本田財団レポート No.148
第 33 回本田賞授与式 記念講演（2012 年 11 月 19 日）「ヒトの脳内水分子を活用したエコテクノロジー」
仏ニューロスピン超高磁場 MRI 研究所長

デニ・ルビアン博士

Ecotechnology of the Water Molecule in the Human Brain
Commemorative lecture at the 33rd Honda PrizeAward Ceremony on the 19th November 2012

Dr. Denis Le Bihan
M.D., Ph.D., Founding Director of NeuroSpin, CEA Saclay

デニ・ルビアン博士
仏ニューロスピン超高磁場 MRI 研究所長
M.D., Ph.D., Founding Director of
NeuroSpin, CEA Saclay

Dr. Denis Le Bihan■生まれ
1957年７月30日

仏ナンテール（フランス国籍）■学 歴
医学（パリ大学）
1987年
仏放射線学委員認定
1984年

パリ大学医学博士

1981年～87年

脳神経外科・核医学科・放射線科研修医

物理学（パリ大学）
1987年
エコール･ポリテクニーク物理科学博士
1985年

核･素粒子物理学 DEA

1984年

基礎物理学 MA

1983年

基礎物理学 BS

人類生物学（パリ大学）
1979年
神経生理学･中枢神経系高等学位
1978年

生物数学･データ処理学・統計学 AEA

1977年

コンピュータ科学高等科卒■職 歴2007年～現在

仏ﾆｭｰﾛｽﾋﾟﾝ(NeuroSpin)超高磁場
MRI 研究所長

2005年～06年、08年～現在京都大学医学研究科附属脳機能総合研究ｾﾝﾀｰ脳機能画像領域客員教授

2000年 ～ 現在

仏連邦脳機能画像研究所(ﾊﾟﾘ)所長

1999年～06年

CEA ﾌﾚﾃﾞﾘｯｸ･ｼﾞｮﾘｵ勤労病院(仏ｵﾙｾｰ)
解剖学･機能的神経画像研究所長

1997年～98年

同研究所副所長兼研究部門長

1994年～96年

同研究所研究方法論部門チーフ

1991年～96年

ｼﾞｮｰｼﾞﾀｳﾝ大学病院(米ﾜｼﾝﾄﾝ D.C.)
放射線科臨床准教授

1989年～91年

同病院放射線科臨床助教授

1990年～94年

米国立衛生研究所(米ﾒﾘｰﾗﾝﾄﾞ州ﾍﾞｾｽﾀﾞ)
放射線診断研究部門チーフ

1987年～90年

同研究所臨床ｾﾝﾀｰ放射線診断科
客員准教授

■Born
July 30, 1957 in Nanterre, France (French citizenship)■Education and Training
Medicine (University of Paris):
1987
French Board Certification in Radiology.
1984
MD, Doctor in Medicine with Distinction, University ofParis.
1981-87 Residency in Neurosurgery, Nuclear Medicine andRadiology.
Physics (University of Paris):
1987
PhD in Physical Sciences, with High Distinction, Ecole
Polytechnique.
1985
Extensive Studies Degree (DEA) in Nuclear andElementary Particles Physics, with Distinction.
1984
Maitrise ("MA") in Fundamental Physics, with HighDistinction.
1983
Licence ("BS") in Fundamental Physics, with HighDistinction.
Human Biology (University of Paris):
1979
Higher Studies Degree in Neurophysiology and Central
Nervous System Functional Exploration.
1978
Extensive Studies Degree (AEA) in Biomathematics,
Data Processing and Statistics, with major in
Mathematical Models in Medicine.
1977
Higher Studies Degree in Computer Sciences.

■Employment History
NeuroSpin, CEA-Saclay, France 2007-present: Director
Kyoto University, Japan: 2005-06, 08-present: Invited Professor,
Graduate School of Medicine, Human Brain Research Center.
Federative Research Institute on Functional Neuroimaging, Paris,
France: 2000-present: Director
Service Hospitalier Frédéric Joliot, CEA, Orsay, France 1999-2006 :Director, Laboratory of Anatomical and Functional
Neuroimaging 1997-98: Vice-Head and Research Director
1994-96: Chief, Research and Methodology Section.
Georgetown University Hospital, Washington, DC, USA, 1991-96:
Clinical Associate Professor of Radiology, Dept. of Radiology,
1989-91: Clinical Assistant Professor of Radiology, Dept. ofRadiology.
National Institutes of Health, Bethesda, MD, USA 1990-94: Chief,
Diagnostic Radiology Research Section (with Tenure) 1987-90:
Visiting Associate, Diagnostic Radiology Department, ClinicalCenter.

■略 歴ルビアン博士は、人間の脳機能の研究に用いられる新画像法開発に多大な貢献をしたことで国際的に高く評価されている。博士は、超高磁場磁気共鳴設備を持つ新研究所
NeuroSpin の創設者兼所長として、マウスから人までの脳を理解するために、超高磁場磁気共鳴画像(MRI)を用いて科学的、臨床的に応用・研究を進めている。また、MRI、画
像、神経科学、放射線医学の分野で250超を寄稿(共著を含む)。仏科学アカデミー会員で、磁気共鳴医学国際協会の金賞(2001年)、全米科学アカデミー及び仏科学アカデミーのLounsbery 賞(2003年)、仏学士院ルイ• D 賞(2003年・S.
Dehaene 博士と共同)等を受賞。仏 National Order of Merit
騎士の称号も受けている。

■Biographical Sketch
Denis Le Bihan has achieved international recognition for his
outstanding contributions to the development of new imaging
methods allowing, in particular studying human brain function.
His work has combined extremely innovative methods, developed
for Magnetic Resonance Imaging (MRI) with the application of thesemethods to questions of the utmost scientific and clinicalimportance. He is a full member of the French Academy of Sciences
and currently the Founding Director of NeuroSpin, a new Instituteaimed at developing and using ultra high field Magnetic Resonanceto understand the brain, from mouse to man. He has authored or
co-authored over 250 articles, book chapters and review articles in
the fields of MRI, imaging, neuroscience and radiology. For his
contributions, he was awarded in 2001 the Gold Medal of theInternational Society for Magnetic Resonance in Medicine. He is
also the 2002 recipient of the Lounsbery Award from the National
Academy of Sciences (USA) and French Academy of Sciences and a
2003 corecipient (with S. Dehaene) of the prestigious Louis D.
Award of the Institut de France. He is Knight of the French
National Order of Merit.

