electric currents when an electric field is applied. Conductivity σ is
defined as a constant of proportionality between electric field E and cur-
rent density j:
j = σE (6.3)
Conductivity has an extremely broad range of values. Metals are repre-

sentative conductors with conductivities around 107 S/m. Conductivities
of typical insulators are as low as 10−15 S/m. Although biological tissues
are usually modeled as conductors, their conductivity is much lower than
metals’ conductivity.
To analyze an electromagnetic wave, it is useful to define the follow-
ing complex permittivity, in which the permittivity and conductivity are
included in the equation’s real and imaginary parts, respectively:
iσ
ε* = ε − (6.4)
ω
where ω is the angular frequency. In some cases, the sign of the imaginary
part may be positive instead of negative. When analyzing the distribution
of an RF wave, the use of complex permittivity enables us to write the wave
equation in a simple form.
6.2.1.2 Frequency Characteristics and Anisotropy

A material’s permittivity and conductivity generally depend on the fre-
quency of an applied field, and this phenomenon is called dispersion.
Because biological tissues have multiple mechanisms for electric con-
duction, such as the drift of ions and the rotation of polar molecules,
tissues exhibit relatively complicated dispersion. As follows, Debye’s
equation of complex permittivity is widely accepted as a model of
dispersion:
ε0 − ε ∞
ε *(ω) = ε ∞ + (6.5)
1+ iωτ
where τ is the relaxation time and where ε0 and ε∞ indicate the respec-
tive permittivities at sufficiently low and high frequencies (compared with
1/τ). With ω ranging from 0 to ∞, a plot of Equation 6.5 on a complex
plane produces a semicircle, which is called a Cole-Cole plot.5 There are
multiple sources of dielectric polarization in a tissue, such as charges on
cell membranes and polar molecules (including water), and these polar-
izations have different relaxation times. With four relaxation times, an
extended version of Equation 6.5 is used for modeling the tissue’s complex
permittivity:
∆ε
4
ε *(ω) = ε ∞ + ∑ 1+ (iωτ
m=1
)
m
m
1−αm +
σi
jωε0
(6.6)
where Δεm indicates the drop in permittivity for a frequency range across
ω = 1/τm, which corresponds to each relaxation time τm; σi indicates the
ionic conductivity. The above empirically defined equation is well fitted
to the measured complex permittivities in a broad frequency range, from
10 Hz to 100 GHz.6,7 Figure 6.1 shows the frequency characteristics of gray
108
106
104
εr
102
100 102 104 106 108 1010

f (Hz)
102
101
σ (S/m)
100
10–1
100 102 104 106 108 1010

f (Hz)
FIGURE 6.1 Frequency characteristics of electric permittivity εr and conductiv-

ity σ of gray matter. (From Safety Committee of the Japan Society of Magnetic
Resonance in Medicine. 2010. MR Safety—Principles, Standards and Clinical
Concerns. Gakken Medical Shujunsha, Tokyo.)
matter’s permittivity and conductivity, obtained by fitting Equation 6.6

to the measured values.8 An increase in frequency causes a decrease in
permittivity and an increase in conductivity. A Cole-Cole plot of a tis-
sue differs from a semicircle because of the tissue’s relatively compli-
cated frequency characteristics. Table 6.1 shows the permittivities and
conductivities of several tissues for 63.9 and 128 MHz.
In addition to the frequency characteristics, another unique prop-
erty of biological tissues’ permittivity and conductivity is their anisot-
ropy. The permittivity and conductivity depend on the direction of the
applied electric field. In nerves and muscles, cells form fibrous micro-
scopic structures, and the cells align in a specific direction. Because the
cell membranes hinder ions’ ability to pass through the membranes,
ions easily move in the direction of fibers but are mostly unable to
move orthogonally. Consequently, conductivity exhibits higher values
in the direction of fibrous structures. Because of cell membranes’ resis-
tance, low-frequency currents flow mainly through extracellular spaces.
Furthermore, because of surface charges on cell membranes, a tissue’s
effective permittivity becomes high when an electric field is applied in
the direction perpendicular to the cell membrane. In a measurement
of the conductivity of the cerebral cortex, the conductivity varied by a
TABLE 6.1 Electric Permittivity and Conductivity of Body Tissues

Relative Permittivity Conductivity (S/m)
Tissue 63.9 MHz 128 MHz 63.9 MHz 128 MHz
Brain gray matter 97.5 73.5 0.511 0.587
Brain white matter 67.9 52.5 0.291 0.342
Cerebellum 116.4 79.7 0.719 0.829
Muscle 72.3 63.5 0.688 0.719
Heart 106.6 84.3 0.678 0.766
Fat 6.5 5.9 0.035 0.037
Bone cortical 16.7 14.7 0.060 0.067
Bone cancellous 30.9 26.3 0.161 0.180
Cerebrospinal fluid 97.3 84.0 2.066 2.143
Blood 86.5 73.2 1.207 1.249
Liver 80.6 64.3 0.448 0.511
Source: Gabriel, C. et al., Physics in Medicine and Biology 41: 2231–2249, 1996; Gabriel,
S. et al., Physics in Mewdicine and Biology 41: 2251–2269, 1996.
factor of 1.7, depending on the measurement direction.9 The anisotro-

pies originating from the membrane structures become prominent when
considerable quantities of ions oscillating in an AC field collide with
membranes. These anisotropies become negligibly small at frequencies
higher than a megahertz.
6.2.1.3 Human Models for Numerical Simulations

of Electromagnetic Fields
Numerical simulations of electromagnetic fields in the human body are
effective for safety assessments of electromagnetic fields. In addition to
computer performance and algorithms, modeling the distributions of per-
mittivity and conductivity in the body is an important endeavor.
Several institutions develop and distribute numerical human models
without charge for noncommercial users.1,2 A few software developers
provide numerical human models specifically for use with their software.
These models are built by segmenting an anatomical data set (obtained
from MRI, CT, or dissected slices of a cadaver) into multiple tissues. Each
voxel in the data set has a labeling number to indicate a particular tissue
type, such as bone or muscle. A model’s typical spatial resolution is 1 mm.
Because there is no method to automatically segment the entire body,
building a model necessitates extensive manual procedures that require
significant effort and time. The aim of such a model is to provide a risk
assessment for exposing the human body to equipment’s electromagnetic
fields. This model is also useful for medical applications, such as electric
and magnetic stimulations, microwave hyperthermia, and electromag-
netic fields in MRI systems.
The National Institute of Information and Communications Technology
(NICT), Japan, develops and distributes numerical human models.1 This
group provides standard male and female models with average body sizes.
These models were built by segmenting a 3D MRI data set into 51 different
tissues with a spatial resolution of 2 mm. The models can be deformed to
assume a variety of postures. A model of a pregnant woman is also avail-
able for evaluating a fetus’s field exposure.10
The above models relate each voxel in the data set to a tissue type. Other
databases should be utilized to ascertain permittivity and conductivity
values of different tissues. The values are estimated for a target frequency
using Equation 6.6.6,7 Because typical models of the human body con-
sist of cubic voxels, the model has immediate applicability to simulation
methods that use cubic cells, such as the finite difference time domain
method, the impedance method, and the scalar-potential finite differ-
ence method. The finite element method is also available.
6.2.2 RF Distribution in a Cylindrical Sample

Analyses of RF fields in a cylindrical sample provide a comprehensive
view of the influence of electric permittivity and conductivity on RF
field distributions. Here, we consider two major effects: dielectric reso-
nance and the skin effect. Both effects are prominent in ultrahigh-field
MRI systems.
A distinctive signal inhomogeneity arises in a sample whose dimen-
sions are comparable to or smaller than the RF fields’ wavelength. This
phenomenon, dielectric resonance, complicates the quantification of
MRI. A typical dielectric resonance effect appears as a brightening
of an image at the center of a sample. MRI frequencies of presently
available scanners range from 8.5 to 340 MHz, which corresponds to
wavelengths in water ranging from 10 to 400 cm. The degree of signal
inhomogeneity resulting from dielectric resonance highly depends on
the sample’s permittivity because the wavelength is directly related to
the permittivity.
The skin effect is the attenuation of the electromagnetic field in the deep
part of a conductive sample. The following equation gives the representa-
tive skin depth (the penetration depth in the sample):
2
l=
µσω (6.7)
At frequencies applicable to ultrahigh-field MRI systems, the skin

depth becomes comparable to the size of the human head, which results
in a clear occurrence of the skin effect.
Figure 6.2 shows the magnitudes and phase angles of magnetic reso-
nance signals obtained from cylindrical phantoms with different radii and
electric properties.11 The measuring frequency of 200 MHz corresponds
to a wavelength of 170 mm in water. Because of dielectric resonance, the
phantom with a = 50 mm (compared to a phantom with a = 30 mm) exhib-
ited more significant inhomogeneity in the RF magnitude. An increase in
conductivity, from 0 to 1.9 S/m (comparable to saline solution), resulted in
the suppression of inhomogeneity. As shown in Figure 6.2, the skin effect
partly counteracted the dielectric resonance.
1.2 π
0.0 –π
(a) (d)
1.2 π
0.0 –π
(b) (e)
1.2 π
0.0 –π
(c) (f)
FIGURE 6.2 Magnitude |ξ| ([a] a = 30 mm, water; [b] a = 50 mm, water; [c] a =
50 mm, saline) and phase angle arg(ξ) ([d] a = 30 mm, water; [e] a = 50 mm, water;
[f] a = 50 mm, saline) of magnetic resonance signals obtained from cylindrical
phantoms with different radii and electric properties. The signals are normalized
by the values at the center of the phantom. (From Sekino, M. et al., Journal of
Applied Physics 97: 10R303, 2005.)
6.2.3 RF Distribution in the Human Head

6.2.3.1 Finite Difference Time Domain Method
The finite difference time domain (FDTD) method is a major computa-
tional technique for analyzing high-frequency electromagnetic fields.
Maxwell’s equations are directly discretized and sequentially solved to
obtain the time evolution and spatial distribution of electromagnetic
fields. Electromagnetic field components are assigned to each computa-
tional cell, as shown in Figure 6.3. The electromagnetic field distributions
z
1
1 1 Ez i, j, k +
Hy i + , j, k + 2 1 1
2 2 Hx i, j + , k+
2 2
1
Ey i, j + ,k
i, j, k 2
y
x 1 1 1
Ex i + , j, k Hz i + , j + , k
2 2 2
FIGURE 6.3 Computational cell for the FDTD method. The electromagnetic
field components are assigned on the edges or faces of each cell. (From Sekino, M.
et al., Journal of Applied Physics 103: 07A318, 2008.)
for each time step can be calculated using the Yee algorithm12,13 when an
RF coil is the wave source. For example, the z component of the electro-
magnetic field is calculated as follows:
σ(i, j,k +1/2)Δt

1−
2ε(i, j,k +1/2) n−1 ⎛
E zn ⎛ i, j,k + ⎞ = E z i, j,k + ⎞
1 1
⎝ 2 ⎠ σ(i, j,k +1/2)Δt ⎝ 2⎠
1+
2ε(i, j,k +1/2)
∆t
ε(i, j,k +1/2) 1
+
σ(i, j,k +1/2)∆t ∆x
1+
2ε(i, j,k +1/2)
⎧ ⎛ i + 1 , j,k + 1 ⎞ − H n−1/2 ⎛ i − 1 , j,k + 1 ⎞ ⎫

× ⎨ H n−1/2 ⎬
⎩
y
⎝ 2 2⎠
y
⎝ 2 2⎠ ⎭
∆t
ε(i, j,k +1/2) 1
−
σ(i, j,k +1/2)∆t ∆y
1+
2ε(i, j,k +1/2)
⎧ 1 ⎫
× ⎨ H xn−1/2 ⎛ i, j + ,k + ⎞ − H xn−1/2 ⎛ i, j − ,k + ⎞ ⎬
1 1 1
⎩ ⎝ 2 2 ⎠ ⎝ 2 2⎠ ⎭ (6.8)

H zn+1/2 ⎛ i + , j + ,k ⎞ = H zn−1/2 ⎛ i + , j + ,k ⎞
1 1 1 1
⎝ 2 2 ⎠ ⎝ 2 2 ⎠
∆t E ny (i +1, j +1/2,k)− E ny (i, j +1/2,k)

+
µ0 ∆x (6.9)
∆t E xn (i +1/2, j +1,k)− E xn (i +1/2, j,k)

+
µ0 ∆y
where E zn and H zn are, respectively, the electric and magnetic field compo-
nents at the nth time step, i, j, and k are the index numbers of the com-
putational cell, and Δt, Δx, and Δy are the length of a time step and the
lengths of the computational cell in the x and y directions, respectively.
At the outer boundaries of a computational model, absorbing boundary
conditions are applied to eliminate the influence of the boundaries. There
is a variety of formulations for the boundary conditions.
6.2.3.2 RF Distribution in the Human Head at Varied Frequencies

Recent advances in superconducting magnets have led to the realization
of ultrahigh-field MRI systems of around 10 T.14 These ultrahigh-field sys-
tems have numerous advantages, such as the acquisition of precise ana-
tomical and functional images in a short acquisition time, quantification
of complicated biomolecules, and imaging of nonproton nuclei. As high
as 500 MHz, the frequencies of such systems cause dielectric resonance
and the skin effect in the human brain. These two effects result in a com-
plicated RF electromagnetic field distribution. The inhomogeneity of the
RF fields may lead to difficulty quantifying images and a regional increase
in the specific absorption rate (SAR). A quantitative estimate of the signal
distribution and SAR is essential for initial evaluation of the advantages
and characteristics of ultrahigh-field MRI systems. The signal inhomo-
geneities and SAR distribution in ultrahigh-field MRI systems have been
evaluated using numerical simulations.13
Figure 6.4 shows the distributions of the electric field and magnetic
field in an axial section for frequencies of 64, 128, 200, and 500 MHz
(corresponding to static magnetic field intensities of 1.5, 3.0, 4.7, and
11.7 T). A numerical model of the human head was constructed using
the NICT database.1 The analyses were conducted using the FDTD
method. At 64 MHz (the frequency commonly used in clinical MRI
64 MHz (1.5 T) 128 MHz (3.0 T)
200 MHz (4.7 T) 500 MHz (11.7 T)
(a) 0 500 V/m
64 MHz (1.5 T) 128 MHz (3.0 T)
200 MHz (4.7 T) 500 MHz (11.7 T)
(b) 0.0 5.0 μT
FIGURE 6.4 Distribution of (a) an RF electric field and (b) an RF magnetic field
in a horizontal section of the human head with different magnetic resonance
frequencies. The increase in frequency causes the occurrence of hot spots that
exhibit high RF absorption. (From Sekino, M. et al., Journal of Applied Physics
103: 07A318, 2008.)
systems), the magnetic field exhibited homogeneous distributions, and

the electric field increased its intensity as the distance from the center
of the head increased. An increase in frequency resulted in considerable
inhomogeneities in the RF electromagnetic fields. The magnetic field at
200 MHz had a high intensity at the center of the head. The electromag-
netic fields at 500 MHz exhibited a complicated amplitude distribution.
Although the calculations were conducted under the same coil current
intensity, the intensity of the electric field increased with an increase in
frequency.
6.3 MAGNETIC RESONANCE IMAGING OF IMPEDANCE

6.3.1 Large Flip Angle Method
When conductive tissues are subjected to an excitation RF field in MRI,
eddy currents are induced in the tissues. This phenomenon can be used to
obtain the impedance distribution of the tissue.15 The basic principle is to
apply the shielding effects of the eddy currents induced in the body to spin
precession. The occurrence of eddy currents results in a reduction in the
net RF fields penetrating the tissues. Because of shielding effects, the flip
angles are reduced by various degrees, depending on the electrical proper-
ties of the tissues.
When a precise 180°, 360°, or 540° excitation pulse is applied to con-
ductive tissues, the tissues do not yield a signal because magnetization’s
transversal components are absent. Conversely, resistive tissues yield sig-
nals because they are less electrically shielded than conducting tissues and
because they simultaneously undergo different flip angles. In addition,
the resistive tissues produce transversal components with magnitudes
determined by the sine wave functions of the flip angles. The difference in
signal, therefore, reflects the tissues’ conductivity. By applying very large
flip angles, conductivity-enhanced MRI can be obtained. The RF fields are
applied at the given Larmor frequency and in the direction perpendicular
to the main static field.
Figure 6.5 shows images of a mouse head with excitation flip angles of
160°, 180°, and 200°. The 180° image shows a slight signal from the brain
and muscle tissues because there were almost no transversal components
of magnetization. Conversely, in the same 180° image, the resistive fatty
tissues, which were transparent to the RF field, yielded a specific signal.
By applying 180° pulses to the conducting cerebrospinal fluid and muscle
tissues, resistive fatty tissues simultaneously received excitation for flip
angles larger than 180° and produced an image signal.
6.3.2 Use of an External AC Field

To obtain conductivity-enhanced images at an arbitrary frequency, an
additional time-varying field parallel to the main static field, B0, is intro-
duced.15,16 The perturbing field is produced by the third coil, which is hereby
denoted the Bc coil. The sample is located inside this coil. The perturbing
field (the Bc field) affects the image’s slice positioning, and the slice selection
fluctuates. Because of shielding effects, conducting tissues are less affected
by the Bc field. Because the frequency of the AC field is independent of the
F2 F2 F2
(cm) (cm) (cm)
3.0 3.0 3.0
3.5 3.5 3.5
4.0 4.0 4.0
4.5 4.5 4.5
5.0 5.0 5.0
5.5 5.5 5.5
6.0 6.0 6.0
6.5 6.5 6.5
3.5 3.0 2.5 2.0 1.5 1.0 0.5 3.5 3.0 2.5 2.0 1.5 1.0 0.5 3.5 3.0 2.5 2.0 1.5 1.0 0.5
F1 (cm) F1 (cm) F1 (cm)
(a) (b) (c)
FIGURE 6.5 Impedance imaging of the mouse head using the large flip angle
method. The images were obtained with different excitation flip angles and were
evaluated in the cerebrospinal fluid. The flips angles were (a) 160°, (b) 180°, and
(c) 200°. (From Ueno, S., and Iriguchi, N., Journal of Applied Physics 83: 6450–
6452, 1998.)
given Larmor frequency, conductivity-enhanced images can be obtained

at any frequency (but only in the direction perpendicular to the AC field).
The AC field is added to the main static field only during the period of
slice selection, and the artifacts in the reading-out and phase-encoding
directions can be eliminated. A series of pre-pulses are applied before slice
selection to dephase the sample’s nuclear spins in the neighboring regions.
When the AC field shifts the sliced position into the neighboring regions,
fewer nuclei are excited and the resulting image intensity weakens.
When two parallel columns with different conductivities are subjected
to imaging, as shown in Figure 6.6, two different regions of each column
are excited by the application of two pre-pulses. The subsequent applica-
tion of slice-selective 90° pulse superimposed on the AC field excites a
thicker slice involving the pre-excited regions in the resistive material.
This excitation is inefficient because spins in the re-excited regions have
lost coherency during the precession phase. Conversely, a thinner slice
that excludes the pre-excited regions excites the conductive material. This
excitation is efficient because the excitation is exclusive to the selected
slice. One approach to evaluate an impedance-enhanced image is to com-
pare images with and without the AC field. Impedance imaging of a phan-
tom with a sinusoidal 100-Hz AC field has been reported.16
Resistive
material
Conducting
material
The excited slice
position by
prepulse (90°)
Resistive
material
Conducting
material
Slice position
on RF pulse
(90°)
Resistive
material
Conducting
material
FIGURE 6.6 Principles of impedance imaging using external AC fields and

prepulses. Because the slice position fluctuates in response to AC fields, a slice-
selective 90° pulse excites a thicker slice infiltrating into the preexcited regions in
the resistive material. The signal intensity of the reexcited regions is very small.
The signal intensity of the region excited by the 90° pulse in the conductive mate-
rial is less affected by the pre-pulses. (From Yukawa, Y. et al., IEEE Transactions
on Magnetics 35: 4121–4123, 1999.)
6.3.3 Conductivity Imaging Using Diffusion MRI

6.3.3.1 Principles
Low-frequency electric currents in living tissues are mainly conducted by
the migration of ions. Because the migrating ions encounter high resis-
tance from cell membranes, most currents flow through extracellular fluid.
Conductivity depends on the viscosity of extracellular fluid because the
balance between the electrostatic force and viscous drag governs an ion’s
drift velocity. The diffusion coefficient of extracellular fluid is also related
to its viscosity, which is described by the Stokes-Einstein equation. On
the basis of these relationships, tissue conductivity can be obtained from
extracellular fluid’s diffusion coefficient. Several research groups have
reported the use of diffusion MRI for mapping tissue conductivity.17–20
Biological tissues have multiple diffusion components with different
diffusion coefficients. In many studies, such diffusion is simply divided
into the fast component and the slow component. As an approximation,

the fast component and the slow component are attributed to extracellular
fluid and intracellular fluid, respectively. The diffusion coefficient and the
fractional volume of the extracellular fluid are approximated by the fast
diffusion coefficient and the fraction of the fast component, respectively.
For each pixel in the image, the fast and slow diffusion components for the
direction of the motion-probing gradient (MPG) were obtained by fitting
the following function to the measured signals:
Si (b)
= f fast,i exp(−bDfast,i )+ f slow,i exp(−bDslow,i ) (6.10)
Si (0)
where i is the index number of the MPG, Si(b) is the signal intensity of the
diffusion-weighted images, b is the b factor of the MPG, Dfast,i and Dslow,i
are the fast and slow diffusion components, respectively, and ffast,i and fslow,i
are the respective fractions of the fast and slow components.
The conductivity of the extracellular fluid is obtained from the fast dif-
fusion coefficient based on the proportionality between conductivity and
the diffusion coefficient. Finally, the effective conductivity of the tissue is
estimated from the extracellular fluid’s conductivity and volume fraction.
The effective conductivity σi for direction i is given by17
2 f fast,i × (8.1×108 )
σi = Dfast,i (6.11)
3 − f fast,i
6.3.3.2 Experimental Results
Figure 6.7 shows the relationships between the b factor and the signal
intensities of diffusion-weighted images of the human brain.18 The regions
of interest were located on the putamen (gray matter), the posterior limb
of the internal capsule (white matter), and the genu of the corpus callo-
sum (white matter). The plots indicate the signal intensities measured with
the following MPG directions: anterior-posterior, right-left, and superior-
inferior. The signals gradually decreased with an increase in the b factor.
The putamen did not demonstrate clear anisotropy in signal attenuation.
In the internal capsule, the application of the MPG in the superior-inferior
direction caused the most rapid signal attenuation. In the corpus callo-
sum, the application of the MPG in the right-left direction caused the
most rapid signal attenuation.
–1
ln(signal)
–2
–3
–4 Anterior-posterior
Right-left
Superior-inferior
1000 2000 3000 4000 5000

(a) b factor (s/mm2)
0
–1
–2
ln(signal)
–3
Right-left
Superior-inferior
1000 2000 3000 4000 5000

(b) b factor (s/mm2)
0
–1
–2
ln(signal)
–3
Right-left
Superior-inferior
1000 2000 3000 4000 5000

(c) b factor (s/mm2)
FIGURE 6.7 Relationships between the b factor and the signal intensities of
diffusion-weighted images in the putamen. The three plots were obtained with
different MPG directions. (a) The putamen did not exhibit clear anisotropy in the
signal attenuations. (b) Signal attenuations in the internal capsule. The applica-
tion of the MPG in the superior-inferior direction caused the most rapid signal
attenuation. (c) Signal attenuations in the corpus callosum. The application of the
MPG in the right-left direction caused the most rapid signal attenuation. (From
Sekino, M. et al., IEEE Transactions on Magnetics 41: 4203–4205, 2005.)
Figure 6.8a through c show images of conductivities estimated using

Equation 6.11. The gray matter’s conductivity does not have a clear depen-
dence on the MPG direction. The white matter contains several regions
where conductivities are highly dependent on the MPG direction. Figure
6.8d and e show images of the mean conductivity (MC) and the anisotropy
index (AI). Regions with high AI values are found in the white matter.
The signals of diffusion-weighted images are derived from both the
intracellular and extracellular fluids. This method provides the tissue con-
ductivity based on only the fast diffusion component, which corresponds
to diffusion in the extracellular fluid. Marked anisotropy in brain regions
is also demonstrated for tissue conductivity. The anatomical structures of
2.6 2.6
0.0 0.0
(a) S/m (d) S/m
2.6 1.0
0.0 0.0
(b) S/m (e)
2.6
0.0
(c) S/m
FIGURE 6.8 Conductivity imaging of the human brain using diffusion MRI.
(a through c) Images of the estimated conductivities in the anterior-posterior,
right-left, and superior-inferior directions, respectively. (d, e) Images of the MC
and AI. (From Sekino, M. et al., IEEE Transactions on Magnetics 41: 4203–4205,
2005.)
the brain’s principal neuronal fiber tracts are well established from previ-
ous anatomical and histological studies. The corpus callosum connects
the right hemisphere and the left hemisphere with several neuronal fibers
that run in the right-left direction. The posterior limb of the internal cap-
sule lies on the pyramidal tract, which mainly consists of neuronal fibers
running in the superior-inferior direction. The diffusion of water mol-
ecules in the extracellular fluid is disturbed by the cell membranes, and
diffusibility is higher in the direction of neuronal fibers than in the other
directions. The high AI values in the internal capsule and corpus callosum
are attributable to the anatomical structures of these regions.
The inhomogeneity and anisotropy of the conductivity in each tissue
is not normally considered in conductivity models for current source
estimations of electroencephalography and magnetoencephalography.
However, the results of current source estimations depend on the spatial
distribution of conductivity in the models. The results of conductivity
imaging show significant inhomogeneity and anisotropy in the white mat-
ter. Therefore, the use of an inhomogeneous and anisotropic conductivity
model is desirable, particularly for estimating current sources in the deep
regions of the brain.
6.3.4 Impedance Imaging Using RF Current

6.3.4.1 Principles
When electric current is applied to a sample during MRI acquisition, the
current causes a change in the MRI signal, which depends on the sample’s
permittivity and conductivity. This phenomenon enables us to estimate
the distribution of tissue impedance. Because of increased attention to the
RF absorption of bodies in ultrahigh-field MRI, methods for mapping tis-
sue impedance and the resulting RF absorption have been developed.21–24
Figure 6.9a shows a schematic of MRI hardware for an impedance imaging
method using RF electromagnetic fields.21 In addition to the conventional
components, a pair of electrodes and an RF transmitter are introduced to
apply electric currents to the sample. Figure 6.9b shows the operational
diagram of the RF transmitters and receiver. The two transmitters operate
at the same frequency and maintain a difference in the phase angle at 0 or
π/2. Two consecutive RF pulses are applied from transmitter A with the
same pulse duration (τ/2) and opposite polarity. An RF pulse is simultane-
ously applied from transmitter B with a duration of τ. The magnetic field
generated from the RF coil rotates around the z axis with the Larmor fre-
quency. In addition, the application of an RF electric current to the sample
Conventional hardware
Superconducting magnet + gradient coil

RF transmitter (A)
RF coil
RF receiver
Sample
RF transmitter (B)
y Electrode
z x Newly introduced hardware

(a)
Permittivity and conductivity encoding
90°y 180°x MRI signal
RF transmitter (A) +x
RF receiver –x
RF transmitter (B)
(b) τ
FIGURE 6.9 Principle of impedance imaging using an RF current. (a) A weak

electric current at the Larmor frequency was applied to the sample through a pair
of surface electrodes. The current was supplied from an external RF transmitter.
(b) The operational diagram of the RF transmitters and receiver. Transmitter A
produces RF pulses with inverted polarities for a duration of τ/2. Transmitter B
simultaneously produces an RF pulse for a duration of τ. (From Sekino, M. et al.,
IEEE Transactions on Magnetics 44: 4460–4463, 2008.)
gives rise to an oscillating magnetic field. An x′-y′-z′ rotating frame with

the x′ and y′ axes rotating at the magnetic resonance frequency is intro-
duced for the following discussion. The phase angle of transmitter A is
adjusted such that the magnetic field generated from the coil (B1) turns
toward the x′ direction. Magnetization M rotates around the externally
applied magnetic field. Assuming that B1 is much stronger than Bx′ and
B ′y, the direction of the total RF magnetic field becomes approximately
x′. During application of B1 in a positive polarity, the magnetization vec-
tor rotates with an angle of (B1 + Bx′ )γ τ/2. The B1 magnetic field is sub-
sequently applied in a negative polarity, and the magnetization vector
rotates with an angle of (−B1 + Bx′ )γ τ/2. Consequently, the angle between
the magnetization and the z axis becomes θ0 = Bx′ γ τ. The remaining RF
pulses in Figure 6.9b enable us to measure θ0 based on the phase angle
of the magnetic resonance signals. In the next step, B1 turns toward the
y′ direction, and θ π/2 = B y′ γ τ is measured. On the basis of the wave equa-
tion of the electromagnetic fields in the sample, the following equation is
derived to estimate permittivity εr and conductivity σ:
∇ 2 (θ0 − iθ π/2 )
ω 02ε0εr µ 0 − iω 0µ 0σ = − (6.12)
θ0 − iθ π/2
6.3.4.2 Experimental Results
Preliminary results of phantom experiments have been reported in a
previous paper.21 An acrylic tube was filled with a solution comprised of
saline (30%) and ethanol (70%). The permittivity and conductivity of the
solution were approximately 40 and 0.14 S/m, respectively. A pair of plati-
num electrodes was attached to both ends of the sample. Using a coaxial
cable, the electrodes were connected to an RF transmitter. Signals were
detected using a birdcage-type RF coil.
As shown in Figure 6.10, images of magnetization angles were obtained
from magnetic resonance signals, and the sample’s permittivity and con-
ductivity were estimated. The lower left part of the sample exhibited a rela-
tively large error in the estimated permittivity and conductivity. The lead
wire caused inhomogeneity in the RF electromagnetic field, which resulted
in an error around the wire. At the center of the sample, we obtained an
estimated relative permittivity of 40 and an estimated conductivity of
2.0 S/m, which are reasonable results. In a part of the image, however, the
results showed errors that are mainly attributable to inhomogeneity in the
field generated by the RF coil.
This methodology has potential advantages over conventional imped-
ance imaging techniques because of its high spatial resolution and its
capacity to measure permittivity. In addition, this method is easily appli-
cable to both biological tissues and human subjects.
6.3.5 Magnetic Resonance Electrical Impedance Tomography

As discussed in the next section, MRI quantitatively visualizes the spa-
tial distribution of electric current.25 The distribution of conductivity can
then be estimated from the measured current.26–28 Compared with con-
ventional EIT, the advantages of this approach are its high spatial distribu-
tions and high robustness with respect to the contact resistance between
the electrodes and the body. Equation 6.13 is an algorithm proposed
θ0 θπ/2
–π π –π π
εr σ
–50 165 –10 33

S/m
FIGURE 6.10 Experimentally obtained images of the phase angle of magnetic

resonance signals θ 0 (upper left) and θπ/2 (upper right), estimated electric permit-
tivity εr (lower left), and estimated conductivity σ (lower right). (From Sekino, M.
et al., IEEE Transactions on Magnetics 44: 4460–4463, 2008.)
in the primary stage of MRI-based EIT to estimate the conductivity

distribution.26
The current distribution in the sample measured using MRI is denoted by
J *, and the respective current and voltage applied to the electrodes attached
to the surface are denoted by I and V*. The aim of the algorithm is to esti-
mate unknown resistivity distribution ρ* using the given values of J *, I, and
V *. The area inside the sample is divided by a computational grid, and ini-
tial resistivity ρ0 is given to each computational grid. Given initial resistiv-
ity ρ0 and measured electrode current I, current density J 0 at each grid and
electrode voltage V 0 is calculated using the finite-element method. Revised
resistivity ρ1 for each node is then obtained by substituting k = 0 into
Jk V *
ρk+1 = ρk
J * V k (6.13)
Iterative calculations for k = 1, 2, 3, …, make resistivity ρk of each node

converge to the true resistivity ρ*.
Magnetic resonance electrical impedance tomography has been dem-

onstrated in both computer simulations and experiments for phantoms,
animals, and humans.
6.4 MAGNETIC RESONANCE IMAGING

OF ELECTRIC CURRENTS
6.4.1 Changes in Magnetic Resonance Signals
Resulting from the Magnetic Field
As the Larmor equation indicates, the precession velocity of magnetiza-
tion is proportional to the strength of the externally applied magnetic
field. Magnetic fields generated by electric currents flowing in a body are
generally much weaker than the main static magnetic field applied in the z
direction. Consequently, the strength of the total magnetic field is the sum
of the main static field and the z component of the additional magnetic
field.29 When an electric current pulse is applied to the body with a pulse
width of τ, the magnetic field generated by the current causes the follow-
ing phase shift in the magnetic resonance signal:
ϕ = γBz τ (6.14)
To map the generated magnetic field, two phase angle images are
acquired with and without the application of an electric current, and the
two images are subtracted.25 Spontaneously generated magnetic fields,
such as neuronal fields, generally have time-varying currents. In this case,
Equation 6.14 is modified as
τ
φ=γ
∫ B (t)dt (6.15)
0
z
The above discussion indicates that only the z component of the mag-
netic field can be measured using MRI. The process of rotating the sample
inside the MRI scanner such that the sample is oriented along the other
two orthogonal directions and then measuring the corresponding mag-
netic field maps provides the three components of the magnetic field vec-
tor. Taking the rotation of the magnetic field gives the electric current
distribution:
1
j= ∇ × B (6.16)
µ0
However, mechanical rotation is possible only in the case of small sam-

ples. Using mathematical approaches to incorporate certain physical con-
straints on the field distribution, the current density distribution can be
estimated from the measured magnetic field distribution.30,31 For example,
the Fourier transform of the z component of Equation 6.16 is given by
i kx2 + k y2
j z′ = − bx′ (6.17)
µ0 ky
where j z′ and bx′ are the Fourier transforms of the z component of the
current density and the x component of the magnetic field, respectively.
According to Equation 6.17, estimating one component of the current
density requires one orthogonal component of the magnetic field to be
mapped.
When the generated magnetic field is strongly inhomogeneous, the field
causes the loss of signal coherence in a voxel, which results in a decrease in
signal magnitude. This effect may occur in close proximity to the current
source. While the measurement based on the phase angle has relatively
high sensitivity to the magnetic field, the image analyses include a some-
what complicated process for phase unwrapping. The measurement using
the signal magnitude allows for simple post processing.
When the intensity of the magnetic field is relatively high, the influ-
ence of the magnetic field can also be observed as a shift in the Larmor
frequency. Numerical simulations based on the Bloch equation provide
a quantitative relationship between the generated field and the signal
intensity.31
6.4.2 Sensitivity to a Weak Electric Current

6.4.2.1 Neuronal Current Dipole
Neuronal activities give rise to ionic currents inside and outside the neu-
ron. The realistic current distribution and the resulting magnetic field
distribution are expected to be complicated. However, the following for-
mula for magnetic fields produced by a current dipole gives a first-order
approximation for neuronal magnetic fields:32
µ0 r − r′
B(r) = Q(r ′)×
r − r ′ (6.18)
3
4π
where B(r) is the neuronal magnetic field at location r, Q(r′) is the cur-
rent dipole at location r′, and μ0 is the permittivity of free space. Here, we
assume that the main static magnetic field, B0, is applied in +z direction
and that the current dipole is located at r′ = (0, 0, 0), pointing in the +x
direction. When B(r) is much smaller than B0, the magnitude of the total
magnetic field can be approximated as33
µ0 Qy
B 0 + B(r) ≈ B 0 + Bz (r) = B 0 + (6.19)
4π (x + y 2 + z 2 )3/2
2
where Bz(r) is the z component of B(r) and Q is the strength of the current
dipole. The frequency shift caused by the neuronal magnetic field is
µ0γ Qy
∆ω = γ ( B 0 − B(r) − B 0 ) ≈ (6.20)
4π (x + y 2 + z 2 )3/2
2
For an image voxel centered at (x0, y0, z0), the following equation gives
the signal intensity normalized by the intensity without a neuronal mag-
netic field:
x0 +hx /2 y0 +h y /2 z0 +hz /2
∫ ∫ ∫
1
S= dx dy dz exp(iTE∆ω) (6.21)
hx hy hz x0 −hx /2 y0 −h y /2 z0 −hz /2
where hx, hy, and hz are the dimensions of the voxel in the x, y, and z direc-
tions, respectively, and TE is the echo time for MRI acquisition. Examples
of calculating the above signal intensity are reported elsewhere.33
6.4.2.2 Theoretical Evaluation of Sensitivity

Magnetic fields arising from neuronal electrical activity are extremely
weak. A magnetic field of 10 pT generated during an echo time of 20 msec,
for example, leads to a phase angle shift of only 5.3 × 10−5 rad. To discuss
the feasibility of detecting neuronal magnetic fields, theoretical evaluation
of sensitivity is essential. Several studies have reported the sensitivity of
MRI to magnetic fields.34–36
Here, we assume that the magnetic fields are detected as a particular
phase angle shift, as explained above. Resulting from noise in the MRI sig-
nal, uncertainty σB in the estimated value of the magnetic field is given by
N
σB = (6.22)
SγTE
where N is the intensity of noise in the MRI signal, S is the signal intensity,
and TE is the echo time.34 The magnetic field can be detected when inten-
sity β is higher than uncertainty σB. Therefore, σB gives the theoretical
sensitivity for magnetic fields.
Magnetization M0, which is induced in a sample by the main static field,
B0, is given by
M 0 = N s γ 2h 2 I(I +1)B0 /3kBTs (6.23)
where Ns is the 1H density of the sample, ħ is Planck’s constant, I is the

spin quantum number, kB is the Boltzmann constant, and Ts is the sample
temperature. When an MRI is obtained with a field of view of L × L and a
slice thickness of h, signal intensity S per voxel is
[1− exp(−TR /T1 )]exp(−TE /T 2* )

S = γB0 B1 M 0 L2h sinθ (6.24)
1− cosθexp(−TR /T1 )
where TR is the repetition time, T1 and T2 are the sample’s relaxation times,
and θ is the flip angle. B1 is the RF field intensity that the unit current flow-
ing through the RF receiver coil produces at the voxel.
In an MRI consisting of n × n voxels, noise N per voxel is
∆N = n 4kBTs∆fR (6.25)
where Δf is the spectral width of the receiver circuit and R is the effective
resistance in the receiver circuit. The resistance is partly caused by the
conductors in the receiver coil and partly caused by the sample. Under
typical MRI conditions in the human head, the resistance caused by the
sample is dominant. Produced by the sample, equivalent resistance R in
the receiver circuit is related to the absorption, which the unit current
flowing in the receiver coil at the Larmor frequency causes in the sample;
namely,
| j|2
R=2
∫ σ
dVs (6.26)
where j is the induced current distribution in the sample, which is caused

by the unit current in the receiver coil, and σ is the conductivity.
A previous study reported the theoretical sensitivity for detecting neu-
ronal magnetic fields in the human brain.35 The effective resistance in the
receiver circuit caused by the human head was evaluated using numerical
simulations on an anatomically realistic model, as shown in Figure 6.11.
The electromagnetic field distributions were calculated using the finite ele-
ment method. The results show that the theoretical sensitivity for mag-
netic fields in the brain is approximately 10−8 T.
(a) (b)
Birdcage
coil I11 I0 I1 I2 I3
I0 – I11 I1 – I0 I2 – I1 I3 – I2
I0 I1 I2 I3
Receiver circuit and amplifier

(c) (d)
FIGURE 6.11 Evaluation of the sensitivity for detecting weak magnetic fields
generated in the human brain. Numerical analyses were conducted on a realistic
human head model and a birdcage-type receiver coil. (a) Coronal and (b) sagit-
tal slices of the model. (c) Three-dimensional view of the model and the receiver
coil. (d) A circuit schematic of the receiver coil. (From Hatada, T. et al., Journal of
Applied Physics 97: 10E109, 2005.)
6.4.2.3 Experimental Evaluation of Sensitivity

Sensitivity to weak magnetic fields has been experimentally evaluated for
phantoms and animals.36–38 One of our studies used columnar phantoms
with electrodes attached to the ends of the column.36 MRI was obtained
from externally applied currents with intensities ranging from 0.75 to
150 A/m2. The experimentally determined sensitivity was approximately
10−8 T, which agreed well with the theoretical prediction.
Measurements of neuronal magnetic fields have been conducted using
sensors located outside the brain. However, MRI detects magnetic fields
generated in close proximity to the current source. Local mappings of
neuronal magnetic fields in the rat brain have been reported when discuss-
ing the possibility of detecting neuronal fields.38 A 16-channel electrode
with a needle length of 3 mm was prepared to measure three-dimensional
potential distributions. The electrode was inserted into the brain through
a cranial window with varied depths ranging from 0.5 to 1.4 mm. Electric
stimulations were delivered to the left hind paw. Somatosensory-evoked
potentials were measured through the electrode, and with a 300-μm spa-
tial resolution, three-dimensional distributions of the current density and
magnetic field were calculated from the potentials.
The peak magnitude of the evoked potential was 807 μV. The maxi-
mum calculated electric current density was 168 μA/cm2, which occurred
21 msec after stimulation. The time and location of the peak current den-
sity were similar to the time and location of electric potentials. The maxi-
mum magnetic flux density within the calculated region was 50 pT. The
neuronal magnetic field caused a phase angle shift in the MRI signal. The
estimated phase angle shift in the rat brain was 5 × 10−5 rad. Without sig-
nal averaging, the experimentally evaluated signal-to-noise ratio for the
rat brain was 200 in a 7-T MRI. The resulting sensitivity for magnetic field
detection was 940 pT. Sensitivity is inversely proportional to the square
root of the number of averaged signal averaging. Data averaging should be
performed with more than 10,000 iterations to detect neuronal magnetic
fields.
6.4.3 Animal Studies
6.4.3.1 Brain Slices
In addition to the magnetic field arising from neuronal electric activi-
ties, associated changes in blood oxygenation cause considerable fluctua-
tion in the magnetic field and result in baseline signal fluctuations. This
situation makes it difficult to detect neuronal magnetic fields. In order to

eliminate baseline signal fluctuations for hemodynamics, experimental
setups under hemoglobin-free conditions have been reported using cell
cultures, turtle brain slices, and rat brain slices.39–41 Among these meth-
ods, an experimental setup was developed to maintain the rat brain slice
in a hemoglobin-free medium and to measure the neuronal electric activ-
ity in an MRI system.39 The developed nonmagnetic sample holder con-
sisted of a multielectrode array (MEA) and a perfusing system, as shown
in Figure 6.12a. The eight-by-eight-channel MEA was fabricated on a
aCSF (pump in)

