Winner of the 2014 Louis-Jeantet Prize for medicine

The information below refers to the time of the award.

Born in 1957, Denis Le Bihan studied medicine and human biology at the University of Paris VI, (Salpêtrière Faculty of Medicine) and physics at the University of Paris XI (Ecole Polytechnique laboratory). In 1987, he joined the Clinical Center of the National Institutes of Health (NIH) in Bethesda, to pursue his research on brain imaging. He returned to France in 1994, where he worked at Service Hospitalier Frédéric Joliot of the Nuclear and Renewable Energy Commission (CEA) at Saclay near Paris, and headed the laboratory of anatomical and functional neuroimaging. In 2005 he became Visiting Professor at the University of Kyoto in Japan, and in 2007 founded NeuroSpin. He is still the Director of this institute at the CEA, which has the goal of developing the use of ultra high field magnetic resonance for the understanding of cerebral functions and pathologies.

Denis Le Bihan has authored numerous publications and is a member of various scientific committees. His scientific contributions are acknowledged throughout the world. He is a Knight of the French national Order of Merit, a full member of the French Academy of Sciences and Academy of Technologies, as well as the European Academy of Sciences. He is the recipient of numerous awards, notably the gold medal of the International Society of Magnetic Resonance in Medicine (2001) and the Richard Lounsbery Award of the French and American Academies of Science (2002). In 2003 he shared (with S. Dehaene) the award of the “Fondation Louis D.” of the “Institut de France”, and in 2012 he won the prestigious Honda Prize.

The diagnosis of neurological diseases

Our brain is made up of 80% of water molecules that are continuously in movement at very low amplitude – so-called Brownian motion. When he was still a student, Denis Le Bihan had the idea of using MRI (magnetic resonance imaging) to observe these minute movements of molecules and to examine the microscopic structure of cerebral tissue. He had thus invented diffusion MRI.

This imaging technique is used throughout the world for the diagnosis of strokes. Strokes are caused by a blood clot forming in an artery, blocking circulation of the blood and leading to the death of neurons. The infarcted area is clearly visible on diffusion MRI images very soon after the stroke, and notably when the lesions are still small in size or multiple. Forms of treatment have hence been developed for dissolving the blood clots and thus improving or even eliminating the symptoms and avoiding the onset of serious disabilities. This technique is now used for the management of patients suffering from a stroke.

Diffusion MRI is also used for cancer detection, on the basis that proliferating cancer cells will act as an obstacle to the water and hence reduce its rate of diffusion.

Denis Le Bihan’s method has for the first time made it possible to build 3D maps of the connections between the neurons in the brain. Already in use among neuroscience specialists, these maps are starting to be used in the medical domain and should in time lead to a better understanding of diseases associated with ageing (like Alzheimer), mental disorders (autism or schizophrenia), problems of addiction or neurological pathologies.

Diffusion MRI is a field Dr. Denis Le Bihan has been introducing and developing over the last 30 years. This ranges from a foundation in the way of measuring and imaging water diffusion with MRI in the body, to clinical applications and newer concepts on the importance of water molecules for brain function.

Among the papers Einstein published in 1905 (apart from the Nobel prize winning paper on the photoelectric effect, and two famous papers on relativity theory) was his PhD thesis on molecular diffusion. The aim was not about diffusion in itself. It was a way of indirectly proving the existence of atoms, as their existence was still controversial at that time, by merging the microscopic (invisible) and macroscopic (visible) worlds. Microscopic Brownian motion was known at the time, but nobody had been able to explain the origin of the random movement of pollen, or other particles, in water. Macroscopic diffusion was also well-known from the ease with which two liquids (such as ink and water) mixed. Einstein identified these as being two aspects of the same physical phenomenon. By explaining Brownian motion and diffusion in terms of the theory of heat (which links to the motion of atoms), support for the existence of atoms could be provided.

Introducing diffusion to MRI

Magnetic Resonance Imaging (MRI) in the 1980s provided information down to a few millimeter resolutions at best, but could not provide information on tissue structure – that is at micrometer resolution needed for fine diagnosis. Dr. Le Bihan’s idea was to exploit the diffusion driven displacements of water molecules in tissues as a way to probe such tissue microscopic structure, while MRI remains at a macroscopic scale. According to Einstein’s theory the diffusion coefficient of water at the temperature of the body means is such that free water molecule would move on distance around 10 micrometers in 50 milliseconds. In the presence of obstacles (such as cell membranes or fibers) water diffusional displacements would be reduced, thus reflecting the presence and the organization of such features in the tissues. Water is the main molecule used for MRI – not least, because the body is made mostly of water. MRI images are obtained by measuring the response of water to a strong, homogeneous magnetic field. However, if the field becomes inhomogeneous, diffusing water molecules experience different fields. Where the molecules are moving faster (high diffusion coefficient), they are more affected by the spatially varying field, and return a weaker signal.

Acute stroke

The first big hit for diffusion MRI was in diagnosing acute stroke (obliteration of a brain artery from a clot). Stroke is the 3rd highest cause of death and the largest cause of disability in developed countries, with a tremendous social and economic impact. Using the newly developed diffusion MRI from Denis Le Bihan, in the 1990’s Michael Moseley in San Francisco discovered that water diffusion decreases dramatically in the areas undergoing the stroke at the onset. This diffusion decrease was found to result from the swelling of dying neurons. It is now possible for patients suspected of acute stroke to be scanned in emergency. The infarcted area is clearly visible on the diffusion MRI images (Fig.1a). Diffusion MRI has revolutionized the management of brain stroke, as it is today the only imaging method which allows diagnostic at an acute stage (within hours of onset) when perfusion therapies can still work, saving life of many patients and sparing them heavy handicaps or disabilities for the rest of their lives.