■出版物『Imagerie par Resonance Magnetique (Bases
Physiques) 』Masson, Paris(1984年)■Publications『Magnetic Resonance Imaging of Diffusion and
Perfusion (Applications to Functional Imaging) 』
Lippincott-Raven Press, N.Y.(1995年)『Water, the forgotten biological molecule (福山秀直共著
2011年) 』 Pan Stanford Publishing, Singapore

Imagerie par Resonance Magnetique: Bases Physiques.

Masson, Paris, 1984. Magnetic Resonance Imaging of Diffusion

and Perfusion: Applications to Functional Imaging.
Lippincott-Raven Press, NY, 1995. Water, the forgotten
biological molecule (with H. Fukuyama), 2011, Pan Stanford
Publishing, Singapore, Le cerveau de cristal, ce que laneuroimagerie nous révèle (in press, Odile Jacob)『Le cerveau de cristal, ce que la neuroimagerie nous
révèle 』(in press, Odile Jacob)

このレポートは、2012 年 11 月 19 日 東京、帝国ホテルにおいて行なわれた第 33 回本田賞授与式記念講演の要旨をまとめたものです。
This report is the gist of the commemorative lecture at the 33rd Honda Prize Award Ceremony at the Imperial Hotel, Tokyo on
19th November 2012.

Ecotechnology of the Water Molecule in the Human Brain
Dr. Denis Le Bihan

It is an immense honor for me to receive this prestigious award. Of course, it is because of mywork, which you have found important for society, but I am extremely pleased that this award
comes from Japan, a country which I deeply affectionate. I have many friends in Japan, andsome of them are here today. I am also very pleased that my daughter, Armelle, could join me.
Unfortunately, however, my wife, Christiane, could not attend this ceremony because today, atthe same time, my second daughter, Carolyn, is graduating from a university in London.
Therefore, our family had to split so that everybody could celebrate.
I would like to truly thank the Honda Foundation, Mr. Ishida and the selection committee, forselecting me for this award. I also would like to convey my sincere appreciation to Mr. Ito, President
and CEO of Honda Motor Co., Ltd., with whom I had such a wonderful discussion this morning.
This award is not solely “my” award, as it is also an award for my family: my parents,
especially my father who passed away a little bit too early, one month ago, he was so proud ofme receiving this prize; my wife and my daughters, and, of course, my many colleagues inFrance and around the world.
Today, I would like to give you the highlights of my work and some explanations about what I
have done. The Honda Award is bound to the concept of ecotechnology and emphasizes how
society can benefit from engineers’ work, inventions, and discoveries. This is a key point. It is
not good to advance something and keep it for yourself. You are really happy, at least this is mycase, only if you can see that your inventions and your work could be useful for society. Also,
this award for me is a tremendous encouragement to continue my research, as I still have
many ideas to pursue. So this award gives me a lot of energy to continue my work.
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■ Progress of Imaging

Fig 1〈Fig 1〉 My work has been dedicated to imaging of the body, mainly the brain. Imaging
started with this man, Dr. Roentgen, who got the first Nobel Prize in Physics in 1901 for the
discovery of the X-ray. With radiography, we can obtain images, but they are mainly of bones. It
was, of course, a big discovery because we could see into the body for the first time, but thelimitation of radiography is that we cannot really see the organs very well.
The second big discovery came when it became possible to see “wet” tissues, organs of thebody, not only dry bones by combining X-ray systems with sensors and computers, so-called“computed tomography” or CT. It was invented by Dr. Hounsfield and Dr. Cormack, who got theNobel Prize in 1979. That was, however, still not enough. Although it was possible to see somediseases, such as tumors in the brain, the structure of the brain itself could not be seen withgreat details.
Then came two men, Dr. Paul Lauterbur, a chemist, and Sir Peter Mansfield, a physicist.
They got the Nobel Prize in Physiology or Medicine in 2003 for their invention of MRI,
Magnetic Resonance Imaging. With MRI, we can see the brain in great detail because the brain
is made out of water and MRI is especially sensitive to water. Over the last 100 years, water
has become very important for the radiologist. To produce images, we started from theelectrons of calcium with X-rays, and now, with MRI, we depend on the hydrogen nucleus, theproton, which is at the heart of the water molecule.

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■ Mechanism and Characteristics of MRI

Fig 2〈Fig 2〉 What is MRI? MRI consists in using a very strong magnetic field produced by amagnet to magnetize water molecules. More precisely, we magnetize the protons, the nuclei ofthe hydrogen atoms. The magnetization of water in the brain is not the same for white matter,grey matter, blood vessels, and skin, for instance. By manipulating the magnetization of watermolecules, using radio waves, radiologists are like magicians which can create at will contrasts
between those tissues within the brain.
Engineers improved the technique a lot, so it is common nowadays to see the vessels comingfrom the aorta going to the brain, or, thanks to very fast imaging methods, to see heart beats
and respiration, and of course, my main subject of interest, to see the brain in great detail.
However, what we see on MRI images is not really a brain. We have to understand that this is
in fact a magnetic image of the water molecules in the brain. Therefore, we have to keep inmind that what we have to see is not really the brain, but a virtual copy of the brain throughthe magnetization of its water molecules.

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Fig 3〈Fig 3〉 Let’s see now what the brain looks like. We all have a brain, but they are all different.
The brain weights a little more than 1 kg. There was a French surgeon, Mr. Broca whosepatient, Mr. Leborne, could not speak. He was aphasic. If you asked him, “What is your name?”
he would say, “Tan, tan tan” “What is the year?” “Tan, tan, tan”, so his nickname was “Tan”.
Soon this patient died, and Broca took the brain for study, and he made two major discoveries.
There are two hemispheres in the brain. Broca had the intuition that his patient could not
speak because the lesion was in the left hemisphere, first discovery. Second, he realized thatthe lesion was in front of the brain. If the lesion were located somewhere else in the brain, thepatient could have other symptoms but not a language problem.
That was a very visionary idea. For more than 150 years, this is how we learned how thebrain works: taking the brain of people after their death and trying to correlate their disease
with a location in the brain. We learned a lot, but of course it was difficult to find normal
volunteers!