O2 + CO2
aCSF (pump out)
Multielectrode array
Space filler 8 × 8 ch.
150 µm
Sinker
Rat brain slice
150 µm
(a)
Space filler
Sinker
Rat brain slice
(b)
FIGURE 6.12 Experimental setup for detecting magnetic fields arising from an
extracted brain slice. A multielectrode array measures and stimulates the living
brain slice. The perfusion of artificial cerebrospinal fluid washes the blood from
the brain slice. (a) Construction of perfusion chamber and perfusing system.
(b) Position relation in perfusion chamber. (From Kim, D. et al., Proceedings of
the Annual International Conference of the IEEE Engineering in Medicine and
Biology Society 1370–1373, 2013.)
glass substrate and recorded the evoked extracellular electrical potential

during electrical stimulation of the brain slice. The perfusion system cir-
culated the artificial cerebrospinal fluid (aCSF) and the mixture gas [O2
(95%) + CO2 (5%)] to maintain cell activities in the slice. The MEA was
equipped with a space filler controlling the aCSF flow and a nonmagnetic
material sinker to achieve the desired contact condition for the MEA.
The relative positions of the space filler, the sinker, and the rat brain slice
in the perfusion chamber are shown in Figure 6.12b. The field excitatory
postsynaptic potentials (fEPSP) were measured with the MEA by electri-
cally stimulating the brain slice. Assuming that the brain slice had uni-
form conductivity, the distribution of current density could be calculated
from the measured distribution of the evoked electric potential. Using
the distribution of current density, the magnetic field intensity arising
from neuronal electrical activity in the brain slice was analyzed. The pos-
sibility of directly detecting the weak neuronal magnetic field could be
experimentally evaluated according to the sensitivity of the MRI system.
Moreover, an MRI acquisition condition for direct detection of neuronal
activity was investigated. However, validation is required to determine
whether the sensitivity of MRI is sufficiently high to detect these neuro-
nal activities.
6.4.3.2 In Vivo Experiments

In vivo experiments have also been performed to measure transient
changes in the signal intensity resulting from neuronal activities in the
rat brain.33 An implantable platinum electrode was attached to the sciatic
nerve for electric stimulation. Pulsed electric stimulations were applied to
the electrodes with a repetition rate of 3 pulses/sec. Measurements were
performed using a 4.7-T MRI system. Functional images were obtained
using a gradient echo sequence. The excitation pulses were applied every
30 msec at ten time points (0, 30, 60, …, and 270 msec) after electric stim-
ulation. The signal intensities of functional images obtained with and
without stimulation were statistically compared using a Student’s t-test.
In addition, the signal intensities of the images acquired at adjacent time
points were compared.
Figure 6.13 shows temporal changes in the signal intensity of func-
tional images. The signals were averaged in regions of interest (ROIs)
located on the left and right somatosensory cortices. In the left ROI, no
clear difference was found between the signals obtained with and without
0.025 Left S1
0.02
Signal intensity
0.015
Stimulation
0.01
0.005
Control
0 50 100 150 200 250
(a) Time after stimulation (msec)
0.025
Stimulation
0.02
Signal intensity
0.015 Control
Right S1
0.01
0.005
0 50 100 150 200 250

(b) Time after stimulation (msec)
FIGURE 6.13 Time courses of the signal intensity in the (a) left and (b) right
somatosensory areas in the rat brain after electric stimulation of the left sciatic
nerve. (From Sekino, M. et al., IEEE Transactions on Magnetics 45: 4841–4844,
2009.)
stimulation. In the right ROI, the signal intensity with stimulation was
higher than the intensity without stimulation at most time points. This
increase in the signal intensity’s baseline was caused by the blood oxygen-
ation level-dependent effect associated with increased blood flow in the
right somatosensory cortex. A transient decrease in the signal intensity
was found at 0 to 30 msec after stimulation. This result is consistent with
a local change in the magnetic field resulting from neuronal activities.
The images were compared at adjacent time points to investigate temporal
changes, as shown in Figure 6.14. A significant difference was observed
between 30 to 60 msec and 60 to 90 msec in the right somatosensory area,
which suggests that these effects arose temporarily from neuronal mag-
netic fields. However, both the somatosensory cortex and other areas of
0–30 msec 30–60 msec 60–90 msec 90–120 msec


0.00
0.05
240–270 msec P value
270–300 msec
FIGURE 6.14 Detection of magnetic fields arising from neuronal activities. The
signal intensities from the images obtained at adjacent time points were com-
pared after electric stimulation. The time “0–30 msec, 30–60 msec” means a
comparison between the image excited at 0 msec (and acquired at 30 msec) and
the image excited at 30 msec (and acquired at 60 msec). Color indicates the level
of statistical significance (P value) in a Student’s t-test. (From Sekino, M. et al.,
IEEE Transactions on Magnetics 45: 4841–4844, 2009.)
the brain showed activations. This findings is perhaps caused by noise in

images because, compared with the strength of neuronal magnetic fields,
the sensitivity of present MRI is not sufficiently high. The signal-to-noise
ratio should be improved in future works.
6.4.4 Human Studies
Several papers have reported human studies seeking to detect neuronal
currents in the brain or the median nerve.42–44 A pioneering work in this
topic used gradient magnetic fields with different polarities to detect neu-
ronal fields and to eliminate signal variations resulting from other effects.42
Measurements were conducted using a 1.5-T MRI system. In addition to
neuronal magnetic fields, the blood oxygenation level and blood volume
affect images. As shown in Table 6.2, functional images were obtained
from gradient fields with different polarities, and the images were edited
to eliminate intensity changes resulting from causes other than neuronal
currents normal to the static magnetic field. Identical effects on Ip and In
are produced by changes in blood’s magnetic susceptibility. Signal inten-
sity changes resulting from causes other than neuronal currents are elimi-
nated in subtracted images of Ip and In. Neuronal currents cause different
effects on Ip and In, and signal intensity changes are observed in subtracted
images (Ip – In and In – Ip). The component of currents normal to the read-
out gradient causes symmetrical signal intensity changes about the com-
ponent’s axis. The parallel component produces asymmetrical intensity
changes. Areas with symmetrical intensity changes were extracted to
avoid misrepresentation by artifacts.
A double-subtracted image was produced for the activated area of the
human brain during repeated tapping of the right hand’s middle fin-
ger and thumb. Figure 6.15 shows a neuronal current map based on the
double-subtracted image. The y component (normal to the static magnetic
field and the readout gradient) of the currents in the activated sensory
area was clearly observed. The currents in the motor area, however, were
not detected because the y component of the currents in the motor area
was too small.
TABLE 6.2 Procedures for Obtaining Neural Current Distribution Images

Image State Polarity of the Read-Out Gradient
I
Ipr Rest p
Ipa Activated p
Inr Rest n
Ina Activated n
II
Ipa − Ipr = Ip → fMRI
Ina − Inr = In → fMRI
III
In − Ip → Current distribution image
Ip − In → Current distribution image
Source: Kamei, H. et al., IEEE Transactions on Magnetics 35: 4109–4111, 1999.
FIGURE 6.15 Neuronal current distribution imaging of the human brain

using readout gradients with reversed polarities. The detected signal from the
activated sensory area has been enhanced bright enough to be clearly visible
on the image. (From Kamei, H. et al., IEEE Transactions on Magnetics 35: 4109–
4111, 1999.)

As discussed in this chapter, the use of MRI in impedance imaging real-
izes millimeter-scale resolutions and measurement of anisotropic conduc-
tivity. Currently, the results of MRI-based impedance imaging have been
put into practical use in electromagnetic field analyses. Recent progress
in ultrahigh-field MRI has raised a safety issue associated with high RF
absorption in the patient’s body. Because of differences in body anatomy
among individuals and variable postures of the MRI scanner, there is a
strong need to map the impedance of the subject’s body. One of the techni-
cal challenges for future impedance imaging is a measurement with arbi-
trary frequency. When a quantitative measurement of impedance at an
arbitrary frequency is realized, the results will be used in even broader
technological fields.
Detection of a neuronal magnetic field using MRI is an attractive but
challenging endeavor. As introduced in this chapter, some previous stud-
ies have provided positive evidence supporting the possibility of detec-
tion. However, the methods for detecting neuronal fields remain to be
established for practical use. Conventional methods of functional imag-
ing provide some brain activity information; for example, fMRI measures
the spatial distribution of the activities, and MEG measures the temporal
changes in the activities. The neuronal-field MRI potentially visualizes the
spatiotemporal dynamics of brain activities and may become a new tech-

nique leading to a deeper understanding of brain function.
Finally, authors would appreciate if readers understand that the con-
tents of this chapter belong to future prospects, and authors have tried to
introduce whatever small or even incomplete data and results of experi-
ments toward MR imaging of impedance or electric currents to be verified
in the future.
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Chapter 7
Magnetic Control
of Biological Cell Growth
Shoogo Ueno and Sachiko Yamaguchi-Sekino
CONTENTS
7.2 Basic Principles for Biomagnetic Effects 188
7.2.1 Effects of Static Magnetic Fields on Biological Systems 188
7.2.1.1 Magnetic Force Acting on a Biological System
in a Homogeneous Magnetic Field 189
7.2.1.2 Magnetic Torque on Biological Cells
in a Homogeneous Magnetic Field 191
in an Inhomogeneous Magnetic Field 192
7.2.2 Effects of Time-Varying Magnetic Fields on Biological
Systems 194
7.2.2.1 Low-Frequency Magnetic Fields and Pulsed
Magnetic Fields 194
7.2.2.2 High-Frequency Magnetic Fields
and Microwaves 195
7.2.3 Effects of Multiplicity of Magnetic Fields and Other
Forms of Energy 196
7.2.3.1 Radical Pair Model and Singlet-Triplet
Intersystem Crossing 196
7.3 Magnetic Orientation of Adherent Cells 197
7.3.1 Polymerization Processes of Fibrin Fibers under Strong
Static Magnetic Fields 197
7.3.2 Fibrin, Collagen, Osteoblast Cells, Endothelial Cells,
Smooth Muscle Cells, and Schwann Cells 198
185
7.4 Bone Growth Acceleration by Static Magnetic Fields 198

7.4.1 Background 198
7.4.2 Magnetic Control of Bone Growth Acceleration 200
7.5 Control of Direction and Growth of Nerve Axons
during Nerve Regeneration by Static Magnetic Fields 202
7.5.2 Magnetic Control of Direction and Growth of Nerve
Cells 203
7.6 Distraction of Leukemic Cells by Magnetizable Beads
and Pulsed Magnetic Force 205
7.6.2 Magnetic Destruction of Leukemia Cells by Physical
Force 207
7.7 Inhibition of Tumor Growth by Pulsed Magnetic Stimulation 209
7.7.2 Magnetic Control of Tumor Growth Inhibition 211
References 212
7.1 INTRODUCTION
Cell proliferation and cell death are fundamental phenomena that help in
maintaining a human body’s condition. The number of cells in the body
increases by cell proliferation and decreases by cell death. Because the
regulation of cell proliferation and death is strongly connected to vari-
ous disorders (e.g., cancer or nerve degeneration), these phenomena are
strictly regulated by genes or proteins. The basic principle utilized in the
magnetic control of cell growth is to control the cells’ physiological status
using physical stimuli from static or time-varying (and pulsed) magnetic
fields. Application of these stimuli might affect the cells’ morphological
and functional (including genetic and protein expression) features. The
greatest advantage of this approach is its noninvasiveness, thus avoiding
patient surgery. Another advantage is that this method subjects the patient
to nonionizing radiation, thereby minimizing risks to operators and
patients from harmful ionizing radiation. Furthermore, the simplicity-of-
handling feature of this method implies that the installation of large facili-
ties such as radiation therapy is not required. For these reasons, attempts
at controlling the cell state by magnetic fields have been the focus of active
research in this decade (Ueno 2012).
Magnetic Control of Biological Cell Growth ◾ 187
Sources of exposure for the magnetic control of cell growth can be static
or time-varying (pulsed) magnetic fields. Magneto-mechanical effects and
magnetically induced electric currents are the basic mechanisms of physi-
cal stimuli in the magnetic control of cell growth. A static magnetic field
generates magneto-mechanical effects known as “magnetic orientation”
and “magnetic force,” although this chapter only focuses on medical appli-
cations of the former effect. Historically, the first instance of the magnetic
control of cell growth by a static magnetic field was the polymerization of
fibrin gel in strong magnetic fields, performed by Torbet et al. (1981) and
Torbet and Ronziere (1984). Torbet el al. demonstrated the polymeriza-
tion of fibrin fibers in an 11 T static magnetic field and reported that the
fibers aligned in a particular direction with respect to the magnetic field
(known as the “magnetic orientation”) when the polymerization was car-
ried out slowly (Torbet et al. 1981). Magnetic orientation has been observed
in various biological molecules such as collagen (Murthy 1984; Torbet
and Ronziere 1984; Kotani et al. 2000), and cells such as osteoblast cells
(Kotani et al. 2000, 2002), Schwann cells (Eguch et al. 2003; Eguchi and
Ueno 2005), vascular endothelial cells, and smooth muscle cells (Umeno
et al. 2001; Umeno and Ueno 2003; Iwasaka and Ueno 2003a,b; Iwasaka et
al. 2003). Owing to these experiments, this phenomenon is now a scien-
tifically established effect of static magnetic fields (WHO EHC 232 2006;
ICNIRP 2009). Medical applications of the magnetic orientation have
been demonstrated in various targets (Ueno and Sekino 2006).
Apart from static magnetic fields, studies on the medical applications of
time-varying magnetic fields (pulsed magnetic fields) are also underway.
Magnetic stimulation, established by Barkar et al. (1985) and developed
by Ueno et al. (1988), is a noninvasive electrical stimulation technique.
Because the promising biological effects of this method toward excit-
able tissues (e.g., brain or neurons) have been shown, various medical
applications of magnetic stimulation have been developed in the fields of
brain science or neurology (Ueno 2012). However, applying magnetically
induced force or currents to cancers has only recently been studied and
the noninvasiveness of this method has been found to be a great advantage
for cancer therapy.
We first review the basic principles for biology-magnetism interaction
(named biomagnetic effects) in Section 7.2 and introduce the physical
background of biological effects caused by exposure to static and time-
varying magnetic fields and their multiplicative use with other forms of
energy. In the latter half of this chapter, attempts on the magnetic control
of tissues for disorders (Section 7.4, bone growth acceleration; Section 7.5,
nerve regeneration; and Sections 7.6 and 7.7, cancers) will be introduced.
7.2 BASIC PRINCIPLES FOR BIOMAGNETIC EFFECTS

7.2.1 Effects of Static Magnetic Fields on Biological Systems
Scientific studies on the short-term effects of static magnetic fields on tis-
sues have already been authorized and published by several organizations
such as the World Health Organization (WHO) (WHO EHC 232 2006)
and the International Commission on Non-Ionizing Radiation Protection
(ICNIRP) (ICNIRP 2004, 2009, 2014). A number of books and review
articles also describe the effects and experimental results related to static
magnetic fields exposure. Chapter 9 of this textbook introduces the effects
and mechanisms of static and time-varying magnetic fields on tissues.
Figure 7.1 illustrates an overview of the biological effects of a static
magnetic field. Biological effects of a static magnetic field can be classi-
fied depending on whether the exposure source is a nonuniform (inhomo-
geneous) or uniform (homogeneous) magnetic field: (1) A physical force/
voltage named “Lorentz force/flow potential” and (2) a rotational force
named “magnetic torque” are established effects of a homogeneous mag-
netic field. The former is a phenomenon that is observed in an electrically
conductive fluid flowing perpendicular to a magnetic field that produces
Static magnetic fields Time-varying magnetic fields
1. Electrodynamic interactions with <100 kHz >100 kHz

moving electrolytes
Physical
effects
2. Induced electric fields and currents

Induced
3. Mechanical translation Heat
current
4. Magnetic orientation
5. Electron spin interactions
F
Biological
effects
B
B0
Nerve Hall effect Forces on Orientation of Nerve Heat

stimulation biomolecules biomolecules stimulation
Effects of multiplication of magnetic fields and other energy
FIGURE 7.1 Basic principles for biomagnetic effects.

a force (Lorentz force) and voltage (flow potential) at right angles to each
other. This effect becomes visible as an artifact in ECGs (electrocardio-
grams), which are recorded under strong static magnetic fields. The latter
effect is a phenomenon that the molecules are aligned in the certain direc-
tion in which molecules are magnetically stable with dependent on their
magnetic anisotropy. Various types of molecules and cells are known to
respond to a static magnetic field as well as exhibit morphological changes.
In an inhomogeneous magnetic field, two major properties affect bio-
logical organisms; these are (1) the “magnetic force” and (2) magnetically
induced currents named “motion-induced currents,” which occur because
of motion in an inhomogeneous field. Magnetic forces are frequently
observed when a paramagnetic material is placed in a magnetic field gra-
dient. This projectile effect is a major concern among magnetic resonance
imaging (MRI) operators from the viewpoint of safe handling of the
equipment. A diamagnetic material such as water also experiences a repul-
sive force when exposed to an inhomogeneous magnetic field. A strong
magnetic field with a high field gradient, on the order of 50–100 T/m, can
generate a partition in water (Ueno and Iwasaka 1994a,b). The latter phe-
nomenon is observable through temporary symptoms, such as dizziness
and headache, near a strong inhomogeneous magnetic field such as that
produced in the vicinity of an MRI system. Proper management and edu-
cation are required to protect MRI operators from these symptoms.
The effect of a static magnetic field on a chemical reaction has been
described as the “radical pair effect” (Ritz et al. 2000; Okano 2008; ICNIRP
2009). The static magnetic field alters the yield of chemical substances by
affecting the intersystem crossing of radicals produced as intermediates in
a photochemical reaction.

in a Homogeneous Magnetic Field
7.2.1.1.1 Magnetic Induction 1 (Lorentz Force/Flow Potential) Magnetic
induction, especially magnetohydrodynamics (MHD), describes the elec-
trodynamic interaction of a magnetic field with conductive fluids such as
blood flow. The basic principle of MHD is that magnetic fields can induce
currents in a moving conductive fluid, which, in turn, creates forces on
the fluid and changes the magnetic field itself. The Lorentz force is defined
as the vector product of the charge velocity and magnetic flux density and
consequently is perpendicular to the direction of electric charge flow (flow
potential) (Kangarlu and Robitaille 2000; ICNIRP 2009). It has been a
concern that blood or the body itself may be subject to Lorentz force and
a flow potential because of magnetic field exposure, because these tissues
are electrically conductive. Indeed, it is well established that when major
arteries of the circulatory system are placed in a magnetic field, an elec-
tric voltage is induced in the blood flowing through them (Kangarlu and
Robitaille 2000).
Figure 7.2a shows examples of magnetic forces acting on biological
systems in homogeneous magnetic fields. The electrical potential (E) that
develops when blood (velocity v) flows in a vessel of cylindrical shape with
a diameter D placed at an angle θ with respect to a static magnetic field B
can be represented by
E = vBD sin θ
Kangarlu and Robitaille estimated that in order to maintain flow in the

aorta against the opposing magnetically induced force, blood pressure
may rise by as much as 28 percent at 10 T (Kangarlu and Robitaille 2000).
However, a hemodynamics study in dogs at 8 T revealed no elevation of
blood pressure during 3 h of exposure (Kangarlu et al. 1999). The authors
concluded from calculations that the change between the total hydrody-
namic vascular pressure to the total MHD-induced vascular pressure is less
than 0.2 percent and that there is no notable pressure effect on the human
circulatory system for fields of up to 10 T (Kangarlu and Robitaille 2000).
Shiga et al. examined the effect of an external inhomogeneous magnetic
R
B
v
Magnetically induced
flow potential
l
Arter y wal
E
P T
Q
Ao Ac
S
(a) (b)
FIGURE 7.2 Magnetic force acting on a biological system in homogeneous mag-

netic fields. (a) Hall effect by the movement of charged particle in a magnetic
field. (b) An artifact in an electrocardiogram due to magnetically induced flow
potential. (From World Health Organization, Environmental Health Criteria 69:
Magnetic Fields, Geneva, Switzerland, p. 56, 1987.)
field on the flow of erythrocytes containing paramagnetic hemoglobin

(Shiga et al. 1993). Red blood cells are known to turn paramagnetic from
diamagnetic when the hemoglobin in red blood cells combines with oxy-
gen (Shiga et al. 1993). The authors demonstrated that the paramagnetic
attraction takes place with venous blood and that the effect depended on
the product of the field strength and its spatial gradient, degree of de-
oxygenation, flow velocity, and the hematocrit (Shiga et al. 1993).
Figure 7.2b shows a change in ECG caused by magnetically induced flow
potential (WHO EHC 69 1987). This magnetically induced flow potential
modifies the ECG’s T-wave amplitude (Togawa et al. 1967). This effect has
been established as an artifact caused by a static magnetic field. Indeed,
no hazardous effects were observed in volunteers at 8 T MRI (Kangarlu
et al. 1999).
7.2.1.2 Magnetic Torque on Biological Cells

in a Homogeneous Magnetic Field
7.2.1.2.1 Magneto-Orientation (Magnetic Torque) Magneto-mechanical
translation (magnetic torque) generates a couple to rotate materials in a
stable direction determined by the anisotropy of a material’s magnetic
susceptibility in a spatially homogenous magnetic field (WHO EHC 232
2006; ICNIRP 2009; Ueno 2012). The torque (magnetic torque) acting on
an object is represented as
1
T = − µ 0 ⋅ B 2∆χsin2θ
2
where B and μ0 are defined above, Δχ is the anisotropy in the material’s

magnetic susceptibility, and θ is the angle between the direction of the
magnetic field and the long axis of the material. Magnetic torque aligns
various biological molecules and cells where the directions of the orienta-
tion depend on the targets. Collagen (Murthy 1984; Torbet and Ronziere
1984; Kotani et al. 2000) and cells such as osteoblast cells (Kotani et al.
2000, 2002), Schwann cells (Eguch et al. 2003; Eguchi and Ueno 2005),
vascular endothelial cells, and smooth muscle cells (Umeno et al. 2001;
Iwasaka and Ueno 2003a,b; Iwasaka et al. 2003; Umeno and Ueno 2003)
have been reported as magnetic torque sensitive. However, Schenck
reported that this force is too small to affect biological material in vivo
owing to the very small (−10–5) values of magnetic susceptibility (Schenck
2000). Details of this effect will also be described in Section 7.3.

in an Inhomogeneous Magnetic Field
7.2.1.3.1 Magneto-Mechanical Translation (Magnetic Force) A spatially
inhomogeneous magnetic field induces magneto-mechanical translation
(magnetic force) (ICNIRP 2004, 2009; WHO EHC 232 2006). Materials
tend to move along the direction of the steepest field gradient when
exposed to an inhomogeneous field. The magnetic force that acts on the
material is proportional to the magnetic flux density (B), the gradient of
the magnetic flux density B (grad B), and the magnetic susceptibility (χ)
of the material. It is represented as
F = [χB (grad B)]/μ0
where μ0 is the magnetic permeability of a vacuum. The direction of the

magnetic force depends on the magnetic properties (ferromagnetic, para-
magnetic, and diamagnetic) of the materials. This force acts to attract mate-
rials to the magnetic source when ferromagnetic materials are exposed
to a static magnetic field and could be of substantial magnitude depend-
ing on the size and susceptibility of the object. One well-known effect of
this force is the “missile effect” or “projectile effect” that occurs around
MRI equipment (Shellock and Kanal 1994; Kangarlu and Robitaille 2000;
Yamaguchi-Sekino et al. 2011). The projectile effect or the magnetic attrac-
tion of ferromagnetic objects within a strong magnetic field might cause
injuries to subjects in their proximity (Kangarlu and Robitaille 2000).
Kangarlu et al. calculated the magnetic force acting on a stainless steel
wrench of mass 100 g within the magnetic field of an 8 T system (Kangarlu
and Robitaille 2000). The magnetic field gradient in their equipment was
7.915 T/m, the maximum force at that position was 42.95 T2/m, and mag-
nitude of the force was calculated as 4.3 N with the χ of an object of den-
sity 8 g/cm3 and a volume of 12.5 cm3 is taken to be 0.01. This will impart
an acceleration of 43 m/s2 on the object.
Exposure to a magnetic field generates a repulsive force on diamagnetic
materials. Ueno et al. observed a so-called “Moses effect” phenomenon, in
which water is parted when exposed to an 8 T magnetic field with a gradient
of 50 T/m (Ueno and Iwasaka 1994a,b). The estimated magnetic force acting
on 100 mL of water is 0.288 N, that is, 1/3 of Earth’s gravity when the product
of the magnetic field and the field gradient is 400 T2/m. Water, a diamagnetic
material, is pushed back by the magnetic force to form two “water walls,” and
the dry “river bed” or dry bottom of the water chamber is seen in between
FIGURE 7.3 Magnetic force acting on biological system in inhomogeneous mag-

netic fields.
the two water walls, similar to Moses parting the Red Sea as described in the
Bible (Ueno 2012). Figure 7.3 is a photograph of the Moses effect. The Moses
effect has been a concerning issue in MRI users; however, the degree of the
acceleration was suppressed to 1 percent of that of gravity when the force
was recalculated for the situation of a whole-body in a 3-T magnet setup.
Schenck calculated that the magnetic force at 10 T leads to a change in pres-
sure between the inside of the magnet to the outside of less than 40 mm of
H2O, suggesting that the effect on blood flow is minor (Schenck 2005).
7.2.1.3.2 Magnetic Induction 2 (Motion-Induced Current) Human body

motion in an inhomogeneous static magnetic field causes time-varying
magnetic fields inside the body and results in the induction of currents
(Schenck et al. 2000; ICNIRP 2004, 2009, 2014; Chakeres and de Vocht
2005; Crozier and Liu 2005; de Vocht et al. 2006; WHO EHC 232 2006;
Yamaguchi-Sekino et al. 2011). This effect is due to electromagnetic induc-
tion in the body caused by the linear or rotational motion in the magnetic
field gradient. In particular, movement along a field gradient generates
changes in the flux linkage that induce an electric current, whereas a lin-
ear motion within a uniform static field does not. For linear movement in
a field gradient, the magnitude of the induced current and the associated
electric field increase with the velocity of the movement and the ampli-
tude of the gradient (ICNIRP 2004, 2009, 2014). Rotational motion in a
uniform field or in a field gradient causes electromagnetic induction and
results in a motion-induced current in a body.
MRI operators are frequently exposed to high magnetic fields from
active-shielded MRI scanners. Motion-induced currents due to the
stray field from a scanner cause temporal sensations such as vertigo,
nausea, magnetophosphenes, and some changes in cognitive functions as

described above (de Vocht et al. 2006; Glover et al. 2007). From de Vocht’s
report, vertigo, metallic taste, and concentration problems were seen to
be more prevalent among workers of MRI-fabrication than in reference
departments (de Vocht et al. 2006). Occupational exposure to magnetic
fields has been the subject of several studies (Hudson 2006; Bradley et
al. 2007; Capstick et al. 2008; Wilén and de Vocht 2010; Karpowicz et al.
2011; McRobbie 2012) and the actual exposure levels from 3-T MRI sys-
tems exceed 1 T (Yamaguchi-Sekino et al. 2014). Exposure guidelines and
a safety survey in MRI applications are introduced in Chapter 9.
7.2.2 Effects of Time-Varying Magnetic Fields on Biological Systems

When a human body is exposed to an electromagnetic field, the biologi-
cal changes occur in accordance with the intensity and frequency of the
field (WHO EHC 238 2007; ICNIRP 2010). The human body responds to
electromagnetic fields owing to its conductivity and dielectric constants
that are frequency dependent (WHO EHC 238 2007; ICNIRP 2010).
Information is transmitted by nerves in the human body in the form of
electrical signals. The coupling mechanism between a low-frequency elec-
tromagnetic field and the exposed body is via an induced electric field by
Faraday’s law that leads to pseudo-nerve information. For example, the exci-
tation threshold of peripheral nerves is 4 V/m at 3 kHz or less (Reilly 1998,
2002; So et al. 2004; ICNIRP 2010). However, sensory changes such as pain or
discomfort occur if the induced electric field in the body exceeds this value.
For this reason, the exposure guideline of low-frequency electromagnetic
field aims at protecting nerves from stimulation effects (ICNIRP 2010).
Exposure to an electromagnetic field at a frequency greater than ~100 kHz
can cause a considerable absorption of energy and a subsequent tempera-
ture increase. Therefore, protection from heat effects is the purpose of expo-
sure guidelines for high frequency electromagnetic fields (ICNIRP 1998).
7.2.2.1 Low-Frequency Magnetic Fields and Pulsed Magnetic Fields

The physical interaction of a time-varying magnetic field with a human
body is well documented (Kato 2006; WHO EHC 238 2007; ICNIRP
2010). Low-frequency magnetic fields induce electric fields and circulating
electric currents within the body based on Faraday’s law. The magnetic
permeability of tissues is the same as that of air, so the field inside a tissue
is the same as the external field and therefore human and animal bod-
ies do not significantly perturb a field (ICNIRP 2010). The magnitudes
of the induced field strength and current density are proportional to the
radius of the loop, the electrical conductivity of the tissue, and the rate of
change in the magnitude of the magnetic flux density (ICNIRP 2010). As
described in the ICNIRP guideline of 2010, the responsiveness of elec-
trically excitable nerve and muscle tissues to electric stimuli, including
those induced by exposure to low-frequency electromagnetic fields, has
been well established (e.g., Reilly 2002; Saunders and Jefferys 2007). On
the basis of a theoretical calculation using a nerve model, the threshold
value of myelinated nerve fibers in human peripheral nervous system has
been estimated as 6 Vpeak /m (Reilly 1998, 2002; ICNIRP 2010). The most
widely established effect of magnetically induced electric currents is mag-
netic phosphenes: the perception of a faint flickering light in the periphery
of the visual field occurring in the retinas of volunteers exposed to low-
frequency magnetic fields (ICNIRP 2010). As mentioned in the ICNIRP
guideline of 2010, the minimum threshold flux density of 5 mT occurs at
20 Hz. The phosphenes are thought to be a result of the interaction of the
induced electric field with electrically excitable cells in the retina.
Transcranial magnetic stimulation (TMS) is an example of a medical
application of pulsed magnetic fields. Various applications of TMS include
neurological diseases, functional mapping of the brain, and cancer thera-
pies (Ueno 2012). A pulsed magnetic field generated by a coil attached to
the scalp is applied to the brain during TMS. The applied magnetic field
typically has an intensity of 1 T and a pulse duration in the submillisecond
range. It induces an electric current in the brain aimed at nerve excita-
tion. Single- or double-pulse stimulation is normally used for diagnosis
and functional mapping of the brain.
7.2.2.2 High-Frequency Magnetic Fields and Microwaves

There is a possibility of a temperature increase in the body on exposure to
electromagnetic fields of frequency higher than 100 kHz (ICNIRP 1998;
Kato 2006). The irreversible structural changes in proteins due to heat cause
dysfunction of cell mechanisms and may lead to cell death. Though exces-
sive heat absorption is harmful to the human body, cancer treatments that
actively utilize a temperature increase by exposure to high-frequency elec-
tromagnetic fields exist: a case in point being “hyperthermia” (Overgaard
1989; Yoo et al. 2006; Japan Society for Thermal Medicine). In general,
exposure to a uniform (plane-wave) high-frequency electromagnetic field
results in a highly nonuniform deposition of energy within a body that
must be assessed by dosimetric measurement and computer calculation.
The specific absorption rate should be minimized to the extent that blood
flow and other bodily heat-transfer mechanisms can dissipate the heat.
The magnitude of the specific absorption rate is a critical problem, par-
ticularly in the case of high-field MRI systems (IEC 2010).
7.2.3 Effects of Multiplicity of Magnetic Fields

and Other Forms of Energy
It has been considered that the contribution of the static magnetic field to
the chemical reaction might not occur because the induction of energy
change by the field exposure is very small. However, several groups have
reported on the interactions of a magnetic field on radical pair reactions
(Schulten 1982; Grissom 1995; Nagakura et al. 1998; Ritz et al. 2000, 2004;
ICNIRP 2009). For instance, a static magnetic field alters the yield of
chemical substances by affecting the intersystem crossing of radicals pro-
duced as intermediates in a photochemical reaction (Nagakura et al. 1998;
ICNIRP 2009). For radicals generated in a living body, the magnetic field
effects have been reported in an in vitro B12 coenzyme reaction system
(Harkins and Grissom 1994).
7.2.3.1 Radical Pair Model and Singlet-Triplet Intersystem Crossing

7.2.3.1.1 Radical Pair Effect and Photochemical Reactions in a Magnetic
Field A change in radical pair recombination rates is one of the few
mechanisms by which a magnetic field can interact with a biological
system (Harkins and Grissom 1994; ICNIRP 2009). The spin-correlated
radical pairs recombine to form reaction products; an applied magnetic
field affects the rate and the extent to which the radical pair converts to a
triplet state (parallel spins) in which recombination is no longer possible
(Figure 7.4) (ICNIRP 2009).
Magnetic field
Singlet Triplet
Singlet product Triplet product

(1products) (3products)
FIGURE 7.4 Radical pair model caused by static magnetic fields.

Using these differences in the radical pair products, Nagakura et al.

reported the magnetic field effect in the photolysis reaction of benzoyl
peroxide solution at room temperature. As a result of the presence of the
magnetic field–favored triplet radicals over the singlet status, yields of
1products are markedly higher than 3products (Nagakura et al. 1998).
7.3 MAGNETIC ORIENTATION OF ADHERENT CELLS

7.3.1 Polymerization Processes of Fibrin Fibers
under Strong Static Magnetic Fields
As briefly described in Section 7.2.1.2, magnetic torque generates a couple
to rotate materials in a stable direction determined by the anisotropy of
a material’s magnetic susceptibility in a spatially homogeneous magnetic
field (WHO EHC 232 2006; ICNIRP 2009; Ueno 2012). Torbet et al. first
observed the magnetic orientation of fibrin (Torbet et al. 1981). Fibrin is a
fibrous, nonglobular protein involved in the clotting of blood. It is formed
by the action of the protease thrombin on fibrinogen which causes the lat-
ter to polymerize. Torbet et al. reported that highly oriented fibrin gels are
formed when polymerization takes place slowly in a strong magnetic field
(Figure 7.5) (Torbet et al. 1981). Scanning electron micrographs indicated
that an alignment of fibrin fibers along to the magnetic field. Torbet and
Ronziere also reported the magnetic orientation at collagen fibers (Torbet
and Ronziere 1984). They showed that the collagen gels formed a high
degree of uniaxial alignment.
H
1 µm
1 µm
(a) (b)
FIGURE 7.5 Polymerization of fibrin fibers under strong static magnetic fields.
Scanning electron micrographs of fibrin prepared without (a) or with (b) mag-
netic field. H represents the direction of the field. The diameter of the fibrin fibers
is −1000 Å. (From Torbet, J. et al., Nature 289: 91–93, 1981.)
Direction of magnetic field
200 µm 200 µm 50 µm
Fibrin Collagen Osteoblasts
50 µm 100 µm 100 µm
Endothelial cells Smooth muscle cells Schwann cells
FIGURE 7.6 Magnetic orientation of fibrous proteins and adherent cells.
7.3.2 Fibrin, Collagen, Osteoblast Cells, Endothelial Cells,

Smooth Muscle Cells, and Schwann Cells
As well as the fibrin and collagen, when diamagnetic materials such as
adherent cells are exposed to strong static magnetic fields of several Tesla,
they align either parallel or perpendicular to the direction of the magnetic
field because of the anisotropy of the magnetic susceptibility of the mate-
rials. For instance, osteoblasts, endothelial cells, and smooth muscle cells
exhibit magnetic orientation under the strong static magnetic fields (Figure
7.6) (Ueno and Sekino 2006). Several Japanese researchers observed the
magnetic orientation of adherent cells such as osteoblasts (Kotani et al.
2000, 2002), vascular endothelial cells, smooth muscle cells (Umeno et al.
2001; Iwasaka and Ueno 2003a,b; Iwasaka et al. 2003; Umeno and Ueno
2003), human kidney cells (Ogiue-Ikeda and Ueno 2004), and Schwann cells
(Eguchi et al. 2003; Eguchi and Ueno 2005) under 8- or 14-T magnetic field
exposures. Direction of the orientation depended on the targets.
7.4 BONE GROWTH ACCELERATION

BY STATIC MAGNETIC FIELDS
7.4.1 Background
In the orthopedic context, trauma to the musculoskeletal system is the most
frequently encountered condition in clinical examinations. Approximately
33 million people in United States are diagnosed with trauma to the
musculoskeletal system every year, and fracture accounts for approxi-

mately 6.2 million cases (Praemer et al. 1992). The fundamental treatments
for fracture are fixation and reset, and recent advancements in the fixing
material and orthopedic surgical methods enable satisfactory recovery.
However, complications such as pseudarthrosis or delayed recovery still
exist in about 5 to 10 percent of the cases (Nakajima et al. 2007).
In the treatment of fractures, bi-side controls (i.e., directional control
and the growth control of bones) are indispensable. So far, several cyto-
kines (the bioreactive proteins released from the cells that react as the
intercellular signaling molecules) and growth factors (the modulators that
promote the proliferation or differentiation to specific cells) are known to
exhibit osteogenic activity. In particular, among the growth factors intrin-
sic to skeletal tissues, bone morphogenetic proteins (BMPs) are known to
promote osteogenic activity the most, and are therefore the most clinically
used factors (Cook 1999; Schmitt et al. 1999). BMPs exhibit osteogenicity,
and they are the only cytokine known to effect ectopic bone formation by
itself. BMPs are also responsible for physiological bone formations such as
skeletal formation or fracture healing; especially, BMP-2 has been investi-
gated in detail because of its strong osteoinductive activity (Sampath et al.
1990; Marie et al. 2002). In addition to the use of chemicals, the effective-
ness of pulsed electromagnetic fields (PEMFs) on fracture healing, spi-
nal fusion, bone defects, bone ingrowth into ceramics, or bone grafts has
been reported (Miller et al. 1984; Bruce et al. 1987; Takano-Yamamoto
et al. 1992; Glazer et al. 1997). However, neither chemical agents, includ-
ing BMPs, nor electrical stimuli such as PEMFs can control the direction
of bone formation. Thus, directional control in the bone growth during
treatment is a matter requiring attention in clinical applications.
Accumulated evidence has revealed that strong magnetic fields of the
order of a Tesla are capable of regulating the orientation of matrix proteins
and cells. As described in Section 7.3, this phenomenon refers to the tend
ency of materials to rotate in a stable direction determined by the anisot-
ropies in their magnetic susceptibility. So far, extracellular matrix proteins
such as collagen fibers (Torbet and Ronziere 1984; Murthy 1984), fibrin
fibers (Torbet et al. 1981; Ueno et al. 1993; Iwasaka et al. 1994), and several
types of cells such as erythrocytes and platelets have been reported to ori-
ent in regular patterns under static magnetic fields (Vassilev et al. 1982;
Yamagishi et al. 1992; Higashi et al. 1993a,b, 1995). Therefore, magnetic
control of bone formation from both the perspectives of growth and direc-
tional control has been proposed as a new approach to fracture treatment.
7.4.2 Magnetic Control of Bone Growth Acceleration

Kotani et al. have demonstrated magnetic control of bone growth acceler-
ation by using static magnetic fields of 8 T (Kotani et al. 2002). Figures 7.7a
through 7.7c illustrate the magnet and experimental setup used in their
study. The intensity of the magnetic field was estimated as 7.84–7.91 T
(Figure 7.7c). To determine the effect of a magnetic field exposure on the
differentiation of cultured mice osteoblast cells (MC3T3-E1 cells), Kotani
et al. examined the alkaline phosphatase (ALP) activity of cultured
MC3T3-E1 cells. After 14 days in culture post a magnetic field exposure for
60 h, cells showed greater ALP expression, compared to unexposed cells
(Figure 7.7d). Matrix nodules were identified by alizarin red staining. They
also showed that the orientation of ALP+ cells and alizarin red–positive
matrix could be maintained parallel to the direction of the magnetic field
ALP (14 days)

Exposed Control
(×1)
y
5 mm 5 mm
z
(a) x
(×100)
y
Magnetic fields (T)
8.20 T 10 µm 10 µm
8.09
8 7.91
4 7.84
0 z
–200 0 200
Distance (mm)
Alizarin red (21 days)
Superconducting magnet
Sample 100 mm Sample
y
700 mm 10 µm 10 µm
100 mm
Water
x
bath
(b) (c) (d)
FIGURE 7.7 Bone growth acceleration by magnetic fields (in vitro experiments).
(a) Photograph of the horizontal cylindrical-type superconducting magnet.
(b) The longitudinal section of the bore and the distribution of the magnetic
field along the z axis. (c) The cross section of the bore and the magnetic field at
the center of the z axis (x-y plane). (d) Effects of the SMF on the differentiation
and matrix synthesis of cultured MC3T3-E1 cells. Fourteen days and 21 days in
culture after 8-T SMF exposure for 60 h; cells were stained with ALP and aliza-
rin red, respectively. Arrows indicate the direction of the magnetic fields. (From
Kotani, H. et al., Journal of Bone and Mineral Research 17: 1814–1821, 2002.)
for 14 and 21 days, respectively, after an exposure for 60 h, although there

was no significant difference between the growth curves of the cultured
MC3T3-E1 cells between the exposed and unexposed groups.
Through in vivo experiments, Kotani et al. also investigated the effect
of a strong static magnetic field on bone formation by using an ectopic
bone formation model in and around subcutaneously implanted BMP-2/
collagen pellets in mice. Twenty-one days after 60 h of 8-T magnetic field
exposure, the BMP-2/collagen pellets were harvested and radiological and
histological analyses were performed. The newly formed bones were found
to extend parallel to the direction of the magnetic field in the exposed group,
and only small spherical-shaped ossicles were seen in the unexposed group.
The bone mineral content of the exposed group was approximately 4 times
greater than that of the unexposed group. Histological examinations
revealed that the pellets were replaced by newly formed bone tissue, includ-
ing bone marrow, in both exposed and unexposed groups (Figure 7.8a).
Exposed
1 mm
Control
1 mm
(a)
10 µm 10 µm
(b) Exposed Control
FIGURE 7.8 Bone growth acceleration by magnetic fields (in vivo experiments).
Histological analyses of the SMF effect on bone formation in and around the
BMP-2/collagen pellets implanted subcutaneously in mice. Twenty-one days
after BMP-2/collagen pellet implantation; samples were obtained and embedded
in paraffin and 5-μm-thick paraffin sections were stained with H&E. (a) Light
microscopic and (b) differential interference contrast microscopic findings of a
representative pellet from each group. The squares in panel a represent respective
areas in panel b. The arrow indicates the direction of the magnetic fields. (From
Kotani, H. et al., Journal of Bone and Mineral Research 17: 1814–1821, 2002.)
Differential interference contrast microscopic analysis showed that the

periphery of the tissues consisted of lamellar bones in the exposed group,
whereas woven bones were partially observed in the unexposed tissue
(Figure 7.8b). The authors thereby suggest that a strong static magnetic field
exposure may increase not only the bone mass but also bone maturation
in vivo.
7.5 CONTROL OF DIRECTION AND GROWTH OF NERVE

AXONS DURING NERVE REGENERATION BY STATIC
MAGNETIC FIELDS
7.5.1 Background
Nerve regeneration is an issue for which a medical resolution is awaited.
Unlike in the central nervous system, the peripheral nervous system (PNS)
has some capability for nerve regeneration (Yiu and Zhigang 2006). However,
there is no solution for complete PNS nerve regeneration in severely damaged
cases. In those cases, scaffolding neurons using biomaterials or biocompat-
ible materials would be useful in nerve regeneration if these materials play
the roles of endoneurial tubes to guide regrowing axons.
Figure 7.9 illustrates the mechanisms of nerve regeneration in PNS.
Schwann cells provide a supportive role in the PNS. These cells form a layer
or myelin sheath along single segments of an axon. However, when axonot-
mesis occurs, a series of degenerative processes take place before regenera-
tion of nerve fibers. This phenomenon is called “Wallerian degeneration”
Wallerian degeneration and

Growth cone
sprouting
Filopodium
Normal Microtubulin
Schwann cell Basal lamina
Neuron
Axonal remnants and Axon Actin fiber
Axonotmesis
myelin debris Neurofilament
Lamellipodium
Lesion Mϕ Schwann cell
Regeneration Schwann cell column
Sprouting
(Bungner band)
Guidance of regenerating axons
FIGURE 7.9 Mechanisms of nerve regeneration in PNS.