Imaging the connections in the brain

White matter is made of fibers connecting brain regions. Another observation of Michael Moseley’s group using Le Bihan’s diffusion MRI method was that water diffusion in brain white matter anisotropic: The diffusion value depends on the direction of measurement, with diffusion being faster along in the direction in which the fibers run. This resulted in Dr Le Bihan’s group to suggest that the orientation of the white matter tracts, which connect different areas of the brain, could be obtained from diffusion measurements in different directions. With Dr Basser at the National Institutes of Health, USA, Dr Le Bihan then introduced “diffusion tensor imaging” which allows to fully exploit anisotropic diffusion. With diffusion tensor imaging and its variants it is today possible to obtain stunning 3D images of the brain connections (Fig.1b). Brain connections underlie brain function, and diffusion MRI is opening up new lines of inquiry for human neuroscience and for treating brain illnesses, aging (Alzheimer), mental health disorders (autism, schizophrenia), addiction and neurological diseases.

Diffusion MRI in cancer diagnosis

Another major field of application for diffusion MRI is now in cancer detection and monitoring. The current gold standard is positron emission tomography (PET) with fluorodeoxyglucose (a sugar-like molecule made radioactive by a cyclotron) that is quickly taken up by the hypermetabolic the cancer cells and sticks there. High radioactivity then signals the presence of cancer cells. However any source of hyper metabolism, such as benign inflammations, causes the same results. The low image resolution of PET is also a drawback. Diffusion MRI can overcome these compromises, showing with exquisite resolution areas where water diffusion has slowed down, presumably because of the cancer cells proliferation, without the need for injecting any tracer (Fig.1c). Successful results have already been obtained in breast, prostate and liver cancer patients.

A new approach to imaging brain function

It is now possible to get images showing (with colors) brain regions activated by various sensorimotor or cognitive tasks (such as language or even consciousness). The current functional brain imaging methods relies on the coupling between blood flow and neuronal activation: blood flow usually increases in activated brain regions. This increase can be detected with MRI according to the BOLD (Blood Oxygen Level Dependant) principle set by Pr Seiji Ogawa at the beginning of the 1990’s, relying on the different magnetic properties of oxygenated and deoxygenated hemoglobin in circulating red blood cells. Although BOLD fMRI has worked very well, there are limitations because the neuronal activation is only indirectly detected to the changes in blood flow. In some situations this increase in blood flow does not occur, although neurons function normally, and the mechanisms of coupling between blood flow and neuronal activation are still not well understood. Furthermore, the blood flow response is slow (much slower than neuronal responses) and not very well localized. Using diffusion MRI Dr. Le Bihan and his team have shown that water diffusion in the brain slows with activity, correlating much better, in time and space, with the underlying neuronal activation. This discovery opens up a new approach to investigate brain function, pointing out that changes in the structure of neural tissue (such as cell swelling) are associated to brain function, and that such minute changes can be detected in the human brain using diffusion MRI.

Further studies on water in the working of the brain

All diffusion MRI applications point to a link between changes in tissue structure (such as cell swelling, cell proliferation, cell shape) and water diffusion, as initially devised by Dr. Le Bihan. Still the exact mechanisms remain to be elucidated. Dr. Le Bihan has recently proposed that those phenomena could, perhaps, be explained by some peculiar features of water in cells. Liquid water is organized in molecular networks and such networks could be profoundly influenced by cell content and, more importantly, cell membranes which could be surrounded by a layer of well-ordered, slow diffusing water molecules. Variations in cell size or shape result in changes in the overall membrane surface present in tissues, which in turn would impact water diffusion. This view remains speculative at this stage, although some hints have been found using diffusion MRI in single neurons and other physical means. Such studies suggest a central role for water in brain function, underlying some degree of coupling between the cell shapes and their functional status. Clearly, diffusion MRI has not yet given its last words, keeping a bright potential for elucidating brain function and for clinical applications.

Fig. 1

Major current applications of diffusion MRI.

A: Diffusion MRI in brain acute stroke. The region with bright signal correspond to brain regions where water diffusion is reduced, as a result of acute cerebral ischemia and associated cytotoxic edema.

B: Diffusion and brain white matter fiber tracking. Water diffusion in brain white matter is anisotropic. As a result it is possible to determine for each voxel of the image the direction in space of the fibers. Using post-processing algorithms the voxels can be connected to produce colour-coded images of the putative underlying white matter tracts. Images courtesy of the NeuroSpin/CONNECT team.

C: Diffusion MRI in cancer. Colored areas correspond to regions of the pelvis (uterus cancer) where the water diffusion coefficient is decreased. Such regions have been shown to match areas where malignant cells are present (primary lesion or metastases).

Denis Le Bihan, MD, PhD

Director, NeuroSpin
NeuroSpin, CEA/SAC/DSV/I2BM,
Bât 145, Point Courrier 156, F-91191 Gif/Yvette,

Telephone: (+33) (0)1 6908 8205/ 3000/ 8197