38Fig 4〈Fig 4〉 Subsequently, everything changed when CT and MRI came, as it became possible toobtain patients’ images where they were still alive. This was a revolution for health care, ofcourse. With those images, we do not need dissection to see the brain of patients or normal
people. Also the link between a lost function and the localization of a lesion could be
immediately found. This possibility which started about 30 years ago has completely changed
the way we can study the brain.

■ Plasticity of Human Brains with MRI

Fig 5〈Fig 5〉 Let us see some examples. We all have brains that look very similar in shape.
However, there are huge differences between people if we look at details. For example, look at
the red line of this structure (left). Its location and shape can change a lot between people. The
location can vary by as much as 1.5 cm, but we still do not understand today the reasons of this39

variability. Our genes are probably responsible, partly, but there could also be mechanicalreasons occurring during brain development. Imaging is clearly a way to get clues about brain
development.
Let’s take another example. This is a study that was performed on London taxi drivers.
London taxi drivers are very high-skilled although I know Japanese taxi drivers are evenbetter. The drivers are trained for two years, navigating in the streets of London. Please look at
this part of the brain with a red square (upper right), which is called the hippocampus and islike our GPS in the brain. Its size in taxi drivers from London is bigger than in normal people.
It means that by learning how to navigate as a taxi driver, they have increased this region of
their brain, the hippocampus. As for bus drivers, there is no difference because bus always uses
the same routes.
Pianists are also very interesting “animals” to study, and so am I. By looking at the images at
the middle on the right, we cannot see the differences by eyes, but with computer software, we
can detect that those regions of the brain are a little bit thicker than in ordinary people. For
instance, coordination between the two hands is very important, and pianists have a little more
grey matter, more neurons, in the related parts of the brain. From those studies, we can saythat we model our brains ourselves depending on our life.
Here is another example to show you that this plasticity can, indeed, be very fast. Youngpeople were trained to juggle balls for a few weeks. In just a few weeks, we can see that someparts of the brain have developed as you develop your muscles by exercise (image on the lower
right). Those regions of the brain are involved in visualizing movement in space.
We can really modify our brain, and this plasticity is especially important when the brain
develops, which starts when we are fetuses growing in the uterus of our mother. Because MRI
does not use any ionizing radiation, we can obtain images without any danger of fetuses during
pregnancy.

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Fig 6〈Fig 6〉 Why are we so interested in doing MRI of fetuses and embryos? These are images
obtained at 24th, 27th, and 32nd weeks of pregnancy. Just to remind you, a normal pregnancy
is 39 weeks. You can see that the brain is becoming more and more complicated over thedevelopment of the brain.

Fig 7〈Fig 7〉 Here is an image (left) which depicts the organization of the brain. The brain is
made of neurons, and the neurons are produced at a very high rate during pregnancy, up to
250,000 neurons per minute. When we are born, we have a capital of 100 billion neurons. After
that, we lose our neurons day after day. In short, we have our capital of neurons at birth.
Neurons are produced in the center of the brain. At the beginning, the future brain is just a
tube with water inside. The neurons are produced at its periphery, at the surface of the tube.
Then, they will migrate to the future surface of the brain which becomes more and more
complex, as it must accommodate such a large number of neurons. It is a little bit like Japan:
The many beaches allow extent the surface of Japan, the brain is doing the same. All the41

neurons will migrate, and they will be installed in a thin ribbon of 2 to 4 mm on the brain
surface which is called gray matter. Then, there is also white matter, which is made of theconnections which the neurons share through extensions called axons.
We can also obtain images of embryos in mice with MRI to see their structure with evenmore details to study brain development. This is an image of a mouse fetus (right). Pregnancy
for mice is 21 days, and this image was obtained at 11 days. I am always amazed by all thesestunning images which we can see with MRI.

■ Brain Function with functional MRI (fMRI)
We have seen examples of what MRI can show us about brain’s anatomy, but what aboutbrain function? When you look at this screen here, or when you hear me, there are many things
going on in your brain. How could we make images of our working brain? For many years, one
way to see the brain working was through awake patients in the neurosurgery suit, and toexcite parts of the brain through electrodes. This sounds like a joke, but it is still used today,
for neurosurgeon to very precisely determine the location to perform their surgery to avoid
functional damages. The brain is not sensitive to pain, so patients do not suffer going out ofanesthesia for a while.

Fig 8〈Fig 8〉 Looking at activity of brain regions without opening the skull has been a dream.
This dream has come true with MRI which can give images of our working brain. This is called
functional MRI. When we look at something, this region of the brain at the back, called thevisual cortex, is very active. This is like the back of a camera, and the world perceived throughour eyes (the lenses) is projected here. How is it possible to make such images?

42Fig 9〈Fig 9〉 This is my great privilege to explain the work of Prof. Ogawa because he is thepioneer who developed this method, this concept. Prof. Ogawa made the hypothesis thatperhaps if we can look at changes in brain blood flow with MRI, which would reveal brain
function. The concept that brain activity and blood flow are related was suggested long ago in
an article published in the 1890s by Dr. Roy and Dr. Sherrington: Regions of the brain where
there is activity have an increased energy demand and increased blood flow. It is a little bit
similar to Tokyo: If there is one area which becomes very active, more taxis will come in. So if
we have a way to see blood flow in the brain, we will have a chance to see its activity.
Then, what Prof. Ogawa noticed was MRI could be made very sensitive to blood flow
variations. Blood contains red blood cells, and that is why blood is red. But the reason why red
blood cells are red is that they contain hemoglobin. Hemoglobin carries oxygen from the lungs
to the organs. Hemoglobin is a complex molecule which hides an atom of iron inside. This ironatom can get magnetized depending on the oxygen load of hemoglobin. In short, one may
consider that hemoglobin-filled red blood cells travelling in the small blood vessels in themagnetic field of the MRI magnet are tiny magnets which will change locally the magnetic fieldaround small vessels. The water molecules nearby are sensitive to those changes in themagnetic field, which will change their magnetization. The effect is tiny, but with computer
software, one can produce images reflecting those changes in the water magnetization near thevessels in the regions where the brain has been activated. Hence, when we look at a screen in
the magnet, there are changes in the magnetization of water in the visual cortex, and we canfollow in great detail what is going on. This is really a wonderful discovery that Prof. Ogawa
made, and his method, called BOLD for Blood Oxygen Level Dependent, is now usedeverywhere in the world.