(Ide 1996). After significant injury, a nerve begins to degrade in an antero-

grade fashion. The axon and the surrounding myelin break down during
this process. Round mast cells as well as phagocytic macrophages that inter-
act with Schwann cells to remove the injured tissue debris can be seen. As
the degradation of the distal nerve segment continues, its connection with
the target muscle is lost, leading to muscle atrophy and fibrosis. Once the
degenerative events are complete, all that remains is a column of collapsed
Schwann cells (bands of Büngner). Axon sprouts with fingerlike growth
cones advance using the Schwann cells as guides. After reinnervation, the
newly connected axon matures and the pre-injury cytoarchitecture and
function are restored. In this phase, Schwann cells play essential roles in
neuronal regeneration of the PNS by guiding the regrowth of axons. In
other words, Schwann cells can serve as scaffolds for nerve regeneration.
Therefore, as in the case of directional control of bone extension mentioned
in Section 7.4, directional control of the Schwann cells in the PNS regenera-
tion is also an important issue in peripheral nerve regeneration.
As mentioned in Sections 7.3 and 7.4, an alignment effect on cells and
biological molecules occurs in static magnetic fields of the order of a tesla.
Controlling the orientation of Schwann cells may be useful in medical and
tissue engineering for promoting PNS regeneration. Section 7.5.2 intro-
duces the application of a strong static magnetic field to Schwann cells
aimed at controlling PNS regeneration.
7.5.2 Magnetic Control of Direction and Growth of Nerve Cells

Eguchi et al. (2003) investigated the magnetic orientation of Schwann
cells by exposure to an 8-T magnetic field. The authors also observed the
growth of Schwann cells in a mixture containing Schwann cells and col-
lagen after the field exposure.
In their study, a magnetic field exposure of 8 T was first given only to
Schwann cells cultured from the sciatic nerves of newborn rats. The authors
used a horizontal-type superconducting magnet that produced 8 T at its
center the same as that reported by Kotani et al. (2002). The flasks with the
Schwann cells and the culture medium were positioned at the center of the
magnet and exposed to an 8-T magnetic field for 60 h at 37°C. The magnetic
orientation of Schwann cells was then observed microscopically. A simi-
lar experiment was carried out for collagen gel alone, and collagen fibers
were found to align perpendicular to the magnetic field after 2-h exposure.
Subsequently, the Schwann cells harvested on the collagen gel were incu-
bated at 37°C in the absence of a magnetic field. Morphological analysis
Control Exposed
(a) 100 µm 100 µm

8 T (60 h)
15.0 mm
Silicone tube 1.5 mm Type I collagen solution
Schwann cells (1.0 × 107 cells/mL)
Control Exposure
Incubation for 2 h 8-T exposure for 2 h (37°C)
(37°C)
Implanted
Wistar rat Magnetic field

Sciatic nerve defect
(b)
COL M-COL
20 µm
Numbers and diameters of myelinated fibers (po. 12 weeks)
COL M-COL
Numbers 274.0 ± 11.7 373.4 ± 27.6**

*p < 0.05
(c) Diameters (µm) 5.53 ± 0.064 5.81 ± 0.087* **p < 0.01
FIGURE 7.10 Magnetic field effects on Schwann cells and nerve regeneration.
(a) Light micrographs of a mixed culture of Schwann cells and collagen on the sec-
ond day in culture after 2 h with and without 8-T magnetic field exposure. Scale bars:
50 mm. (b) Set up for in vivo experiment. (c) Morphological examination with tolu-
idine blue staining. The number and the diameter of regenerated axons increased
significantly in the M-COL group compared with the COL group by histological
evaluation. (b and c, From Eguchi, Y. et al., Bioelectromagnetics 36: 233–243, 2015.)
of the Schwann cells was performed microscopically after 60 h for the two
groups, namely, the exposed group (magnetically aligned collagen) and the
control group (unaligned collagen). As shown in Figure 7.10a, light micro-
graphs of a mixed culture of Schwann cells and collagen indicated that cells
cultured with magnetically oriented collagen aligned along the collagen
fibers oriented perpendicular to the magnetic field.
The same author also investigated the effectiveness of using magneti-
cally aligned collagen (after exposure to a maximum 8-T magnetic field)
for nerve regeneration in both an in vitro and in vivo model (Eguchi et al.
2015). Eguchi et al. investigated the orientation of Schwann cells embedded
in collagen gel within a silicone tube as an artificial nerve guide to bridge
sciatic nerve defects. A collagen-cell suspension by mixing collagen type
I solution with culture medium containing Schwann cells were prepared
(Figure 7.10b). As shown in Figure 7.10b, the collagen-cell suspensions were
seeded into a silicone tube (length, 15.0 mm; inner diameter, 1.5 mm) and
the tube was exposed to an 8-T magnetic field for 2 h with the axis perpen-
dicular to the magnetic field. The sciatic nerve trunk was cut in the cen-
tral part of the thigh and the silicone tubes were affixed to both stumps
of the nerve (Figure 7.10b). Four groups were examined: collagen gel only
(COL), magnetically aligned collagen gel (M-COL), collagen gel mixed with
Schwann cells (S-COL), and magnetically aligned collagen gel mixed with
Schwann cells (M-S-COL). The ratio of infiltrating regenerated nerves was
higher in the M-COL group compared to the COL group at 8 weeks post-
operation, and there were no significant differences between the two groups
with and without Schwann cells. The number and diameter of regenerated
axons increased significantly in the M-COL compared with the COL group
at 12 weeks post-operation (Figure 7.10c).
The authors demonstrated that magnetically oriented collagen pro-
moted nerve regeneration using both an in vitro and in vivo model and also
suggest that magnetically aligned collagen acts as a scaffold for Schwann
cells and in combination with aligned Schwann cells can also be used for
biohybrid nerve guide implants to bridge nerve lesions.
7.6 DISTRACTION OF LEUKEMIC CELLS BY MAGNETIZABLE

BEADS AND PULSED MAGNETIC FORCE
7.6.1 Background
Treatment modalities for eradicating cancer cells using heat from electro-
magnetic waves, particularly involving “hyperthermia,” have widely been
investigated (Overgaard 1989; Yoo et al. 2006; Japan Society for Thermal
Medicine). Hyperthermia is a type of cancer treatment in which a body
tissue is exposed to high temperatures (42°C–43°C) for 30–60 min (Japan
Society for Thermal Medicine). The idea of using heat to treat cancer is
based on the fact that temperatures higher than 42.5°C lead to the death
of somatic cells. Research reports indicate that hyperthermia may render
some cancer cells more sensitive to radiation or chemotherapy, in addition
to a killing effect by heating itself. Numerous clinical trials of hyperther-
mia for a variety of cancers such as breast cancer, melanoma (malignant
melanoma), cervical cancer, colorectal cancer, bladder cancer, and cervi-
cal lymph node metastasis have been demonstrated (Yoo et al. 2006; Japan
Society for Thermal Medicine).
However, irradiation of only the targeted tumors noninvasively
remains an issue. For example, to accomplish sufficient localization of
heat requires the implantation of an electrode to the body, instead of using
a whole-body electrode. In addition, whole-body electrodes are ineffec-
tive for deep-seated tumors, implying that only invasive methods using
implanted antennas are available for deep-site tumors.
Alternatively, hyperthermia using harmless magnetizable particles as
a method to treat targeted tumors has been reported (Yanase et al. 1997;
Hafeli and Pauer 1999; Wada et al. 2001; Ogiue-Ikeda et al. 2003, 2004).
The most important properties of magnetic particles for clinical diagnos-
tics and medical therapies are nontoxicity, biocompatibility, injectability,
and high-level accumulation in the target tissue or specific organ, i.e.,
being strictly and spatially confined to the planned region of the internal
body. However, the possibility that the drugs might damage normal tis-
sues as they circulate throughout the body before reaching their target
remains. Further, although magnetized particles are accumulated only in
the cancer tissue, application of a whole-body electrode for hyperthermia
may induce heat inside the normal tissue as well as the cancer because of
poor localization.
Instead, pulsed magnetic stimulation has recently been proposed as
a source of electromagnetic field for cancer therapy using magnetizable
particles (Ogiue-Ikeda et al. 2003, 2004). As introduced earlier, pulsed
magnetic stimulation is a method for stimulating biomedical tissues non-
invasively and with good localization. The next section introduces a new
method to destruct targeted cells by using magnetizable beads and pulsed
magnetic force.
7.6.2 Magnetic Destruction of Leukemia Cells by Physical Force

Ogiue-Ikeda investigated a new method to destruct targeted cells by
using magnetizable particles and pulsed magnetic force (Ogiue-Ikeda et
al. 2003, 2004). The cells were combined with the beads by an antigen-
antibody reaction (cell/bead/antibody complex), aggregated by a magnet,
and subsequently stimulated by a magnetic stimulator. The first step of
this idea is to allow cancer cells and magnetized beads to react via an
antigen-antibody reaction and then collect them using a permanent mag-
net. Pulsed magnetic stimulation was then applied to the cells and the
induced magnetic force was expected to destroy cells by physical force.
The authors used TCC-S leukemic cells (expressing CD33 on the surface)
(Kano et al. 2001; Ogiue-Ikeda et al. 2001) extracted from a patient with
chronic myelogenous leukemia and Dynabeads Pan Mouse IgG (Dynal,
Oslo, Norway) as magnetizable beads. Dynabeads are monosized superpara-
magnetic macroporous particles containing narrow pores in which magne-
tizable materials may be distributed in a volume-filling manner. The beads
were coated with a monoclonal antibody specific for the Fc region of mouse
immunoglobulin G (IgG). TCC-S cells and anti-CD33 mouse IgG antibodies
(Cytotech, Hellebaek, Denmark) were then mixed gently. After the binding of
cells and beads by an antigen-antibody reaction, the cell/bead/antibody com-
plexes were isolated using a magnetic particle concentrator (MPC-2, Dynal,
Oslo, Norway) and then aggregated by a magnet (diameter, 10 mm; thickness,
12 mm; 450 mT) placed under the tube. Monophasic pulses of 150 μs and
a maximum of 2.4 T produced at the center of the coil of a circular-shaped
magnetic stimulator (inner diameter, 15 mm; outer diameter, 75 mm) (Nihon
Kohden, Tokyo, Japan) were applied to the cells. The magnetic forces acting
on each of the beads and the aggregated cell/bead/antibody complexes were
expected to be approximately 1.8 × 10–9 N and 0.036 N, respectively. The sam-
ples were stimulated 10 times at 5-sec intervals.
Ogiue-Ikeda et al. performed two types of experiments (Ogiue-Ikeda et
al. 2003, 2004). In the first, the authors established a procedure to destruct
targeted cells by using magnetizable particles and a pulsed magnetic force
by the methodology shown in Figure 7.11 (Ogiue-Ikeda et al. 2003). The
cells were classified into four groups: (1) cells, (2) cell/bead (diameter 4.5 ±
0.2 mm) mixture, (3) cell/antibody complex, and (4) cell/bead/antibody
complex. Each group consisted of four subgroups: (a) without magnet,
nonstimulated; (b) without magnet, stimulated; (c) with magnet, non-
stimulated; and (d) with magnet, stimulated (Figure 7.11). The viability of
Mixture of TCC-S cells

Cells Mixing gently for 2 h at 2°C–8°C and anti-CD33 mouse
IgG
Addition of beads Addition of beads
Mixing gently for Mixing gently for

2 h at 2°C–8°C 2 h at 2°C–8°C
a b c d a b c d a b c d a b c d
Nonstimulated Magnet Nonstimulated Nonstimulated Nonstimulated
Stimulated Stimulated Stimulated Stimulated

Group 1 Group 2 Group 3 Group 4
FIGURE 7.11 Methodology of physical destruction of leukemia cells by pulsed mag

netic field. (From Ogiue-Ikeda, M. et al., IEEE Trans Nanobioscience 2: 262– 265,
2003.)
the aggregated and stimulated cell/bead/antibody complexes was signifi-

cantly decreased and the cells were observed to have been destructed by
the penetration into or rupturing of the cells by the beads.
The authors then examined how bead size affected the results (Ogiue-
Ikeda et al. 2004). Two types of magnetizable beads (diameter, 4.5 ± 0.2 mm
and 2.8 ± 0.2 mm) were used in the second experiment. After stimulation,
cell destruction was observed (Figure 7.12a). The viabilities of the stimulated
groups were significantly lower than those of the control groups, for both 4.5-
and 2.8-mm beads (Figure 7.12b). In addition, the viabilities of the stimulated
groups containing the 4.5-mm beads were lower than those containing the
2.8-mm beads. Furthermore, the viabilities of the stimulated groups with the
4.5-mm beads decreased as the number of beads increased (Figure 7.12b).
From these two studies, the authors propose that instantaneous pulsed
magnetic forces cause the aggregated beads to forcefully penetrate or rup-
ture the target cells and conclude that the use of a large number of mag-
netizable beads of a large diameter can effectively destroy cells targeted by
an antigen-antibody reaction.
Nonstimulated Stimulated
(a) Scale bars = 4.5 µm

100
80
Viability (%)
60
40
20
0
Control1 2 3 4 Control1 2 3 4
(b) 4.5 µm beads 2.8 µm beads
FIGURE 7.12 Physical destruction of leukemia cells by pulsed magnetic fields.

(a) A scanning electron micrograph of a TCC-S cell combined with beads by
an antigen-antibody reaction. (b) Viabilities of the cell/bead/antibody complexes
with and without magnetic stimulation. (b, From Ogiue-Ikeda, M. et al., IEEE
Trans Magnetics 40: 3018–3020, 2004.)
7.7 INHIBITION OF TUMOR GROWTH

BY PULSED MAGNETIC STIMULATION
7.7.1 Background
Instead of a thermal effect such as hyperthermia, attempts at cancer therapy
using direct electrical effects have been carried out since 1950s. Table 7.1
summarizes electrical stimulation and cancer therapy efforts. Electrical
stimulation, using, for example, direct current (DC), is known to induce
various biological responses including antitumor effects (Humphrey and
Seal 1959; David et al. 1985; Nordenstrom 1989) and/or immunomodula-
tory effects; a relationship between the antitumor effects has been suggested
(Sersa et al. 1992; Chou et al. 1997; Miklavcic et al. 1997; Cabrales et al. 2001).
Mechanisms underlying these biological effects by DC involve not only pH
changes but also inhibition of cell division and/or protein synthesis, acti-
vation of lysosome, and influence on immune systems (Harguindey 1982;
Sersa et al. 1992; Chou et al. 1997; Cabrales et al. 2001). However, as is the
case with hyperthermia, deep-site stimulation is not possible by electrodes
placed on the body surface. Furthermore, an implantation of electrodes is
also required for the enhancement of anticancer effects by DC.
TABLE 7.1 Electric Stimulation and Cancer Therapy

Method Condition Application Mechanism
Direct current (DC) 0.5–5 mA Kidney cancer Heat
2 hours/day Epidermoid cancer pH change
etc… Rectal cancer Inhibition of cell
division
Activation of lysosome
Inhibition of protein
synthesis
Activation of immune
system
Electrochemotherapy 1000–2000 Epithelial cancer Enhancement of
(ECT) V/cm Bone cancer anticancer agents
Hyperthermia Radio wave Recurrence breast Heat
Microwave cancer Activation of immune
Malignant melanoma system
Cervical cancer
Rectal cancer
Cervical lymph node
metastasis
Attempts at noninvasive anticancer therapy using noninvasive meth-

ods instead, such as with electric currents from magnetic stimulation,
have been investigated (Yamaguchi et al. 2004, 2005, 2006a,b). Magnetic
stimulation induces eddy currents in the body, and the resultant biologi-
cal responses have been reported in regard to neurological tissues such as
from the hippocampus (Ueno 2012). However, the effects of magnetically
induced eddy currents on tumors and immune systems have not been
studied in detail. Additionally, the mechanisms underlying antitumor
effects of magnetic stimulation have not been classified sufficiently. In the
next section we introduce a report on the anticancer effects of magnetic
stimulation and the possible mechanisms.
Another approach for cancer therapy by electrical stimulation is known
as electrochemotherapy (ECT). ECT uses electrical pulses, which have an
enhancing effect on anticancer agents (Sersa et al. 2008). The reduction of
adverse events in chemotherapy has been a key factor in the improvement
of the quality of life. However, implantation of an electrode is required for
deep-site stimulation and for enhancing the efficacy of anticancer treat-
ment. Thus, novel approaches are required to develop a noninvasive ther-
apy that can be used to target cancer while enhancing the effectiveness of
the treatment. In the next section, investigations on the combinational use
of anticancer agents and magnetic stimulation are described.
7.7.2 Magnetic Control of Tumor Growth Inhibition

Yamaguchi et al. investigated the effects of pulsed magnetic stimulation on
tumor development processes and immune functions in mice (Yamaguchi
et al. 2004, 2005, 2006a,b). A circular coil (inner diameter, 15 mm; outer
diameter, 75 mm) was used in the experiments (Figure 7.13a and b).
Stimulus conditions were pulse width, 238 μs; peak magnetic field, 0.25 T (at
the center of the coil); frequency, 25 pulses/sec; dosage, 1000 pulses/sample/
day; and magnetically induced eddy currents in mice, 0.79–1.54 A/m2. In
an animal study, B16-BL6 melanoma model mice were exposed to pulsed
magnetic stimulation for 16 days from the day of injection of cancer cells
(Figure 7.13b). A study of the tumor then revealed a significant tumor weight
decrease in the stimulated group (54 percent of the nonexposed group)
(Figure 7.13c and d). In a cellular study, B16-BL6 cells were also exposed
to the magnetic field (1000 pulses/sample and eddy currents at the bottom
of the dish equal to 2.36–2.90 A/m2); however, the magnetically induced
eddy currents were found to have no effect on cell viabilities. Cytokine pro-
duction in mice spleens was measured to analyze the immunomodulatory
effect after pulsed magnetic stimulation. Tumor necrosis factor (TNF-α)
production in mice spleens was significantly activated after an exposure to
2.25
2
Tumor weight (g)
1.75 ***
1.5
Coil 1.25
1
Tumor Tumor 0.75
0.5
0.25
0
(c) Stim (+) Sham
Stim 0.25 T Sham
(a) (b)
(d)
FIGURE 7.13 Inhibition of tumor growth using pulsed magnetic stimulation.

(a) Example of tumor mouse on day 17, induced by injection of B16-BL6 cells.
(b) Magnetic stimulation coil (75 mm outer diameter, 25 mm inner diameter)
was placed on the right side of mice. (c) The tumor weights of each group on
day 17 were expressed as mean ± SE. ***P < 0.001; n = 14. (d) Specimen treated
by (left) magnetic stimulation and that of (right) sham group. The arrow shows
where tissue necrosis occurred. Magnification 400×. (From Yamaguchi, S. et al.,
Bioelectromagnetics 27: 64–72, 2006a.)
120
% Control (TCC-S + RPMS)
100
80 **
*
60
: Control
40 : 0.1 T 1000 pulses
: 0.25 T 1000 pulses
20 : 0.5 T 1000 pulses
: 0.25 6000 pulses
0
TCC-S + RPMS TCC-S +Imatinib 100 nM
+ RPMS
FIGURE 7.14 Combination effects of magnetic stimulation (RPMS) and an

anticancer agent (imatinib). (From Yamaguchi, S. et al., IEEE Transactions on
Magnetics 42: 3581–3583, 2006b.)
the stimulus condition described above. The authors concluded that these
results showed the first evidence of antitumor and immunomodulatory
effects brought about by the application of repetitive magnetic stimulation
and also suggested the possible relationship between antitumor effects and
the increase of TNF-α levels caused by pulsed magnetic stimulation.
Next, the combined effect of magnetic stimulation and an anticancer
agent was examined on human chronic myelogenous leukemia-derived
cell line TCC-S using molecular target drug (selective tyrosine kinase
inhibitor) imatinib mesylate (imatinib). The stimulus conditions were
determined as follows: 0.1, 0.25, and 0.5 T; 25 pulses/sec; 1000, 3000, and
6000 pulses/day. TCC-S cells were cultured with 100 nM imatinib and
exposed to RPMS at 1, 12, 24, 36, 48, and 56 h after drug treatment. The
combined effect of magnetic stimulation and imatinib depended on
the stimulus intensity and the pulse dose (Figure 7.14). To further clar-
ify the effect of magnetic stimulation on human normal lymphocytes,
they too were exposed to magnetic stimulation with or without imatinib.
Magnetic stimulation was found to have no effect on the viability of nor-
mal lymphocytes. These results indicate that magnetic stimulation pos-
sibly improves the effectiveness of anticancer agents.
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Chapter 8
Effects of Radio
Frequency Magnetic
Fields on Iron Release
and Uptake from and
into Cage Proteins
Oscar Cespedes and Shoogo Ueno
CONTENTS
8.1.1 Interactions of Radio Frequency Magnetic Fields
with Iron Release and Uptake 220
8.1.2 Possible Medical Consequences and Applications
of RF Magnetic Fields on Iron Biochemistry 221
8.2 Iron Cage Proteins 222
8.2.1 Introduction to Ferritins and Their Physiological Role 222
8.2.2 Iron Release and Absorption 224
8.2.2.1 Spectroscopic Techniques in the Determination
of Iron Contents 224
8.2.2.2 Function of the Symmetry Points in Iron
Release and Uptake 225
8.2.2.3 Role of Iron in Oxidative Stress and Dementia 227
8.3 Magnetic Properties of Ferrihydrite Bionanoparticles 229
8.3.1 Nanoscale Magnetism 229
219
8.3.1.1 Superparamagnetism 230

8.3.1.2 Ferrimagnetism in Iron Oxides and Surface
Effects 230
8.3.2 Power Absorption and Dissipation 232
8.3.2.1 Néel and Brownian Relaxation 233
8.3.2.2 AC Susceptibility 234
8.4 Magnetic Field Effects on Iron Release 235
8.4.1 Experimental Setup and Titration Measurements 235
8.4.2 Changes in Iron Release 236
8.4.3 Effects of Reducing Agents 241
8.5 Magnetic Field Effects on Iron Uptake 242
8.5.1 Raman Spectroscopy during RF Exposure 242
8.5.2 Changes in Iron Uptake 243
8.6 Role of the Threefold Symmetry Point and Future Considerations 245
8.6.1 Effects of Cationization at the Threefold Symmetry Point 245
8.6.2 Fluorescence Determination of Iron Contents 248
8.6.3 Summary of the Effects, Future Considerations to RF
Magnetic Fields Exposure, and Their Effects on Iron
Cage Proteins 249
Acknowledgments 253
References 253
8.1 INTRODUCTION
8.1.1 Interactions of Radio Frequency Magnetic
Fields with Iron Release and Uptake
Most biological components are diamagnetic or paramagnetic and only
interact weakly with magnetic fields. For this reason, the effect of nonion-
izing radio frequency (RF) radiation in biology is commonly described
in terms of heating.1 However, iron is an essential element to most living
organisms, including, of course, humans. A healthy adult needs between
10 (males) and 18 mg (females) of iron per day, the highest concentra-
tion of any metallic element.2 Although it has a crucial role in biochemical
mechanisms such as oxygen transport and redox processes, iron is also a
potential toxic agent to cells via the Fenton reaction. Therefore, it requires
a complex set of regulatory mechanisms to meet the demands of the body
while avoiding accumulation or release in the wrong environment.3
A key constituent in the chemical control of iron is ferritin. This cage
protein is the main form of storage for mineral iron in biology, to the
Effects of RF Magnetic Fields on Iron Release and Cage Proteins ◾ 221
point that the clinical assessment of iron content in blood is done via
ferritin concentration. The role of the protein is to oxidize and store
iron ions in the form of a ferrihydrite nanoparticle. Ferritin proteins
have also been associated with the function of the mitochondria.4,5 This
emphasizes the role of the protein in protecting against oxidative dam-
age, given that most of the iron must pass through the organelle to par-
ticipate in biological processes.4–6 The core nanoparticle can contain up
to 4500 iron ions, which results in a high magnetic moment and a super-
paramagnetic magnetization at room temperature. The only compo-
nents found in biology with a higher magnetic moment than ferritin are
mineral biogenic magnetite nanocrystals. These have also been consid-
ered as a possible transducer for field effects,7,8 but no effect was observed
in the mortality rates of magnetic bacteria when the nanocrystals were
exposed to RF fields.9,10
Being the organic bioelement with the highest magnetic moment,
it is perhaps not unexpected that ferritin shows strong effects even at
weak magnetic fields and relatively low frequencies in the RF range. The
inner superparamagnetic ferrihydrite nanoparticle increases its internal
energy when exposed to alternating magnetic fields via Néel absorption/
relaxation. This energy is irradiated to the surrounding proteic cage,
altering the protein ability to uptake and release iron. Proteins exposed
during several hours have iron intake and chelation rates up to a factor of
3 smaller than control samples although for concentrations not observed
in physiological conditions. These results are examined more closely in
the following sections, as they open new paths of research for biological
effects of alternating magnetic fields.
8.1.2 Possible Medical Consequences and Applications

of RF Magnetic Fields on Iron Biochemistry
In recent studies, we have shown that exposure to an RF magnetic field
affects the ability of horse spleen ferritin to release and uptake iron.
However, in ferritin without an inner superparamagnetic nanoparticle,
RF magnetic fields have no effect. The results were attributed to the energy
released by the inner superparamagnetic nanoparticle due to the magne-
tization lag.11–13 If this hypothesis is correct, the effect of the RF magnetic
field will depend not only on the applied field but also on the magnetic
properties of the ferrihydrite nanoparticle inside ferritin. Proteins from
different animal species, individuals, and organs have different magnetic
properties.14 In particular, although the susceptibility will be roughly
proportional to the amount of iron in the body, the relaxation times and
frequency dependence of power dissipation will vary greatly with the type
of ferritin. From estimates of the power released, it is easy to see that the
energy loss by the nanoparticle inside ferritin is unlikely to lead to a ther-
mal effect at the concentrations usually found in the body, even at rela-
tively large magnetic fields and frequencies. This is due to the relatively
low susceptibility of ferrihydrite (as compared to, for example, magnetite
nanoparticles) and to the low concentration of ferritin in healthy organ-
isms. It is also difficult to estimate how much power is transmitted to the
organic cage or how well the peptides may dissipate the energy into the
surrounding medium. If the effects were to be significant for in vivo exper-
iments, there are two possible considerations: Will the RF exposure result
in impaired protein function? And, can we use this exposure to regulate
iron chemistry?
As for the first question, any damage to the role of ferritin in biochem-
istry may have serious consequences to the health of an organism. For
example, it could result in iron release in the brain, which would then
lead to oxidative-stress related illnesses, e.g., some forms of dementia.
However, a priori it seems that the frequency and amplitude of the fields
that would be needed for these severe effects would have to be very large,
unlikely to be found in any natural environment. These large RF fields
would probably generate effects via heating of the bio-environment.
On the other hand, it is possible to generate a controlled exposure
to high-frequency/amplitude magnetic fields without generating dipo-
lar electric heat, see the numerous experiments in hyperthermia.15–17
Similarly, it might be possible to expose certain regions in the body to
alternating magnetic fields so that the iron release/uptake is done more
slowly, which could be beneficial in case of chelating agents being present
in the body, genetic misregulations, etc. Further research could also help
to distinguish the mechanisms affecting iron release from those in iron
uptake, in which case the magnetic field exposure could be used to stimu-
late one above the other.
8.2 IRON CAGE PROTEINS

8.2.1 Introduction to Ferritins and Their Physiological Role
The iron cage protein ferritin is present in living organisms from bacteria
to humans. In order to make use of iron chemistry without generating
radicals that can lead to oxidative stress, organisms need to capture the
harmful Fe (II) ions, oxidize, and store them in a safe manner. This is
done inside the peptidic cage of ferritin as a relatively harmless ferrihy-
drite nanoparticle (9H2O·5Fe2O3) with small concentrations of P, Cs, Cd,
Zn, Cu, and S. Ferritin will later deliver the iron ions under certain chemi-
cal signals or agents when it is needed for metabolic purposes. The proteic
cage (apoferritin) is formed by 24 subunits about 180 peptides each and
arranged in a 4-3-2 symmetry to form a roughly spherical cage of 440 kDa
in mass and 12 nm in diameter. The inner cavity is roughly 8 nm in size,
so it can store particles with up to 4500 iron ions. A typical ferritin protein
contains of the order of 1000–1500 ions.18 Usually, ferritin is found mostly
in the liver and the spleen, the main places for iron storage, but in some
pathologies, ferritin can also be found in high concentrations in other
organs, such as the heart and the brain. In order to ensure that the iron
is protected in the different biological environments, ferritin has evolved
into a very stable and robust configuration. The peptidic arrangement
only dissociates at extreme conditions with temperatures above 80°C or
at pH extremes of 2.8 and 11.2, unlikely to be found in environments that
host living organisms (see Figure 8.1).
Peptidic cage
(apoferritin)
~12 nm
Ferrihydrite
nanoparticle
FIGURE 8.1 Ferritin is a protein for iron storage. It is composed of an outer

organic cage (apoferritin) formed by 24 subunits of about 130 peptides each
arranged in a 4-3-2 symmetry to form a rough sphere some 12 nm in size. Iron is
stored in an inner ferrihydrite nanoparticle (ferric hydroxide: 5Fe2O3·9H2O) up
to some 8 nm in size.
8.2.2 Iron Release and Absorption

8.2.2.1 Spectroscopic Techniques in the Determination of Iron Contents
The methods to detect iron release from (or absorption into) ferritin are
commonly based on optical titration experiments. During titration, the
optical density (OD) of a ferritin solution with the desired chemicals is
measured. In the case of iron release, an iron chelator should be added to
the ferritin solution in order to extract the metal ions. This chelator can be
ferrozine, 6-Hydroxidopamine (6-OHDA) or meso-2,3-dimercaptosuccinic
acid (DMSA), for example. To test the effects of RF magnetic fields in ferritin,
we measure the iron release rates using ferrozine, a molecule with a very
strong affinity for Fe (II). When ferrozine is added to a ferritin solution,
the molecules bind one iron ion per every three ferrozine molecules. Once
it combines with the iron ion released by the protein, ferrozine acquires a
very strong molar absorption coefficient at 562 nm of ε = 29,700 M–1cm–1.
This gives a characteristic purplish color to the ferritin solution (originally
red-yellow). By measuring the OD at that wavelength, we can determine
the amount of Fe-ferrozine generated down to the nM scale, and hence the
number of iron ions released. This reaction is usually slow because ferritin
is naturally protected against strong chelators.19 Release rates are typically
of order 0.5 ions per ferritin and hour in our experiments.
Iron levels in all the chemicals employed are nominally below
0.1–1 ppm. Mixture of ferrozine with the solution without ferritin does
not give rise to any measurable titration at the concentrations used in our
study. The change in OD at 562 nm after 1 hour of adding the ferrozine is
below our limit of detection 10−3 over 1 cm. This implies that the amount
of trace or contaminant iron is ≲10 nM. Addition of reducing agents (e.g.,
6-OHDA) does not change this value. On the other hand, the iron con-
centration due to the ferrihydrite nanoparticles is of order 1–10 mM, at
least 5 to 6 orders of magnitude more abundant than any iron impurity
present in the solution. When ferritin is added, the typical change in OD
at 562 nm we measure after 1 hour is of the order of 0.01 (1 μM) without
reducing agents and 0.1–1 (≳100 μM) with reducing agents, so trace iron
cannot account for it.
The reducing agents 6-OHDA and DMSA can also be used to survey
iron release from ferritin. They can be used in combination with ferrozine
as optical marker or measured by themselves at wavelengths of 480 and
562 nm, respectively. However, the results we obtained using these chela-
tors on their own were noisier and had worse reproducibility than using
ferrozine. Owing to changes in the solution turbidity while the chemical

are still not well mixed, we only considered the iron release and change in
OD during the equilibrium state, a few minutes after adding the chelators.
Iron intake, on the other hand, does not need a chemical chelator or
optical agent to be monitored. It can be followed by measuring the OD
of a ferritin solution with iron (II) ions at 310 or 420 nm, with ε of 2745
and 550 (mol·cm)–1, respectively. In our experiments, the data is averaged
over 14 to 20 samples and the error bars are the standard error of the
mean. The use of buffers is generally avoided in order not to increase the
solution conductivity and the subsequent heating effects during magnetic
field exposure. The changes in OD during iron uptake are some 10 times
smaller than when measuring iron release using ferrozine. For a typical
measurement, this implies an increase of OD of 5 × 10−3 (10−3) at 310 nm
(420 nm) when all ferritin molecules incorporate one iron ion.
8.2.2.2 Function of the Symmetry Points in Iron Release and Uptake

Although the research is still ongoing, there is a more or less established
consensus that the iron release in ferritins takes place through the three-
fold symmetry point of the molecule. At these (eight) points, three subunits
form the edges of a parallelepiped with a small pore in between them. This
is where the weakest subunit interactions occur, with the three interact-
ing subunits that surround the pore linked by just three side chain-main
chain hydrogen bonds (lysine-glutamine).20 This interaction is weaker
than the pair or quadruple interactions in the two- and fourfold points,
and much weaker than the bonds in each subunit, let alone the covalent
bonds within each peptide and the atomic bonds within the ferrihydrite
nanoparticle. Therefore, when considering the effects of RF magnetic
fields, these threefold symmetry points are where the power released from
the nanoparticle may be expected to result in more significant changes
(see Figure 8.2).
Some iron chelators (e.g., 6-OHDA) can easily penetrate the protein
through the empty space between the three protein subunits in order to
reduce and release the ions. Ferrozine, owing to its relatively large size
and negative charge in neutral pH, takes much longer to infiltrate inside
the cage if at all. When considering aggregation and precipitation of the
protein in solution, the threefold symmetry point plays as well an essential
role: They act as hydrophilic terminals that ensure the solubility of the
protein. This is due to the strong negative charge density at the pore, which
(a) (b)
(c)
Charge
FIGURE 8.2 (a) Molecular representation of the polar threefold symmetry point,
exit point for Fe (III) ions, and the protein aggregation center. (b) Zoom on the
six carboxyl groups from the glutamic acids (COO−) that form the hydrophilic
terminals at the threefold symmetry point. (c) Charge distribution at the sym-
metry point.
originates from the six carboxyl groups of aspartic and glutamic acids at
the terminals. If the threefold point is blocked, for example, because of a
rapid release and aggregation of iron at the pore, the proteins may aggre-
gate and precipitate. The fourfold symmetry point is nonpolar and there-
fore does not contribute to molecular aggregation. Whereas iron release
seems to take place predominantly or exclusively at the threefold symme-
try point, iron uptake occurs probably at the two- and fourfold symmetry
points.21,22
The process of ferroxidation by which iron ions are oxidized and later
incorporated into the core ferrihydrite nanoparticle is similar to that of
Fenton chemistry (see Section 8.2.2.3). Ferroxidase enzyme molecules in
the proteic cage act as catalysts and binding agents to facilitate the oxi-
dation and incorporation of iron (II). These ferroxidase centers are com-
monly found at the protein symmetry point with four helical bundles,
although they can also be present in the two subunit links. For some bac-
terial ferritins, these centers may also be found at all 24 subunits. The role
of the ferroxidase is to act as catalyst in the reactions:23
2Fe (II) + O2 + 4H2O → 2Fe(O)OHnanoparticle + H2O2 + 4H+ (8.1)
2Fe (II) + O2 + H2O2 + 2H2O → 2Fe(O)OHnanoparticle + 4H+ (8.2)
Ferritins without a ferroxidase center can still incorporate iron and form a
mineral core, but the process is slower and these proteins can probably func-
tion only in environments low in iron and/or where it is not essential.
8.2.2.3 Role of Iron in Oxidative Stress and Dementia

Iron is needed for the good functioning of the body thanks to its polyva-
lent role in oxidation and reduction of electrons. However, it is a strong
generator of oxidative stress via free radicals generated in the Fenton
chemistry.24–26 The simplest representation of the Fenton reaction is:24
Fe(II)+ H2O 2 → Fe(III)+ [ H2O −2 ] → OH + OH− (8.3)
However, this mechanism is thermodynamically unfavorable and

therefore unlikely to occur without the mediation of a ligand (L) such as
EDTA, phosphate, or a biological chelator:
L-Fe (II) + H2O2 → L-Fe(H2O2)2+ → L-Fe (III) + OH + OH− (8.4)
or through the generation of an iron (IV) species:
→ L-Fe4+ + 2OH− (8.5)
or by oxidizing a substrate (R):
+R → L-Fe (III) + OH− + ROH (8.6)

Given its relationship to oxidative stress and the formation of free

radicals, it has been speculated that the presence of iron in the brain
could be associated to neurodegenerative disorders. Recently, biomagne-
tite nanocrystals27 and ferrihydrite28 have been associated to Alzheimer’s
disease. For example, the superior temporal gyrus brain tissue from 11
patients with Alzheimer’s disease and 11 age-matched control subjects
shows an exponential correlation between the concentrations of the Fe
(II)-ion-containing iron oxide, magnetite (Fe3O4), and the fraction of
those particles that are smaller than 20 nm in diameter. There was also
some potential evidence of particles being originated from ferritin pro-
teins. A correlation between ferritin levels and onset of dementia has
been studied,29 although other factors, such as gender and age, make it
difficult to find a straight correlation. The relationship between iron and
dementia may simply be due to the role of iron in lipid peroxidation, e.g.,
during the breaking of the cell membrane by β-amyloid in Alzheimer’s
disease.30
Conditions such as neuroferritinopathy and Friedreich ataxia are asso-
ciated with mutations in genes that encode proteins that are involved
in iron metabolism, and as the brain ages, iron accumulates in regions
that are affected by Alzheimer’s and Parkinson’s disease. High concen-
trations of reactive Fe (II) can increase oxidative stress-induced neuronal
Reduction and release