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■ Applications of functional MRI

Fig 10〈Fig 10〉 It is now time to see examples of what we can see with functional MRI. You
understood that that there is activation at the back of your brain when you see the world. Now,
please close your eyes and think about a cat. The question is “where is the cat in your brain?”
The response can be obtained with MRI. When we say “cat,” the person in the magnet, incomplete darkness, will think about a cat. What do we see on the images? This image (lower
right) is a zoom of the back of the brain, the visual cortex, and we see that the magnetization of
the water molecules has changed there, just by thinking about a cat. It shows that this part ofthe brain, which we use to see the real world, is also used to see the “inner” world, our mental
images. That was a big discovery. If you ask to the person in the magnet, “Could you see
whether the cat has pointed ears?” he has to look back at his mental image, and we see that
there is an even bigger response (figure at the bottom), a bigger change in the magnetization of
the water molecules.
Consequently, the obvious question that Prof. Sadato, who is also here today, asked was“what about blind people, people who have never seen in their life?” They have a visual cortex,
but what do they do with it? The result he showed (although using another method, not MRI),
was that when people who are congenitally blind read Braille with their fingers, they activate
the visual cortex. Literally they see and read with their fingers. From this result, we can justthink that it is good that nature is able to recycle a little bit of the brain circuits, but I haveanother hypothesis. My idea is that there are some tiny circuits in the brain that are
genetically programmed to perform basic tasks. Yet, the way we use them varies from person toperson, depending on how those basic circuits are connected. Blind people also have the circuits,44and their circuits are working normally, but they are connected differently because they do notreceive visual inputs. For normal people, the connections are with the eyes, while for blind
people the connections are with other senses; touches of the fingers, audition, etc. A group from
Israel has recently shown that blind people trained to make mental images from sounds also
activate the visual cortex as well. This is also a great discovery.
We can see even further into our brain and get close to mind reading. Our visual cortex is“retinotopic” which means it is a little bit like a camera, in short, at the back of the brain, what
we see up is projected down, what is left goes to right, and so on. Then, if we look at a verticalbar, we activate the visual cortex in a particular way, different from the way activated bylooking at a horizontal object. We can also see that in our MRI images.

Fig 11〈Fig 11〉 The experiment we did consisted in having people in the total darkness, and we
asked them just to think about a vertical or horizontal flashing bar without telling us. Then bylooking at the images (upper left), we could predict with high success rate which orientation
people were thinking about, horizontal or vertical. Some experiments we have done recently at
NeuroSpin with Dr. Bertrand Thirion and Dr. Stanislas Dehaene showed that we could evenpredict letters imagined by subjects placed in the MRI magnet. We ask them in the darkness,“Could you think about big ‘H,’ big ‘M, and big ‘R’?” and based on the MRI images we could
determine very accurately which letters they were thinking about. Yes, we can read the mind,
to some extent.
The potential of this “mind reading” ability could be very useful. I have been amazed to see
the performances of the Honda robot ASIMO. Could we, someday, pilot such skillful robots with
our mind? Just consider handicapped people, this would change their life. Of course current

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MRI scanners would not be convenient at all, too heavy and cumbersome, but it could be donewith lighter technologies, such as EEG, electroencephalograph. The activity of the brain could
be monitored, and the signal transformed to drive a robot, an artificial hand, just by thought.

Fig 12〈Fig 12〉 functional MRI can do even more. Those images (upper right) have been obtainedin a young lady who is in a comatose state because of a car accident, so she cannot move anddoes not react to any stimulus. Dr. Owen suggested putting this patient in the MRI scanner.
Once installed in the scanner, they asked the patient “What is your name?” Of course, as thelady is in a coma, nothing happened physically, but on the MRI images, her Broca’s area which
is linked to language lighted up! In short, this lady understood the question and was
responding in mind, what MRI images could show us. Next, the doctors asked her “Could you
think that you are playing tennis?” Again, as the lady is in a coma, nothing happens physically.
However with MRI, we can see that the regions that are now activated in the patient are thesame that are those activated in normal people thinking about playing tennis. Following that,they asked, “Could you think that you are moving in your house and are looking at different
things?” And again, you see this network of regions which got activated are the same regions
activated by normal, conscious people. The BOLD fMRI method of Prof. Ogawa’s is now
opening a huge field, as it is now becoming possible to communicate with some patients in acoma. I do not want to say all of them, because so far, apparently, it works in about 15% to 20%of them. One way to communicate with them is to say, for instance, “To answer a question ‘Yes,’
just think you are playing tennis. If you want to say ‘No,’ think you are moving in your house.”
Then, we can see the differences in images, very quickly. I have heard about one patient in acoma state who is now writing a book that way.

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■ Invention of diffusion MRI (dMRI)

Fig 13〈Fig 13〉 Now I will switch to what I have invented: diffusion MRI. The roots of diffusion
MRI, in fact, started very early in the work of Einstein. In 1905, he published several papers:
one paper on the photoelectric effect for which he got a Nobel Prize many years later. He also
published papers on the relativity theory with the very famous equation, E = mc . At the sametime, he was just finishing his PhD thesis in physics which was on molecular diffusion. To
begin with, what is diffusion exactly?

Fig 14〈Fig 14〉 Before Einstein, what people considered as diffusion was very advanced science, as
J. van‘t Hoff got a Nobel Prize for this work. If you mix up two liquids with different colors likewater and red wine, after some time they get completely mixed. This is what was called
diffusion. Equations were written to describe the effect, but the reason for this mixing was notknown at that time. This reason is Brownian motion. Brownian motion was discovered by Mr.

47

Brown, a botanist, who observed pollen in water under his microscope. He could see that all
particles were shaking all the time. This phenomenon is called Brownian motion and is true forany atom or molecule in the universe. However, the existence of atoms was not yet establishedin 1905.

Fig 15〈Fig 15〉 If we drink the wine a little bit too much, we may experience random walk. The
idea of Einstein’s was that perhaps the random walk of atoms or molecules could explain
diffusion, and he wrote this equation that links the displacement of the molecules with time(lower left). If his equation could predict diffusion well, then it would be established that atoms
and molecules do exist and are responsible for the diffusion process. If we give molecules a
short time to diffuse, they will not go very far. If you give them more time, they will go further
and further away. Statistically, in fact, they individually explore more and more space, but the
average center of their position (if one considers millions of molecules) will not move, staying inthe same place. That is the diffusion theory set up by Einstein.