Ferritin Fe2+
(Fe3+) Oxidation and intake
Fenton
Iron storage reaction
and metabolism
Oxidative stress Cancer
Iron deficiency Iron overload Iron shuttle to

(haemochromatosis) cell membrane
Amyloid-β mediated
lipid peroxidation
Cell rupture
synapse disruption
Anemia Fibromyalgia
thrombocytosis stroke Alzheimer’s
etc. etc. disease
FIGURE 8.3 Potential physiological pathways for iron-related illnesses and the
role of ferritin function.
vulnerability, and iron accumulation might increase the toxicity of the

environment in neurodegenerative disorders.31 To determine precisely
the role of ferritin in these diseases, further methods to study and image
the iron content in vivo would likely be needed, and also to separate iron
in form of ferrihydrite within ferritin with free particles and/or stored
in malfunctioning proteins with different oxidation states, i.e., as Fe (II)
ions (see Figure 8.3). Studying the accumulation and cellular distribution
of iron during ageing must be correlated also with protein and genomic
deficiencies.
From the point of view of RF effects, we have seen no evidence that, at
least at the amplitudes and frequencies we have used, the functioning of
ferritin could result in an increased release of harmful iron ions. On the
contrary, it would seem that iron release is slowed by the magnetic fields
more significantly that iron absorption, which would result in a net iron
deficiency for the experimental conditions and chemicals used. Even then,
the concentrations used for our study are orders of magnitude above those
found in any healthy organism. However, studies into the form of the iron
stored (i.e., the oxidation state), the size, and the composition of the parti-
cles and exposures under different exposure conditions would be needed.
Furthermore, therapies to regulate iron biochemistry using RF magnetic
fields could be considered.
8.3 MAGNETIC PROPERTIES OF FERRIHYDRITE

BIONANOPARTICLES
8.3.1 Nanoscale Magnetism
Here, we give a brief description of magnetic phenomena in iron oxide
magnetic nanoparticles—and, in particular, the characteristics of the
ferrihydrite nanoparticle inside ferritin. The physics of these materi-
als have been studied in depth, in particular, since the discovery of their
application for hyperthermia, drug delivery, and other biochemical pro-
cesses.15,32–34 Ferritins, or rather the inner ferrihydrite nanoparticles, are
conventionally characterized through superconducting quantum interfer-
ence device (SQUID) magnetometers and Mössbauer spectroscopy. The
reason to use these techniques is partly due to the very small moment of
the samples used, that requires a highly sensitive magnetometry tool, and
the fact that iron is the magnetic ion in ferrihydrite. Here, magnetization
and AC susceptibility measurements are taken from liquid-frozen samples
using a SQUID.
8.3.1.1 Superparamagnetism
In order to minimize their internal energy, ferro-, ferri-, and anti-
ferromagnetic materials form domains with aligned magnetization.
These domains can have sizes from ~0.1 to 100 μm, depending on the
exchange energy, temperature, and magnetic anisotropy of the mate-
rial. If the magnetic material is nanostructured below the single domain
size, its magnetic behavior is different from that of conventional fer-
romagnets or paramagnets. The particle behaves then as a single mac-
rospin whose direction fluctuates owing to the thermal energy but can
also be aligned in a magnetic field. Below a certain temperature, the
magnetization direction at the measuring speed is blocked, and the
hysteresis loop has a net remanence and coercivity different from zero.
Above the blocking temperature, the nanomaterial has no coercivity
or remanence but still has a very large susceptibility well above that
of conventional paramagnets, hence the name of superparamagnetic
particles. Different from paramagnets with a constant susceptibility,
superparamagnets above the blocking temperature display two differ-
ent susceptibilities for low and high magnetic fields, the characteristic
sigma shape.
One of the most common methods to study superparamagnetic nano
particles is to measure the difference between zero field cooled and field
cooled low field susceptibility. If the particles are cooled with no field
applied below the blocking temperature, only a small percentage of the par-
ticles will align once a small field is applied. As the temperature increases,
more particles can surmount the energy barrier with the aligned state and
the magnetization increases with increasing temperature. Once the sys-
tem reaches the blocking temperature, the magnetization reaches a maxi-
mum and then decays as the magnetic energy becomes weaker compared
to the temperature. However, if the sample is cooled in a field, particles
that are aligned with the field at high temperatures are frozen in the high
magnetization state as we cross the blocking temperature, and, as we cool
down the sample, more particles go into a high magnetization state. In the
case of the ferrihydrite nanoparticles in ferritin, this blocking temperature
is of the order of 10–20 K (see Figure 8.4).
8.3.1.2 Ferrimagnetism in Iron Oxides and Surface Effects

Most iron oxides and hydroxides are antiferromagnetic or ferrimagnetic
materials. The highest magnetization is found in magnetite (Fe3O4), where
2.5 τN = 0.13 ns
5
ln f
0
2.0
' (10–3 m3/kg) 50 60 70
1.5 1000/T (K)
0.1 Hz
1 Hz
1.0 10 Hz
100 Hz
1 kHz
0.5
0 10 20 30 40 50 60
Temperature (K)
FIGURE 8.4 Real component of the susceptibility χ′ and the dependence of the
blocking temperature (TB) with the measuring frequency for superparamagnetic
ferrihydrite nanoparticles (ferritin solution). The dependence using Equation 8.11
leads to a Néel relaxation time τN of 0.13 ns (τ0 = 3 psec). Here, the AC field was set
to 0.5 mT and DC field to zero.
uncompensated Fe (II) spins give rise to a magnetization of some 470 emu/cc

above the Verwey transition (TV ~ 120 K). Maghemite (γ-Fe2O3) also has
a high magnetization of ~400 emu/cc. Other iron oxides and hydroxides
such as ferrihydrite in particular have a large saturation field and small
magnetization arising from frustrated magnetic interactions and partly
uncompensated spins.
In ferri/antiferromagnetic particle, the surface spins will not be
matched by a layer with opposite magnetization. Surface canting of
the spins, or misalignment due to shape and magnetocrystalline aniso
tropy, can take place. These uncompensated spins are not significant in
bulk owing to the very small fraction of surface atoms. However, in
nanometer-size particles such as the ferrihydrite found in ferritin, cant-
ing and uncompensated spins contribute to a net magnetization of some
500–1500 μB at low temperatures and fields of several Tesla.35 This is
small compared to the magnetization of a magnetite particle of similar
size (~10,000 μB at 10–100 mT), but it is enough to give rise to a measur-
able susceptibility even at low fields of the order of mT.14 At room tem-
perature, the samples behave as weak superparamagnets, with a small
but positive susceptibility.
8.3.2 Power Absorption and Dissipation

When a magnetic material is exposed to an alternating magnetic field,
it absorbs and dissipates power. The amount of energy the magnet can
store is equal to the area of its hysteresis loop, which is therefore called its
energy product:
∆U = −µ 0 !∫ M dH (8.7)
where μ0 is the magnetic permeability in vacuum, H is the magnetic field
intensity, M is the magnetization, and ΔU is the energy absorbed/dissipated
per cycle.
In the case of nanoparticles, the physical description of the power
absorption can be more complicated. Having no coercivity, the area of
the hysteresis loop of a superparamagnetic nanoparticle is nominally
zero and therefore should dissipate no energy. However, for sufficiently
fast alternating magnetic fields, the nanoparticles’ magnetization lags the
external applied field. In that case, the imaginary component of the sus-
ceptibility is different from zero, and this results in an energy gain by the
nanoparticle of:
2π/ω
∆U = 2µ 0 H χ′′
2
0
∫ sin ωt dt (8.8)
0
2
where χ″ is the imaginary component of the susceptibility and ω is the

angular frequency of the applied magnetic field H0.
As discussed in Section 8.3.1, the protein is a roughly spherical pep-
tidic cage formed by 24 subunits of some 180 peptides each, arranged in
a 4-3-2 symmetry and with an inner ferrihydrite nanoparticle of up to
4500 iron ions and 4 nm in radius inside. We will show in the follow-
ing sections that RF magnetic fields have an effect on protein aggregation
and iron release from ferritin at high concentrations. We hypothesize that
a novel mechanism of interaction between RF magnetic fields and bio
molecules is responsible for these changes. In this mechanism, the ferri-
hydrite nanoparticles dissipate power under an RF field, and, within a few
hours after exposure, the released energy affects the protein functioning.
Although the mechanism is based on the same power dissipation from
nanoparticles as in hyperthermia experiments, the power loss is small and

has not macroscopic (thermal) effect due to the small protein concentra-
tions, which is of order of μM in our study and nM in the organism.
The power loss of a superparamagnetic nanoparticle in an alternating
magnetic field depends on the frequency and amplitude of the applied field
and on the magnetic susceptibility and relaxation time of the nanopar-
ticle.17,36 In the following sections we will show the magnetic properties of
the ferritin samples used in our study and give an estimate for their dis-
sipated power. This power is far from the values required to denaturalize
or alter the structure of the protein, but here it might be able to promote
higher dynamical states, i.e., low-energy vibrations, in the protein. Further
evidence for protein alterations and the role of the inner nanoparticle is
found from comparisons of iron uptake and release rates between control
and RF exposed proteins.
8.3.2.1 Néel and Brownian Relaxation

The magnetization of a nanoparticle may follow the direction of an external
AC field using one of two mechanisms: the so-called Néel and Brownian
relaxations. In the first case, the magnetization rotates within the particle,
whereas in the second one the particle itself rotates physically when follow-
ing the applied magnetic field. Obviously, the particle can only do so if it is
free to move, i.e., if it is in a solution. In the Néel mechanism, the particle
does not move, but the spins rotate within it trying to align themselves
with the AC field. The characteristic time that determines how fast the
magnetization of the nanoparticle can rotate depends on the mechanism
of relaxation of the nanoparticle and is expressed as (τ)–1 = (τN)–1 + (τB)–1,
with τN and τB the Néel and Brownian relaxation times, respectively. The
particles will always relax through the fastest mechanism, which depends
on the size of the particle, its magnetic anisotropy and the viscosity of the
medium.
The Néel relaxation time τN can be written as:14,36,37
τ N = τ0 exp ⎛⎜
KV ⎞
(8.9)
⎝ kBT ⎟⎠
with τ0 the characteristic attempt time, K the magnetic anisotropic energy,

V the particle volume, kB Boltzmann’s constant, and T the temperature.
τ0 and K can be found from the AC magnetic susceptibility measurements

using the Néel-Arrhenius relation, which in our case can be expressed as:
K
TB =
f (8.10)
kB ln ⎛⎜ ⎞⎟
⎝ f0 ⎠
with TB the Blocking temperature, f0 the attempt frequency (1/τ0), and f the
frequency of the applied magnetic field. By plotting ln(f) versus 1/TB, K/kB
is the slope, and ln(f0) the crossing with the abscise. In ferritin samples we
obtain τ0 ~3 × 10–11 s and K ~ 370 K, which gives τN ~ 10–10 s (Figure 8.4).
On the other hand, the Brownian relaxation time τB is:
3ηVH
τB = (8.11)
kBT
with η the medium viscosity (~1 mPa · s–1) and VH the hydrodynamic
particle volume (~10−25–10−24 m3 for ferritin). The result is that τB ~ 10−7–
10−8 s ≫ τN ⇨ τN ≅ τ, so the relaxation mechanism for ferrihydrite
nanoparticles in ferritin is of Néel type, i.e., the particle, and the protein
around it, will not move will the magnetic field.
8.3.2.2 AC Susceptibility
If the magnetic field varies faster that the characteristic time for the mag-
netization (τN or τB), the particle finds itself in the “wrong” magnetic state
after each cycle; that is, it is not aligned with the magnetic field. This rep-
resents an energy gain that is then dissipated in the form of spin waves
and/or heat. From Equation 8.8, it can be derived that the power loss of a
superparamagnetic nanoparticle in a magnetic field is:36
2 πf τ
P = πµ 0 χ0 H 02 f × (8.12)
1 + (2 πf τ)2
where χ0 is the DC magnetic susceptibility, f is the frequency of the applied

field, and τ the characteristic time of the nanoparticle as seen in the previ-
ous section. The magnetic susceptibility of ferritin χ0 at room temperature
and low fields is of order 2.2 × 10–6 m3 kg–1 (Figures 8.4 and 8.5).
150
FC
(10–6 m3/kg)
100
50
ZFC
0
4 16 28 40 160
Temperature (K)
FIGURE 8.5 Zero field cooled – field cooled (ZFC – FC) magnetic susceptibility
χ for a saturated ferritin solution. The curve is characteristic of superparamag-
netic nanoparticles with a blocking temperature of ~15 K (note the log x-scale).
In order to calculate the dissipated power, the defining experimental

parameter is the ω·B product. For the experiments we performed, ω·B is
about 190 Ts–1. They are operated at frequencies below 10 MHz (period of
magnetic field >> τN), which gives a constant power of some 5–10 μWkg–1.
However, the magnetic susceptibility we use to calculate the values of
the dissipated power is that measured in hysteresis fields of up to 10 mT,
whereas the AC fields used here do not exceed 120 μT. There is as well a
large uncertainty in the characteristic attempt time of the nanoparticle
(τ0 ~10−11–10−10), which may also lead to lower relaxation times.
We must emphasize that the power calculated using Equation 8.12 is
the power dissipated by the inner ferrihydrite nanoparticle and not the
power absorbed by the medium or the protein. The power density is sev-
eral orders of magnitude below the power usually generated in hyper-
thermia experiments with magnetite or maghemite because of the much
smaller susceptibility of the ferrihydrite nanoparticle. It is roughly equiva-
lent to the power dissipated by a nanoparticle with a magnetic moment
of 630 μB,17 in agreement with previous estimates for the low-coercivity
magnetic moment of ferritin.35,37
8.4 MAGNETIC FIELD EFFECTS ON IRON RELEASE

8.4.1 Experimental Setup and Titration Measurements
For our experiments we use ferritin from equine spleen, which is the
most readily available. The RF magnetic fields were generated via a power
source connected to a set of Helmholtz coils. They are calibrated to pro-
duce 2.8838 mT per Ampere, with a deviation of less than 2 percent at the
sample space. The fields vary from up to 120 μT at 250 kHz to 15 μT at

2 MHz. The fields are smaller at higher frequencies because the coils have
higher impedance while the applied RF power is constant. The field mag-
nitude was chosen to be high enough to generate an effect but well below
the heating limit. The period of the magnetic field at those frequencies is
below the lifetime of the radicals involved in Fenton reaction38 but above
the relaxation time of the ferrihydrite nanoparticle, which should give an
invariant effect for constant frequency-field product. Other experimental
details can be found.11–13
The electric field (E) in the ferritin solution is measured with an oscil-
loscope MS-5100A from Iwatsu Electric Co. (Tokyo, Japan) connected to
electrodes dipped in the ferritin solution and spaced by 1 cm. It varies
from 0.1 V/m (250 kHz) to 0.4 V/m (2 MHz). This variation may be due
to changes in coil impedance and reflected power. Solution conductivity s
is of order 10–3 S/m. The resultant specific absorption rate (SAR) is calcu-
lated as σ/ρ E2, with ρ the medium density39 and varies roughly from 10−8
to 10−7 W/kg. No heating effect is expected. The control and exposed sam-
ples’ temperature remains equal within our 0.1°C limit of detection during
the exposure and the titration measurements (no field exposure during the
measurements). Samples are kept in the same light conditions. The coils are
not around the sample but above and below. Background radiation (50 Hz to
10 MHz) is measured to be the same inside and outside the coils.
Optical titration measurements were carried out with 1 nm and 10−4
wavelength and OD resolution, respectively. Only the release in the equi-
librium state, after the initial burst, is considered, as discussed in Section
8.4.2. Each titration measurement was carried out in 14 to 20 samples, half
of which were control and half exposed. Error bars are the added standard
error of the mean of the control and the exposed samples. Large devia-
tions from the mean (≳40 percent) are due to an error in adding the che-
lating agent to some samples and therefore discarded. All measurements
reported hereafter were done after (not during) field exposure.
8.4.2 Changes in Iron Release

Here, we consider the iron chelation speed (iron release) when using fer-
rozine as only a reducing and chelating agent. Iron release measurements
frequently use ferrozine as a color marker in combination with other
agents such as 6-OHDA to facilitate the chelation of iron from the pro-
tein.19 However, the use of several chemicals would at first complicate the
data analysis. When ferrozine is added to a solution of ferritin proteins,
the molecule may penetrate the proteic cage through the threefold sym-
metry points. The protein is then well protected against strong, nega-
tively charged, iron chelators such as ferrozine. When using ferrozine as
chelating agent, we found that samples previously exposed to magnetic
fields of 1 MHz and 30 μT released up to 40 to 50 percent less iron than
control samples.11 We define the magnetic field effect on the change of
iron released as ΔFereleased ≡ (Fereleased|control − Fereleased|exposed)/Fereleased|control,
where Fereleased|control and Fereleased|exposed are the total iron released 1 hour
after adding the chelating agent discounting the initial burst in control
and exposed samples, respectively. This effect was dependent on several
parameters, including the magnetic field amplitude and frequency, the
exposure time, the ferritin and ferrozine concentration, and the pH of the
solution.
The variation of the magnetic field effect with chemical concentrations
of ferrozine and ferritin (Figure 8.6) can be explained as due to pH varia-
tions and changes in the intermolecular interactions. The pH of the ferri-
tin solution decreases when the acidic ferrozine is added, which will result
in iron reduction and increased rates of release. On the other hand, the
protein itself and the NaCl solution in which it is dissolved act as a buf-
fer to the pH change. Higher rates of iron release due lower pH will affect
both control and exposed samples, decreasing the magnetic field effect.
The reason for smaller effects at lower ferritin concentrations (1 μM) may
60
Ferritin concentration
14 µM
3.5 µM
1 µM
40
∆Fe released (%)
20
0
50 µM 100 µM 200 µM
Chelator (ferrozine) concentration
FIGURE 8.6 Changes in iron release after exposure to magnetic field as a func-
tion of the chemical concentrations of ferritin and ferrozine (chelating agent)
used.
also be due to the buffer effect of the proteins or to a decrease in proteic

interactions, which being energetically weaker, on the order of 8 kJM–1
instead of 300 kJM–1 for protein subunit interaction,40,41 would be expected
to be more affected by the irradiated energy.
To test this hypothesis, we studied the effect of a pH 7 buffer. We used
solutions with 3.5 μM ferritin and 50 μM ferrozine concentrations. The
magnetic field reduced the iron released by 53 ± 5% when 10 percent of pH
7 buffer was added after the magnetic field exposure, 27 ± 6% when the
buffer was added before the magnetic field exposure and 42 ± 6% when
no buffer was added. Adding the pH buffer after RF exposure rather than
before ensures that the solution conductivity remains low. The effect of a
temperature increase is to induce faster iron release, not slower as seen
after exposure to RF magnetic fields, with rates 4 times higher in samples
cultured at 45°C than at 25°C. Therefore, a temperature change induced
by the RF fields would have the opposite effect to the one reported here.
Adding buffer before exposure is actually when the effect is smallest. We
hypothesize that this is because the pH buffer acts as a protecting agent
against the effect of the magnetic field. On the other hand, the effect is
higher when the pH buffer is added after the measurement; the pH buffer
ensures that the iron release is not overly fast and avoids iron reduction
due to low pH.
Because all these measurements are done after the RF magnetic field
exposure, it is expected that the protein will eventually relax to its origi-
nal state. In our measurements of ΔFe versus time, the maximum effect
occurs 5 to 30 min after the addition of the ferrozine and afterward the
effect decays slowly over several hours. As expected, the effect depends on
the exposure time of the proteins to the RF magnetic fields. However, even
though the effect initially increases from 17 percent after 1 hour expo-
sure to 40 percent after 3 hours, it eventually decreases once the expo-
sure exceeds 5 hours, dropping to 22 percent after being exposed for nine
hours. This is due to a degradation of the protein and/or the ferrihydrite
core when the solutions have been kept for long time at room temperature
without physiological conditions. The degradation can be observed by
comparing the amount of iron chelated in proteins freshly prepared with
that of older solutions: about 4 times more iron is chelated from proteins
left at in solution at room temperature after nine hours than when the
solution was fresh.
The effect has a power dependence on the applied magnetic field: ΔFe ∝
B . Still, it is invariant at constant ω × B, with ω the angular frequency
1/2
of the field. On the other hand, if the effect depended on the electrical
field, such as due to induced polarization changes, it would be expected to
increase at higher frequencies because the measured electrical field gener-
ated by the coils at 15 μT and 2 MHz is 4 times higher than at 120 μT and
250 kHz (see Figure 8.7). The effect should also in that case vanish shortly
after stopping the applied field, in a time scale similar to the dipolar relax-
ation, i.e., the relaxation of the electrical dipoles in the protein cage. In
fact, the equivalent effect obtained for constant products is in agreement
with a mechanism mediated by the RF power dissipation of superpara-
magnetic nanoparticles as calculated in Equation 8.12.
Assuming that the energy irradiated by the nanoparticle is responsible
for the effects in iron chelation, it remains the question of what are the
changes induced by the irradiated power that lead to the slower release
50
40
∆Fe released (%)
30
20 3 hours exposure
ω × B = 190 Ts–1
10
0
(a) 250 500 1000 2000
f (kHz)
50 3 hours exposure
500 kHz
40
∆Fe released (%)
30
20
10
(b) 0 10 20 30 40 50 60
B (µT)
FIGURE 8.7 Dependence of the change in chelated iron after 3 hours of RF

magnetic field exposure as a function of (a) the field frequency maintaining
the frequency × amplitude product constant and (b) with the magnetic field
amplitude.
rates. This release rate by ferrozine is determined by the chelation of

iron and the dynamics of the ferrozine molecules going in and out of the
proteic cage; i.e., the rate is probably decided by how fast ferrozine can
penetrate in the proteic cage and reduce iron atoms from the ferrihydrite
nanoparticle or by how many iron ions it can obtain from the proteic cage
itself without penetrating. Therefore, the effect must originate either in the
nanoparticle or in the entry-exit process (see Figure 8.8).
We then consider the potential effect that the RF magnetic field may
have on the eight pores at the threefold symmetry axis of the protein,
the entry and exit point for ferrozine and discussed in Section 8.2.2.2.
In Fourier-transformed infrared measurements (FTIR) of ferritin solu-
tions exposed to RF fields, we do not observe any significant change in
the protein structure. This was expected, as the energy released by the
nanoparticle should not be sufficient to break any proteic link. It is pos-
sible, however, that the effect of the power release affects not the structure
but the charge distribution in or around the protein pores. Because ferro-
zine is a negatively charged molecule, a change in the charge distribution
due to the RF field would result in an effect in the ferrozine chelation rate.
The effect of RF magnetic fields on the charge state of the threefold
symmetry points is supported by aggregation experiments. The carboxyl
groups at the threefold points form hydrophilic terminals that increase
pH 2 buf.
Exposed
Control
0.25% vol
2 hours
Stirring
FIGURE 8.8 The threefold point act as hydrophilic terminals essential to pro-
tein solubility. Surface protonation and a sudden release of iron via pH reduction
and iron reducing agents lead to blocking of the negative terminals and protein
precipitation. This effect is quenched in solutions exposed to RF magnetic fields.
protein solubility. When the pH of a ferritin solution is lowered to a value

of 3 to 4 in the presence of a high concentration of iron chelators or other
iron reducing agents, surface protonation, and the fast release of Fe (II)
block the negative carboxyl groups, which in turn lead to the aggregation
and precipitation of the proteins in the solution.42,43
In ferritin solutions exposed to the magnetic fields of 1 MHz and 30 μT,
the blocking of the hydrophilic terminals in conditions of low pH and
high chelators concentration takes longer or does not happen at all unless
the pH is further lowered. To generate aggregation and precipitation,
exposed samples require 22 percent volume of pH 2 buffer in comparison
with 4 percent for control samples (1 mM ferrozine in both cases). The
effect depends on the exposure time and is accumulative.
8.4.3 Effects of Reducing Agents

So far, we have discussed only the changes in the iron release rate after
adding ferrozine as chelating agent. However, the action of different chela-
tors may be affected by the RF fields differently. The 6-Hydroxidopamine
(6-OHDA), in particular, is an interesting iron reducing agent given its role
in models of Parkinson’s disease.44–46 In contrast with ferrozine, 6-OHDA
is a small, positively charged molecule that chelates iron by entering into
the proteic cage with relative ease.19 If an iron reducing agent such as
6-OHDA is added to a ferritin-ferrozine mixture, the Fe (III) in the fer-
rihydrite nanoparticle is reduced to Fe (II) and leaves the protein. It can
then be easily bound, without the ferrozine going inside the peptidic cage.
Therefore, the chelation rates are much faster and depend on the entry of
the reducing agent and the reduction rates (see Figure 8.9).
Differently from using ferrozine on its own, the RF magnetic field does
not change the iron release rate induced by 6-OHDA.12 Because ferrozine
is negatively charged, whereas 6-OHDA is positive, the difference in RF
magnetic field effect may point in the direction of a mechanism mediated
by the charge distribution at the protein. When testing another negatively
charged iron chelator (Meso 2,3-dimercaptosuccinic acid or DMSA), we
observe again that iron release is again slower for proteins exposed to RF
magnetic fields, although the effect is weaker in DMSA. The effect of the
RF magnetic fields cannot be in the chelating agents directly, because
these are added after the exposure. Therefore, we may conclude that the RF
magnetic field effect can indeed be related to the charge state of the protein
and, in particular, to the threefold symmetry pore. Chelators with positive
or neutral charge that can gain easy access to the inner nanoparticle such
0.08
DMSA
∆OD 562 nm
0.04
0.00
(a)
0.08
∆OD 480 nm
6-OHDA
0.04
0.00
(b) 0 2 4 6 8 10 12 14 16 18 20 22 24
Time (hours)
FIGURE 8.9 Changes in the optical absorption after the addition of (a) meso
2,3-dimercaptosuccinic acid (DMSA) and (b) 6-hydroxydopamine (6-OHDA)
between control and samples exposed for 5 hours to fields of 1 MHz and 30 μT.
as 6-OHDA are not affected by exposure to RF magnetic fields; at least for

the frequencies and amplitudes employed in our experiments.
8.5 MAGNETIC FIELD EFFECTS ON IRON UPTAKE

8.5.1 Raman Spectroscopy during RF Exposure
The horse spleen ferritin samples have a magnetic susceptibility at room
temperature of 2.2 × 10–6 m3kg–1 and their Néel relaxation time is of
0.1 nsec, with a characteristic attempt time of 3 × 10–11 sec. Using the
expression for released power by a magnetic nanoparticle in Equation 8.12
gives a total energy dissipation of some 20 JM–1 after a typical exposure
of three hours in fields of 1 MHz and 30 μT. Because this energy is much
smaller than the intermolecular and subunit cohesion energies,40,41 it is not
expected that the magnetic fields will damage the structure of the protein,
and no changes are observed in the IR spectra at 1000–4000 cm–1 of fer-
ritins exposed to RF fields. However, this energy could be enough to incre-
ment the population of low-energy vibrational states. It has been shown
that, given spatiotemporal symmetry, an increase in the population of a

vibrational mode may result in a growth or broadening in the anti-Stokes
region of the Raman spectrum associated with the excited state.47 In order
to look for changes in the protein structure and dynamics, we took Raman
measurements of ferritin solutions before, during, and after an RF mag-
netic field was applied.13 The samples had concentrations of 30–50 mg/mL.
Although intensity filters were used to reduce the laser intensity and avoid
sample heating, samples were left for three hours exposed to the laser for
thermalization before the measurement. Temperature in the chamber was
constant during the experiment. We observe such an asymmetric increase
in the low-energy region of the anti-Stokes spectrum measured during the
application of a magnetic field (1 MHz and 30 μT). The change is of up to
13 percent of the initial spectrum at low frequencies. On the other hand,
the Stokes spectrum shows a smaller and less defined growth at frequencies
below 80 cm–1. For a rough calculation of the energy absorbed by the proteic
cage, the low-frequency anti-Stokes Raman spectrum appears displaced by
about 0.6 cm–1, compared to some 0.03 cm–1 for the Stokes spectrum. This
is equivalent to an energy E = hν ∙ 6 × 1023 ≈ 7 J/M. Our estimate for the
dissipated power would be of the order of 1–2 J/M for a 10-min exposure
(Raman measurement time). The disagreement may be due to an underes-
timation of the relaxation time, which could lead to larger power loss.
The vibrational frequencies with increased population could be charac-
teristic of breathing or backbone vibration modes involving many atoms.
These low-frequency modes in molecular dynamics are still about 6 orders
of magnitude faster than the applied fields, 0.1–1 THz vibrations compared
with 0.1–1 MHz fields. The temperature during the experiment remains
constant and the Raman intensity goes back to its original value once the
field is removed. As the exposure time is increased, the energy dispersed
through vibrations and/or Brownian motion can lead to changes in pro-
tein function that remain once the field is removed. However, the Raman
spectrum of the ferritin solution was dominated by a fluorescence sig-
nal and very sensitive to the experimental conditions, so further work is
needed in order to confirm a change in the protein dynamics.
8.5.2 Changes in Iron Uptake

There is also an effect of RF magnetic fields on the ability of ferritin to
uptake Fe (II) ions, although it is weaker than for iron chelation. In these
experiments, Fe (II) ions were added to ferritin/apoferritin solutions as
ammonium iron sulfate 6-hydrate (Mohr’s salt). When iron ions added to a
ferritin solution are uptaken by the protein, there is an increase in the opti-
cal absorption of the solution. The changes in OD at 310 and 420 nm have
been calibrated as ε = 2745 and 550 per mol of iron uptaken and centime-
ter of solution, respectively.48,49 The temperature of the samples, measured
during and after the field exposure and during the titration measure-
ments, is once again equal for control and exposed samples within 0.1°C.
Measurements are done after (not during) field exposure.
As it was the case for iron release (Section 8.4.2), we define the mag-
netic field effect on the change of iron uptaken by the protein as ΔFeuptake ≡
(Feup|control − Feup|exposed)/Feup|control, where Feup|control and Feup|exposed are the
concentrations of iron uptaken 1 hour after adding the Fe (II) ions in con-
trol and exposed samples, respectively. We found that the ability of ferritin
to oxidize and store iron is reduced after being exposed to RF magnetic
fields, i.e., ΔFeuptake > 0. The change is a function of the molecular con-
centrations, exposure time and ω·B product (Figures 8.10 and 8.11). The
iron absorbed in 3.5 μM ferritin solutions exposed to field of 30 μT (H =
25 Am–1) at 1 MHz for five hours (total energy released ~ 35 JM–1), is
20 ± 10% smaller than for control samples for added iron concentrations
between 0.25 and 1 mM. However, for the same conditions in apoferritin
(protein without inner ferrihydrite nanoparticle), the effect is not signifi-
cant: ΔFeuptake (apoferritin) = 1 ± 4%. The effect depends on the relative fer-
ritin-iron concentrations, and it has not statistical significance for large Fe
(II) concentrations (~1 mM). The fact that there is no effect in apoferritin
40 3 µM ferritin
1 µM ferritin
3 µM apoferritin
Decrease in iron uptake (%)
30
20
10
250 µM 500 µM 1 mM
Fe2+ concentration
FIGURE 8.10 Changes in iron uptake after exposure to magnetic field as a func-
tion of the chemical concentrations of iron cations and ferritin.
ω × B = 190 Ts–1
30 2 hours exposure
∆Fe uptake (%)

20
10
0
100 1000
f (kHz)
FIGURE 8.11 Changes in iron uptake 2 hours exposure to RF magnetic fields as

a function of the field frequency maintaining the frequency × amplitude product
constant.
reinforces our hypothesis that the mechanism of interaction is mediated by

the nanoparticle: in proteins without a ferrihydrite core, there is no effect.
In agreement with our hypothesis of a mechanism governed by Equation
8.1, the effect remains roughly the same if the product ω·B is constant, even
over large frequency ranges: ΔFeuptake ∝ ω × B when the frequencies are such
that ω–1 ≪ τN. The relatively weak effect measured at low ferritin and/or
high iron concentrations may be due to the rapid decrease of the effect after
the iron salt is added from an initial 50 to 17 percent after one hour. For
iron release, the decrease over one hour was much smaller, going from 55 to
42 percent. The rapid decrease of the effect in iron uptake results in a com-
paratively smaller effect after one hour at high field-frequency products and a
nonsignificant effect at field-frequency products below 190 Ts–1. However, the
results shortly after adding the iron are not reliable owing to the small signal
measured in the first minutes and the initial changes to the solution optical
density when mixing Mohr’s salt. The larger difference in the early stages
of the experiment may be due to a loss power effect over the proteic region
responsible for the early formation of the diferric peroxo complex50 rather
than an effect over the incorporation of the iron ions to the nanoparticle.
8.6 ROLE OF THE THREEFOLD SYMMETRY POINT

AND FUTURE CONSIDERATIONS
8.6.1 Effects of Cationization at the Threefold Symmetry Point
Our hypothesis to explain the effect of the RF fields on the Fe (III) release,
Fe (II) uptake and protein solubility is related to the charge distribution
at the threefold symmetry point, As we saw in the previous section, the

pore at the center of the three subunits has a net negative charge around
it because of the presence of six carboxyl groups in the peptides at the
union, each subunit contributing with one glutamic and one aspartic acid.
Owing to this negative charge, it also has the characteristic of being able
to trap cations, so in a ferritin sample, this negative charge is, at least par-
tially, screened by the solution and/or compensated by cations, so if the
irradiated power has altered the charge distribution around the pore, the
entrance of charged molecules through it will also be affected. The pore
is involved in iron exchange, and, in some cases, it is the entry point for
chelating agents, so it has an essential role in the protein function as stud-
ied here.
Ferrozine is a large, acidic molecule that would find difficult to pen-
etrate the proteic cage, although diffusion over long periods of time may
be possible.19 Another possibility is that other acidic molecules, say, from
the pH buffer employed, act as reducing agents, liberating the Fe (II) ions
that are then bound by three ferrozined molecules. Directly after adding
the ferrozine, there is a sudden increase in the OD of the ferritin solution.
This is probably due in part to a general increase of the absorbance of the
solution with the added chemicals and partly to the quick combination
of ferrozine with Fe (II) ions present in the solution. These ions may have
been previously reduced by the acidic molecules in the buffer. As men-
tioned in Section 8.4.2, we do not take into account this initial burst in our
results because it is too fast to measure accurately; this takes place in a few
seconds. However, we find that this initial ratio of formation of the iron-
ferrozine complex is roughly the same for control and exposed samples.
As the chelator reaches equilibrium with the ferritin, i.e., when the fer-
rozine may penetrate inside the cage, the release in exposed samples falls
behind. The effect reaches a maximum after some 20 min and then slowly
decays over several hours. It is therefore possible that the magnetic field
reduces the screening effect of the solvent or removes the attached metal-
lic ions, increasing the effective negative charge at the threefold symmetry
axis and making more difficult for ferrozine and other acidic molecules to
penetrate through the pore, delaying iron release in particular at low pH.
However, small changes in the charge distribution around the pore,
or in the solvent ionic screening, can greatly modify the entry times of
charged molecules such as ferrozine.
In cationized ferritin,12,51 the six carboxyl groups from the glutamic
acids that form the hydrophilic terminals at the threefold symmetry point
are neutralized with N,N dimethyl-l,3propanediamine (NNPD). The

NNPD could be functionalized to other carboxyl or negative molecules at
the protein surface, but only at the threefold symmetry pore are there six
free COO− groups. Because the charge distribution after cationization is
different, changed from negative to neutral, an effect of the RF magnetic
fields on the charge distribution around the threefold symmetry point
should now give a different result. The entry pore will now also be smaller
owing to the attached molecules that reduce the pore frame. This results in
slower chelation rates by up to a factor 2 to 3 (see Figure 8.12).
70
60
∆Fe release (%)
50
Ferrozine
40 chelation
30
20
10
0
(a) 0 5 10 15
Time (hours)
0
–10
2 hours exposure
–20
ω × H = 190 Ts–1
∆Fe release (%)
–30
–40
–50
–60
–70
(b) 500 1000 5000

f (kHz)
FIGURE 8.12 (a) The effect has a maximum just 20 min after the addition of
the iron chelator (note that the magnetic field exposure is stopped previous to
the measurement) and then decays slowly over several hours. (b) Effect of RF
magnetic fields in the iron release from cationized ferritin when using ferrozine
as chelating agent. The change has the opposite sign than for natural ferritin with
negatively charged threefold symmetry points.
We find that the exposure to the same fields that resulted in a factor 2
slower release rate in ferritin (500 kHz to 2MHz; 60–15 μT), now result
in faster release rates from exposed ferritin. Furthermore, the effect now
extends over longer periods of time, with a roughly constant increase of 30
to 50 percent one day after the magnetic field exposure has been stopped
and the ferrozine added. Following our initial argument, we would con-
clude that the charge redistribution induced by the magnetic effect has
now the effect of making it easier for the negative ferrozine to penetrate
the proteic cage across the now neutralized carboxyl groups.
8.6.2 Fluorescence Determination of Iron Contents

The ferrihydrite nanoparticle inside ferritin is not fluorescent, but it
absorbs the photons emitted by the organic fluorophores at the peptide
cage (see Table 8.1 and Figure 8.13), quenching the photoemission. This can
be used to determine the iron content inside the protein. Usually, physi-
ological iron levels are measured in function of ferritin concentration. To
test whether the changes in the rates of iron chelation are due to changes
in the oxidation states of the iron ions or in the amount of iron inside
the nanoparticle, we have used fluorescence measurements. The proteic
cage apoferritin shows fluorescence because of almost equal contributions
from tryptophan and tyrosine residues, with strong absorbance around
275 nm and emission at 325 nm. We have found that it is also possible to
determine the average amount of iron inside the protein by measuring the
fluorescence polarization. A reduction in the nanoparticles size induced
by the RF magnetic fields would have as consequence an increase in the
fluorescence of the proteins. However, measurements show no change in
fluorescence emission or polarization after RF exposure. Therefore, we can
conclude that the RF magnetic fields do not affect directly the size or iron
content of the inner ferrihydrite nanoparticle.
TABLE 8.1 Fluorescent Characteristics of Peptidesa

Absorbance Emission Quantum Yield
Tryptophan 93 (peptide 280 nm (5600 300–348 nm 0.2 f
position) relative absorbance)
Tyrosine 12,18,22,24,30,168 274 nm (1400) 303 nm 0.14 f
Phenylalanine 257 nm (200) 282 nm 0.04 f
39,41,54,82,132,137,170
a After Gabor Mocz in http://dwb.unl.edu/Teacher/NSF/C08/C08Links/pps99.cryst.bbk
.ac.uk/projects/gmocz/fluor.htm.
700
600
λ Emission 1
500 4
10
40
400 80
Y 120
300 160
200
300 400 500 600 240
(a) λ Excitation 280
500
Fluorescence polarization (mP)
400
300
200
100
0
0 500 1000 1500
(b) Iron content (ions)
FIGURE 8.13 (a) Change in fluorescence between apoferritin and ferritin.

(b) The fluorescence polarization as a function of the iron content in ferritin.
8.6.3 Summary of the Effects, Future Considerations to RF Magnetic

Fields Exposure, and Their Effects on Iron Cage Proteins
The effects due to the suggested new mechanism of interaction between
ferritin with RF fields can be resumed as follows:
• Reduction in the iron chelation rate by negatively charged molecules

such as ferrozine and DMSA. No changes when the molecule used
was 6-OHDA (positively charged).
• Stronger effects when the ferritin concentrations were high and/or
the chelator concentrations were low.
• Increase in the iron chelation rate for cationized ferritin when using
the same molecules; opposite effect to standard protein.
• Effect is increased when a pH buffer is added previous to the expo-

sure and reduced when the buffer is added after the exposure.
• An increased protein solubility in exposed proteins when acidic pH

buffers were added.
• A reduced rate in the oxidation and incorporation of Fe (II) ions for

exposed proteins.
The effect does not seem to be thermal or electric, as the temperature

in the exposed and control samples remain constant, and the effect does
not depend on the electrical field or sample conductivity. Furthermore,
changes due to an increased temperature would be opposite to those
measured, e.g., increased iron released rates rather than decreased. The
relationships with the pH of the solution and, in particular, the inverse
effect observed in cationized ferritin indicate a mechanism mediated by
the charge distribution in the protein and around the threefold symme-
try point. At the same time, the constant effect for equivalent frequency-
amplitude products point to an interaction mediated by the power
dissipation of the superparamagnetic ferrihydrite nanoparticle.
Although the described effects only happen at large ferritin concen-
trations not found in healthy organisms, individuals with high levels of
iron (hematomacrosis) or exposed to large fields may be affected. Given
the role of Fe (II) in oxidative processes via the Fenton reaction, a protein
malfunction would have serious consequences. This could be at the origin
of some RF magnetic field effects in oxidative-stress related disorders.
Another hypothesis for a relationship between oxidative stress and
magnetic fields arises from the well-established band splitting on free
radicals in a magnetic field. However, reproducible experimental effects
due to band splitting on free radicals have been measured only for fields of
the order of, or above the hyperfine interaction, i.e., above some 1 mT (and
generally fields of the order of 10–100 mT are employed). Some of the best
experiments are performed at low temperatures to reduce the effect of the
thermal energy (see, for example, the work of van Dijk and coworkers52).
This kind of experiment with controlled conditions, only one chemical
species, reproducible results and a clear dependence on magnetic field is,
in our opinion, a better indication of the fields involved than experiments
done for example on comet analysis for DNA strands, which are not a
direct measurement of radical lifetime, have little reproducibility and
many variables with a complex procedure.
Another consideration when using RF, rather than DC magnetic fields,
is that once the period of the magnetic field is comparable with the life-
time of the free radical, the band split effect decreases as the frequency
increases. The lifetime of free radicals is for example 4 μsec (→ 40 kHz)
for a free radical involved in Fenton chemistry.38,53 If our effect was due
to changes in the Fenton reaction, as we increase the frequency from
250 kHz to 2 MHz, the effect should quickly decrease because of (1) the
reduced averaged field over the lifetime of the radical and (2) the fields
used at 250 kHz are 4 times higher than those at 2 MHz: from 60 to 15 μT.
In fact, at frequencies of the order of 1 MHz, the averaged field over the
radical lifetime would be zero, and no effect would be expected. However,
we do measure an effect, and it remains constant over the frequency range.
We think that if the effect was due to changes in the Fenton chemistry, the
use of pH buffers would surely reduce it because the buffer would control
the oxidation state of iron. We see in our measurements that it is not the
case. Finally, the addition of chelating agents is done after the exposure.
Our measurements are performed at frequencies of 0.25 to 2 MHz,
but ferrihydrite nanoparticles can have small relaxation times down to
10 psec.14 In theory, the described mechanism could vary with ω·B up to
much higher frequencies, with a dependence only on B once the period of
the field is smaller than the relaxation time of the nanoparticle.36 However,
measurements at higher frequencies would be necessary to asses this
hypothesis and the effects at higher frequencies. In the case of physiologi-
cal experiments, the iron/ferritin levels together with the frequency and
amplitude of the magnetic (not only electric) field should be considered.
From this calculation, it is easy to see that the energy loss by the nanopar-
ticle inside ferritin is unlikely to lead to a thermal effect at the concentra-
tions usually found in the body, even at relatively large magnetic fields
and frequencies. This calculation is nevertheless independent of the effects
that the loss power may have on the proteic cage itself or on whether our
suggested mechanism is indeed the correct explanation for the observed
effects (see Figure 8.14).
We do not know what the implications could be. For example, our
estimates calculate that to denaturalize human spleen ferritin we would
need fields of the order of 100 mT at frequencies of 100 kHz operating for
about 15 min, but these fields are one order of magnitude higher than the
104 Heating rate limit = 1.6 W/kg over 100 g

(1–10 mg ferritin iron per 100 g of tissue)
102
W/kg ferritin iron
Denaturalization limit
(10' exposure)
100
Mobile phone
in
tin rit bands
rri fer
10–2 fe en
leen s ple Microwave
sp rse 100 µT
an Ho ovens
10–4 Hu
m
Experiment
10–6
102 103 104 105 106 107 108
f (kHz)
FIGURE 8.14 Differences in the effect of iron releasing agent using the time scale
for a ferrihydrite nanoparticle with τN ~ 0.13 nsec. The denaturalization limit
assumes that all the power dissipated is absorbed by the protein, which is not
likely and would need to be probed experimentally.
commonly employed in hyperthermia and the estimation depends on the

magnetic characteristics of the nanoparticle. It would depend on the body
region the relaxation time of the ferrihydrite nanoparticle varies with
the organ, the amount of iron, etc. More studies would also be needed to
determine how the protein dissipates the energy to the medium. We do
not think it is likely that the effect could cause macroscopic heating in
addition to the heat generated by the artificial nanoparticles, due to the
relatively low ferritin iron concentrations; in the brain, the maximum is of
some 200 ng/g of tissue, found in the globus pallidus.
Extrapolating to higher-frequency fields, such as those used by mobile
phones, microwave ovens, and other applications, is just speculation.
However, if the RF magnetic field effect described in the previous sections
is confirmed and if its origin is indeed in the power released by the super-
paramagnetic nanoparticle, there is no physical reason why the mecha-
nism we describe could not maintain the frequency field dependence up to
or near to the GHz range. The period of the magnetic fields we employed
in these research is below the lifetime of the radicals involved in Fenton
reaction, but above the relaxation time of the ferrihydrite nanoparticle.
This relaxation time is usually 10 to 100 psec for horse spleen ferritin
but can go up to 10 nsec (~16 MHz) in thalassemic human spleen ferri-
tin.14 At periods above the relaxation time, the frequency field relation is
maintained, but below the relaxation time of the nanoparticle only a field
dependence would be expected, limiting the experiments we could do to
confirm the mechanism. Given the characteristic time of the ferrihydrite
nanoparticle, which can be as low as 10 to 100 psec in some ferritins but
depends on many factors, even at higher frequencies the power dissipa-
tion would theoretically remain constant as long as the field amplitude
was maintained. That is, in principle, the effect at 1 μT and 1 GHz would
be approximately equivalent to also 1 μT at 10 GHz, but it could be similar
to 10 mT at 100 kHz. Of course, at those frequencies other factors, such as
molecular vibrations, would also play a role and may change the dissipa-
tion and absorption mechanisms. Furthermore, experiments in vitro with
high ferritin concentrations may differ very significantly from tests in vivo
and biological effects due to proteic relaxation, chemical buffer, and other
environmental considerations.
ACKNOWLEDGMENTS
We thank Bioelectromagnetics for the permission to reproduce ideas and
results as reported in References 11,13.
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Chapter 9
Safety Aspects
of Magnetic and
Electromagnetic Fields
Sachiko Yamaguchi-Sekino,
Tsukasa Shigemitsu, and Shoogo Ueno
CONTENTS
9.2 Mechanisms for Biological Interaction 262
9.2.1 Static Magnetic Field 262
9.2.2 Gradient (Time-Varying) Magnetic Field 263
9.2.3 Radio Frequency Electromagnetic Field 264
9.3 Biological Effects Related to MRI 265
9.3.1.1 In Vivo Studies 266
9.3.1.2 In Vitro Studies 269
9.3.1.3 Human Experimental and Epidemiological
Studies 270
9.3.4 Possible Health Effect Related to MRI Operation 274
9.4 Exposure Guidelines Related to MRI 276
9.4.4 Movement-Related Magnetic Field 280
259
9.4.5 Guidelines on the Protection of Patients Undergoing

MRI Examinations 282
9.5 Occupational Exposure during MRI 288
9.5.1 Worker Exposure Assessment 289
9.5.2 European Electromagnetic Fields Directive 291
9.6 Conclusion 296
Acknowledgments 297
References 298
9.1 INTRODUCTION
The magnetic resonance imaging (MRI) was introduced into the diagnostic
imaging technology in medicine in the early 1980s. It originally comes from
the technique of nuclear magnetic resonance (NMR). In 1970s, Damadian
observed the differences of the relaxation times between tumor and nor-
mal tissues and proposed the use of NMR as imaging for the detection of
cancer (Damadian 1971). In Japan, during the 1970s, using NMR, Abe et
al. proposed and measured noninvasively detection of the biological image
information by magnetic focusing method (Abe et al. 1974).
The basic principle and the technical development of imaging forma-
tion using NMR were proposed by Lauterbur, who developed the MRI
(Lauterbur 1973). The Nobel Prize in Medicine and Physiology was
awarded in 2003 to Lauterbur and Mansfield for the fundamental appli-
cation of a static magnetic field in combination with a gradient (time-
varying) magnetic field and the development of the image acquisition and
processing (Mansfield and Maudsley 1977). In this way, the root of MRI is
known as nuclear magnetic resonance. To avoid alarming the public and
medical experts, the word “nuclear” was deleted from the term magnetic
resonance, although it has nothing to do with radioactivity.
The operation of MRI basically utilizes three different types of elec-
tromagnetic field, the strong static magnetic field, the rapidly changing
gradient (time-varying) magnetic field, and the radio frequency electro-
magnetic field. The static magnetic field is the main magnetic field in MRI.
It aligns the proton spins and generates a total magnetization in the human
body. The static magnetic field is responsible for a measure of the proton
density. It is usually generated by a strong superconducting magnet. The
increase in the static magnetic field strength goes toward improvements in
image resolution. Today, the commercially available MRI system typically
has a static magnetic field strength of up to 3 T. The gradient magnetic
Safety Aspects of Magnetic and Electromagnetic Fields ◾ 261
field is used to localize aligned protons in the image reconstruction pro-

cess. The exposure to the gradient (time-varying) magnetic field with fre-
quencies in the kHz range is the character to the MRI technique. The radio
frequency electromagnetic fields in the range of 10 to 400 MHz are used to
excite the protons within the stable magnetic fields.
The objective of this chapter is to describe some of the recent informa-
tion on the biological effects and safety aspects of electromagnetic fields
related to MRI. Section 9.2 is a short description of the plausible mecha-
nisms of electromagnetic fields related to MRI. Section 9.3 introduces the
evaluation of the biological effects of static magnetic field, gradient (time-
varying) magnetic field, and radio frequency electromagnetic fields as well
as the health effects of these three fields as they relate to MRI. Recently
published documents are used to provide an overview of the three differ-
ent electromagnetic fields with the addition of a brief review of more recent
experimental observations (ARPANSA 2014; HPA 2008, 2012; IARC
2002, 2013; ICNIRP 2003a, 2009d; NRPB 2003; WHO 2006a,b). Indirect
interactions between human and medical devices (or metal implants) are
not considered because of the newest research results and evidence-based
information on the biological and health effects.
Through a discussion of biological and health effects, Section 9.4 re
views and summarizes safety guidelines that provide a consideration in
human risk for both patients and medical staff on limiting the operation
to static magnetic fields as well as the other electromagnetic fields for MRI
(ICNIRP 1998, 2003b, 2009b, 2010, 2014).
Section 9.5 covers the health risk assessments associated with the envi-
ronment and during the operation of MRI system, with an emphasis on
occupational exposure. In order to understand the hazard identification,
measurement, work-environment risk assessment, and health survey of
the working staffs, occupational exposure, and the MRI safety policy and
procedure should be reviewed. In Europe, there have been attempts to
create a Directive on the protection of occupational exposure of workers
to the risks from physical agents. The Directive applies to occupational
exposure, not patient exposure, to electromagnetic fields. The progress,
update, scope, and conditions of the EU electromagnetic fields Directive
will be given shortly to meet the request of protection of MRI working
staffs and employers. Followed by the evaluation of the biological and
health effects, Section 9.5 concludes with a discussion of safety issues
related to MRI in clinical diagnosis, with the highlighting of the guide-
lines and existing MRI standard. Within these frameworks, Section 9.6
discusses the conclusion remarks on the biological and human health

issues related to MRI.
9.2 MECHANISMS FOR BIOLOGICAL INTERACTION

Basically, the interaction between the static magnetic field and biological
tissues including the human body are proposed and established on the
basis of experimental results. The other two, gradient magnetic field and
radio frequency electromagnetic field interaction, are primarily based on
Faraday’s law of induction.
9.2.1 Static Magnetic Field

The physical mechanisms of interactions between static magnetic
fields and biological systems are basically well investigated. There are
three established mechanisms: (1) magnetic induction, (2) magneto-
mechanical interactions, and (3) electronic interactions (ICNIRP
2003a; WHO 2006a).
1. There are two types of interaction for magnetic induction.

The electrodynamic interactions with moving charged particles
can lead to an induced electric field. The change in electrocardio-
grams (ECG) is a well-known example of this electrodynamic inter-
action. These induced electrical potentials have been experimentally
observed by ECG changes on mammalians (e.g., rat, rabbit, dog,
baboon, and monkey) in the presence of a static magnetic field
(Gaffey and Tenforde 1981; Tenforde 1983).
In the presence of a static magnetic field, the electrical potential
is induced. This is the result of the Lorenz force exerted on mov-
ing charged particles (electrolytes) in the blood. The induced electric
potential is given by
ϕ = ν ∙ B ∙ d ∙ sin θ
where ν is the velocity, d is the diameter of the artery, and θ is the

angle between the direction of the blood flow and the magnetic
field. Kinouchi et al. carried out the detailed theoretical treatment
of the effects of magnetic fields on blood flow by using the Navier-
Stokes equation (Kinouchi et al. 1996). In the case of magnetic fields
perpendicular to the blood flow, they found a reduction in the flow

rate of blood.
In addition to electrodynamic interaction, induced electric fields
and currents are created by gradient (time-varying) magnetic fields
in MRI technique or by the movement of subject in the static mag-
netic fields, which are accordance with Faraday’s law of induction.
The amplitude of the induced electric fields and currents increases
with movement speed and with the degree of gradient.
2. There are two types of interactions for magneto-mechanical effects.
The first type is magneto-orientation: This concerns the orien-
tation of paramagnetic molecules in the static magnetic field. This
effect is involved in magneto-reception in certain species of ani-
mal including fish and birds. The second type of interaction is the
magneto-mechanical translation. This occurs in the presence of a
field gradient for paramagnetic or diamagnetic materials (Ueno and
Iwasaka 1994a,b).
3. The third mechanism is electronic spin interaction.
This interaction can affect the rate of recombination of pairs of
free radicals in chemical reaction intermediates. It seems that this
mechanism plays a part in the navigation systems of certain birds.
Okano gave the excellent review on the role of free radicals in biol-
ogy (Okano 2008).
9.2.2 Gradient (Time-Varying) Magnetic Field

The gradient magnetic field serves for the spatial localization in the image
reconstruction process in MRI technique. Exposure to gradient magnetic
field induces time-varying electric fields and currents in human body. It is
considered time-varying magnetic field below 1 kHz. Many studies have
investigated the biological effects of low-frequency time-varying magnetic
fields (up to 100 kHz) (IARC 2002; ICNIRP 2003a; NIEHS 1998; WHO
1987, 2007a).
The coupling between the time-varying magnetic field and the body is
summarized below from the document of International Commission on
Mon-Ionizing Radiation Protection (ICNIRP 2010). For magnetic fields,
the permeability of tissue is the same as that of air so the field in tissues
is the same as the external field. Human and animal bodies do not sig-
nificantly perturb the field. The main interaction of magnetic fields is the
Faraday induction of electric fields and associated currents in the tissues.
Key features of dosimetry for exposure of humans to low-frequency mag-
netic fields include
• For a given magnetic field strength and orientation, higher electric

fields are induced in the bodies of larger people because the possible
conduction loops are larger.
• Induced electric field and current depend on the orientation of the
external magnetic field to the body. Generally, induced fields in the
body are greatest when the field is aligned from the front of the back
of the body, but for some organs the highest values are for different
field alignments.
• Weakest electric fields are induced by a magnetic field oriented along
the principal body axis.
• Distribution of the induced electric field is affected by the conductiv-
ity of the various organs and tissues.
As mentioned above, in the patient during MRI examination, the time-

varying magnetic field in this range induces the electric currents in the
body by the Faraday’s law of induction. The induction stimulates nerves
and muscles. The nerve stimulation may cause discomfort. Electric fields
may also be induced by movement in static magnetic field.
In the case of sinusoidal magnetic fields with amplitude B0 and fre-
quency f, the magnitude of the induced current density is given by
J = π · r · f · σ · B0
This means that the induced currents are proportional to the loop
radius r and tissue conductivity σ. A well-known biological effect of mag
netic fields in this range is the induction of visual sensations called
magnetophosphene.
9.2.3 Radio Frequency Electromagnetic Field

Sheppard et al. quantitatively evaluated potential mechanisms of interac-
tion between radio frequency electromagnetic fields and biological systems
(Sheppard et al. 2008). They categorized biophysical mechanisms as

established and proposed. The established mechanisms are dielectric
relaxation and ohmic loss, which lead to elevated temperature in tissue
through heating. On the other hand, the radical pair mechanism is one of
the proposed.
Exposure to radio frequency electromagnetic fields can induce heat-
ing in biological tissues. So, biological effects caused by radio frequency
electromagnetic fields ranging between 100 kHz and 300 GHz can be
divided into two categories: thermal effects and nonthermal effects.
Thermal effects are due to tissue heating, and nonthermal effects are due
to unknown mechanism.
The devices operating with radio frequency electromagnetic fields have
been introduced for therapeutic and diagnostic applications. The thera-
peutic application comprises cancer treatment with hyperthermia and
tissue heating. The latter is mainly associated to MRI, which generates
detectable MR signals. Before the 1980s, there were no reports concerning
the thermophysiologic responses of humans exposed to radio frequency
electromagnetic fields during MRI procedures.
Heating is classically given by a quantity of specific absorption rate
(SAR) with units of watts per kilogram (W/kg). The SAR is derived from
the square of electric field strength in tissue.
2
σE
SAR =
2ρ

where σ is the tissue conductivity, ρ is the tissue density, and E is the

(instantaneous) electric field within the tissue. For a time-varying electric
field with sinusoidal, the factor of 1/2 may be omitted and the root mean
square (rms) value of the field substituted. The SAR cannot be measured
directly in humans and is usually estimated from computer-based simula-
tion models of the human body.
9.3 BIOLOGICAL EFFECTS RELATED TO MRI

This section is divided into the three types of electromagnetic field uti-
lized MRI systems. It gives an overview of the findings about the biologi-
cal effects of static magnetic field, the gradient (time-varying) magnetic
field, and radio frequency electromagnetic field. In each section, the bio-
logical effects related to each field are summarized and evaluated briefly.
In parallel with the brief introduction of recent studies in each section, the
evaluation was conducted with the help of authoritative reviews by well-
recognized organizations such as World Health Organization (WHO)
and the International Commission on Non-Ionizing Radiation Protection
(ICNIRP).

Apart from investigating interaction mechanisms, a large number of stud-
ies have been conducted in the last 50 years on the possible biological and
health effects of the static magnetic fields ranging from geomagnetic field
level (micro Tesla) to several Tesla in magnetic flux densities. In vivo and
in vitro investigations have included experiments on animal cognition and
behavior, cell growth, cell proliferation, cell cycle, apoptotic cell death, tis-
sue development, the cardiovascular system, cancer, the reproductive sys-
tem, teratogenicity, the neuro-endocrine system, circadian rhythms, and
haematologic parameters. Studies on human volunteers were conducted
to assess the health risk of short-term exposure to high static magnetic
fields. Its endpoints included the central nervous system, behavioral and
cognitive functions, sensory perception, cardiovascular system, and brain
activity. In addition, few epidemiological studies related to static magnetic
fields generated from DC supply in industries have been conducted.
There have been many comprehensive reviews on the biological and
health effects of the static magnetic field (HPA 2008; ICNIRP 2003a;
Ueno and Okano 2012; Ueno and Shigemitsu 2007; WHO 1987, 2006a;
Yamaguchi-Sekino et al. 2011).
9.3.1.1 In Vivo Studies

Here, three research areas are considered for the evaluation of the biologi-
cal effects of static magnetic fields: (1) cancer-related endpoints, (2) repro-
duction and development, and (3) physiological and behavioral response.
In terms of cancer-related issues, in vivo studies have been conducted
using animals to investigate the potential carcinogenicity of static mag-
netic fields. These studies were carried out for genotoxic and carcinogenic
effects, through direct, initiation, or promotional means. Mevissen et al.
investigated the effect of the magnetic field of 15 mT for 13 weeks on the
incidence of DMBA-induced tumor in rats (Mevissen et al. 1993). There
are no significant effects on the incidence. Compared with control groups,
the number of tumors per animal was not affected, although the weight
per tumor was significantly increased.
Several studies have been conducted on the possible teratogenic effects

of exposure to static magnetic fields. Most studies have investigated possi-
ble effects on the embryo and fetus. A German research group investigated
and reported, in two associated papers, the effect of repetitive exposure
of mice to static magnetic field (Zahedi et al. 2014; Zaun et al. 2014). The
group evaluated possible risks of strong static magnetic fields for embryo
implantation, gestation, organogenesis, and embryonic development. The
mice were exposed daily for 75 min during the entire course of pregnancy at
the bore entrance (the position of MRI medical staff) or at the bore isocen-
ter (the position of patients) of a 1.5- and 7-T MRI scanner. At the entrance
positions, the magnetic gradient fields were presented, from 0.2 to 1 T for
1.5-T MRI scanner and from 0.6 to 1.4 T for 7-T MRI scanner. Exposures
started at day 1.5 of pregnancy for 18 days. After delivery, development
of the offspring was monitored. No effects of any static magnetic fields
were observed with regard to pregnancy rate, duration of pregnancy, litter
size, still births, malformation, sex distribution, or postpartum death of
offspring (Zahedi et al. 2014). The effects were a slight delay in weight gain
in the groups exposed at both positions in the 1.5-T MRI scanner or at the
entrance of the 7-T MRI scanner and a slight but significant delay in the
opening of the eyes in all exposed groups. Further, Zaun et al. investigated
the effect of daily exposure in utero to MRI-generated static magnetic field
during prenatal development on germ cell development and fertility of
exposed offspring in adulthood (Zaun et al. 2014). Offspring at 8 weeks
were mated with unexposed mice. In the in utero-exposed male mice, no
exposure effect was measured on the weight of testes and epididymis or
on sperm count, sperm morphology, or fertility. In the in utero-exposed
female mice, there was no effect on fertility in terms of pregnancy rate
and litter size. However, in the offspring of the exposed female mice in the
bore or at the entrance of a 7-T MRI scanner, a reduced placental weight
was observed. This correlated with a decrease in embryonic weight only in
those mice exposed at the strongest magnetic field. These studies indicate
possible effects of repetitive exposure on fertility and development.
The research group of Houpt et al. published a series of studies on the
effects of strong static magnetic field on behavior of animals (Cason et
al. 2009; Houpt and Houpt 2010; Houpt et al. 2011). In the past, it was
reported that vertigo is a side effect of exposure to the high magnetic
fields in MRI. So, Cason et al. tested the effect of static magnetic field,
14.1 T on the vestibular apparatus in the inner ear. Chemically, labyrinth-
ecotomized rats (injection of sodium arsanalite, destroying the hair
cells) and intact rats (sham-labyrinth-ecotomized with saline injection)

were exposed to the 14.1 T for 30 min. Intact rats acquired a profound
conditioned taste aversion (CTA), saccharin avoidance, and labyrinth-
ecotomized rats did not acquire a CTA and showed a high preference for
saccharin, which is similar to sham-exposed rats. Significant increase in
c-Fos expression was observed in intact rats, but magnetic field exposure
did not elevate c-Fos levels in labyrinth-ecotomized rats. This result dem-
onstrated that an intact inner ear is necessary for all the observed effects
of exposure to high static magnetic fields in rats. In another study from
the same group, rats were preexposed two times to a 14.1-T static magnetic
field for 30 min on two consecutive days (Houpt and Houpt 2010). This
result showed that repeated treatment to the 14.1 T causes habituation.
Here, the habituation included locomotor circling, rearing, and condi-
tioned taste aversion. Compared to a sham-exposed rat, the preexposed rat
showed less locomotor circling and an attenuated CTA. Rearing was sup-
pressed in all magnet-exposed groups regardless of pre-exposure. Further,
Houpt et al. tested the effects on the movement of rat though 14.1-T static
magnetic field (Houpt et al. 2011). Only momentary passage of the rat into
and out of the static magnetic fields was enough to suppress rearing and
induce a significant CAT. They concluded that in rats, movement though
the steep gradient of a high magnetic field has some behavioral effects,
but sustained exposure to the homogeneous center of the magnetic field is
required for the full behavioral consequences.
The document of the WHO stated, that “A large number of animal
studies on the effects of static magnetic fields have been carried out. Most
of those considered relevant to human health have examined the effect of
fields considerably larger than the natural geomagnetic field. A number
of studies have been carried out of fields in the millitesla region, compa-
rable to relatively high industrial exposure. More recently, with the advent
of superconducting magnetic technology and MRI, studies of behavioral,
physiological and reproductive effects have been carried out at flux densi-
ties around, or exceeding, 1 T. Few studies, however, have examined pos-
sible chronic effects of exposure, particularly in relation to carcinogenesis.
The most consistent responses seen in neurobehavioral studies suggest
that the movement of laboratory rodents in static magnetic fields equal
to or greater than 4 T may be unpleasant, inducing aversive responses
and conditioned avoidance. Such effects are thought to be consistent with
magnetohydrodynamic effects on the endolymph of the vestibular appara-
tus. The data are otherwise variable. There is good evidence that exposure
to fields greater than about 1 T (0.1 T in larger animals) will induce flow
potentials around the heart and major blood vessels, but the physiologi-
cal consequences of this remain unclear. Several hours of exposure to
very high flux densities of up to 8 T in the heart region did not result in
any cardiovascular effects in pigs. In rabbits, short and long exposures to
fields ranging from geomagnetic levels to the millitesla range have been
reported to affect the cardiovascular system, although the evidence is not
strong” (WHO 2006a, p. 5).
9.3.1.2 In Vitro Studies

In vitro studies investigating the effects of static magnetic fields have
covered a wide range of biological systems from bacteria to animal and
human cells. The endpoints cover various issues, including genotoxic
effects, mutation, chromosomal damage, DNA damage, cell viability, pro-
liferation, differentiation, cellular responses, gene expression, and signal
transduction.
Ikehata et al. reported that the effects of exposures to static magnetic
field of 2 and 5 T for 20 min up to 48 h in a bacterial mutation test using
Salmonella typhimurium and Escherichia coli strains (Ikehata et al. 1999).
They observed no effect on mutagenicity or growth rate of bacterial strains.
Sakurai et al. have studied the effect of strong static magnetic fields up
to 10 T with gradient field of 0–41.7 T/m on insulin-secreting cells and
on myotube orientation of a mouse-derived myoblast cell line (C2C12)
(Sakurai et al. 2009, 2012). First, after insulin-secreting cells exposed to
above the static magnetic field for 0.5 or 1 h, the insulin secretion, mRNA
expression, glucose-stimulated insulin secretion, insulin content, cell pro-
liferation, and cell number were analyzed. This result suggested that the
high static magnetic field of MRI systems might not cause cell prolifera-
tive or functional damage on insulin-secreting cells. In the experiment,
where effects of above static magnetic field on the orientation of myotubes
formed from a mouse-derived myoblast cell line, C2C12 are performed.
Cell cultures were exposed for 6 days. The results indicated that the forma-
tion of oriented myotube is dependent on the magnetic flux density and
the gradient magnetic field. The myogenic differentiation and cell number
were not affected for any of the experimental conditions.
Zhao et al. exposed human-hamster hybrid cells, mitochondria-
deficient cells, and double-strand break repair-deficient cells to 8.5 T
(Zhao et al. 2011). Adenosine triphosphate (ATP) content was significantly
decreased in human-hamster cells exposed to 8.5 T but not 1 or 4 T for
either 3 or 5 h. ATP content significantly decreased in the two deficient

cell lines exposed to 8.5 T for 3 h. With further incubation of 12 or 24 h
without static magnetic field exposure, ATP content could retrieve to the
control level in human-hamster hybrid cells but in the two deficient cell
lines. The levels of reactive oxygen species (ROS) in the three cell lines
were significantly increased by exposure to 8.5 T for 3 h. They indicated
that the cellular ATP content was reduced by 8.5 T for 3 h and was medi-
ated by ROS.
Lee et al. investigated the genotoxic potential of 3-T MRI scans in cul-
tured human lymphocytes in vitro by analyzing chromosome aberra-
tions (CA), micronuclei (MN), and single-cell electrophoresis (Lee et al.
2011). They exposed human lymphocytes to the condition of a routine
brain examination protocol and observed a significant increase in the fre-
quency of single-strand DNA breaks following exposure to a 3-T MRI.
The frequency of both CAs and MN in exposed cells increased in a time-
dependent manner. Their results suggest that exposure to 3-T MRI induces
genotoxic effects in human lymphocytes.
The document of the WHO stated that “a number of different bio-
logical effects of static magnetic fields have been explored in vitro.
Different levels of organization have been investigated, including cell
free systems (employing isolated membranes, enzymes, or biochemical
reactions) and various cell models (using both bacteria and mamma-
lian cells). Endpoints studied included cell orientation, cell metabolic
activity, cell membrane physiology, gene expression, cell growth and
genotoxicity. Positive and negative findings have been reported for all
these endpoints. However, most data were not replicated. The observed
effects are rather diverse and were found after exposure to a wide
range of magnetic flux densities. There is evidence that static magnetic
fields can affect several endpoints at intensities lower than 1 T, in the
mT range. Thresholds for some of the effects were reported, but other
studies indicated nonlinear responses without clear threshold values”
(WHO 2006a, p. 4).
9.3.1.3 Human Experimental and Epidemiological Studies

Studies on human volunteers exposed up to 8 T have been investigated to
assess the relationship between exposure to high static magnetic fields and
human health. Endpoints investigated have included central and periph-
eral nerve function, brain activity, neurobehavioral and cognitive func-
tions, sensory perception, cardiac function, blood pressure, heart rate,
serum proteins and hormone levels, body, and skin temperature (WHO
2006a).
The document of the WHO stated that “The results do not indicate that
there are effects of static magnetic field exposure on neurophysiological
responses and cognitive functions in stationary volunteers, nor can they
rule out such effects. A dose-dependent induction of vertigo and nausea
was found in workers, patients and volunteers during movement in static
fields greater than about 2 T. One study suggested that eye-hand coordina-
tion and near visual contrast sensitivity are reduced in fields adjacent to
a 1.5 T MRI unit. Occurrence of these effects is likely to be dependent on
the gradient of the field and the movement of the subject. A small change
in blood pressure and heart rate was observed in some studies, but were
in the range of normal physiological variability. There is no evidence of
effects of static magnetic fields on other aspects of cardiovascular physi-
ology, or on serum proteins and hormones. Exposure to static magnetic
fields of up to 8 T does not appear to induce temperature changes in
humans” (WHO 2006a, p. 7).
In the past, several epidemiological studies have been conducted to
examine mortality and cancer incidence among workers exposed to static
magnetic fields at aluminum reduction and chloralkali plants. Historically,
Marsh et al. presented the occupational exposure study (Marsh et al. 1982).
This study with 320 male workers carried out the occupational exposure
to static magnetic fields ranging from about 3 to 15 mT generated from
large electrolytic cells. The control group was 186 male workers. Although
the cohort was small, they found that there are significant increases in
heart disease and cancer. Barregard et al. carried out very limited occupa-
tional study on workers exposed to static magnetic field from 4 to 29 mT
(average 14 mT) (Barregard et al. 1985). They studied mortality and can-
cer incidence among workers in a Swedish chloralkali plant where about
100 kA direct currents are used to produce chlorine. The exposed group
comprised of 157 men employed between 1951 and 1983, and their mortal-
ity has been compared with that of Swedish men using calendar-year and
age-specific mortality rates. Cancer incidence has been compared with the
expected incidences among Swedish men. They reported that there is no
increased mortality among the exposed men. No excess incidence of can-
cer is found.
Regarding the human and epidemiological studies, a document stated
that “Increased risks of various cancers, e.g., lung cancer, pancreatic can-
cer, and haematological malignancies, were reported. But results were
not consistent across studies. The few epidemiological studies published

to date leave a number of unresolved issues concerning the possibility of
increased cancer risk from exposure to static magnetic fields. Assessment
of exposure has been poor, the number of participants in some of the stud-
ies has been very small, and these studies are thus able to detect only very
large risks for such rare diseases. The inability of these studies to provide
useful information is confirmed by the lack of clear evidence for other,
more established carcinogenic factors present in some of the work envi-
ronments. Other noncancerous health effects have been considered even
more sporadically. Most of these studies are based on very small numbers
and have numerous methodological limitations. Other environment with
a potential for high fields have not been adequately evaluated, e.g., those
for MRI operators. At present, there is inadequate date for a health evalu-
ation” (WHO 2006a, p. 8).

After the review and evaluation of low-frequency electric and magnetic
fields (IARC 2002; ICNIRP 2003a; NIEHS 1998; WHO 1987, 2007a), the
International Agency for Research on Cancer (IARC) classified power fre-
quency magnetic fields as possibly carcinogenic to humans (Group 2B).
This classification was strongly influenced by epidemiological studies that
have observed increased risks of childhood leukemia at magnetic fields
greater than 0.3–0.4 μT (IARC 2002).
Many laboratory studies of the effects of extremely low frequency mag-
netic field on the cells have shown no induction of genotoxicity and have
not yet provided good explanation of the cause of leukemia. Although epi-
demiological studies in children show an increased risk of childhood leu-
kemia exposed to extremely low frequency magnetic field, there is a lack of
supporting evidence for such an effect from animal studies and/or in vitro
studies. In addition, there is no plausible mechanism.
Owing to the absence of a plausible mechanism and no induction of
cancer in animals study, the expert report has not concluded that there is
no causal relationship between the magnetic field exposure and the risk
of childhood leukemia (SCENIHR 2009, 2013). In the same way, Leitgeb
revealed that the assumption of a causal link between magnetic field
exposure and childhood leukemia is no longer plausible and hence that
the magnetic field’s classification as possibly carcinogenic needs revision
(Leitgeb 2014).

During MRI examinations, patients are exposed to the radio frequency
electromagnetic field. In his review article, Shellock discussed the charac-
teristics of radio frequency electromagnetic field–induced heating associ-
ated with MRI procedure (Shellock 2000). He emphasized thermal and
other physiologic responses in human subjects due to heating.
The possible effects of radio frequency electromagnetic fields have been
reviewed (Ahlbom et al. 2004; ARPANSA 2014; HPA 2012; IARC 2013;
ICNIRP 2009d; NRPB 2003). These possible effects of radio frequency
electromagnetic field exposure have been evaluated with the in vitro and
in vivo studies covering areas including the genotoxicity, carcinogenicity,
cell transformation, cell proliferation, apoptosis, gene expression, intra-
cellular signaling, cellular physiology, neurotransmitter, electrical activ-
ity, blood-brain barrier, autonomic functions, behavior, endocrine system
(melatonin), auditory system, immunology, haematology, reproduction,
and development. The studies in humans are covered from neurocognitive
cancers (e.g., brain tumor and acoustic neuroma) and noncancers (e.g.,
reproduction, morbidity, and hypersensitivity) to epidemiological studies.
In May 2011, after the review and evaluation of scientific papers by 30
experts from 14 countries, the IARC assessed the carcinogenicity of radio
frequency electromagnetic fields and classified them as a possibly carcino-
genic to humans (Group 2B). The IARC monograph on radio frequency
electromagnetic field was published in May 2013 (Baan et al. 2011; IARC
2013). The above classification was based on (1) there is limited evidence in
humans for the carcinogenicity of radio frequency electromagnetic fields,
based on positive association between glioma and acoustic neuroma and
exposure to radio frequency electromagnetic fields from wireless phones
(epidemiological studies), (2) there is limited evidence in experimental
animals for the carcinogenicity of radio frequency electromagnetic fields,
and (3) there is “weak mechanistic evidence” relevant to radio frequency
electromagnetic field-induced cancer in humans. The evidence for other
exposures and outcomes was considered insufficient for any conclusion.
There was a minor opinion in the monograph that current evidence in
humans was inadequate, therefore permitting no conclusion about a
causal association.
Using this evaluation and the classification made by the IARC to revise
and update the Environmental Health Criteria (EHC) document on radio
frequency fields, the WHO opened a first draft monograph of EHC of
radio frequency electromagnetic field. The draft document will be final-

ized by an expert group and will be published in the series of EHC.
9.3.4 Possible Health Effect Related to MRI Operation

After the publication of the EHC in 2006, there have been several stud-
ies on the health effects of exposure to static magnetic fields related to
MRI. It is well accepted that the high static magnetic field leads to the mild
sensory effect for vertigo, metallic taste, and magnetophosphene. These
effects are not considered to be hazardous per se. However, they may result
in a loss of working ability during practice. MRI workers experience expo-
sure to static magnetic fields on an almost daily basis. It is important to
characterize potential hazards. A number of studies have evaluated poten-
tial neurologic and vestibular effects of exposure to static magnetic fields
up to 8-T range.
De Vocht et al. assessed health complaints and cognitive performance in
workers with static magnetic fields ranging from 0.5 to 1.5 T from a MRI
manufacturing company (De Vocht et al. 2006). They noted that vertigo,
metallic taste, and concentration complaints were significantly and com-
plaints were more frequently reported in the workers compared with the
control. The workers moving rapidly through the static magnetic field
reported more complaints than those who moved slower. In addition, they
studied the effects of stray fields from a 7-T magnet on neurobehavioral per-
formance, specifically, cognitive function of head movements in 27 healthy
volunteers (average 25.0 years with 18–51 years; male 13; female 14) (De
Vocht et al. 2007). The stray magnetic fields were designed to 1600, 800, and
2 mT (negligible exposure). The order of exposure was assigned at random
and was masked by placing volunteers in a tent to hide their position relative
to the magnet bore. Volunteers completed a test battery assessing auditory
working memory, eye-hand coordination, and visual perception. During
three sessions the volunteers were instructed to complete a series of stan-
dardized head movements to generate additional time-varying fields (~300
and ~150 mT/srms). No effects were observed on working memory. They sug-
gest that there are effects on visual perception and eye-hand coordination,
but these were weak. The magnitude of these effects may depend on the
magnitude of time-varying fields and not so much on the static field.
The subjects and operators reported vertigo-like sensations or percep-
tion of movement in and around high field during MRI. For this effect, the
change of firing rates of hair cells by induced currents, magnetohydrody-
namics (MHD), and the forces induced by the static magnetic fields due
to the magnetic susceptibility differences of tissues have been proposed as

possible mechanisms. Glover et al. examined three possible mechanisms
of vertigo and concluded that magnetic field–induced vertigo results from
both magnetic susceptibility difference between vestibular organs and
surrounding fluid, and induced currents acting on the vestibular hair cells
(Glover et al. 2007). In this way, the mechanism depends on movement
though magnetic fields or magnetic fields with high spatial gradients.
Heinrich et al. conducted a meta-analysis of studies published from
1992 to 2007 in order to evaluate whether cognitive processes, sensory
perception, and vital signs might be influenced by static magnetic fields
in MRI (Heinrich et al. 2011). Vital signs such as blood pressure and heart
rate were not affected. With regard to effects on sensory perception, there
was an increase of dizziness and vertigo caused by movement during gra-
dient magnetic field exposures. They mentioned that the number of stud-
ies is very small and the experimental setup of some of analyzed studies
makes it difficult to accurately determine the effects of static magnetic
fields by themselves. Further, Heinrich et al. presented the results of a
study on how cognitive functions in health subjects undergoing MRI are
acutely impaired by static magnetic fields (Heinrich et al. 2013). The cog-
nitive functions such as eye-hand coordination, attention, reaction time,
and visual discrimination were not impaired by a static magnetic field in
MRI systems (0, 1.5, 3.0, and 7.0 T). Dizziness, nystagmus, phosphenes,
and head ringing were related to the strength of the static magnetic field,
although there were no significant effects on cognitive function at any
static magnetic strength. Sensory perceptions did vary according to field
strength. They concluded that static magnetic fields as high as 7.0 T did
not have a significant effect on cognition.
Van Nierop et al. showed that the neurocognitive functioning is modu-
lated when human volunteers were only exposed to movement in stray field
from a 7-T MRI scanner (Van Nierop et al. 2012). The healthy volunteers
were tested in a sham (0 T), low (0.5 T), and high (1.0 T) exposure condi-
tions. The volunteers are simultaneously exposed to movement-induced
time-varying magnetic fields at each exposure conditions. The attention
and concentration were negatively affected when exposed to time-varying
magnetic field with static magnetic field of 7-T MRI scanners. The visuo-
spatial orientation was also affected after exposure. Further, Van Nierop
et al. studied vertigo of subjects exposed to only stray magnetic fields with
movement-induced time-varying magnetic fields (Van Nierop et al. 2013).
They evaluated the postural body sway of subjects sitting in front of a 7-T
MRI for 1 h followed by the movement of their heads for 16 sec. The pos-
tural body sway was expressed in sway path length, sway area, and sway
velocity. The healthy volunteers performed two tasks, standing with eyes
closed and feet in parallel and then in tandem position, after standardized
head movements in a sham, low-exposure (stray magnetic fields: 0.24 T
with time-varying magnetic field of 0.49 T/sec) and high-exposure con-
ditions (0.37 T with 0.70 T/sec). The results show that sway path length,
sway area, and the velocity of body movements were significantly higher
with higher static magnetic fields. They commented that the investigation
of the practical safety implications of this finding for surgeons and others
working near MRI scanner is needed.
9.4 EXPOSURE GUIDELINES RELATED TO MRI

The static magnetic field, the gradient (time-varying) magnetic field, and
the radio frequency electromagnetic field are used to operate MRI equip-
ment. Here, relevant ICNIRP guidelines are introduced briefly (ICNIRP
1998, 2009a, 2010, 2014).
The ICNIRP is independent groups of experts. The responsibility of
the ICNIRP is (1) to evaluate the science-based information on the effects
of NIR and (2) to provide the recommendations, statements, and advice
on the protection against harmful effects of the NIR. The ICNIRP devel-
ops basic guidelines and exposure limits to protect the exposure from
NIR. These guidelines contain exposure limit both for workers and the
general public. The ICNIRP publishes timey recommendations of expo-
sure guidelines and statements, informing and advising us on the specific
topics related to protection issues.
In 1998, the ICNIRP opened the guideline document for limiting
exposure to time-varying electric, magnetic, and electromagnetic fields in
the frequency range up to 300 GHz and in 2010 updated that document for
the frequency range from 1 Hz to 100 kHz. The ICNIRP also published the
updated guideline for the static magnetic field (ICNIRP 2009b). Guidelines
are also established for movement-induced electric fields or time-varying
magnetic fields below 1 Hz in order to prevent sensory effects such as ver-
tigo associated with body movement (ICNIRP 2014). In addition, ICNIRP
gave the statement on protection of patients during the MRI procedure
(ICNIRP 2004, 2009c).
Guidelines of the ICNIRP are established for the protection of humans
exposed to electric and magnetic fields in the low-frequency range, from
1 Hz to 100 kHz (ICNIRP 2010). This document is extended to 10 MHz,
which covers the prevention of nervous system functions. The ICNIRP set
the basic restrictions in terms of the induced electric field strength in the
body to prevent perception of nerve stimulation.
Guidelines for exposure above 100 kHz are covered in another docu-
ment (ICNIRP 1998). Between 100 kHz and 10 GHz, basic restrictions
consider the SAR to prevent whole-body and localized tissue heating.
For frequencies from 10 to 300 GHz, basic restrictions are set in terms
of power density to prevent heating effects in tissue at or near the body
surface (ICNIRP 1998).
As mentioned in the ICNIRP document, induced electric field strength
and SAR cannot be measured directly. So the reference level was set by
ICNIRP. For practical exposure assessment purposes, the ICNIRP has
provided the reference level in terms of the strength of electric and mag-
netic fields. The reference levels are obtained from the basic restrictions by
mathematical modeling.