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Fig 16〈Fig 16〉 Brownian motion has been used in many different ways. I was very surprised lastyear when I visited a very fine wine maker in Bordeaux. The owner paid a very expensive priceto buy this barrel, which is supposed to improve Brownian motion and make good wine. I do
not believe it, but the owner did, apparently. This is the power of marketing.

Fig 17〈Fig 17〉 When I was young, circa 1985, I had the idea that perhaps diffusion could be usedwith MRI, a little bit like Einstein who used diffusion to prove the existence of atoms or
molecules which nobody could see. Look at this image (upper right): there is a lesion there, andeven if you are not a doctor you know well that there is something abnormal. Yet, the resolutionof the images is only millimeters. To get some information on the nature of this lesion, one
needs to see the lesion at a much finer scale so as to see individual cells, which are 100 to 1,000
times smaller. My idea was that perhaps water molecules diffusing in the tissues and thelesions could hit obstacles such as cell membranes, fibers, etc. By watching their diffusion, one49

could get precious information on what water molecules have encountered in the tissue, acting
as spies or probes for us. We are very lucky because in 50 thousands of a second (time interval
used with MRI), at the brain temperature (37℃), water molecules diffuse on distances in theorder of 15 ㎛, 15 millionths of a meter, based on Einstein’s equation. We are at the right scale,
about the size of cells in tissues. The concept behind diffusion MRI is that although the images
have a coarse resolution, like millimeters, we can provide information about the microscopic
world and the structure of the tissues.

Fig 18〈Fig 18〉 This is how diffusion started. I do not want to bother you with physics details about
the method but just mention that for normal MRI, you have to use a very strong andhomogeneous magnetic field. For diffusion MRI, in order to label the random walk of watermolecules, we have to vary the magnetic field from left to right or from top to bottom. When we
make the field change in space, and if the molecules move due to diffusion, we will have somekind of way to label their displacements. This is what I invented in 1985 with one of mycolleagues, Dr. Eric Breton. I simplified the theory to keep simple equations and gave the letter“b”, following my name, to one of the parameter inside the equation which everybody is using
today for diffusion MRI, although many of my colleagues do not know it! Indeed, Dr. Stejskal
and Dr. Tanner pioneered the field, showing in 1965 how diffusion could be measured. My
contribution was to incorporate their idea with MRI, so as to make, for the first time, images ofdiffusion, which is maps of organs in our body, notably the brain, where the diffusion coefficientis shown using a gray scale or color scale in each point of the image.
This image below is a slice of the brain obtained by normal MRI. When we add variations inspace of the magnetic field, for instance from left to right, the MRI signal goes down due to50

diffusion. This effect is different for each point within the brain, and we can get images for eachpoint of the Brownian motion of water molecules.

■ Applications of diffusion MRI ①: Acute Stroke Diagnosis

Fig 19〈Fig 19〉 Now, what do we do with diffusion MRI? We can diagnose stroke at the acute phase,make images of the connections within the brain, diagnose cancer… applications are many!

Fig 20〈Fig 20〉 Let’s start with the very first major application of diffusion MRI. The lesion of thepatient I showed you earlier (Fig 17) is in fact a stroke. The patient had a clot in an artery, so
the neurons depending on this artery there do not get blood supply anymore, and they are
dying. Stroke is the third common cause of death and the first cause of long-term disability byfar. After stroke, 30% patients who survive need daily assistance, and 70% have impaired51

occupational capacity. The societal cost is huge for healthcare, but also for productivity loses.
You can see how terrible this disease is.
In 1990, my colleague Dr. Michael Moseley in the United States was working on a model ofstroke in the cat. He was using my new diffusion MRI method and discovered that the diffusion
coefficient of water was going down during stroke at the acute phase (image on the right). In
short, in the regions of the brain where neurons are dying, the diffusion of water molecules
slowed down. Because I had just invented diffusion MRI, it was possible to obtain such images
fort the first time. Nowadays, this is done in common practice in hospitals, but at that time
there was no way to diagnose stroke at the acute stage, when treatment might still be possible.
With the CT scanner it takes many hours before stroke lesions become visible.
If you have symptoms such as difficulty in speaking, moving your arms and legs, feeling
dizzy or something wrong with your vision, or having a very strong, unusual headache, thenmaybe you are undergoing a stroke. During a stroke, millions of neurons are dying every
minute. After six hours, it is too late. The neurons are dead; they will never recover again.
However, if you can go to the emergency room of a stroke center and get an emergency MRI, it
is possible to save your neurons, and your life, because we can give some drugs that will
dissolve the clot instantaneously. Once the blood clot goes away, the neurons get the oxygenand sugar they need, and then all of a sudden the symptoms disappear, for ever. The patient isdefinitely cured.
This is how we can save the lives of people undergoing stroke, but only 1% of them benefit
today from this technique so far. In modern countries like Japan and France, we have MRI
systems and emergency departments, but most people do not realize when they are sufferingfrom a stroke, until too late. Thus, we have to educate the public. I think that the Honda Prizeis definitely along this philosophy that society will benefit from invention if we educate andhelp people to understand it. I am very honored that the Honda Foundation recognizes thiswork because it can save the lives of people, and my hope is that it will save the lives of more
and more people than today.

52

Fig 21〈Fig 21〉 With diffusion MRI, we can also predict how these areas affected by stroke willchange in time. We can predict that this patient, for instance, will get worse as the affected
region will extend in a few days, and his MRI images will turn to like this image (right). We
have to act promptly and aggressively to save this patient. In other patients, we can predictthat the stroke will not evolve, so there is no need to do anything if the patient has no major
symptom. With diffusion MRI, we can decide which patients need treatment or not inemergency.