The limits introduced by the ICNIRP for the general public and occupa-
tional exposure to static magnetic fields are shown in Table 9.1 (ICNIRP
TABLE 9.1 ICNIRP Guideline on the Limits of Exposure to Static

Magnetic Fieldsa
Exposure Characteristics Magnetic Flux Density
Occupationalb
Exposure of head and of trunk 2T
Exposure of limbsc 8T
General publicd
Exposure of any part of the body 400 mT
Source: Reproduced from ICNIRP, Health Physics 96: 504–514, 2009.
a ICNIRP recommends that these limits should be viewed operationally as
spatial peak exposure limits.

b For specific work applications, exposure up to 8 T can be justified if the
environment is controlled and appropriate work practices are imple-

mented to control movement-induced effects.
c Not enough information is available on which to base exposure limits
beyond 8 T.
d Because of potential indirect adverse effects, ICNIRP recognizes that
practical policies need to be implemented to prevent inadvertent harmful

exposure of persons with implanted electronic medical devices and
implants containing ferromagnetic material, and dangers from flying
objects, which can lead to much lower restriction levels such as 0.5 mT.
2009b). The acute exposure of the general public should not exceed 400 mT
(any part of the body). The term “general public” refers to the entire pop-
ulation including individuals of all ages and varying health status. For
occupational exposure, the ICNIRP has a 2-T limit for the head and trunk
and an 8-T limit for limbs in controlled situations.

The ICNIRP published a guideline for limiting exposure to time-varying
electric and magnetic field in the frequencies range between 1 Hz and
100 kHz (ICNIRP 2010). This guideline has two separate guidances, one
for occupational exposure and one for exposure of the general public.
Occupational exposure refers to healthy adults exposed to time-varying
electric and magnetic fields from 1 Hz to 10 MHz at their workplaces.
Basic restrictions for human exposure to time-varying electric and
magnetic fields in the frequencies range between 1 Hz and 10 MHz are
shown in Table 9.2. Basic restrictions are specified in terms of the induced
TABLE 9.2 Basic Restrictions for Human Exposure to Time-Varying Electric

and Magnetic Fields from 1 Hz to 10 MHz
Internal Electric Field
Exposure Characteristic Frequency Range (V m–1)
Occupational Exposure
CNS tissue of the head 1–10 Hz 0.5/f
10–25 Hz 0.05
25–400 Hz 2 × 10–3f
400 Hz–3 kHz 0.8
3 kHz–10 MHz 2.7 × 10–4f
All tissues of head and body 1 Hz–3 kHz 0.8
3 kHz–10 MHz 2.7 × 10–4f
General Public Exposure

CNS tissue of the head 1–10 Hz 0.1/f
10–25 Hz 0.01
25–1000 Hz 4 × 10–4f
1000 Hz–3 kHz 0.4
3 kHz–10 MHz 1.35 × 10–4f
All tissues of head and body 1 Hz–3 kHz 0.4
3 kHz–10 MHz 1.35 × 10–4f
Source: Reproduced from ICNIRP, Health Physics 99: 818–836. Erratum. 2011.
100: 112, 2010.
Note: f is the frequency in hertz. All values are rms. In the frequency range above
100 kHz, RF specific basic restrictions need to be considered additionally.
TABLE 9.3 Reference Levels for Occupational Exposure to Time-

Varying Electric and Magnetic Fields (Unperturbed rms Values)
from 1 Hz to 10 MHz
Magnetic Field
E-Field Strength Strength Magnetic Flux
Frequency Range E (kV m–1) H (A m–1) Density B (T)
1–8 Hz 20 1.63 × 105/f 2 0.2/f 2
8–25 Hz 20 2 × 104/f 2.5 × 10–2/f
25–300 Hz 5 × 102/f 8 × 102 1 × 10–3
300 Hz–3 kHz 5 × 102/f 2.4 × 105/f 0.3/f
3 kHz–10 MHz 1.7 × 10–1 80 1 × 10–4
Source: Reproduced from ICNIRP, Health Physics 99: 818–836. Erratum.
2011. 100: 112, 2010.
Note: f in hertz.
electric field strength to prevent nervous system response including

peripheral (PNS) and central nerve stimulation (CNS) and the induction
of retinal phosphenes (magnetophosphenes).
Reference levels shown in Table 9.3 are obtained from the basic
restrictions by mathematical modeling. Because of the physical quan-
tity of the induced electric field (V/m) and SAR in the body cannot be
measured directly, the reference levels up to 10 MHz are set using of
the strength of electric and magnetic fields (unperturbed values) in the
ICNIRP guideline (ICNIRP 2010). According to ICNIRP, occupational
exposure below the reference levels assured that the basic restrictions
are not exceeded.

The revised guideline from ICNIRP covers only the exposure limit
in the frequency range up to 100 kHz (ICNIRP 2010). This document
replaces the low-frequency part of the 1998 guidelines of ICNIRP. To
meet the responsibility of ICNIRP, the ICNIRP is now revising and
drafting the guidelines for high-frequency range between 100 kHz and
300 GHz. So, before replacing the exposure limits in this range, one can
use existing exposure limits of the 1998 guideline for the protection of
human.
Here, the radio frequency electromagnetic field covers the frequency
from 100 kHz to 300 GHz. From the 1998 ICNIRP guideline between 100
kHz and 10 GHz, basic restrictions on SAR are provided to prevent whole-
body heat stress and excessive localized tissue heating. In the frequency
range between 100 kHz and 10 MHz, basic restrictions are provided on
both current density and SAR (Table 9.4). As shown in Table 9.5, basic
restrictions between 10 and 300 GHz are provided on power density to
prevent excessive heating in tissue at or near the body surface (ICNIRP
1998).
Reference levels for occupational exposure are shown in Table 9.6.
In the frequency range between 100 kHz and 300 GHz, the exposure
basic restriction and reference level are still based on the 1998 ICNIRP
guidelines until there is a revision of the guidelines for the high-
frequency portion of the electromagnetic spectrum between 100 kHz
and 300 GHz.
According to guidelines (ICNIRP 1998, 2010), when the reference levels
are exceeded, assessments with measurement and calculation are neces-
sary to estimate whether the basic restrictions are exceeded.
9.4.4 Movement-Related Magnetic Field

In 2014, the ICNIRP published a document for the protection of work-
ers moving in static magnetic fields or being exposed to magnetic fields
with frequencies below 1 Hz (ICNIRP 2014). This document provides
guidelines for the protection of workers against established adverse direct
health effects and to avoid sensory effects that may be annoying and
impair working ability.
The protection of patients during MRI examinations will be given
in Section 9.4.5 following from the ICNIRP statements (ICNIRP 2004,
2009c). Table 9.7 presents the basic restrictions and reference levels of this
guideline (ICNIRP 2014). The basic restrictions have been defined for the
change in external magnetic flux density, ΔB, and for the induced internal
electric field, V/mpeak. The induced internal electric field cannot be directly
measured, so compliance can be demonstrated using reference level. In
this guideline, the controlled and uncontrolled exposures are considered
as two tiers. For controlled exposure, the basic restrictions are intended
to be used in work environments. The work environment given by the
ICNIRP is where access is restricted to workers who have been trained to
understand the biological effects that may result from exposure and where
the workers are able to control their movements to prevent annoying and
disturbing sensory effects. For uncontrolled exposures, restrictions apply
to all other occupational situations.
TABLE 9.4 Basic Restrictions for Time-Varying Electric, Magnetic, and Electromagnetic
Fields up to 10 GHz
Current Density Localized Localized
for Head and Whole-Body SAR (Head SAR
Exposure Frequency Trunk (mA m–2) Average SAR and Trunk) (Limbs)
Characteristics Range (rms) (W kg–1) (W kg–1) (W kg–1)
Occupational Up to 1 Hz 40 – – –
exposure 1–4 Hz 40/f – – –
4 Hz–1 kHz 10 – – –
1–100 kHz f/100 – – –
100 kHz– f/100 0.4 10 20
10 MHz
10 MHz– – 0.4 10 20
10 GHz
General Up to 1 Hz 8 – – –
public 1–4 Hz 8/f – – –
exposure 4 Hz–1 kHz 2 – – –
1–100 kHz f/500 – – –
100 kHz– f/500 0.08 2 4
10 MHz
10 MHz– – 0.08 2 4
10 GHz
Source: Reproduced from ICNIRP, Health Physics 74(4): 494–522, 1998.
Note: 1. f is the frequency in hertz.
2. Because of electrical inhomogeneity of the body, current densities should be aver-
aged over a cross section of 1 cm2 perpendicular to the current direction.
3. For frequencies up to 100 kHz, peak current density values can be obtained by
multiplying the rms value by √2 (~1.414). For pulses of duration tp, the equiva-
lent frequency to apply in the basic restrictions should be calculated as f = 1/(2 tp).
4. For frequencies up to 100 kHz and for pulsed magnetic fields, the maximum cur-
rent density associated with the pulses can be calculated from the rise/fall times
and the maximum rate of change of magnetic flux density. The induced current
density can then be compared with the appropriate basic restriction.
5. All SAR values are to be averaged over any 6-min period.
6. Localized SAR averaging mass is any 10 g of contiguous tissue; the maximum
SAR so obtained should be the value used for the estimation of exposure.
7. For pulses of duration tp, the equivalent frequency to apply in the basic restric-
tions should be calculated as f = 1/(2 tp). Additionally, for pulsed exposures in the
frequency range 0.3 to 10 GHz and for localized exposure of the head, in order to
limit or avoid auditory effects caused by thermoelastic expansion, an additional
basic restriction is recommended. This is that the SA should not exceed 10 mJ kg–1
for workers and 2 mJ kg–1 for the general public, averaged over 10 g tissue.
TABLE 9.5 Basic Restrictions for Power Density

for Frequencies between 10 and 300 GHz
Exposure Characteristics Power Density (W m–2)
Occupational exposure 50
General public 10
Source: Reproduced from ICNIRP, Health Physics 74(4): 494–
522, 1998.
Note: 1. Power densities are to be averaged over any 20 cm2 of
exposed area and any 68/f 1.05-min period (where f is
in gigahertz) to compensate for progressively shorter
penetration depth as the frequency increases.
2. Spatial maximum power densities, averaged over
1 cm2, should not exceed 20 times the values above.
The ICNIRP recommended that ΔB should not exceed 2 T during any

3-sec period to prevent transient sensory effects such as vertigo and nausea
from motion-induced electric field below few hertz. The ICNIRP also recom-
mended that the induced electric field should not exceed the basic restric-
tion of 1.1 V/mpeak to prevent stimulation of peripheral nerves in controlled
exposure. In uncontrolled exposures, the basic restrictions are based on pro-
tection against magnetophosphenes and peripheral nerve stimulation. The
reference level for peak dB/dt has been set to 2.7 T/sec as shown in Table 9.7.
The basic restrictions and reference levels above 1 Hz for occupational
exposure are equal to the occupational guidelines of the ICNIRP (1998,
2010).
9.4.5 Guidelines on the Protection of Patients

Undergoing MRI Examinations
The protection of patients undergoing MRI examinations is given in
detail in the ICNIRP statements. In 2004, the ICNIRP opened the state-
ment on the protection of patients undergoing medical MRI procedures
(ICNIRP 2004). After the publication of this statement, ICNIRP has pub-
lished revised guidelines on occupational and general public exposure to
static magnetic fields (ICNIRP 2009b). In light of these updated guide-
lines, ICNIRP has decided to issue an amendment of the statement con-
cerning patient exposure to static magnetic fields (ICNIRP 2009c).
The ICNIRP introduced three tiers of exposure: normal operating
mode, controlled operating mode (under medical supervision), and exper-
imental operating mode (with special ethical approval) in MRI statements
TABLE 9.6 Reference Levels for Occupational Exposure to Time-Varying Electric,

Magnetic, and Electromagnetic Fields up to 300 GHz
E-Field H-Field Equivalent Plane
Strength Strength Wave Power
Frequency Range (V m–1) (A m–1) B-Field (μT) Density Seq (W m–2)
Up to 1 Hz – 1.63 × 10 5 2 × 105 –
1–8 Hz 20,000 1.63 × 105/f 2 2 × 105/f 2 –
8–25 Hz 20,000 2 × 104/f 2.5 × 104/f –
0.025–0.82 kHz 500/f 20/f 25/f –
0.82–65 kHz 610 24.4 30.7 –
0.065–1 MHz 610 1.6/f 2.0/f –
1–10 MHz 610/f 1.6/f 2.0/f –
10–400 MHz 61 0.16 0.2 10
400–2000 MHz 3f 1/2 0.008f 1/2 0.01f 1/2 f/40
2–300 GHz 137 0.36 0.45 50
Note: 1. f as indicated in the frequency range column.
2. Provided that basic restrictions are met and adverse indirect effects can be
excluded, field strength values can be exceeded.
3. For frequencies between 100 kHz and 10 GHz, Seq, E2, H 2, and B2 are to be aver-
aged over any 6-min period.
4. For peak values at frequencies up to 100 kHz, see Table 9.4, note 3. For peak val-
ues at frequencies exceeding 100 kHz. Between 100 kHz and 10 MHz, peak values
for the field strengths are obtained by interpolation from the 1.5-fold peak at
100 kHz to the 32-fold peak at 10 MHz. For frequencies exceeding 10 MHz, it is
suggested that the peak equivalent plane wave power density, as averaged over the
pulse width, does not exceed 1000 times the Seq restrictions or that the field
strength does not exceed 32 times the field strength exposure levels given in the
table.
5. For frequencies exceeding 10 GHz, Seq, E2, H2, and B2 are to be averaged over any
68/f 1.05-min period (f in gigahertz).
6. No E-field value is provided for frequencies <1 Hz, which are effectively static
electric fields. Electric shock from low impedance sources is prevented by estab-
lished electrical safety procedures for such equipment.
(ICNIRP 2004). As a three-tier approach, the ICNIRP recommends the

following:
1. Static magnetic field

a. For normal operating mode, there should be an upper limit for
whole-body exposure of 4 T including effects on fetuses and
infants.
TABLE 9.7 Exposure Basic Restrictions for Controlling Movement in Static Magnetic Fields and Exposure to a Time-Varying Magnetic
Field below 1 Hz
Basic Restrictions Reference Levels
Internal Electric Field Strength

Frequency f (Hz) ΔB (T)a Bpeak to peak (T) [V m–1 (peak)] dB/dt [T s–1 (peak)]
Critical effect Vertigo due to Vertigo due to PNS effects due to Phosphenes due to PNS effects due to Phosphenes due to
movement in static time-varying movement in static movement in static movement in static movement in static
B-field B-field B-field and due to B-field and due to B-field and due to B-field and due to
time-varying B-field time-varying B-field time-varying B-field time-varying B-field
Exposure Uncontrolled Uncontrolled Controlled Uncontrolled Controlled Uncontrolled
conditionb
0 2
0–1 2
0–0.66 1.1 1.1 2.7 2.7
0.66–1 1.1 0.7/f 2.7 1.8/f
Note: For controlled exposure, the reference levels for a magnetic flux density may be converted to dB/dt by using dB0 /dt = 2πf 2BRMS, where B0 is the
peak value of the sinusoidal magnetic flux density and BRMS is the root-mean-square value.
a The maximum change of magnetic flux density ΔB is determined over any 3-sec period.
b For controlled exposure conditions, a ΔB of 2 T may be exceeded.
b. For controlled operating mode, there should be an upper limit

for whole-body exposure of 8 T under medical supervision; and
c. For experimental operating mode above 8 T, a special ethical
approval is required. No upper limit has been specified, but a pro-
gressively cautious approach is suggested for increasingly high
magnetic flux densities due to uncertainties regarding possible
effects of flow potentials on heart function. In light of these pos-
sible effects, it is determined that patients should only be exposed
to such fields with appropriate clinical monitoring.
In addition, there is a need to ensure that patients should be moved
slowly into the magnetic bore, in order to avoid the possibility of ver-
tigo and nausea. Thresholds for motion-induced vertigo have been
estimated to be around 1 T/sec for durations for greater than 1 sec,
thus avoiding these sensations of induced electric fields and currents
that arise as a consequence of motion in a static magnetic field.
2. Time-varying magnetic fields
a. For normal operating mode, it is recommended that the maxi-
mum exposure level should be a limit on the rate of change of
the magnetic field (dB/dt) of 80 percent of the median perception
threshold for peripheral nerve stimulation, as defined in the rec-
ommendations (ICNIRP 2004).
b. For controlled operating mode, there should be a limit on dB/dt
of 100 percent of the median perception threshold.
c. For experimental operating mode, ICNIRP does not provide any
explicit guidance for the procedures.
Here, the median perception threshold is defined by the following
equation in the ICNIRP (2004): dB/dt = 20(1 + 0.36/τ) T/sec, where
τ is the effective stimulus duration of the induced electrical stimulus
in milliseconds. ICNIRP provided no explicit guideline for experi-
mental operating mode.
3. Radio frequency electromagnetic fields
In order to avoid possible adverse thermal effects in patients dur-
ing MRI examinations, ICNIRP has provided the limit for patients
to protect against the rise of body and tissue temperature.
About the protection of patients undergoing MRI examinations,

the recommended SAR limits for environmental temperature below
24°C and average time of 6 min are summarized in Table 9.8 (ICNIRP
2004). These SAR limits are for whole body and for the head, trunk,
and extremities. These SAR levels should not be exceeded in order to
limit temperature rise to the values given Table 9.9.
With respect to the application of the SAR levels defined in Table 9.8,
the following points should be taken into account (ICNIRP 2004):
TABLE 9.8 Recommended SAR Level at Environmental Temperature below 24°C

Averaging Time: 6 min
Local SAR
Partial-Body SAR (Averaged over 10 g Tissue)
Whole Body
SAR (W kg–1) (W kg–1) (W kg–1)
Body region → Whole Any, except Head Head Trunk Extremities
Operating mode ↓ body head
Normal 2 2−10a 3 10b 10 20
Controlled 4 4−10a 3 10b 10 20
Restricted >4 (4−10)a >3 10b >10 >20
Short-term SAR The SAR limit over any 10-sec period should not exceed three times
the corresponding average SAR limit.
a Partial-body SARs scale dynamically with the ratio r between the patient mass exposed
and the total patient mass:

1. Normal operating mode: SAR = (10–8 · r) W kg–1.
2. Controlled operating mode: SAR = (10–6 · r) W kg–1.
The exposed patient mass and the actual SAR levels are calculated by the SAR
monitor implemented in the MR system for each sequence and compared to the
SAR limits.
b In cases where the eye is in the field of a small local coil used for RF transmission, care
should be taken to ensure that the temperature rise is limited to 1°C.
TABLE 9.9 Basic Restrictions for Body Temperature Rise and Partial-Body Temperature
Spatially Localized Temperature Limits
Rise of Body Core
Operating Mode Temperature (°C) Head (°C) Trunk (°C) Extremities (°C)
Normal 0.5 38 39 40
Controlled 1 38 39 40
Restricted >1 >38 >39 >40
Source: Reproduced from ICNIRP, Health Physics 87: 197–216, 2004.
• Partial-body SARs scale dynamically with the ratio r between the

patient mass exposed and the total patient mass. For r→1 they
converge against the corresponding whole-body values. For r→0,
they converge against the localized SAR level of 10 W/kg defined
by ICNIRP for occupational exposure of head and trunk (ICNIRP
1998).
• Recommended SAR restrictions do not relate to an individual MR
sequence but rather to running SAR averages computed over each
6-min period, which is assumed to be a typical thermal equilibration
time of smaller masses of tissue (Brix et al. 2002).
• Whole-body SARs are valid at environmental temperatures below
24°C. At higher temperatures, they should be reduced, depending on
actual environmental temperature and humidity.
It is recommended that the user requests detailed information on the

energy deposition within the patient’s body from the manufacturer of MRI
devices. In addition the monitoring of the real-time temperature may be
performed during MRI procedures in the controlled operating mode for
patients and should be performed in all cases in the experimental operat-
ing mode.
Table 9.10 summarizes the ICNIRP recommended limits for patient
exposure during MRI from guidelines (ICNIRP 2004, 2009c). These limits
apply only to patients. The workers related to MRI examinations remain
subject to the ICNIRP occupational guidelines with the protection of
movement-induced adverse health effects arising from exposed to time-
varying magnetic fields below 1 Hz (ICNIRP 2009b, 2010, 2014).
TABLE 9.10 Summary of Recommended Limits for Patient Exposure for Static,
Gradient, and Radiofrequency during MRI Procedure
Gradient Radiofrequency Field
dB/dt as a Temperature Limits (°C)
Static Percentage of Maximum
Magnetic Median Core
Operating Field in Perception Temperature
Mode Bore (T) Threshold (%) Rise (°C) Head Trunk Extremities
Normal <4 80 0.5 38 39 40
Controlled <8 100 1 38 39 40
Experimental >8 100 >1 >38 >39 >40
9.5 OCCUPATIONAL EXPOSURE DURING MRI

The assessment of occupational exposure is an important issue and
is needed for human health studies of MRI working staff. However,
there is the difficulty in exposure assessment. In order to study the
assessment of the occupational exposures, there are a number of
approaches (Bongers et al. 2014; Bradley et al. 2007; De Vocht et al.
2009; Fuentes et al. 2008; Karpowicz et al. 2007; Karpowicz and Gryz
2006, 2013; Riches et al. 2007b; Schaap et al. 2013; Yamaguchi-Sekino
et al. 2014).
The first approach is to record the movements of working staff during
their activities in the MRI examinations and correlate these with the mag-
netic field maps obtained from the calculation and measurement around
MRI scanners.
The second approach is to develop the magnetic field dosimeter and
to record working staff’s exposures with time elapse to static and time-
varying magnetic fields with dosimeter during the working day.
The third approach is related more to the epidemiological study. One
can identify and carefully characterize specific tasks of MRI working
staff and the time spent on a worker’s specific task and then measure the
temporal and magnitude of the actual exposure of the worker. From the
determinations of the specific task and actual exposure of the worker, one
can formulate a job-exposure matrix. In an epidemiological study, this
job-exposure matrix can be retrospectively used to estimate occupational
exposures for different workers over a long period of time.
Using a questionnaire survey, Schaap et al. designed an assessment
of the size and characteristics of the population who are occupationally
exposed to electromagnetic fields from MRI scanners. In addition, they
identify variability in job and workplace characteristics that determine
the probability and type of exposure (Schaap et al. 2013). The survey
results show that personal exposure measurements should be performed
to characterize and quantify occupational exposure levels. Further, it is
necessary to identify the role of exposure determinants in the MRI work
environments.
Recently, the newly proposed Directive 2013/35/EU opened to the
member states of European Union (EU Directive 2013/35/EU 2013). This
Directive covers the limits of occupational exposure to the electromag-
netic fields. This new Directive exempts MRI workers from electromag-
netic field exposure limit.
9.5.1 Worker Exposure Assessment

In order to clarify health effects of MRI workers, the measurement and
assessment of worker exposure level around MRI system and the evaluation
of MRI-related static magnetic fields exposure are needed (Andreuccetti
et al. 2013; Bongers et al. 2014; Börner et al. 2011; Bradley et al. 2007; De
Vocht et al. 2009; Febles Santana et al. 2014; Fuentes et al. 2008; Hansson
Mild et al. 2013; Kännälä et al. 2009; Karpowicz and Gryz 2006; Li et al.
2007; Liu and Crozier 2004; Riches et al. 2007a; Yamaguchi-Sekino et al.
2014; Wang et al. 2008).
The techniques have been used to estimate personal occupational expo-
sure to MRI-related electromagnetic fields. There are four substantive
studies where magnetometers were worn by MRI workers, specifically the
radiologic technologist and engineering staff, during their routine duties.
Bradley et al. investigated static magnetic field exposures in one open
0.6-T MRI magnet, four closed bore systems of 1.5-T MRI magnet, and
one 3-T closed bore magnet (Bradley et al. 2007). The worker carried the
dosimeter in the pocket. In this study, peak and 24 h time-averaged static
magnetic fields were reported. Fuentes et al. measured and recorded the
occupational exposure levels of static magnetic field, peak magnetic field
(B), peak dB/dt, and average B in and around 1.5-, 2-, and 4-T MRI sys
tems during their routine work (Fuentes et al. 2008).
Using a personal magnetic field dosimeter, De Vocht et al. monitored
occupational exposure for MRI system engineering staff performing vari-
ous tasks during routine work in 1-, 1.5-, and 3-T MRI systems (De Vocht
et al. 2009). They reported task-based, time-weighted average exposures to
static magnetic field as well as complementary task durations. Task level
exposures (mT-min) were calculated based on the measurement data and
were compared with task level exposures obtained from the historical
exposure level and task durations.
On the other hand, Yamaguchi-Sekino et al. using a tri-axis Hall mag-
netometer, carried out occupational exposure monitoring of magnetic
fields during routine examinations in 3-T MRI systems from two insti-
tutes (Yamaguchi-Sekino et al. 2014). A magnetometer was attached to
a subject’s chest during monitoring. Four radiologic technologists with
magnetometers participated, and the exposure levels were recorded for
56 patients by workers and data acquisition of 103 samples. The relation-
ship between the exposure levels and working duties was analyzed. The
working duties are sorted into four categories: (1) MRI examination of
the body and neck, (2) MRI examination of the body or extremities, (3)
escort or assist patient, and (4) other work contents. The highest exposure
was detected during MRI examination of the head or neck. The maximum
stray fields were 628 ± 28 mT at the edge of the bed from one institute
and 373 ± 2 mT at the edge of the bed from another institute. The reason
why the stray magnetic field is different between the two institutes is that
the sizes of the magnet and bore are different because they are from dif-
ferent suppliers.
Kännälä et al. examined the assessment of occupational exposure to
gradient magnetic fields and time-varying magnetic fields generated by
motion in nonhomogeneous static magnetic fields of two MRI scanners
(1 T open and 3 T conventional) (Kännälä et al. 2009). These magnetic
components can be measured simultaneously with an induction coil set
up detecting the time rate of change of magnetic flux density (dB/dt). As
a result, the highest motion-induced dB/dt was 0.7 T/sec for the 1-T MRI
scanner and 3 T/s for the 3-T MRI scanner when only the static magnetic
field was present.
Andreuccetti et al. proposed and tested the procedure for assessing
occupational exposure due to MRI gradient magnetic fields and movement-
induced effects in the static magnetic field (Andreuccetti et al. 2013). Their
procedure considered two exposures of low-frequency switched gradient
magnetic field and movement-induced effects in the static magnetic field.
The radio frequency electromagnetic field was not taken into consideration.
They tested in two 1.5-T whole-body MRI scanners and one 3-T head-only
MRI scanner and evaluated exposure due to switched gradient magnetic
fields in the location inside the magnet room where operators usually stay
during those particular medical procedures. Movement-induced effects
were evaluated considering the actual movements of volunteer operators
during work activity by measuring the perceived time-varying magnetic
field. The result was analyzed based on the ICNIRP 1998 and 2010 guide-
lines. Exposure to switched gradient magnetic fields in 1.5-T MRI scanner
mostly resulted in noncompliance with the ICNIRP 1998 occupational
levels, while at the same time, it showed as always compliant with the
ICNIRP 2010 ones. Movement-induced effects resulted potentially non-
compliant only in the case the operator moved the head inside the bore of
1.5-T MRI scanner.
There have been no epidemiological studies related to MRI operations.
It is needed and very important from the point of long-term human health
effects to conduct well-designed epidemiological studies of MRI workers.
In order to do this, Hansson Mild et al. proposed an exposure categoriza-

tion for the different professions working with MRI equipment (Hansson
Mild et al. 2013). As a basis for exposure assessment in epidemiological
studies obtained from the estimation of exposure levels of electromag-
netic field of about 100,000 workers, they define exposure in three catego-
ries, depending on whether people are exposed to only the static magnetic
fields, to the static magnetic plus switched gradient magnetic, or to the
static plus switched gradient magnetic plus radio frequency fields.
As a questionnaire-based descriptive pilot study, Wilén and De Vocht
provided an indication of the self-reported prevalence of health com-
plaints related to working with MRI systems (Wilén and de Vocht 2011).
Fifty-nine nurses with on average 8 (±6) years’ experience with MRI scan-
ning procedures attended this study. In total, 9 nurses reported regularly
experiencing at least one of the health complaints attributed to arise or
be aggravated by their presence in the MRI scanning room. The results
indicated that reporting of adverse symptoms was not related to the level
of occupational workload/stress. However, reporting of health complaints
was related to the strength of the magnet the nurses worked with, with
57 percent of symptoms reported by those nurses working with both 1.5-
and 3-T MRI scanners.
9.5.2 European Electromagnetic Fields Directive

In relation to the exposure of workers, the European Directive 2004/40/
EC “on the minimum health and safety requirements regarding the expo-
sure of workers to the risks arising from physical agent (electromagnetic
fields)” was published from the Council and Parliament of the European
Union (EU Directive 2004/40/EC 2004). The aims of this Directive are
to prevent occupational exposure to electromagnetic fields. This Directive
set general rules for the obligation of employers.
The Directive was fundamentally based on the ICNIRP guidelines
(ICNIRP 1998) and used the exposure limit values of ICNIRP. After the
appearance of European Directive 2004/40/EC, the MRI community
across Member States was concerned about the impact of implementa-
tion of this Directive on the use of MRI because of human risk assess-
ments, manufacturing, and running costs (Keevil and Krestin 2010). So,
the EU Directive 2004/40/EC was amended by EU Directive 2008/46/
EC in April 2008. The EU Directive 2008/46/EC was adopted, delaying
transposition deadline of the original Directive until 2012 (EU Directive
2008/46/EC).
The ICNIRP published two guidelines, one for static magnetic field and
one for low-frequency electromagnetic fields (up to 100 kHz) (ICNIRP
2009b, 2010). Using these guidelines, the European Commission finally
proposed a Directive replacement. This newly proposed EU Directive
2013/35/EU covers all known direct biophysical effects and other indirect
effects caused by electromagnetic fields (up to 300 GHz) (EU Directive
2013/35/EU 2013). The Directive addresses short-term effects and does
not cover suggested long-term effects. It does not cover the risks resulting
from contact with live conductors. Finally, Member States are required to
have transposed EU Directive 2013/35/EU into their respective national
legislation framework by July 1, 2016.
The EU Directive 2013/35/EU covers exposure limit value and action
levels of static electric, static, magnetic, and time-varying electric, mag-
netic, and electromagnetic fields with frequencies up to 300 GHz. The fol-
lowing discussions are focused on the issues related to MRI.
The basic restrictions in the ICNIRP become “exposure limit values”
in the 2013 Directive and reference levels in the ICNIRP become “action
levels.” The Directive introduces two tiers of ELVs: sensory effects ELV
and health effects ELV.
1. Exposure limit values (ELVs) and action levels (ALs) in the frequency
range from 0 Hz to 10 MHz
a. ELVs
– ELVs below 1 Hz are limits for static magnetic field. For static
magnetic field, the 2013 Directive sets exposure limit values
identical to those in guidelines (ICNIRP 2009b).
– ELVs for external magnetic flux density from 0 to 1 Hz
– Sensory effects ELV is the ELV, 2 T for normal working
conditions and is related to vertigo and other physiologi-
cal effects related to disturbance of the human balance,
resulting from the movement in a static magnetic field.
– Health effects ELV is 8 T for controlled working conditions.
– ELVs for frequencies between 1 Hz and 10 MHz are limits
for induced electric fields in the body from exposure to time-
varying electric and magnetic fields.
– Health effects ELVs for internal electric field strength from

1 Hz to 10 MHz are related to electric stimulation of all
peripheral and central nervous system tissues in the body
including the head.
– Sensory effects ELV for internal electric fields from 1 to
400 Hz are related to electric field effects on the central ner-
vous system in the head, i.e., retinal phosphenes and minor
transient changes in some brain functions.
b. ALs for exposure to magnetic fields shown in Table 9.11.
– Low action levels (low ALs) in the 2013 Directive for frequen-
cies below 400 Hz are derived from the sensory effects ELV
TABLE 9.11 ALs for Exposure to Magnetic Fields from 1 Hz to 10 MHz

Magnetic Flux Magnetic Flux Magnetic Flux Density ALs
Density Low Density High for Exposure of Limbs to a
ALs(B) [μT] ALs(B) [μT] Localized Magnetic Field
Frequency Range (RMS) (RMS) [μT] (RMS)
1 ≤ f < 8 Hz 2.0 × 105/f 2 3.0 × 105/f 9.0 × 105/f
8 ≤ f < 25 Hz 2.5 × 104/f 3.0 × 105/f 9.0 × 105/f
25 ≤ f < 300 Hz 1.0 × 103 3.0 × 105/f 9.0 × 105/f
300 Hz ≤ f < 3 kHz 3.0 × 105/f 3.0 × 105/f 9.0 × 105/f
3 kHz ≤ f ≤ 10 MHz 1.0 × 102 1.0 × 102 3.0 × 102
Source: Reproduced from EU Directive 2013/35/EU, Official Journal of the European
Union 56: 1–21, L179, 2013.
Note: 1. f is the frequency expressed in hertz.
2. The low ALs and the high ALs are the RMS values that are equal to the peak val-
ues divided by 2 for sinusoidal fields. In the case of non-sinusoidal fields, the
exposure evaluation carried out in accordance with Article 4 shall be based on
the weighted peak method (filtering in the time domain), explained in practical
guides referred to in Article 14; but other scientifically proven and validated
exposure evaluation procedures can be applied, provided that they lead to
approximately equivalent and comparable results.
3. ALs for exposure to magnetic fields represent maximum values at the workers’
body position. This results in a conservative exposure assessment and automatic
compliance with ELVs in all non-uniform exposure conditions. In order to sim-
plify the assessment of compliance with ELVs, carried out in accordance with
Article 4, in specific non-uniform conditions, criteria for the spatial averaging of
measured fields based on established dosimetry will be laid down in the practical
guides referred to in Article 14. In the case of a very localized source within a
distance of a few centimeters from the body, the induced electric field shall be
determined dosimetrically, case by case.
and for frequencies above 400 Hz, from the health effects
ELVs for internal electric field.
– High action levels (high ALs) are derived from the health effects
ELV for internal electric fields related to electric stimulation of
peripheral and autonomous nerve tissues in head and trunk.
2. ELVs and ALs in the frequency range from 100 kHz to 300 GHz.
a. ELVs
– Health effects ELVs between 100 kHz and 6 GHz are limits
for energy and power absorbed per unit mass of body tissue
generated from exposure to electric and magnetic fields.
– Sensory effects ELVs from 0.3 to 6 GHz are limits on absorbed
energy in a small mass tissue in the head from exposure to
electromagnetic fields.
– Health effects ELVs between 6 and 300 GHz are limits for
power density of an electromagnetic wave incident on the
body surface.
– Sensory effect ELVs from 0.3 to 6 GHz are related to avoid-
ing auditory effects caused by exposure of the head to pulsed
microwave radiation.
b. ALs for exposure to electric and magnetic fields shown in Table 9.12.
– ALs (B) are derived from the SAR or power density and ELVs
based on the thresholds related to internal thermal effects
caused by exposure to (external) electric and magnetic fields.
This EU Directive 2013/35/EU retains the derogation. Article 10 of the

Directive is the scope of the derogations from the exposure limit values. It
said that the exposure may exceed the ELVs if the exposure is related to the
installation, testing, use, development, maintenance of, or research related
to the MRI equipment for patients in the health sector, provided that cer-
tain conditions are met. These conditions are as follows:
1. Risk assessment has been carried out in accordance with Article 4

has demonstrated that the ELVs are exceeded.
TABLE 9.12 ALs for Exposure to Electric and Magnetic Fields from 100 kHz
to 300 GHz
Electric Field Strength Magnetic Flux Density Power Density
Frequency Range ALs(E) [V m–1] (RMS) ALs(B) [μT] (RMS) ALs(S) [Wm–2]
100 kHz ≤ f < 1 MHz 6.1 × 102 2.0 × 106/f –
1≤ f < 10 MHz 6.1 × 108/f 2.0 × 106/f –
10 ≤ f < 400 MHz 61 0.2 –
400 MHz ≤ f < 2 GHz 3 × 10–3 f ½ 1.0 × 10–5 f ½ –
2 ≤ f < 6 GHz 1.4 × 102 4.5 × 10–1 –
6 ≤ f ≤ 300 GHz 1.4 × 102 4.5 × 10–1 50
Source: Reproduced from EU Directive 2013/35/EU, Official Journal of the European
Union 56: 1–21, L179, 2013.
Note: 1. f is the frequency expressed in hertz.
2. [ALs(E)]2 and [ALs(B)]2 are to be averaged over a 6-min period. For RF pulses,
the peak power density averaged over the pulse width shall not exceed
1000 times the respective ALs(S) value. For multifrequency fields, the analysis
shall be based on summation, as explained in the practical guides referred to in
Article 14.
3. ALs(E) and ALs(B) represent maximum calculated or measured values at the
workers’ body position. This results in a conservative exposure assessment and
automatic compliance with ELVs in all non-uniform exposure conditions. In
order to simplify the assessment of compliance with ELVs, carried out in accor-
dance with Article 4, in specific non-uniform conditions, criteria for the spatial
averaging of measured fields based on established dosimetry will be laid down in
the practical guides referred to in Article 14. In the case of a very localized source
within a distance of a few centimeters from the body, compliance with ELVs shall
be determined dosimetrically, case by case.
4. The power density shall be averaged over any 20 cm2 of exposed area. Spatial
maximum power densities averaged over 1 cm2 should not exceed 20 times the
value of 50 W m–2. Power densities from 6 to 10 GHz are to be averaged over any
6-min period. Above 10 GHz, the power density shall be averaged over any 68/
f 1.05-min period (where f is the frequency in gigahertz) to compensate for pro-
gressively shorter penetration depth as the frequency increases.
2. Given the state of the art, all technical and/or organizational mea-
sures have been applied.
3. Circumstances duly justify exceeding the ELVs.
4. Characteristics of the workplace, work equipment, or work practices
have been taken into account.
5. Employer demonstrates that workers are still protected against
adverse health effects and against safety risks.
On the basis of the above conditions, exposure related to MRI equip-

ment for patients is not subject to the ELVs in the Annex.
Article 14 of this new Directive contains words, stating that the estab-
lishment of documented working procedures, as well as specific informa-
tion and training measures for workers exposed to electromagnetic fields
during MRI-related activities related to above five conditions (refer to
Article 10 (1)a).
Overall, Stam summarized, in his review article, the origin of European
Directive and its contents (Stam 2014). In addition, he compared mag-
netic field exposure level in high-risk workplace with the limits set in the
revised Directive.
9.6 CONCLUSION
The MRI is the most successful technique in medicine, particularly, in
clinical practices. In this chapter, we provided an overview and evaluation
of the biological and health effects resulting from three kinds of electro-
magnetic fields (static magnetic field, gradient [time-varying] magnetic
field, and radio frequency electromagnetic field) with the newest results,
highlighting ICNIRP guidelines of occupational exposures, and European
EMF Directives and its impact for MRI community. The electromagnetic
fields associated with MRI have been used in medical technology without
a concomitant risk of adverse health effects. Our scientific understanding
of the biological and health effects of electromagnetic field has gradually
improved from much research.
The WHO produced and planned three documents of EHC on the
possible health effects of exposure to (1) static, (2) extremely low fre-
quency (ELF), and (3) radio frequency electromagnetic fields. After
publication of EHC documents, the WHO opened their research rec-
ommendations of MRI-related electromagnetic fields (WHO 2006b,
2010). The available data on possible effects of MRI examinations rel-
evant to the safety of patients and worker are not sufficient to draw
conclusions.
Since the introduction of MRI, patients, MRI staff, and other work-
ers exposed to electromagnetic field associated with MRI have increased.
Protection of workers requires occupational exposure assessment in MRI-
working environments. In addition, in MRI environments, there has been
no epidemiological research to assess the possible long-term health effects
in patients, volunteers, and medical and MRI staffs. Because the health
risk assessment for MRI procedures is incomplete, it is needed to address
well-organized and high-quality research associated with exposure to

MRI-related electromagnetic fields.
This chapter reviewed the current guidelines, their scope, and statement of
protection of patients related to MRI, based on the origination from ICNIRP
guidelines. The ICNIRP produced a guideline on time-varying electromag-
netic field up to 300 GHz in 1998 and updated it for the frequency range
1 Hz to 100 kHz in 2010. The guideline on time-varying electromagnetic
field below 1 Hz was published in 2014. The revision of the guideline for the
frequency range from 100 kHz to 300 GHz is now under way. The ICNIRP
produced a document on static magnetic field exposure in 1994, and it was
updated in 2009. For the protection of patients or volunteers in MRI, state-
ments from the ICNIRP appeared in 2004 and 2009. These documents are
based on a review of exposures encountered during an MRI examination.
The European Directive 2013/35/EU was officially adopted to protect
against effect of occupational exposure to electromagnetic field in the fre-
quency range up to 300 GHz based on the ICNIRP. An important aspect
of this new Directive and its impact to MRI community is shown in this
chapter. The derogation for MRI in this new Directive will ensure that
MRI scanners allow the use of diagnostic application. However, the guide-
lines of ICNIRP will hopefully apply toward the protection of MRI-related
workers.
Finally, as a new activity, the WHO is considering developing an inter-
national standard for electromagnetic field exposure. The progress report
2013–2014 of international EMF project said “Member states are increas-
ing interested in clear guidance based on harmonized standards and their
application within a national framework of protection. The development
of non-ionizing safety standards has been proposed by a Member State
using the example of the International Ionizing radiation Basic Safety
Standards developed as a collaborative approach between different UN
organisations” (WHO 2014). The WHO International EMF project is set
to develop the international harmonized global EMF exposure standard
as “Safety standards.”
ACKNOWLEDGMENTS
We thank Dr. Ikehata of Railway Technical Research Institute, Dr. Okano
of Hakuju Institute for Health and Science, Dr. Sakurai of Gifu Pharma
ceutical University, Dr. Yamazaki of Central Research Institute of Electric
Power Industry, and Dr. Watanabe of NICT for their kind support on this
manuscript.
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Chapter 10
New Horizons
in Biomagnetics
and Bioimaging
CONTENTS
10.1 Advances in Biomagnetics 306
10.1.1 Deep Brain Stimulation for Therapeutic Application 306
10.1.2 Combination of TMS with DTI and EEG 307
10.1.3 Biomagnetic Approaches to Treatments of Cancer
and Other Diseases 309
10.2 Advances in Bioimaging 309
10.2.1 MEG and Multimodal Integration 309
10.2.2 Combination of SQUIDs and Ultra-Low Magnetic
Field MRI 309
10.2.3 Advances in MRI 310
10.2.4 Magnetic Particle Imaging and Microwave Imaging 311
10.2.5 Molecular Imaging 312
References 312
Through the principles and applications of biomagnetic stimulation and

imaging we discussed in the previous chapters, the field of biomagnet-
ics is fertile ground for new research into the relationship between liv-
ing organisms and magnetism. Applying an interdisciplinary approach,
it covers a wide range of fields from medicine and biology to physics and
bioengineering.
305
In this chapter, we discuss the recent advances in biomagnetics and bio-

imaging to envision new horizons in the interdisciplinary fields.
10.1 ADVANCES IN BIOMAGNETICS
10.1.1 Deep Brain Stimulation for Therapeutic Application
A method of deep brain stimulation (DBS) with implanted electrodes has
been used for the treatments of brain dysfunctions. The DBS has brought
good news1 for patients who are afflicted with, for example, unbearable
chronic pain, resistant movement, and affective disorders including major
depression. Although DBS is a powerful tool, it is an invasive method to
insert and implant electrodes inside the deeper parts of the brain.
If an alternative noninvasive method for deep brain stimulation is
introduced, new horizons will be opened in this area. The transcranial
magnetic stimulation (TMS) is a promising potential tool for the realiza-
tion of deep brain stimulation. In researching deep TMS (dTMS), several
attempts have been reported. There are several coil configurations poten-
tially suitable for dTMS; double cone, H-coil, and Halo coils.
The double-cone coil2–4 operates on the same principle as the figure-
eight coil configuration where a pair of opposing directed time-varying
magnetic fields around a target increase induced electric fields in the tar-
geted areas. The two circular coils have a fixed angle between them, and
their diameter is larger than that of the figure- eight coil. The double-cone
coil induces a greater electric field intensity to stimulate the deeper brain
regions compared with other coils. However, the surrounding large areas
in the brain are also stimulated.
Another coil configuration for dTMS is called the H-coil.5,6 The H-coils
have complex winding patterns based on numerical calculations of three-
dimensional brain phantom models to achieve effective stimulation of
deep brain structures and are used for the treatment of a variety of psychi-
atric and neurological disorders. Although the H-coils are used for clini-
cal applications, nontargeted areas of the brain are also stimulated.
A family of dTMS coil designs, called the Halo coil, was proposed to
increase the induced electric fields at depth in the brain.7 The Halo coil
system is composed of a small coil on the top of the head and a large cir-
cular coil around the head.
Computational studies were carried out in order to evaluate the focal-
ity of these three types of coil configurations.8,9 Three-dimensional dis-
tributions of the induced electric fields in realistic head model by dTMS
New Horizons in Biomagnetics and Bioimaging ◾ 307
coils were calculated by an impedance method, and the results were com-
pared with that of a standard figure-eight coil.10,11 Simulation results show
that double cone and H-coils have deep field penetration at the expense
of induced higher and wider spread electric fields in superficial cortical
regions. The combination of the Halo coil with a circular coil produce
deeply penetrating electric fields the same as double cone and H-coils, but
the stimulation in superficial brain tissues are much higher.10,11 Further
studies are needed for better dTMS with better focality.
The studies on TMS and reward circuits in the brain are important
and interesting for the understanding of the neuronal connectivity in the
brain as well as for the potential treatments of brain dysfunctions such as
depression and Parkinson’s disease. For example, Wassermann et al. have
studied reward-related activity in the human motor cortex,12 modulation
of corticospinal excitability by reward,13 reward processing abnormalities
in Parkinson’s disease,14 and so on. The study concludes that TMS of the
human primary motor cortex M1 may be useful as a quantitative measure
of reward-related activity.12
It seems that repetitive transcranial magnetic stimulation (rTMS), tran-
scranial direct current stimulation (tDCS), and other brain stimulation
techniques are promising for treatments of depression and other psychi-
atric disorders.15,16
In 2011, Fitzgerald reviewed the current state of development and appli-
cation of a wide range of brain stimulation approaches in the treatment of
psychiatric disorders.17 The brain stimulation methods that he reviewed
include vagus nerve stimulation, rTMS, tDCS, electroconvulsive therapy,
and magnetic seizure therapy. The review concludes that it appears likely
that the range of psychiatric treatments available for patients will grow
over the coming years to progressively include a number of novel brain
stimulation techniques.17
In 2013, Fitzgerald et al. examined a double-blind, randomized trial
of deep rTMS for autism spectrum disorder and came to the following
conclusion: Deep rTMS to bilateral dorsomedial prefrontal cortex yielded
a reduction in social relating impairment and socially related anxiety.18
Further studies are needed in the area of deep transcranial magnetic
stimulation.
10.1.2 Combination of TMS with DTI and EEG

Many studies have been published on the topic of spatiotemporal pat-
terns of brain electrical activities elicited by TMS in a high spatial and
temporal resolution. These are combinations of TMS with diffusion ten-

sor imaging (DTI), TMS with electroencephalographic (EEG) measure-
ments, TMS with functional magnetic resonance imaging (fMRI), and
so on.
The invention of DTI and in vivo fiber tractography19,20 contribute to the
studies on DTI-based neural trajectories in TMS. De Geeter et al.21,22 stud-
ied a DTI-based model for TMS and effective electric fields along realistic
neural trajectories for modeling the stimulation mechanisms of TMS. De
Geeter et al. focused on the stimulation of the hand area of the left pri-
mary motor cortex, M1, with a figure-eight coil10,11 to get deeper insights
on the stimulation mechanisms. Including realistic neural geometry in
the model demonstrates the strong and localized variations of the effec-
tive electric field between the tracts themselves and along them due to the
interplay of factors such as the tract’s position and orientation in relation
to the TMS coil, the neural trajectory, and its course along the white and
gray matter interface.22 Thus, the studies using DTI and TMS are useful to
visualize exciting fronts and neural trajectories and also to improve and
integrate the early proposed models of nerve excitation elicited by mag-
netic stimulation.23–30
EEG measurements just after the onset of brain stimulation by TMS
with a figure-eight coil10,11 are important to study dynamic neuronal con-
nectivity in the brain in a high temporal (msec) and high spatial (mm)
resolution. Ilmoniemi et al. successfully measured neuronal electrical
responses to magnetic brain stimulation.31 The combination of TMS with
simultaneous EEG has enabled us to study dynamic intra- and interhemi-
spheric connectivity for the deeper understanding of cortico-cortical and
interhemispheric interactions, cortical inhibitory processes, cortical plas-
ticity and oscillations, and so on.32–40
The combination of TMS with fMRI or DTI is also interesting and
important. It is rather difficult to combine TMS with simultaneous fMRI
or DTI, but data of fMRI and DTI are used for studying the effects of TMS
on the changes in functional organization of the brain.
Pascual-Leone et al. reviewed studies on measuring and manipulating
brain connectivity with resting state functional connectivity MRI (fcMRI)
and TMS, classifying many publications into three general network prop-
erties: anatomical connectivity, functional connectivity, and response to
perturbation/stimulation.41 TMS is a useful noninvasive method to assess
brain connectivity in human subjects noninvasively for controlled, indi-
vidualized neuronal network modulation.
10.1.3 Biomagnetic Approaches to Treatments

of Cancer and Other Diseases
Magnetic control of cell growth and cancer therapy are important and
challenging fields of research. Magnetic destruction of cancer cells42 and
magnetic suppression of cancer cell growth by electromagnetic pulses43
are promising, and further in vivo studies using rodents are essential for
future clinical use.
Studies on magnetic cell orientation and its use for bone growth accel-
eration44 and nerve regeneration45 are also very exciting and challenging
subjects.
Studies on iron cage proteins (ferritins) exposed to microwaves are
promising and exciting46,47 for potential treatments of Alzheimer’s and
Parkinson’s diseases in the future.
All topics discussed here require further studies for medical applications.
10.2 ADVANCES IN BIOIMAGING
10.2.1 MEG and Multimodal Integration
With its high temporal resolution, magnetoencephalography (MEG) has
been a powerful tool to study and diagnose noninvasively the human
brain function in the millisecond time scale. A variety of studies have been
reported, for example, gamma phase locking,48 resting cortical dynam-
ics,49 intra- and interfrequency brain network structure.50 entrainment
of alpha oscillations,51 real-time MEG neurofeedback training,52 visual
object recognition related to feedback and feedforward inputs,53 and lan-
guage processing in atypical development.54
The combination of MEG and electroencephalographic (EEG) mea-
surements can reduce ambiguities in data from usage of only one of the
modalities.55 The combination of MEG with fMRI56,57 has accelerated
functional brain studies such as the study on human emotion cogni-
tion58 and gamma and alpha oscillations related to working memory per-
formance.59 Combining MEG with other noninvasive tools will further
developments to neuroscience and clinical medicine.
10.2.2 Combination of SQUIDs and Ultra-Low Magnetic Field MRI

Clarke et al. and others showed that MRI at ultra-low magnetic fields of
~100 μT, Larmor frequencies of kHz, was possibly available by combin-
ing superconducting quantum interference device (SQUID) sensors.60,61
Clarke’s group reported the concept of SQUID-based MRI at ultra-low
fields (ULFs) with readout magnetic fields as low as 132 μT and using
pulsed pre-polarization.60 In ULF-MRI, precession signals are detected
at ~μT magnetic fields using highly sensitive SQUID sensors. Compared
with conventional MRI with high magnetic fields of a few Teslas order, sig-
nal acquisition times or imaging times in ULF-MRI tend to be long. Many
studies on SQUID-detected ULF-MRI have been reported in the 2000s
and 2010s regarding distinct imaging with a shorter imaging time.62–69
10.2.3 Advances in MRI
In contrast with ULF-MRI, projects of ultra-high magnetic field MRI
(UHF-MRI) are also very important to get ultra-clear and distinct imag-
ing. Big projects for UHF-MRI have been promoted and are now being pro-
moted by different institutions, for example, by a group at the University
of Minnesota in the United States conducted by Ugurbil70 and by a group
at NeuroSpin in France conducted by Le Bihan.71 Larmor frequency, or
resonant frequency (RF), proportionally increases with increase in mag-
netic field. Many important issues need to be resolved in UHF-MRI such
as safety, superconducting coils, gradient coils, and RF coils related to the
inhomogeneity in RF field distributions and coil design, etc. The issues on
parallel transmission and RF coil design were studied72–74 to overcome the
problem in RF field inhomogeneity.
Diffusion tensor MRI (DTI) and in vivo fiber tractography invented by
Basser et al.19,20 have become powerful tools in the imaging of ultra-fine ana-
tomical structures of neuronal fibers in the human brain. Functional MRI
(fMRI) based on blood oxygenation level dependent (BOLD) effects invented
by Ogawa et al.56,57 has become a powerful tool to reveal the functional orga-
nization of the human brain. Data obtained by these two tools have enabled
us to study anatomical and functional connectivity in the brain. Polonara
et al. studied the topography and connectivity of the corpus callosum in
patients with partial callosal resection using both fMRI and DTI.75
Thomas et al. evaluated the inherent limit for anatomical accuracy
of brain connections derived from DTI tractography by comparing the
DTI data with the data obtained from tracer studies in the macaque.76
Anatomical accuracy is highly dependent upon parameters of the tractog-
raphy algorithm, with different optimal values for mapping different path-
ways. The results by Thomas et al. suggest there is an inherent limitation in
determining long-range anatomical projections based on boxel averaged
estimates of local fiber orientation obtained from DTI data that is unlikely
to be overcome by improvements in data acquisition and analysis alone.76
To further understanding of diffusion coefficients in the brain, the rela-

tionship between membrane permeability and extra- and intra-cellular
diffusion coefficients was studied using rat brain and human subjects.77–79
Studies on imaging electrical impedance and neuronal currents based
on MRI have been reported. Further studies are needed in the areas of
MR-based neuronal current imaging or MR neuroimaging.
10.2.4 Magnetic Particle Imaging and Microwave Imaging

Recent advances in magnetic nanotechnology and biochemistry have
accelerated studies on applications of magnetic nanoparticles for medi-
cal diagnoses and treatments such as hyperthermia, drug delivery system,
and magnetic particle imaging (MPI). This newly developing field, which
we call nanobiomagnetics or biomedical nanomagnetics, covers a variety
of fields from diagnostics to therapy that includes development, function-
alizing and optimizing magnetic nanoparticles for targeting, drug and
gene delivery, image enhancements and hyperthermia, for example, like
Krishnan’s group80 at the University of Washington, USA is promoting.
Other groups have studied magnetic sensing and imaging of sentinel
lymph nodes in patients with lung or breast cancer.81–85 Detection of senti-
nel lymph nodes is crucially important for early detection of cancer before
metastasis.
MPI methods have difficulty in detecting deeply seated target cells
from the surface of the body because magnetic fields from the magnetic
particles combined with cancer cells attenuate rapidly at the surface of the
body. Empuke et al.86 developed highly sensitive magnetic nanoparticle
imaging using cooled-Cu/HTS (high-critical-temperature superconduc-
tor) pickup coils. Empuke et al. demonstrated the detection of 100 μg of
magnetic nanoparticles and obtained a clear contour map of the magnetic
fields from the particles at the distance between the target and pickup coil
of 100 mm.
Persson et al.87 developed two different brain diagnostic devices based
on microwave technology, and they associated two first proof of princi-
ple measurements that the systems can differentiate hemorrhagic from
ischemic stroke in acute stroke patients, as well differentiate hemorrhagic
patients from healthy volunteers. The system was based on microwave
scattering measurements with an antenna system worn on the head. This
system will certainly contribute to quick diagnosis so that ischemic stroke
patients may receive acute thrombolytic treatment at hospitals, dramati-
cally reducing or eliminating symptoms.87
10.2.5 Molecular Imaging
Studies of molecular imaging have been rapidly accelerated for medical appli-
cations in the 2000s through the 2010s. Brain research through advancing
innovative neurotechnologies (BRAIN) initiative was introduced by President
Obama in the United States, on April 2, 2013, and a National Institutes of
Health (NIH) Workshop on clinical translation of molecular imaging probes
and technology was held on August 2, 2013, in Bethesda, Maryland.88,89
Pettigrew, director of the national institute of biomedical imaging and bio
engineering (NIBIE) at the NIH, stated that “This high-priority BRAIN
initiative on next-generation human imaging technologies is a striking call
for teams of our best and brightest minds from multiple disciplines to think
big, aim high, and reach far beyond previous boundaries in human imaging
science.”89
Studies on in vivo imaging using rodents are promising and closest to
human imaging, and new strategies for fluorescent probe design in medi-
cal diagnostic imaging were reviewed by Kobayashi et al.90 Among them,
Urano et al., for example, developed a method of selective molecular
imaging of viable cancer cells with a pH-activatable fluorescence probe.91
Urano’s group also developed a unique method of rapid cancer detection
by topically spraying a γ-glutamyltranspeptidase (GGT)-activated fluores-
cent probe.92 This probe is practical for clinical application during surgical
or endoscopic procedures because of its rapid and strong activation upon
contact with GGT on the surface of cancer cells.
The future of science and medicine will be rapidly progressing with the
integration of advanced technologies, including biomagnetics, bioimaging,
drug delivery system, and nanobioscience.93
Biomagnetics and bioimaging are thus leading medicine and biology
into new horizons through their novel applications of magnetism and
imaging technology. With the increasing integration of medicine and
engineering, biomagnetics and bioimaging are merging into a new science
that encompasses a wide range of fields including their diverse cultures to
create a new and original discipline.
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Index
Page numbers followed by f and t indicate figures and tables, respectively.
A ALs (action levels) exposure to magnetic

fields, 293–294, 293t, 295t
Absorption Alzheimer’s disease, iron in, 228
iron, 224–229 Ammonium iron sulfate 6-hydrate, 243, 245
oxidative stress and dementia, Animal studies
227–229, 228f B16-BL6 melanoma model, 211
spectroscopic techniques, 224–225 biological effects of static magnetic
symmetry points, function, field, 266–269
225–227, 226f BMP-2/collagen pellets, 201
power, in ferrihydrite bionanoparticles, destruction of leukemia cells by
232–235 physical force, 207–209, 208f, 209f
AC susceptibility, 234–235, 235f head with excitation flip angles, 159,
Néel and Brownian relaxation, 160f
233–234 MC3T3-E1 cells, 200
AC (alternating current) MRI of electric currents, 174–178
external field, use of, 159, 160, 161f brain slices, 174–176, 175f
susceptibility, in ferrihydrite in vivo experiments, 176–178, 177f,
bionanoparticles, 234–235, 235f 178f
Acceleration, bone growth tumor growth inhibition by pulsed
by static magnetic fields, 198–202 magnetic stimulation, 211–212,
background, 198–199 211f, 212f
magnetic control, 200–202, 200f, 201f Anisotropy, 15
ACSF (artificial cerebrospinal fluid), MEA of biological tissues, 152–153
and perfusion system of, 176 Anisotropy index (AI), images, 164f
Action levels (ALs) exposure, to magnetic Anticancer agents, 209–210, 210t, 212
fields, 293–294, 293t, 295t Antitumor effects, 209–212
Action potential, 44–46, 44f, 95 α nuclei, 125
“Active” area, 95 Apoferritin
ADC, See Apparent diffusion coefficient fluorescence determination, 248, 249f
(ADC) formation, 223, 223f
Adenosine triphosphate (ATP) content, in Apparent diffusion coefficient (ADC), 139
human-hamster cells, 269–270 Artificial cerebrospinal fluid (aCSF), MEA
AI (anisotropy index), images, 164f and perfusion system of, 176
Alkaline phosphatase (ALP) activity, of Asa, M. M., 5
MC3T3-E1 cells, 200–201 ATP (adenosine triphosphate), 269–270
321
322 ◾ Index
Auditory evoked responses, 110–111, 111f, fibrins, 198, 198f

112f osteoblast cells, 198, 198f
Autism spectrum disorder, rTMS for, 307 polymerization processes of fibrin
Avogadro’s number, 124 fibers, 197, 197f
Schwann cells, 198, 198f
smooth muscle cells, 198, 198f
B
nerve regeneration, 202–205
Barker, A. T., 6 background, 202–203, 202f
Basser, P. J., 11 Schwann cells, magnetic field on,
Baule, G., 4 203–205, 204f
B16-BL6 melanoma model, 211 overview, 186–188
Beamformer, 107–108, 108f tumor growth inhibition, 209–212
BEM, See Boundary Element Method background, 209–210, 210t
(BEM) pulsed magnetic stimulation on,
Bihan, D. Le, 11 211–212, 211f, 212f
Bioimaging Biological effects, related to MRI, 265–276
advances in, 309–312 gradient (time-varying) magnetic field,
MEG and multimodal integration, 272
309 health effect related to operation,
molecular imaging, 312 274–276
MPI and microwave imaging, 311 RF electromagnetic field, 273–274
MRI, advances in, 310–311 static magnetic field, 266–272
SQUIDs and ULF-MRI, human experimental and
combination, 309–310 epidemiological studies,
Biological cell growth, magnetic control 270–272
of, 186–212 in vitro studies, 269–270
biomagnetic effects, basic principles, in vivo studies, 266–269
See also Biomagnetic effects Biological interaction, mechanisms for,
multiplicity of magnetic fields and 262–265
other energy forms, 196–197 gradient (time-varying) magnetic field,
static magnetic fields on biological 263–264
systems, 188–194 RF electromagnetic field, 264–265
time-varying magnetic fields on static magnetic field, 262–263
biological systems, 194–196 Biological systems, magnetic fields on
bone growth acceleration, 198–202 static, 188–194, See also Static
ALP activity, of MC3T3-E1 cells, magnetic fields
200–201 magnetic force in homogeneous
background, 198–199 magnetic field, 189–191, 190f
in vitro experiments, 200–201, 200f magnetic force in inhomogeneous
in vivo experiments, 201–202, 201f magnetic field, 192–194
distraction of leukemic cells, 205–209 magnetic torque in homogeneous
background, 205–206 magnetic field, 191
magnetic destruction by physical overview, 188f
force, 207–209, 208f, 209f time-varying, 194–196
magnetic orientation of adherent cells, high-frequency magnetic fields and
197–198 microwaves, 195–196
collagen, 198, 198f low-frequency and pulsed magnetic
endothelial cells, 198, 198f fields, 194–195
Index ◾ 323
Biological tissues, electric properties, history of, 1–7

148–154 magnetism of living systems and
frequency characteristics and materials, 14–16
anisotropy, 150–153, 151f, 152t measurements of magnetic fields, 8–9
human models for numerical modern, 4–7
simulations of EMFs, 153–154 MRI, 10–11
permittivity and conductivity, 148–150 phenomena, 7–8, 7f
Biomagnetic effects, basic principles, pulsed magnetic fields, 12
188–197 RF magnetic fields, 12
multiplicity of magnetic fields and stimulation, 9–10, See also Biomagnetic
other energy forms, 196–197 stimulation
photochemical reactions, 196–197, therapeutic applications, 10
196f Biomagnetic signals
radical pair model, 196–197, 196f cortical neural activity, 94–95
singlet-triplet intersystem crossing, current dipole modeling of synaptic
196–197, 196f activities, 95–96, 95f
static magnetic fields on biological MEG, See Signals, MEG
systems, 188–194, See also Static Biomagnetic stimulation, 9–10
magnetic fields advantages of, 26–27
magnetic force in homogeneous basic principles, 24–26, 26f, 27f
magnetic field, 189–191, 190f in brain research, See Brain research,
magnetic force in inhomogeneous applications in
magnetic field, 192–194 cerebellum, 53, 54f
magnetic torque in homogeneous coil navigation system, 40–41, 40f
magnetic field, 191 driving circuit, 36–40, 37f, 38f
overview, 188f ECT vs. TMS, 51–53, 52f
time-varying magnetic fields on future prospects, 55–56
biological systems, 194–196 mechanisms of, 43–48, 44f, 47f
high-frequency, 195–196 in medicine, See Medicine,
low-frequency, 194–195 applications in
microwaves, 195–196 multimodal imaging, 41–42, 42f
pulsed magnetic fields, 194–195 numerical analyses, 48–54, 51f, 52f,
Biomagnetic forward problem, 97 54f, 55f
Biomagnetic inverse problem, 100, 101f reaction maps, 41
Biomagnetic measurements, See stimulator coils, 28–36, 28f, 31f, 33f, 35f
Magnetoencephalography (MEG) Biomagnetism, See Biomagnetics
Biomagnetics Biomineralization, 6
advances in, 306–309 Biot-Savart’s law, 97
approaches to treatments of cancer Biphasic waveforms, 25, 27f
and other diseases, 309 Bladder cancer, hyperthermia for, 195,
DBS for therapeutic application, 205–206
306–307 Blakemore, R. P., 6
TMS with DTI and EEG, 307–308 Bloch equation, 170
cell manipulation/orientation/growth, Blood flow, magnetic forces on biological
11–12 systems, 189–190, 190f
electromagnetic induction in living Blood oxygenation level dependent
tissues, 12–13, 14t (BOLD), 11
ELF magnetic fields, 12 effects, 310
324 ◾ Index
BMP-2/collagen pellets, in mouse, 201 changes in iron release, 236–241

β nuclei, 125 changes in iron uptake, 243–245,
BOLD-fMRI, 11, 15 244f, 245f
Bone growth acceleration, by static ferrihydrite bionanoparticles, See
magnetic fields, 198–202 Ferrihydrite bionanoparticles
background, 198–199 ferrozine and, See Ferrozine
magnetic control, 200–202, 200f, 201f in Friedreich ataxia, 228
Bone morphogenetic proteins (BMPs), for horse spleen, 221
osteogenic activity, 199 in iron biochemistry, 222
Boundary element method (BEM), 98–99 in liver and spleen, 223
Brain, numerical model, 50–51, 51f neuroferritinopathy, 228
BRAIN (brain research through overview, 222–223
advancing innovative in Parkinson’s disease, 228
neurotechnologies) initiative, physiological role, 222–223, 223f
312 release and absorption, iron, 224–229
Brain mapping, functional, 63–69 ferroxidation process, 227
EEG evoked by TMS, 66, 67f, 68 ferrozine, 224–225
figure-eight coils, 63–64, 64f function of symmetry points,
medical applications, 68–69, 68f 225–227, 226f
principles, 63–68 OD of ferritins, 224, 225
spatial resolution of, 64–66, 65f, 66f oxidative stress and dementia,
Brain research, applications in 227–229, 228f
brain mapping, See Brain mapping, spectroscopic techniques, 224–225
functional threefold symmetry point on, 249–253,
cognitive neuroscience, 69–71 252f
overview, 62–63 Cancers, See also specific entries
paired-pulse stimulation, 71–72 anticancer agents, 209–210, 210t, 212
repetitive magnetic stimulation, biomagnetics approaches for, 309
72–76 detection of sentinel lymph nodes for,
virtual lesion, 69 311
Brain research through advancing hyperthermia for, 195, 205–206, 209,
innovative neurotechnologies 210t
(BRAIN) initiative, 312 mortality and incidence, 271
Brain slices, 174–176, 175f NMR for, 260
Breast cancer, hyperthermia for, 195, related issues, in vivo studies, 266–269
205–206 therapy
Brenner, D., 5 DC, 209, 210t
Brownian motion, 139, 243 ECT, 210, 210t
Brownian relaxation, 233–234 electric stimulation and, 209–210,
210t
magnetic stimulation for, 187
C
tumor growth inhibition, 209–212,
Cage proteins, iron 210t, 211f, 212f
ferritins, See also Ferritins Carbon-13 MRI, 141, 141f
in Alzheimer’s disease, 228 Cationization, at threefold symmetry
apoferritin, 223, 223f, 248, 249f point, 245–248, 247f
cationized, at threefold symmetry Cell body (soma), 94, 95f
points, 246–248, 247f Cell death, regulation of, 186
Index ◾ 325
Cell growth, 11–12 Conductivity(ies)

magnetic control of, See Biological cell of biological tissues, 148–150
growth frequency characteristics and,
Cell manipulation, 11–12 150–153, 151f, 152t
Cell orientation, 11–12 of extracellular fluid, 162
Cell proliferation, regulation of, 186 imaging using diffusion MRI, 161–165
Cerebellum, magnetic stimulation, 53, experimental results, 162–165, 163f,
54f 164f
Cervical cancer, hyperthermia for, 195, principles, 161–162
205–206 Controls, magnetic
Cervical lymph node metastasis, of biological cell growth, See Magnetic
hyperthermia for, 195, 205–206 control, of biological cell growth
Chemical reactions, magnetic fields on, Cooling systems, coils, 34–35
6–7 Cortial motor threshold (CMT), 46
Circular coils, 28–30, 28f, See also Cortical neural activity, biomagnetic
Stimulator coils signals, 94–95
Circulatory system, magnetic forces on, CTA (conditioned taste aversion), 268
189–190, 190f Current dipole modeling, synaptic
CMT, See Cortial motor threshold (CMT) activities, 95–96, 95f
Cognitive neuroscience, applications in, Current MRI, 11
69–71 Currents
episodic memory, 69–70, 70f, 71f AC
P300 evoked potentials, 70–71 external field, use of, 159, 160,
Cohen, D., 4, 5 161f
Coil array, 31–32, 31f susceptibility, in ferrihydrite
Coil current, 35–36, 35f bionanoparticles, 234–235, 235f
Coil navigation system, 40–41, 40f DC, for cancer, 209, 210t
COL (collagen gel only), 205 Eddy current
Cole-Cole plot occurrence of, 159
defined, 150 shielding effects of, 159
frequency characteristics and, 152 on tumors, 210
Collagen fibers, 197, 199, 203 electric, See Electric currents
Collagen gel mixed with Schwann cells motion-induced, on biological system,
(S-COL), 205 189, 193–194
Collagen gel only (COL), 205 RF, impedance imaging using, 165–167
Collagens experimental results, 167, 168f
COL, 205 principles, 165–167, 166f
magnetic orientation in, 187, 198, 198f source estimations, 165
M-COL, 205 Cylindrical sample, RF distribution in,
M-S-COL, 205 154, 155f
for nerve regeneration, 205
S-COL, 205
D
Colorectal cancer, hyperthermia for, 195,
205–206 D’Arsonval, Jacques-Arsene, 3, 3f, 25
Conditioned taste aversion (CTA), 268 DBS (deep brain stimulation), for
Conductive fluids, magnetic forces therapeutic application, 306–307
on biological systems, 189–191, DC (direct current), for cancer, 209, 210t
190f Dc SQUID, 92–93, 93f
326 ◾ Index
Debye’s equation, of complex permittivity, AC susceptibility, 234–235, 235f

150 Néel and Brownian relaxation,
Deep brain stimulation (DBS), for 233–234
therapeutic application, Distraction, of leukemic cells, 205–209
306–307 background, 205–206
Deep TMS (dTMS), for DBS, 306–307 magnetic destruction by physical force,
Degeneration, Wallerian, 202, 203 207–209, 208f, 209f
De Magnete, 2 Distributed source imaging, MEG,
Dementia, iron in, 227–229, 228f 105–108
Dendrites, 94, 95f beamformer, 107–108, 108f
Destruction, magnetic minimum-norm estimates, 106–107
of leukemia cells by physical force, 207, Distribution, RF
208f, 209, 209f in cylindrical sample, 154, 155f
Deuterium MRI, 142 in human head, 155–158
Diamagnetic materials, 14–15 FDTD method, 155–157, 156f
Diamagnetism, 6 at varied frequencies, 157–158, 158f
Dielectric resonance effect, 154, 155f DMSA (meso-2,3-dimercaptosuccinic
Diffusion coefficient, of extracellular fluid, acid), reducing agent, 224–225,
161–162 241–242, 242f
Diffusion MRI, conductivity imaging Donnan’s effect, 43
using, 161–165 Double-cone coils, 28f, 30, See also
experimental results, 162–165, 163f, Stimulator coils
164f in dTMS, 306
principles, 161–162 Driving circuit
Diffusion tensor imaging (DTI), 11 analysis of, 38–40, 38f
TMS and EEG, combination, 307–308 hardware, 36–38, 37f
in vivo fiber tractography and, 310 DTI, See Diffusion tensor imaging (DTI)
Diffusion weighted imaging (DWI), 11, DTMS (deep TMS), for DBS, 306–307
139–140, 139f DWI, See Diffusion weighted imaging
Meso-2,3-Dimercaptosuccinic acid (DWI)
(DMSA), reducing agent,
224–225, 241–242, 242f
E
Dipolar current in volume conductor,
97–98, 97f Earth, magnetic fields, 2, 2f
Dirac delta function, 96 Echo-planar imaging (EPI) technique,
Direct current (DC), for cancer, 209, 210t 128, 138–139
Direction, control ECT, See Electroconvulsive therapy (ECT)
in nerve regeneration, 202–205 Eddy currents
background, 202–203, 202f brain mapping and, 64, 64f, 68
magnetic control, 203–205, 204f magnetic flux and, 123–124
Directives, European EMF, 291–296, 293t, nerve excitation and, 5
295t occurrence of, 159
Dispersion shielding effects of, 159
defined, 150 on tumors, 210
model of, 150 EEG, See Electroencephalography (EEG)
Dissipation, power EHC (Environmental Health Criteria),
in ferrihydrite bionanoparticles, 273–274
232–235 Eigendecomposition, 104
Index ◾ 327
Electrical impedance tomography (EIT) protection of patients, MRI

MRI-based, 167, 168–169 examinations and, 285–287,
principle of, 147 286t
Electric currents, MRI of, 146–181 safety aspects, 260–297
advantages in imaging, 147–148 biological effects related to MRI,
animal studies, 174–178 265–276, See also Biological
brain slices, 174–176, 175f effects
in vivo experiments, 176–178, 177f, biological interaction, mechanisms
178f for, 264–265, See also Biological
changes in signals, from magnetic interaction
field, 169–170 exposure guidelines related to MRI,
goals, 148 276–287, See also Exposure
human studies, 178–180, 179t, 180f guidelines
weak, sensitivity to, 170–174 occupational exposure during MRI,
experimental evaluation, 174 288–296, See also Occupational
neuronal current dipole, 170–171 exposure
theoretical evaluation, 171–173, 173f overview, 260–262
Electric properties, of biological tissues, Electromagnetic induction, 13, 14t, 24
148–154 Electromotive force (EMF), 122, 123–127,
frequency characteristics and 123f, 124f, 127f
anisotropy, 150–153, 151f, 152t Electrophysiology, 43–46
human models for numerical action potential, 44–46, 44f
simulations of EMFs, 153–154 Donnan’s effect, 43
permittivity and conductivity, 148–150 peripheral nerve stimulation, 47–48
Electric stimulation, for cancers, 209–210, resting membrane potential, 43
210t resting motor threshold, 46
Electrochemotherapy (ECT), for cancer, TMS, 46–47
210, 210t ELF, See Extremely low frequency (ELF)
Electroconvulsive therapy (ECT), 10 magnetic fields
side effects, 51 ELVs (exposure limit values), 292–293, 294
single ECD model, 101 Emerging coil designs, 32–34, 33f
vs. magnetic stimulation, 51–53, 52f numerical methods in, 53–54, 55f
Electroencephalography (EEG), 41 EMF, See Electromotive force (EMF)
EEG evoked by TMS, 66, 67f, 68 EMFs, See Electromagnetic fields (EMFs)
current source estimations of, 165 Endothelial cells, magnetic orientation in,
TMS and DTI, combination, 307–308 187, 198, 198f
Electromagnetic fields (EMFs) Energy, forms
biological effects, 12–13, 14t multiplicity of magnetic fields and,
components, 155, 156f 196–197
distributions, 155, 156 photochemical reactions, 196–197,
human models for numerical 196f
simulations of, 153–154 radical pair model, 196–197, 196f
RF singlet-triplet intersystem crossing,
biological effects related to MRI, 196–197, 196f
273–274 Environmental Health Criteria (EHC),
biological interaction in, 264–265 273–274
exposure guidelines related to MRI, EPI, See Echo-planar imaging (EPI)
279–280, 281t, 282t, 283t technique
328 ◾ Index
Epidemiological studies protection of patients, MRI

biological effects of static magnetic examinations and, 282, 283,
field, 270–272 285–287
Epileptic surgery, MEG and, 91–92 ICNIRP recommended limits,
Episodic memory, 69–70 287t
Equivalent current dipole, 101–105, 106f RF electromagnetic fields, 285–287,
multidipole model, 101–103, 104f 286t
multiple signal classification, 104–105, static magnetic field, 283, 285
106f time-varying magnetic fields, 285
single ECD model, 101 RF electromagnetic field, 279–280,
Escherichia coli, 269 281t, 282t, 283t
European EMF Directives, 291–296, 293t, static magnetic field, 277–278, 277t
295t Exposure limit values (ELVs), 292–293,
Evaluation, of sensitivity 294
experimental, 174 Exposure(s)
theoretical, 171–173, 173f ELVs, 292–293, 294
Excitatory postsynaptic potentials to magnetic fields, ALs and, 293–294,
(EPSPs), 72, 95 293t, 295t
Experimental evaluation, of sensitivity, occupational, See Occupational
174 exposure
Experimental results RF, Raman spectroscopy, 242–243
conductivity imaging using diffusion sources, for magnetic control of
MRI, 162–165, 163f, 164f biological cell growth, 187
impedance imaging using RF current, worker exposure assessment, 289–291
167, 168f External AC field, use of, 159, 160, 161f
Experimental setup, RF magnetic fields on Extremely low frequency (ELF) magnetic
iron release, 235–236 fields, 4, 8, 12
Experiments
in vitro
F
biological effects of static magnetic
field, 269–270 Faraday, Michael, 13, 24
magnetic control of bone growth Faraday’s law
acceleration, 200–201, 200f of induction, 262, 263, 264
MRI of electric currents, 176–178, pseudo-nerve information, 194
177f, 178f Fast low-angle shot (FLASH), 138
in vivo FcMRI (functional connectivity MRI),
biological effects of static magnetic TMS and, 308
field, 266–269 FDA, See Food and Drug Administration
magnetic control of bone growth (FDA)
acceleration, 201–202, 201f FDTD (finite difference time domain)
MRI of electric currents, 176–178, method, 155–157, 156f
177f, 178f FE, See Field echo (FE) imaging
Exposure guidelines, related to MRI, FEM, See Finite element method (FEM)
276–287 Fenton reaction, 220
gradient (time-varying) magnetic field, FEPSP (field excitatory postsynaptic
278–279, 278t, 279t potentials), measurement, 176
movement-related magnetic field, 280, Ferrihydrite bionanoparticles
282, 284t in ferritin, 221
Index ◾ 329
magnetic properties, 229–235 Ferroxidase enzyme, 227

ferrimagnetism in iron oxides and Ferroxidation, process of, 227
surface effects, 230, 231 Ferrozine, in iron release and absorption
nanoscale magnetism, 229–231 cationized, at threefold symmetry
superparamagnetism, 230, 231f points, 246–248, 247f
power absorption and dissipation, changes in, 236–241
232–235 chemical concentrations, 237–238,
AC susceptibility, 234–235, 235f 237f
Néel and Brownian relaxation, effects in iron chelation, 238–240,
233–234 239f
Ferrimagnetism, in iron oxides and effects in nanoparticle/entry-exit
surface effects, 230, 231 process, 240, 240f
Ferritins, 220–229 spectroscopic technique, 224–225
in Alzheimer’s disease, 228 Fibers
apoferritin collagen, 197, 199, 203
fluorescence determination, 248, 249f fibrin, See Fibrins
formation, 223, 223f nerve, See Nerve fibers
cationized, at threefold symmetry neural, 11
points, 246–248, 247f neuronal, 41, 53, 165
changes in iron release, 236–241 Fibrins
concentrations, 237–238, 237f magnetic orientation in, 187, 197–198,
effects in iron chelation, 238–240, 239f 197f, 198f
effects in nanoparticle/entry-exit polymerization processes, 197, 197f
process, 240, 240f Field echo (FE) imaging, 128, 130, 130f
FTIR of, 240 Field excitatory postsynaptic potentials
changes in iron uptake, 243–245, 244f, (fEPSP), 73, 74
245f measurement, 176
ferrihydrite bionanoparticles, See Figure-eight coil, 28f, 30, See also
Ferrihydrite bionanoparticles Stimulator coils
ferrozine and, See Ferrozine brain mapping, 63–64, 64f
in Friedreich ataxia, 228 Finite difference time domain (FDTD)
horse spleen, 221 method, 155–157, 156f
in iron biochemistry, 222 Finite element method (FEM), 48–49
iron release and absorption, 224–229 FLASH, See Fast low-angle shot (FLASH)
ferroxidation process, 227 Flow potential
ferrozine, 224–225 conductive fluids and, 189–191, 190f
function of symmetry points, defined, 188–189
225–227, 226f Fluorescence determination, of iron
OD of, 224, 225 contents, 248, 248t, 249f
oxidative stress and dementia, Fluorine MRI, 142
227–229, 228f FMRI, See Functional magnetic resonance
spectroscopic techniques, 224–225 imaging (fMRI)
in liver and spleen, 223 Food and Drug Administration (FDA), 63
neuroferritinopathy, 228 Forward problem in biomagnetism, 101f
overview, 222–223 Fourier transformation, 129, 130, 132
in Parkinson’s disease, 228 Fourier-transformed infrared
physiological role, 222–223, 223f measurements (FTIR), of
Ferromagnetic materials, 15–16 ferritin, 240
330 ◾ Index
Fracture, treatments for, 199 H-coils, in dTMS, 306, 307