■ Applications of diffusion MRI ②: Cancer Diagnosis

Fig 22〈Fig 22〉 In cancer also, diffusion MRI is making a bigger and bigger impact. The diagnosisof cancer is not so easy so far. We usually rely on a radioactive false sugar (FDG) withpositron-emission tomography (PET), another technique than MRI, to detect regions that arecancer lesions or metastases which consume a lot of the injected FDG. The problem is thatspecificity is not very high because banal inflammation lesions give positive results mimicking

53cancer, although they are not. Besides, the images that are obtained with PET are not so crisp,
so we often merge them with those acquired with CT scanners using combined PET-CT
machines. Despite those limits, FDG-PET is working well and considered as the reference
method.
However, Prof. Takahara in Japan showed that my method of diffusion MRI can be usedinstead of PET. He showed that in regions of the body where cells proliferate, as in cancer,
Brownian motion decreases. Because the MRI images are very crisp, this method is getting
more and more attention as a method to detect or monitor cancer. You can also use diffusion
MRI to see whether chemotherapy works or not at an early stage. If the drug fails, it takes
several weeks or months before we know if it is working or not, and then it might be too late toswitch to another treatment. With diffusion MRI, one can see if the drug is working or not very
early, and decide to switch immediately to another drug if necessary.
In breast cancer, with Dr. Iima from Kyoto University, we showed that some lesions diagnosed
with cancer by mammography could be established with diffusion MRI not as cancer lesions infact. Ladies sometimes get surgery or very invasive treatments for nothing because the lesion is,indeed, not a cancer or a cancer evolving very slowly in life which just requires monitoring. There
was no need to remove the breast. This is a conceptual revolution: to make the diagnosis of “nocancer” instead of suspecting cancer each time a lesion is seen with mammography.

■ Applications of diffusion MRI ③: Mapping of Brain Connectivity

Fig 23〈Fig 23〉 Another major application of diffusion MRI is that diffusion can be used to see theconnections in the brain. I explained earlier that white matter was made of the connections
between neurons. It has been established by Dr. Moseley that the Brownian motion of watermolecules seen with diffusion MRI is faster along the fibers than perpendicular to the fibers.
54

This is exactly like when you have cars running on the highway, they go in the direction of the
highway and not perpendicular to the highway. So in 1991, when I was in the United States,with my student, Dr. Philippe Douek, we showed that if we measure diffusion in two directions,
we can determine the orientation is of the fibers in the brain. In the image (lower right),
vertical direction is shown in red; horizontal in blue; or in-between in green. The images werevery crude at that time, but it was the first time we could obtain images of the direction of theconnection fibers in the brain, thanks again to diffusion MRI.

Fig 24〈Fig 24〉 Soon after, with Dr. Peter Basser and Dr. James Mattiello you can see in this black
and white photo from 1992, we developed the concept of diffusion tensor imaging, which fully
exploits the sensitivity of diffusion MRI to orientation in space. With this framework, we can
now obtain images of the brain connection fibers for each point of the image in all orientations.
The next step came in 1998 as it was shown how to connect all those points together to makeimages of the connections themselves. This was first proposed by another Japanese scientist,
Prof. Susumu Mori, who works at Hopkins University in the United States. By using amathematical algorithm, he showed that it was possible to connect the points within the
diffusion MRI images and obtain images of the connections like can be seen in this image(lower right).

55

Fig 25〈Fig 25〉 Look at those gorgeous images (foreside). They are examples of the connections of
the human brain. The United States NIH have injected $30 million to make the first atlas of
the connections within the brain. In Europe, we do not have so much money, but we haveanother project called the Connect Project (downside). We got only $2 million, but we have been
the first to complete an atlas of human brain connections in a group of 80 subjects.

56Fig 26〈Fig 26〉 Those astonishing images (right) of the connections in the brain are part of thisatlas, fruit of the work of my colleagues, especially Dr. Cyril Poupon at NeuroSpin. They are
not artwork, but represent the real connections within the brain of a normal subject. It takes
only 15 minutes to get such pictures of one’s brain connections. Just go into the MRI scanner
and wait… you can even sleep if you like. 15 minutes later, we have all the images required tomap the connections like that. Dr. Van Wedeen at MIT just published an article a few months
ago showing that inside the brain is like in a computer, with ribbons of fibers (left). Plasticity inthe brain probably comes from the way those connections get established or disappear in time.

57

Fig 27〈Fig 27〉 Let me give you some examples of plasticity in the brain and it can be seen from theconnection maps obtained with diffusion MRI. I told you that language is generally in the left
hemisphere of the brain. Babies, 2- 4-month-old babies, do not speak. However, we can see that
their connection fibers are already asymmetric (upper left). The fibers are more developed in
the left hemisphere, so the baby will be prepared to use the left hemisphere to speak.
This is work by Dr. Jessica Dubois, my former student (upper right). Pianists also develop
connections in the brain depending on the number of hours spent practicing in their life. Whenthey are children, a few thousand hours are enough to deeply modify connections. Between 11
and 17 years of age, it takes more hours of practice to modify them. By adult age, it is more andmore difficult. Therefore, this is my advice, if you would like to play the piano, it is better tostart early than late!
In dyslexia, it has been shown that some connections could be faulty. One can see from theimage on the right middle that in dyslexic people, who are very bad at reading, the connections
are bad in some parts of the brain involved with language and reading. However, when they
improve their reading abilities thanks to some rehabilitation, one can see that the connections
get better. Functional performance, and plasticity, is linked to brain connections.
And for schizophrenic patients, it has been shown recently that some connections in theirbrain were apparently wrong. Schizophrenic patients most often hear voices. Actually they doreally hear voices, as we can see that from functional MRI (lower right). This is not a surprise.
In fact, we always hear voices, we speak to ourselves, but we know that the voices come from us,

58not from strangers. If some connections are faulty between frontal regions where thoughts
originate and the temporal regions which make “inner sounds” (like mental images in thevisual cortex), both may appear shifted in time, not related. It is a little bit like watching amovie with the sound and the images out of synchrony, which is very uncomfortable. This is, sofar, a hypothesis for the symptoms of schizophrenia which may result indeed, as with otherdisorders, such as autism, abnormalities in the connections and the synchronization between
brain regions.