Frei, E. H., 4 Head, human
Frequency(ies) RF distribution in, 155–158
biomagnetic phenomena and, 7–8, 7f, 13 FDTD method, 155–157, 156f
characteristics, permittivity and at varied frequencies, 157–158, 158f
conductivity and, 150–153, 151f, Hemorrhagic patients, 311
152t High-field MRI systems, 11, 12
varied, RF distribution in human head High-frequency magnetic fields, on
at, 157–158, 158f biological systems, 195–196
Friedreich ataxia, iron in, 228 Hippocampus, ischemic tolerance of,
FTIR (Fourier-transformed infrared 73–75, 75f
measurements), of ferritin, 240 History, biomagnetics, 1–7
Fujiki, M., 10 Hodgkin-Huxley equations, 46
Functional brain mapping, See Brain Hodgkin-Huxley model, 46
mapping, functional Home treatment, magnetic stimulator for,
Functional connectivity MRI (fcMRI), 81–82, 82f
TMS and, 308 Homogeneous magnetic field, biological
Functional magnetic resonance imaging system in
(fMRI), 11, 69, 122, 140, 141f magnetic forces, 189–191, 190f
on BOLD effects, 310 magnetic torque, 191
spatial distributions of neuronal Human exposure, to time-varying electric
activities, 148 and magnetic fields, 278–279,
TMS with, 308 278t
Human-hamster cells, ATP content in,
269–270
G
Human studies
Gaussian excitation, 128 biological effects of static magnetic
Glial cells, 94 field, 270–272
Gradient field, 128–129, 129f head, RF distribution in, 155–158
Gradient magnetic fields FDTD method, 155–157, 156f
biological effects related to MRI, 272 at varied frequencies, 157–158, 158f
biological interaction in, 263–264 MRI of electric currents, 178–180,
exposure guidelines, related to MRI, 179t, 180f
278–279, 278t, 279t for numerical simulations of EMFs,
Gradiometric pickup coils, MEG, 93–94, 94f 153–154
Gray matter, permittivity and conductivity 6-Hydroxidopamine (6-OHDA), reducing
frequency characteristics of, 151–152, 151f agent, 224–225, 241–242, 242f
on MPG direction, 164 Hyperthermia, 12, 195, 205–206, 209, 210t
Growth, biological cell
magnetic control of, See Biological cell
I
growth, magnetic control of
IARC (International Agency for Research
on Cancer), 272, 273
H
ICNIRP, See International Commission
Halo coils, in dTMS, 306, 307 on Non-Ionizing Radiation
Hardware Protection (ICNIRP)
driving circuit, 36–38, 37f IEC, See International Electrotechnical
MEG, 92–94 Commission (IEC)
Index ◾ 331
IEEE Transactions on Magnetics, 4 International Commission on Non-

IFCN, See International Federation of Ionizing Radiation Protection
Clinical Neurophysiology (ICNIRP), 4
(IFCN) document, 263, 276–277, 280
IgG (immunoglobulin G), 207 effects of static magnetic fields by,
Image contrast, 135–137, 136f, 137f 188
Imatinib mesylate, 212 EU EMF Directive, 291–296, 293t, 295t
Immunoglobulin G (IgG), 207 guideline, 195, 276–277, 278, 279, 280,
Immunomodulatory effects, 209–212 291–296, 293t, 295t
Impedance, MRI of, 11, 146–169 protection of patients, MRI
advantages in imaging, 146–147 examinations and, 282, 283,
conductivity imaging using diffusion 285–287, 286t, 287t
MRI, 161–165 recommendation, 282
experimental results, 162–165, 163f, responsibility, 276, 279
164f International Electrotechnical
principles, 161–162 Commission (IEC), 4
EIT, 167, 168–169 International Federation of Clinical
external AC field, use of, 159, 160, Neurophysiology (IFCN), 46
161f Inverse problem, MEG, 100, 101f
large flip angle method, 159, 160f Inversion-recovery (IR) image, 137
overview, 146–147 IPAT2, See Standing for integrated parallel
with RF current, 165–167 acquisition techniques square
experimental results, 167, 168f (iPAT2)
principles, 165–167, 166f IR, See Inversion-recovery (IR) image
sample, influence on, See also Sample Iriguchi, N., 11
impedance Iron biochemistry, RF magnetic fields on
electric properties of biological medical consequences and
tissues, 148–154 applications, 221–222
RF distribution in cylindrical Iron contents
sample, 154, 155f determination, spectroscopic
RF distribution in human head, techniques in, 224–225
155–158 fluorescence determination of, 248,
Inhibition, of tumor growth by pulsed 248t, 249f
magnetic stimulation, 209–212 Iron oxides, ferrimagnetism in, 230, 231
background, 209–210, 210t Iron release, RF magnetic fields on,
magnetic control, 211–212, 211f, 212f 220–253
Intensity, magnetic field, 7–8, 7f cage proteins, 222–229
Interactions ferritins, See Ferritins
biological, mechanisms for, oxidative stress and dementia,
262–265 227–229, 228f
gradient (time-varying) magnetic spectroscopic techniques, 224–225
field, 263–264 symmetry points, function,
RF electromagnetic field, 264–265 225–227, 226f
static magnetic field, 262–263 changes in, 236–241
of RF magnetic fields on iron release/ chemical concentrations of ferritin
uptake, 220–221 and ferrozine, 237–238, 237f
International Agency for Research on effects in iron chelation, 238–240,
Cancer (IARC), 272, 273 239f
332 ◾ Index
effects in nanoparticle/entry-exit overview, 220–222

process, 240, 240f Raman spectroscopy during exposure,
experimental setup and titration 242–243
measurements, 235–236 threefold symmetry point and future
ferrihydrite bionanoparticles, considerations, 245–253
magnetic properties, 229–235 effects and future considerations,
AC susceptibility, 234–235, 235f 249–253, 252f
ferrimagnetism in iron oxides and effects of cationization at, 245–248,
surface effects, 230, 231 247f
nanoscale magnetism, 229–231 fluorescence determination of iron
Néel and Brownian relaxation, contents, 248, 248t, 249f
233–234 Irvin, D. D., 5
power absorption and dissipation, Ischemic stroke patients, 311
232–235 Iwasaka, M., 11
superparamagnetism, 230, 231f
interactions, 220–221
J
overview, 220–222
reducing agents, 241–242, 241f Japan Society for Thermal Medicine, 195,
threefold symmetry point and future 205–206
considerations, 245–253 Josephson junction, SQUID, 92
effects and future considerations,
249–253, 252f
K
effects of cationization at, 245–248,
247f Kamei, H., 11
fluorescence determination of iron K space, 133–135, 134f, 135f
contents, 248, 248t, 249f
Iron uptake, RF magnetic fields on,
L
220–253
cage proteins, 222–229 Labyrinth-ecotomized rats, 267–268
ferritins, See Ferritins Large flip angle method, 159, 160f
oxidative stress and dementia, Larmor equation, 148–149, 169
227–229, 228f Lauterbur, Paul Christian, 10
spectroscopic techniques, 224–225 Lead field, MEG, 99–100
symmetry points, function, Leukemic cells, distraction
225–227, 226f by magnetizable beads and pulsed
changes in, 243–245, 244f, 245f magnetic force, 205–209
ferrihydrite bionanoparticles, background, 205–206
magnetic properties, 229–235 magnetic destruction by physical
AC susceptibility, 234–235, 235f force, 207–209, 208f, 209f
ferrimagnetism in iron oxides and Long-term potentiation (LTP), 72–73,
surface effects, 230, 231 72f
nanoscale magnetism, 229–231 Lorentz force, 42
Néel and Brownian relaxation, conductive fluids and, 189–191, 190f
233–234 defined, 188–189
power absorption and dissipation, Lovsund, P., 3
232–235 Low-frequency magnetic fields, on
superparamagnetism, 230, 231f biological systems, 194–195
interactions, 220–221 LTP, See Long-term potentiation (LTP)
Index ◾ 333
M tumor growth inhibition, 209–212

background, 209–210, 210t
Maass, J. A., 5
pulsed magnetic stimulation on,
Maghemite, 231
211–212, 211f, 212f
Magnetically aligned collagen gel
“Magnetic curtain,” 15
(M-COL), 205
Magnetic fields
Magnetically aligned collagen gel mixed
biological effects, 12–13, 14t
with Schwann cells (M-S-COL),
biological effects related to MRI
205
gradient (time-varying), 272
Magnetic control, of biological cell
static, 266–272
growth, 186–212
biological interaction in
biomagnetic effects, basic principles,
gradient (time-varying), 263–264
See also Biomagnetic effects
static, 262–263
multiplicity of magnetic fields and
on biological systems
other energy forms, 196–197
homogeneous, 189–191, 190f
static magnetic fields on biological
inhomogeneous, 192–194
systems, 188–194
multiplicity, other energy
time-varying magnetic fields on
forms and, 196–197, See also
biological systems, 194–196
Multiplicity of magnetic fields
bone growth acceleration, 198–202
static, See Static magnetic fields
ALP activity, of MC3T3-E1 cells,
time-varying, 194–196, See also
200–201
Time-varying magnetic fields
background, 198–199
exposure guidelines related to MRI
in vitro experiments, 200–201,
gradient (time-varying), 278–279,
200f
278t, 279t
in vivo experiments, 201–202,
movement-related, 280, 282,
201f
284t
distraction of leukemic cells, 205–209
static, 277–278, 277t
background, 205–206
intensities, 7–8, 7f
destruction by physical force,
protection of patients, MRI
207–209, 208f, 209f
examinations and
magnetic orientation of adherent cells,
static, 283, 285
197–198
time-varying, 285
collagen, 198, 198f
resonance signals from, changes in,
endothelial cells, 198, 198f
169–170
fibrins, 198, 198f
RF, on iron release/uptake, 220–253
osteoblast cells, 198, 198f
polymerization processes of fibrin
iron cage proteins, 222–229,
fibers, 197, 197f
See also Cage proteins
Schwann cells, 198, 198f
medical consequences and
smooth muscle cells, 198, 198f
applications, 221–222
magneto-mechanical effects, 187
overview, 220–222
nerve regeneration, 202–205
properties of ferrihydrite
background, 202–203, 202f
bionanoparticles, See
Schwann cells, magnetic field on,
Ferrihydrite bionanoparticles
203–205, 204f
safety aspects, 260–297
overview, 186–188
biological effects related to MRI,
sources of exposure for, 187
See Biological effects
334 ◾ Index
biological interaction, mechanisms power absorption and dissipation,

for, See Biological interaction 232–235
exposure guidelines related to MRI, AC susceptibility, 234–235, 235f
See Exposure guidelines Néel and Brownian relaxation,
occupational exposure during MRI, 233–234
See Occupational exposure Magnetic resonance (MR), 122
overview, 260–262 signals, 123–127
on Schwann cells, nerve regeneration Magnetic resonance angiography (MRA),
and, 203–205, 204f 122, 137–138
static, See Static magnetic fields PC method, 138
of stimulator coils, 35–36, 35f TOF method, 138
Magnetic forces Magnetic resonance imaging (MRI), 4,
on biological system 10–11, 41, 42
homogeneous magnetic field, advances in, 310–311
189–191, 190f application techniques, 137–142
inhomogeneous magnetic field, biological effects related to, 265–276
192–194 gradient (time-varying) magnetic
defined, 187 field, 272
pulsed, distraction of leukemic cells by, health effect related to operation,
205–209 274–276
background, 205–206 RF electromagnetic field, 273–274
destruction by physical force, static magnetic field, 266–272
207–209, 208f, 209f of electric current, See also Electric
Magnetic induction, conductive fluids currents
and, 189–191, 190f advantages in imaging, 147–148
Magnetic nanoparticles, 12 animal studies, 174–178
Magnetic nerve stimulation, 5–6, 25 changes in signals, from magnetic
Magnetic orientation, 197–198 field, 169–170
in biological molecules and cells, 187 goals, 148
cell, 11–12 human studies, 178–180, 179t, 180f
collagen, 187, 198, 198f overview, 147–148
defined, 187 weak, sensitivity to, 170–174
endothelial cells, 198, 198f electromagnetic field, types, 260
fibrins, 198, 198f electromotive force, 123–127, 123f,
medical applications of, 187 124f, 127f
osteoblast cells, 187, 198, 198f EPI technique, 128, 138–139
polymerization processes of fibrin exposure guidelines related to, 276–287
fibers, 197, 197f gradient (time-varying) magnetic
Schwann cells, 187, 198, 198f, 203, field, 278–279, 278t, 279t
205 movement-related magnetic field,
smooth muscle cells, 198, 198f 280, 282, 284t
Magnetic particle imaging (MPI), 311 protection of patients, MRI
Magnetic properties, of ferrihydrite examinations and, 282, 283,
bionanoparticles, 229–235 285–287, 286t, 287t
nanoscale magnetism, 229–231 RF electromagnetic field, 279–280,
ferrimagnetism in iron oxides and 281t, 282t, 283t
surface effects, 230, 231 static magnetic field, 277–278, 277t
superparamagnetism, 230, 231f fcMRI, TMS and, 308
Index ◾ 335
FE imaging, 128, 130, 130f Magnetic resonance spectroscopy, 140

fMRI, 140, 141f Magnetic stimulation
on BOLD effects, 310 biological effects, 187
spatial distributions of neuronal for cancer therapy, 187
activities, 148 medical applications of, 187
TMS with, 308 Magnetic susceptibility, 15, 16
frequency of signal, 148 Magnetic torque
image contrast, 135–137, 136f, 137f on biological systems in homogeneous
of impedance, 146–169, See also magnetic field, 191
Impedance defined, 188, 189
advantages in imaging, 146–147 Magnetite, 6, 16
conductivity imaging using Magnetizable beads, distraction of
diffusion MRI, 161–165 leukemic cells by, 205–209
EIT, 167, 168–169 background, 205–206
external AC field, use of, 159, 160, destruction by physical force, 207–209,
161f 208f, 209f
large flip angle method, 159, 160f Magnetization, 123–124, 123f, 124f
overview, 146–147 Magnetization angles, images, 167, 168f
with RF current, 165–167 Magnetocardiography (MCG), 4, 9
sample, influence on, 148–158 Magnetoencephalography (MEG), 4, 5, 8–9
k space, 133–135, 134f, 135f auditory evoked responses, 110–111,
magnetic resonance angiography, 111f, 112f
137–138 BEM, 98–99
magnetic resonance spectroscopy, 140 clinical applications, 91–92
occupational exposure during, 288–296 current source estimations of, 165
assessment, 288 dipolar current in volume conductor,
EU EMF Directive, 291–296, 293t, 97–98, 97f
295t distributed source imaging, 105–108
worker exposure assessment, 289–291 equivalent current dipole, 101–105,
of other nuclei than protons, 141–142, 106f
141f gradiometric pickup coils, 93–94, 94f
overview, 121–122 hardware, 92–94
perfusion and diffusion imaging, history of, 90–91, 91f
138–140, 139f inverse problem, 100, 101f
phase encoding, 131–133, 132f, 133f lead field, 99–100
related to operations, 290–291 Maxwell’s equation, 96
SE imaging, 127, 127f, 128, 130, 133, MEG inverse problem, 100, 101f
133f multichannel MEG system, 93–94, 94f
spin-warp imaging technique, 127–137 multimodal integration and, 309
SQUIDs and ULF, combination, multimodal neuroimaging, 112–114,
309–310 113f
1-T MRI scanner, 290 neural source reconstruction, 100–108
1.5-T MRI scanner, 290 primary current, 96
7-T MRI scanner, 275–276 signal generation, 96–100, See also
UHF-MRI, 310–311 Signals, MEG
Magnetic resonance signals, from SQUID systems, 4, 8, 9, 90–91, 92–93, 93f
magnetic field visual evoked responses, 109–110, 109f,
changes in, 169–170 110f
336 ◾ Index
Magnetohydrodynamics (MHD), 274–275 MIP, See Maximum intensity projection

principle of, 189 (MIP)
Magneto-mechanical effects Missile effect, defined, 192
interactions for, 263 Mobile telephony, 12, 13
in magnetic control of cell growth, 187 Models
Magneto-mechanical translation, 191, of dispersion, 150
192–193 human, See Human studies
Magnetophosphene, 3–4, 25 mouse, See Mouse models
Magnetopneumography (MPG), 9 radical pair, 196–197, 196f
Magnetotactic bacteria, 6 Modern biomagnetics, 4–7
Magnusson, C. E., 3 Mohr’s salt, 243, 245
Mansfield, Peter, 10 Molecular imaging, 312
Maximum intensity projection (MIP), 138 Monophasic waveforms, 25, 27f
Maxwell, James C., 13 Moses effect, 8, 11, 15
Maxwell’s equations, 13 defined, 192–193, 193f
for electromagnetic fields, 155 Mössbauer spectroscopy, 229
MEG, 96 Motion-induced currents
MC (mean conductivity), images, 164f on biological system, 189, 193–194
McFee, R., 4 Motion-probing gradient (MPG)
MCG, See Magnetocardiography (MCG) diffusion components for, 162
M-COL (magnetically aligned collagen gray matter’s conductivity on, 164
gel), 205 Motor evoked potential (MEP), 46, 63
MC3T3-E1 cells, ALP activity, 200–201 Mouse models
MEA (multielectrode array), eight-by- B16-BL6 melanoma, 211
eight-channel, 175–176, 175f biological effects of static magnetic
Mean conductivity (MC), images, 164f field, 266–269
Medicine, applications in BMP-2/collagen pellets, 201
diagnosis of nervous system, 76–77 destruction of leukemia cells by
functional brain mapping, 68–69, physical force, 207–209, 208f,
68f 209f
overview, 63 head with excitation flip angles, 159,
treatment of neurological diseases 160f
home treatment, 81–82, 82f labyrinth-ecotomized, 267–268
neuropathic pain, 79–80 MC3T3-E1 cells, 200
Parkinson’s disease, 77–79, 78f MRI of electric currents
psychiatric diseases, 80–81 brain slices, 174–176, 175f
safety, 82 in vivo experiments, 176–178, 177f,
MEG, See Magnetoencephalography 178f
(MEG) tumor growth inhibition by pulsed
Melanoma, hyperthermia for, 195, magnetic stimulation, 211–212,
205–206 211f, 212f
MEP, See Motor evoked potential (MEP) Movement-related magnetic field
MHD (magnetohydrodynamics), 274–275 exposure guidelines related to MRI,
principle of, 189 280, 282, 284t
Microwave imaging MPG, See Magnetopneumography
on biological systems, 195–196 (MPG)
MPI and, 311 MPI (magnetic particle imaging), 311
Minimum-norm estimates, 106–107 MR, See Magnetic resonance (MR)
Index ◾ 337
MRA, See Magnetic resonance Nerve fibers

angiography (MRA) equivalent circuit of, 44f
MRI, See Magnetic resonance imaging in peripheral nervous system, 47–48, 195
(MRI) regeneration, 202f
M-S-COL (magnetically aligned collagen Nerve regeneration, direction and growth
gel mixed with Schwann cells), of nerve axons and, 202–205
205 background, 202–203, 202f
Multichannel MEG system, 93–94, 94f magnetic control, 203–205, 204f
Multidipole model, 101–103, 104f mechanisms in PNS, 202f
Multielectrode array (MEA), eight-by- Neural source reconstruction, MEG,
eight-channel, 175–176, 175f 100–108
Multimodal integration, MEG and, 309 distributed source imaging, 105–108
Multimodal neuroimaging, 41–42, 42f, equivalent current dipole, 101–105, 106f
112–114, 113f Neuroferritinopathy, 228
Multiple signal classification (MUSIC), Neuromagnetism, 5
104–105, 106f Neuronal current dipole, 170–171
Multiplicity of magnetic fields, other Neuronal plasticity, 75–76
energy forms and, 196–197 Neuropathic pain, treatment of, 79–80
photochemical reactions, 196–197, 196f NIBIE (National Institute of Biomedical
radical pair model, 196–197, 196f Imaging and Bioengineering), 312
singlet-triplet intersystem crossing, NICT (National Institute of Information
196–197, 196f and Communications
Musculoskeletal system, trauma to, Technology), 153
198–199 NIH (National Institutes of Health), 312
MUSIC (multiple signal classification), Nilsson, S. E. G., 3
104–105, 106f NMR, See Nuclear magnetic resonance
(NMR)
N,N dimethyl-l,3propanediamine
N
(NNPD), 247
Nanoscale magnetism, of ferrihydrite Nonthermal effects, 265
bionanoparticles, 229–231 Nuclear magnetic resonance (NMR), 122
ferrimagnetism in iron oxides and for cancer, 260
surface effects, 230, 231 principle and technical development, 260
superparamagnetism, 230, 231f Numerical methods
National Institute of Biomedical Imaging in coil design, 53–54, 55f
and Bioengineering (NIBIE), finite element method, 48–49
312 scalar potential finite difference
National Institute of Information and method, 49–50
Communications Technology Numerical model, brain, 50–51, 51f
(NICT), 153 Numerical simulations
National Institutes of Health (NIH), 312 of EMFs, human models, 153–154
Néel-Arrhenius relation, 234
Néel relaxation, 233–234
O
Nerve axons
growth control in nerve regeneration, Oberg, P. A., 3, 5
202–205 Occupational exposure
background, 202–203, 202f assessment, 288
magnetic control, 203–205, 204f defined, 278
338 ◾ Index
Directive 2013/35/EU, 288 Peripheral nerve stimulation, 47–48

during MRI, 288–296 activating function, 47–48
EU EMF Directive, 291–296, 293t, stimulation site, 48
295t Peripheral nervous system (PNS)
worker exposure assessment, for nerve regeneration, 202
289–291 mechanisms, 202f
to time-varying electric and magnetic Schwann cells in, 202–203
fields, 279t Permittivity, of biological tissues, 148–150
OD (optical density), of ferritin, 224, 225 Debye’s equation, 150
Oersted, Hans C., 13 frequency characteristics and, 150–153,
Ogawa, Seiji, 11, 15 151f, 152t
6-OHDA (6-hydroxidopamine), reducing P300 evoked potentials, 70–71
agent, 224–225, 241–242, 242f Phase angle shift, in MRI signal, 174
Ohm’s law, 45 Phased-contrast (PC) method, 138
Optical density (OD), of ferritin, 224, 225 Phase encoding, 131–133, 132f, 133f
Orientation, magnetic, See Magnetic Phenomena, biomagnetic, 7–8, 7f
orientation electromagnetic induction, 12–13, 14t
Osteoblast cells, magnetic orientation in, magnetism of living systems/materials,
187, 198, 198f 14–16
Osteogenic activity, BMPs for, 199 Phosphenes, magnetic, 195
Oxidative stress, iron in, 227–229, 228f Photochemical reactions, in magnetic
field, 196–197, 196f
Physical force, magnetic destruction of
P
leukemia cells by, 207, 208f, 209,
Pain, TMS and, 26 209f
Paired-pulse stimulation, 71–72 Physiological background, biomagnetic
Paramagnetic materials, 15 signals
Parkinson’s disease (PD) cortical neural activity, 94–95
iron in, 228, 241 current dipole modeling of synaptic
treatment of, 77–79, 78f activities, 95–96, 95f
“Parting of water,” See Moses effect PNS (peripheral nervous system)
Patients, protection for nerve regeneration, 202
MRI examinations and, 282, 283, mechanisms, 202f
285–287 Schwann cells in, 202–203
ICNIRP recommended limits, Polymerization, of fibrins, 197, 197f
287t Power absorption and dissipation
RF electromagnetic fields, 285–287, ferrihydrite bionanoparticles, 232–235
286t AC susceptibility, 234–235, 235f
static magnetic field, 283, 285 Néel and Brownian relaxation,
time-varying magnetic fields, 285 233–234
PC, See Phased-contrast (PC) method Pregnancy, biological effects of static
PD, See Parkinson’s disease (PD) magnetic field in, 267
PEMFs (pulsed electromagnetic fields), on Primary current, 96
fracture healing, 199 Projectile effect, defined, 192
Peptides, fluorescent characteristics of, Properties, electric
248, 248t of biological tissues, 148–154
Perfusion imaging, 138–140 frequency characteristics and
Perfusion system, in brain slice, 175f, 176 anisotropy, 150–153, 151f, 152t
Index ◾ 339
human models for numerical exposure guidelines related to MRI,

simulations of EMFs, 153–154 279–280, 281t, 282t, 283t
permittivity and conductivity, protection of patients, MRI
148–150 examinations and, 285–287, 286t
Protection, patients waves
MRI examinations and, 282, 283, MRI signal as, 148
285–287 propagation velocity, 149
ICNIRP recommended limits, 287t wavelength, 149
RF electromagnetic fields, 285–287, Radio frequency (RF) magnetic fields,
286t 12, 13
static magnetic field, 283, 285 Radio frequency (RF) magnetic fields, on
time-varying magnetic fields, 285 iron, 220–253
Proton density, 125 biochemistry, medical consequences
Pseudarthrosis, 199 and applications, 221–222
Psychiatric diseases, treatment of, 80–81 cage proteins, 222–229
Pulsed electromagnetic fields (PEMFs), on ferritins, See Ferritins
fracture healing, 199 oxidative stress and dementia,
Pulsed magnetic fields, 9, 12 227–229, 228f
on biological systems, 194–195 spectroscopic techniques, 224–225
Pulsed magnetic force, distraction of symmetry points, function,
leukemic cells by, 205–209 225–227, 226f
background, 205–206 on iron release, See also Iron release
magnetic destruction by physical force, changes in, 236–241, 237f, 239f,
207–209, 208f, 209f 240f
Pulsed magnetic stimulation experimental setup and titration
tumor growth inhibition by, 209–212 measurements, 235–236
background, 209–210, 210t interactions, 220–221
magnetic control, 211–212, 211f, overview, 220–222
212f reducing agents, 241–242, 242f
on iron uptake, See also Iron uptake
changes in, 243–245, 244f, 245f
R
Radical pair effect, 189, 196–197, 196f overview, 220–222
Radiofrequency (RF) Raman spectroscopy during
current, impedance imaging using, exposure, 242–243
165–167 magnetic properties of ferrihydrite
experimental results, 167, 168f bionanoparticles, 229–235
principles, 165–167, 166f AC susceptibility, 234–235, 235f
distribution in cylindrical sample, 154, ferrimagnetism in iron oxides and
155f surface effects, 230, 231
distribution in human head, 155–158 nanoscale magnetism, 229–231
FDTD method, 155–157, 156f Néel and Brownian relaxation,
at varied frequencies, 157–158, 233–234
158f power absorption and dissipation,
electromagnetic fields 232–235
biological effects related to MRI, superparamagnetism, 230, 231f
273–274 threefold symmetry point and future
biological interaction in, 264–265 considerations, 245–253
340 ◾ Index
effects and future considerations, gradient (time-varying) magnetic

249–253, 252f field, 272
effects of cationization at, 245–248, health effect related to operation,
247f 274–276
fluorescence determination of iron RF electromagnetic field, 273–274
contents, 248, 248t, 249f static magnetic field, 266–272
Raman spectroscopy, RF exposure and, biological interaction, mechanisms for,
242–243 262–265
Rapid-rate transcranial magnetic gradient (time-varying) magnetic
stimulation, See Repetitive TMS field, 263–264
Reaction maps, 41 RF electromagnetic field, 264–265
Reactive oxygen species (ROS), levels of, 270 static magnetic field, 262–263
Reading-out of the signal, 129 exposure guidelines related to MRI,
Receivers, RF, 165, 166f 276–287
Reducing agents, on iron release, 241–242, gradient (time-varying) magnetic
241f field, 278–279, 278t, 279t
Regions of interest (ROIs), 140, 176–177 movement-related magnetic field,
Reite, M., 5 280, 282, 284t
Relaxation time, 125–127 protection of patients, MRI
Release, iron, See Iron release examinations and, 282, 283,
Repetitive TMS (rTMS), 307 285–287, 286t, 287t
brain research, 72–76 RF electromagnetic field, 279–280,
ischemic tolerance of hippocampus, 281t, 282t, 283t
73–75, 75f static magnetic field, 277–278, 277t
long-term potentiation (LTP), 72–73, 72f occupational exposure during MRI,
neuronal plasticity, 75–76 288–296
therapeutic application, 10, 63 assessment, 288
Resting membrane potential, 43 EU EMF Directive, 291–296, 293t,
Resting motor threshold (RMT), 46 295t
Results, experimental worker exposure assessment,
conductivity imaging using diffusion 289–291
MRI, 162–165, 163f, 164f overview, 260–262
impedance imaging using RF current, Salmonella typhimurium, 269
167, 168f Sample impedance, on MRI, 148–158
RF, See Radiofrequency (RF); Radio electric properties of biological tissues,
frequency (RF) magnetic fields 148–154
RMT, See Resting motor threshold (RMT) frequency characteristics and
ROIs, See Regions of interest (ROIs) anisotropy, 150–153, 151f, 152t
Romani, G. L., 5 human models for numerical
ROS (reactive oxygen species), levels of, 270 simulations of EMFs, 153–154
RTMS, See Repetitive TMS (rTMS) permittivity and conductivity,
148–150
RF distribution in cylindrical sample,
S
154, 155f
Safety aspects, of magnetic and EMFs, RF distribution in human head,
260–297 155–158
biological effects related to MRI, FDTD method, 155–157, 156f
265–276 at varied frequencies, 157–158, 158f
Index ◾ 341
SAR, See Specific absorption rate (SAR) signal inhomogeneities and, 157
Scalar potential finite difference (SPFD) from square of electric field strength,
method, 49–50 265
Schwann cells Spectroscopic techniques, in
magnetic orientation in, 187, 198, 198f, determination of iron contents,
203, 205 224–225
in medical and tissue engineering, 203 SPFD, See Scalar potential finite difference
nerve regeneration and (SPFD) method
magnetic field on, 203–205, 204f Spin echo (SE) signal, 127, 127f, 128, 130,
in PNS, 202–203 133, 133f
S-COL (collagen gel mixed with Schwann Spinning nuclei, 125–126
cells), 205 Spin-warp imaging technique, 127–137
SE, See Spin echo (SE) signal image contrast, 135–137, 136f, 137f
Sekino, M., 11 k space, 133–135, 134f, 135f
Sensitivity, to weak electric currents, 170–174 nuclei distributed in first direction,
experimental evaluation, 174 128–129, 129f
neuronal current dipole, 170–171 nuclei distributed in second direction,
theoretical evaluation, 171–173, 173f 129–131, 130f, 131f
Sentinel lymph nodes, imaging, 311 nuclei distributed in third direction,
Shielding effects, of eddy currents, 159 131–133, 132f, 133f
Shimming, 126 SQUID, See Superconducting quantum
Signals, MEG interference devices (SQUID)
beamformer, 107–108, 108f Standing for integrated parallel
distributed source imaging, 105–108 acquisition techniques square
equivalent current dipole, 101–105, (iPAT2), 137
106f Static magnetic fields, 13, 14
generation, 96–100 biological effects related to MRI,
inverse problem and, 100, 101f 266–272
minimum-norm estimates, 106–107 human experimental and
neural source reconstruction from, epidemiological studies, 270–272
100–108 in vitro studies, 269–270
“Silent” source, magnetically, 100 in vivo studies, 266–269
Single ECD model, 101 biological interaction in, 262–263
Singlet-triplet intersystem crossing, on biological systems, 188–194
196–197, 196f magnetic force, 189–194, 190f
Singular value decomposition (SVD), 103 magnetic torque in homogeneous
Skin effect, 154, 155f magnetic field, 191
Slice-selective excitation of nuclei, overview, 188f
128–129, 129f bone growth acceleration by, 198–202
Smooth muscle cells, magnetic orientation background, 198–199
in, 187, 198, 198f magnetic control, 200–202, 200f, 201f
Soma (cell body), 94, 95f exposure guidelines related to MRI,
Somatosensory-evoked potentials, 174 277–278, 277t
Spatial resolution, brain mapping, 64–66, in MRI, 260
65f, 66f in nerve regeneration, 202–205
Specific absorption rate (SAR), 13 background, 202–203, 202f
calculation, 236 Schwann cells, magnetic field on,
quantity, 265 203–205, 204f
342 ◾ Index
polymerization processes of fibrin T

fibers, 197, 197f
TCC-S leukemic cells, 207, 212
TDCS (transcranial direct current
examinations and, 283, 285
stimulation), 307
Stevens, H. C., 3
Theoretical evaluation, of sensitivity,
Stewart, O., 10
171–173, 173f
Stimulation site
Thermal effects, 265
peripheral nerve stimulation, 48
Thompson, S. P., 3
TMS, 46–47, 47f
Three-dimensional, TOF MRA, 138
Stimulator coils
Threefold symmetry point, in iron release/
circular coils, 28–30, 28f
uptake, 225–227, 226f, 245–253
coil array, 31–32, 31f
cooling systems, 34–35
249–253, 252f
double-cone coil, 28f, 30
effects of cationization at, 245–248, 247f
emerging designs, 32–34, 33f
fluorescence determination of iron
figure-eight coil, 28f, 30
magnetic field and current,
Time-of-flight (TOF) method, 138
measurement of, 35–36, 35f
Time-varying magnetic fields, 13
Stokes-Einstein equation, 161
biological effects related to MRI, 272
ST segment shift, 4
biological interaction in, 263–264
Superconducting quantum interference
on biological systems, 194–196
devices (SQUIDs), 4, 8, 9, 90–91,
high-frequency magnetic fields and
92–93, 93f
microwaves, 195–196
dc SQUID, 92–93, 93f
low-frequency and pulsed magnetic
Josephson junction, 92
fields, 194–195
magnetometers, 229
exposure guidelines, related to MRI,
multichannel SQUID, 93–94
278–279, 278t, 279t
ULF-MRI and, combination, 309–310
Superparamagnetism, of ferrihydrite
examinations and, 285
bionanoparticles, 230, 231f
TIRM image, 137
Surface effects, ferrimagnetism in, 230,
Tissues, biological
231
electric properties of, 148–154
Susceptibility, AC
frequency characteristics and
in ferrihydrite bionanoparticles,
anisotropy, 150–153, 151f, 152t
234–235, 235f
human models for numerical
SVD, See Singular value decomposition
simulations of EMFs, 153–154
(SVD)
permittivity and conductivity,
Symmetry points, threefold
148–150
in iron release/uptake, 225–227, 226f,
Titration measurements
245–253
RF magnetic fields on iron release,
235–236
249–253, 252f
TMS, See Transcranial magnetic
effects of cationization at, 245–248,
stimulation (TMS)
247f
TNF-α (tumor necrosis factor)
fluorescence determination of iron
production, 211–212
TOF, See Time-of-flight (TOF) method
Synaptic activities, current dipole
Torbet, J., 6
modeling, 95–96, 95f
Index ◾ 343
Torque, magnetic V
on biological systems in homogeneous
Varied frequencies, RF distribution in
magnetic field, 191
human head at, 157–158, 158f
defined, 188, 189
Virtual lesion, 69
Transcranial direct current stimulation
Visual evoked responses, 109–110, 109f,
(tDCS), 307
110f
Transcranial magnetic stimulation (TMS),
Visual perception, 3–4, 25
6, 25, 26, 26f, 46–47
Volume conductor, dipolar current in,
applications of, 195
97–98, 97f
for DBS, 306–307
DTI and EEG, combination, 307–308
dTMS, 306–307 W
EEG evoked by TMS, 66, 67f, 68
Wallerian degeneration, defined, 202, 203
FDA clearance for, 63
Water
rTMS, 307
relative permittivity of, 149
stimulation site, 46–47, 47f
Weak electric currents, sensitivity to,
vs. ECT, 51–53, 52f
170–174
Transmitters, RF, 165–166, 166f
experimental evaluation, 174
TSE image, 137
neuronal current dipole, 170–171
Tumor growth inhibition
theoretical evaluation, 171–173, 173f
by pulsed magnetic stimulation,
Weizmann Institute of Science, 4
209–212
WHO (World Health Organization), 188,
background, 209–210, 210t
266, 268, 270, 271
magnetic control, 211–212, 211f, 212f
William, Gilbert, 2–3, 2f
Tumor necrosis factor (TNF-α)
Worker exposure assessment, 289–291
production, 211–212
World Health Organization (WHO), 188,
T1-weighted images, 136–137, 136f
266, 268, 270, 271
T2-weighted images, 136–137, 136f, 137f
U Y
Ueno, S., 5, 6, 11, 15 Yee algorithm, 156

Ultra-high magnetic field MRI (UHF-
MRI), 310–311
Z
Ultra-low magnetic field MRI (ULF-MRI)
SQUIDs and, combination, 309–310 Zeeman interaction, 6

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Principles and Applications of

Boca Raton London New York

CRC Press is an imprint of the

No claim to original U.S. Government works

International Standard Book Number-13: 978-1-4822-3921-8 (eBook - PDF)

Chapter 2 ◾ Principles of Biomagnetic Stimulation 23

Chapter 3 ◾ Applications of Biomagnetic Stimulation

Chapter 4 ◾ Biomagnetic Measurements 89

Chapter 5 ◾ Principles of Magnetic Resonance Imaging 121

Chapter 6 ◾ Prospects for Magnetic Resonance Imaging

Chapter 7 ◾ Magnetic Control of Biological Cell Growth 185

Chapter 8 ◾ Effects of Radio Frequency Magnetic Fields

Chapter 9 ◾ Safety Aspects of Magnetic

Chapter 10 ◾ New Horizons in Biomagnetics

Biomagnetics covers a vast field in the multidisciplinary world of physics,

hazardous to the body under examination. Safety issues of medical nonin-

Seiji Ogawa, PhD

Biomagnetics is an interdisciplinary field where magnetics, biology, and

Chapter 1. Introduction (Shoogo Ueno)

A history of biomagnetic research is described, introducing Gilbert’s

The history and principles of magnetic nerve and muscle stimu-

Chapter 3. Applications of Biomagnetic Stimulation for Medical

Potential medical applications of TMS and repetitive TMS, called

described first. Studies of treatments of depression by TMS and rTMS

obtained by in vitro and in vivo experiments. Recent advances in MR

Chapter 9. Safety Aspects of Magnetic and Electromagnetic Fields

We thank the chapter authors for their intellectual contributions. Further,

University of Technology, Hawthorn, Australia (2008). Dr. Ueno was

Oscar Cespedes Tsukasa Shigemitsu

Norio Iriguchi Shoogo Ueno

and biomagnetism are used interchangeably. Biomagnetics has a long his-

Magnetic force is animate or imitates life; and in many things sur-

WILLIAM GILBERT, 1600

William Gilbert, Father of Magnetism

De Magnete, William Gilbert (1600)

FIGURE 1.1 William Gilbert (1544–1603) and the Earth.

FIGURE 1.2 Jacques-Arsene d’Arsonval (1851–1940). (From Wikipedia, the free

studied the magnetophosphenes in a dark room and observed that the

1.1.2 Modern Biomagnetics in the 1970s and 1980s

After the success of Cohen’s MEG study, magnetic fields evoked by

Basic studies of magnetic nerve stimulation have opened a new area of

103 Magnetic stimulation

Blood flow change via

10–9 Lung (MPG)

Heart (MCG) Mobile telephone

FIGURE 1.3 Various biomagnetic phenomena observed or used at different fre-

1.2.2 Biomagnetic Measurements of Magnetic

1.2.3 Biomagnetic Stimulation and Magnetic Treatments

For therapeutic applications of magnetic brain stimulation, rapid-rate

1.2.4 Magnetic Resonance Imaging of the Living System

Seiji Ogawa (1934–)63 of Japan proposed a functional MRI (fMRI) based

1.2.5 Magnetic Control of Cell Manipulation,

Magnetic alignment or magnetic orientation of biological materials is

1.2.6 Biological Interactions of ELF, Pulsed, and RF Magnetic Fields

1.3 FUNDAMENTAL BASES FOR UNDERSTANDING

where σ is electrical conductivity (S/m) and ρm is the mass density (kg/m3)

TABLE 1.1 Mechanisms of Biological Effects of Electromagnetic Fields

1.3.2 Magnetism of Living Systems and Materials

Chapter 2 ◾ Principles of Biomagnetic Stimulation 23

Chapter 3 ◾ Applications of Biomagnetic Stimulation

Chapter 4 ◾ Biomagnetic Measurements 89

Chapter 5 ◾ Principles of Magnetic Resonance Imaging 121

Chapter 6 ◾ Prospects for Magnetic Resonance Imaging

Chapter 7 ◾ Magnetic Control of Biological Cell Growth 185

Chapter 8 ◾ Effects of Radio Frequency Magnetic Fields

Chapter 9 ◾ Safety Aspects of Magnetic

Chapter 10 ◾ New Horizons in Biomagnetics

1.1.2 Modern Biomagnetics in the 1970s and 1980s

1.2.2 Biomagnetic Measurements of Magnetic

1.2.3 Biomagnetic Stimulation and Magnetic Treatments

1.2.4 Magnetic Resonance Imaging of the Living System

1.2.5 Magnetic Control of Cell Manipulation,

1.2.6 Biological Interactions of ELF, Pulsed, and RF Magnetic Fields

1.3 FUNDAMENTAL BASES FOR UNDERSTANDING

1.3.2 Magnetism of Living Systems and Materials

2.1.2 Advantages of Magnetic Stimulation

2.2.1.4 Emerging Coil Designs

2.2.1.6 Measurement of Magnetic Field and Coil Current

2.2.2.2 Analysis of Driving Circuit

2.2.3 Coil Navigation System

2.2.4 Multimodal Imaging Using Magnetic Stimulation

2.3 MECHANISMS OF MAGNETIC STIMULATION

2.3.2 Transcranial Magnetic Stimulation

2.3.3 Peripheral Nerve Stimulation

2.4 NUMERICAL ANALYSES OF MAGNETIC

2.4.1.2 Scalar Potential Finite Difference Method

2.4.2 Numerical Model of the Brain

2.4.3 Analyses of Transcranial Magnetic Stimulation

2.4.3.2 Magnetic Stimulation to the Cerebellum

2.4.4 Use of Numerical Methods in Coil Design

2.5 SUMMARY AND FUTURE PROSPECTS

3.2 FUNCTIONAL MAPPING OF THE BRAIN

3.2.1.2 Spatial Resolution of Brain Mapping

3.3 APPLICATIONS IN BRAIN RESEARCH

3.3.2 Applications in Cognitive Neuroscience

3.3.2.2 Influence on P300 Evoked Potentials