■ Applications of diffusion MRI ④: Water Diffusion fMRI

Fig 28〈Fig 28〉 The last application of diffusion MRI which I want to introduce today is for imaging
brain function. I explained that the method of Prof. Ogawa is great, so why do we need better?
It works very well, but we know that sometimes there are limitations. If we look at how thebrain works by looking at blood flow, we are not really looking at the neurons but looking at
something indirect. Furthermore, mechanisms linking the change in blood flow with neuronal
activity are not very well established. Also, we can think that there are different regions of thebrain with different functions, but using the same vessels, this method cannot separate them.
Based on those points, we have discussed many times with Prof. Ogawa, and I have proposed
another way: perhaps with diffusion MRI, we can also see how the brain works. My idea is thatwhen neurons get activated, they change in shape. There is some swelling of brain cells, anddiffusion MRI is very sensitive to the structure of the tissues. Then, this was my hypothesis:
instead of looking at the increase in the blood flow from activation, maybe we can see howbrain tissue structure is changing during activation through cell swelling.

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Fig 29〈Fig 29〉 We did this experiment in Kyoto. In the images (upper left), the top is diffusion
fMRI (DfMRI), and the down is BOLD fMRI. Both are working very well, and we can see thevisual cortex. When the people are looking at flickering image, we see a very strong activationin the visual cortex. With BOLD fMRI, one sees the change in magnetization induced by thestimulation. However, the peak of the response occurs late, well after the end of the stimulation.
This is because we are looking at the blood flow. The blood flow response is slow and is delayedcompared to neuronal activity.
With DfMRI, what we could see from the figure (right) in the activated region is that the
diffusion of water is slowing down just each time the visual system is stimulated. When thevisual stimulus is off, water diffusion gets faster again. The main point is that we observedthat this curve changed much faster than BOLD fMRI. There is a fast change in diffusion, andthe maximal response, occurs right at the end of the simulation, which is what we expect fromneuronal activity.

60

Fig 30〈Fig 30〉 In short, diffusion fMRI is very different than BOLD, not vascular like, but isrelated to something going on in the tissue itself. We recently performed at experiment at
NeuroSpin with Dr. Tsurugizawa to confirm this mechanism in rat brains. We stimulated theforepaw of the rats, which induced a brain response visible with diffusion fMRI and BOLD
fMRI. However, after giving a drug called nitroprusside to the rats, drug which suppresses theincrease in blood flow, we could see that response of the BOLD fMRI disappeared because it islinked to blood flow. However, the diffusion fMRI response remained unaffected. This
experiment clearly shows that diffusion fMRI offers something new to make images of brain
activation, directly linked to brain cells and not blood flow.

■ Importance of Mysterious Molecule: Water

Fig 31〈Fig 31〉 How could our thoughts alter Brownian motion of water? We need to explore water
to explain it. Water is a wonderful, strange molecule with many special properties. There is one
property of water that is unfortunately very famous, and that is that solid water, ice, floats on

61

top of water. It should not, as for other liquids, when cooled and turned to solid, their “ice” goesto the bottom because it is denser. It is the opposite for water. For the Titanic, this feature hadturned to a disaster…. Lately we have started to understand the structure of water, but there
are still many mysteries about water.
Water has been very important for life, but, unfortunately, may also lead to death by its
absence, or its presence. The terrible tsunami you witnessed in Japan was clearly a dramatic
example of the destructive power of water. But there is a lot to fear also from the lack of water
which is essential to life. We always think about CO2 as an important molecule to watch for the
future. The water molecule has about the same size, tiny, but I believe that we will have more
problems with H2O than with CO2 in the 30 to 50 years to come. In any case, both their fatesare entangled through our planet climate.

Fig 32〈Fig 32〉

Water is very important in Kyoto to such an extent that there are temples

dedicated to water, and the water of Kiyomizu temple is especially pure. There are different
kinds of water, depending on its content. The water in Kyoto is not the same as the water inParis. When people drink it, it could be good for the brain. There are many temples wherewater is seen as a very important source to get a pure mind. Sake also requires very pure, very
good water. So do Kimonos, also. To make the colors of the kimonos in Kyoto, the quality of thewater in the rivers is very important.
So water is very important, and nature has developed many tricks around it. For instance,
the lotus leaves are always very clean. The reason of its cleanliness is the structure of thesurface of the leaves (lower right). In a normal plant (foreside), water will adhere to the leaves,slide and not take the dirt. However, the leaves of the lotus (downside) present a surface whichmakes the water molecules to roll, taking the dirt away. In today’s buildings, people use this62

technology to make self-cleaning windows.

Fig 33〈Fig 33〉 Brain contains 80% water. Nine molecules out of ten in the brain are water. Take
this sushi for example (foreside), how do you know it is fresh? Take your chopsticks and press
on the sushi, and then the water will come out. The fish is dead, so how is that possible? In fact,
the water molecules are present, and they are glued to the proteins that are contained in thesushi, for many hours. This shows you that water molecules are not free in cells. Water
molecules are most often bound to some structures such as proteins.
What I am proposing is that next to the surface of the membranes of the cells, some watermolecules are glued to the membranes, and those water molecules are slower to diffuse. If thecell swells, its membrane surface increases and a quantity of water becomes bound to themembrane as well. This could explain why the Brownian motion of water in general is slowing
down during activation. As cells swell when they get activated, the quantity of slow diffusing
water in the activated region increases. This is just a hypothesis, but we should really pay
more attention to water and its role in brain function.

63

Fig 34〈Fig 34〉 To summarize this part, we can look at brain function with BOLD fMRI very well,
but we can also do it with diffusion fMRI. However, the mechanisms are completely different. I
believe that water molecules are not just there in the brain to give us good or beautiful images.
Water molecules may be a very important actor of the function of the brain. Perhaps shall we
say that our ability to think may be dependent on water molecules?

64

■ Hypothesis from diffusion MRI

Fig 35〈Fig 35〉

In summary, water molecules can help us to understand dynamic changes

occurring in our brain, but many people perhaps do not know or tend to overlook thateverything in our brain is dynamic in fact. Neurons parts called dendritic spines are dancing
all the time. This movement is crucial to their function. I think that diffusion MRI is sensitive
to the dance of the brain cells.
A second point is that I said that we do not know really well why there is increased blood flow
during activation, which is used with BOLD fMRI. In the past, Egyptians, when they werepreparing their mummies, were throwing away the brain because they considered the brain
merely as a radiator, just to evacuate heat. They thought that emotions were coming from theheart, and that the brain was just there to cool down the blood. So is the expression, “coldblood”. It is known that water has a very strong heat transfer capacity. One reason for theincrease in blood flow during brain activation could perhaps be to cool down the regions of thebrain that are activated. I saw ASIMO this morning, and he is using a lot of energy to “think”
too, so there are fans to cool down ASIMO “brain”. For the human brain, we use water to cool it
down, which may overheat, as shown in the right figure by Dr. Tasaki. This is why, to teaseProf. Ogawa, I told him that his BOLD fMRI method should be called COLD fMRI instead
because it is related to the variations of blood flow used to cool the activated brain tissue.

65Fig 36〈Fig 36〉 A last point is that all those changes in the shape of the neurons may reflect sometransformation or transmission of information. Let’s say I am in the Tokyo metro which is very
crowded. If somebody is sneezing or coughing, everybody will feel something! That may happen
in the brain. Brain cells, neurons or astrocytes, change shape all the time when they are
activated, and the other cells nearby “feel” something, which, in turn, may activate them too.
This is the same principle as piezoelectric transducers that we have in our quartz watches:mechanical variations are transformed into electrical potential. This mechanism will be much
faster than the transmission mechanism we know today from synapses and the release of
neurotransmitters. I call this new mechanism “wireless connectivity”. Locally, neurons cancommunicate by touching each other, but once they are ready to export information to anothercluster of neurons at a distance, then they use neurotransmission. Neurotransmission is very
efficient to transmit information at a distance, but it is relatively slow and perhaps not
optimized for information processing within clusters on neurons.

66

■ The Future of MRI

Fig 37〈Fig 37〉 We are close to the end of my talk now, so let me introduce to you vision for the
future. We have seen that we can look at brain function with the method of Prof. Ogawa, evenof comatose patients. We can see connections in the brain with diffusion MRI, but we need to go
further away. We have only about 20,000 genes, but neurons are 100 billion, and each neuron isconnected to 10,000 more other neurons. This enables brain plasticity. In order to explain thebrain more, we have to go to another scale.
My idea is that there is a neural code like a genetic code. Along the surface of the brain, there
are small islands of neurons that are dedicated to specific tasks, and each task is probably
determined by genes. You cannot modify them just overnight, but the way those small clustersof neurons are connected in time, and space is changing all the time. This is plasticity whichmakes up higher order cognitive functions. This is how we can speak French, Japanese, orEnglish. In order to see those islands, we need to have a microscope in vivo. We need to see thebrain at a different scale, which I call the mesoscale. Once we have understood this neural code,
it would be possible for us to understand diseases such as Alzheimer’s disease or psychiatricdisorders. We may even think about ways to reprogram the brain.

67

Fig 38〈Fig 38〉 To do so, we need to improve the resolution of MRI, and the only way to do that is toincrease even higher the magnetic field we use with MRI. This is the magnet that Prof. Ogawa
mentioned in his speech. At CEA, we are very proud to have ingenious physicists who made themagnets in the LHC in Geneva; the magnets that have been used to discover the Higgs boson.
The same technologies can be used to make magnets for MRI. Those people are also involved in
the ITER project, as you know well because the head of ITER is Japanese, Dr. Osamu Motojima.
It is in Cadarache in France and is also led by CEA. They will use very special magnets, too.
We are currently making this huge magnet for MRI, about 5 m in size. As you see, it is madeof discs, like pancakes (lower right). We call them pancakes because we are French, I guess!
There will be many of them, 170. The niobium-titanium superconducting material used tomake up the wires comes from Japan. It is sent to the United States where it is formatted tothe designed shape, 10 filaments in a U-shaped gutter, 9 mm by 4 mm. The accuracy for
positioning this wire is within 25 μm, and there will be 182 km in total. Once we have all thesepancakes aligned together, the magnetic force will reach 8,000 tons, and still, nothing should
move within the magnet. You can understand that it is a beautiful piece of engineering that ourcolleagues from CEA are putting together in collaboration with Alstom, a French company
located in Belfort.

68Fig 39〈Fig 39〉 With this device, we expect to be able to have a global picture, to understand how
the brain works, and to understand how the brain is sometimes unfortunately affected byterrible diseases during development and aging. Japan and France are facing big problems
with an aging population, the need for rehabilitation, psychiatric disorders, and so on. Thisshould be also the spirit of Honda Foundation, to promote interaction between people,
understand different cultures, and respect each other. We are also thinking about driving
interfaces between our mind and objects around us. Can you think about driving your car by
your mind without touching anything? For handicapped people, that would be a dream. I knowthat sometime this dream will come true. If, with diffusion MRI, we can contribute a little tothis dream, I will be extremely happy.

69

■ Conclusion

Fig 40〈Fig 40〉 This is NeuroSpin. And again, diffusion MRI would not have been possible without the
support, the help of many, many colleagues there. I could not put everybody on the slide, or I would
need 10 slides. I would like to just mention a few colleagues through the history of diffusion MRI.
I started in France, and Prof. Bousser, a neurologist, introduced me to several key people so that I
could start working on diffusion on my own. When I went on to diffusion MRI, I was still a resident anda PhD student in physics. I then moved to the United States and was also very lucky to be working
with great people like Dr. Robert Turner and Dr. Peter Basser while we developed diffusion tensor
imaging. And then, I went back to France and later started to collaborate with Japan and Kyoto
University, so Prof. Hidenao Fukuyama, Dr. Toshihiko Aso, Mr. Shinichi Urayama, assistant proferror,
Dr. Satoru Kohno, and many people who helped me develop functional MRI with diffusion. I also thankProf. Kaori Togashi and Dr. Iima who are now using diffusion MRI in the body for clinical applications.
Of course, there are many people from CEA who really were supportive, responding to myproject. To just name a few, when I talked about NeuroSpin, Prof. Andre Syrota who was my boss
when I conceived NeuroSpin immediately understood that it was a great idea and madeeverything so that it could happen. Bernard Bigot, our general administrator, was and is still very
supportive. Dr. Gilles Bloch, who is here, is an MRI and MR spectroscopy specialist by training, so
he also understands me very well (we worked together in the past). Also, I want to thank all mymany colleagues who are not here today. I hope that you will have a chance to visit NeuroSpin
someday. Again, I am very thankful for Honda Foundation for giving me this award, which is atreasure for me. I thank you again very much.
■ This report can be viewed in the Honda Foundation’s website.
You may not use the proceedings for the purposes other than personal use without the express
written consent of The Honda Foundation.
70発行責任者
Editor in chief

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聡
Satoshi Matsuzawa

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