Some bits of History

Human brain imaging with functional magnetic resonance is among the most recent developments in a field that came into existence barely 20 years ago. Today, scientists use fMRI to follow changes in brain activity as stroke patients start to regain lost abilities, with the aim of developing better strategies for treatment and therapy. They use fMRI to investigate the developing neural networks for language, hearing, vision, and motor systems in an infant listening to her mother's voice. They can also try to understand the subtle abnormalities in brain activation of children diagnosed with attention deficit hyperactivity disorder, as well as the memory difficulties of patients suffering from schizophrenia.
The underlying phenomenon that makes all this possible is known as nuclear magnetic resonance, and the path to its discovery started with early investigations into the nature of the atom. Although the idea of the atom dates to the ancient Greeks, gaining objective knowledge of it--and of its constituent parts--has come about in just the last hundred years or so. In 1897, physicist J. J. Thomson at Cambridge University in England discovered the electron followed by Ernest Rutherford's discovery of the atomic nucleus. Over the next few decades, a number of brilliant theoretical physicists--including Max Planck, Niels Bohr, Erwin Schrodinger, and Werner Heisenberg--built on one another's work to advance our understanding of the structure and properties of the atom and atomic particles. In so doing, they revolutionized physics, producing a new language and theory known as quantum mechanics.
THE EXPERIMENTS OF I. I. RABI
In 1929, Isidor Isaac Rabi began teaching quantum mechanics at Columbia University. Over the next decade his research group used a technique called molecular beam resonance to study the magnetic properties of atoms and molecules. At the time of Rabi's experiments, physicists knew that the atomic nucleus is composed of two types of particles, positively charged protons and neutral particles called neutrons. Surrounding this nucleus in a kind of fuzzy cloud are negatively charged electrons. Physicists also had discovered that electrons, protons, neutrons--and in many cases the nuclei themselves--behave as though spinning about their axes, just like planets. This results in a property called spin angular momentum, which has both magnitude and direction. Such a spinning particle generates a magnetic field and associated "magnetic moment"--acting like a tiny bar magnet with north and south poles. When placed in a strong external magnetic field, the "magnetic moment" of a nucleus tends to align with (parallel to) or against (antiparallel to) the external field. Parallel alignment corresponds to a lower energy state than antiparallel alignment.
Rabi's experiments involved passing a beam of lithium chloride molecules through a vacuum chamber and manipulating the beam with different magnetic fields. By studying how the magnetic field affected the path of the molecules, he could learn about the magnitudes of the magnetic moment of the nucleus. With the appropriate stimulus, he predicted, the magnetic moments of the nuclei could be induced to flip, or change their orientation relative to the magnetic field. In 1937, following a suggestion by Dutch physicist Cornelius J. Gorter, Rabi and his group added a new wrinkle to their experiments: They bathed the molecular beam in radio waves--electromagnetic signals in the radiofrequency, or broadcasting, range--while varying the magnetic field strength.
They did this because of another feature of spinning particles. In an external magnetic field, atomic particles spin with a wobble called precession, much like a child's top wobbles about the vertical when it is tipped slightly. The magnetic moment of an atomic nucleus wobbles at a characteristic frequency that depends on its type (hydrogen vs. lithium, for instance) and also on its environment. For example, increasing the magnetic field strength increases this frequency, while decreasing the field strength lowers it.
Rabi and his team adjusted the magnetic field strength until they induced the magnetic moments of the nuclei to flip, which occurs when the frequency of the radio signal matches the nuclei's characteristic precessional frequency. When this match--the resonance frequency--occurs, a nucleus absorbs energy from the radio signal that is precisely equal to the difference between its two energy states and thus jumps to the higher state. A flip also occurs when a nucleus emits that energy in falling back from the higher to the lower energy state. Whether the nucleus was excited to the higher energy state or falling to the lower one, Rabi could detect the transition. His technique is now called magnetic resonance or, more precisely, molecular beam magnetic resonance.
Rabi's group applied the new technique to deduce unprecedented details of the internal interactions of molecules. They discovered a series of resonances within a single molecule that allowed them to "see" how individual atoms are bound together and how their nuclei are affected by neighboring atoms. These extraordinary experiments and the development of molecular beam magnetic resonance as a technique for studying the magnetic properties and internal structure of molecules, atoms, and nuclei resulted in Rabi winning the 1944 Nobel Prize in physics.
Within a few months of these experiments, Rabi's group would try a variation: manipulating the radio frequency rather than the strength of the magnetic field. This method--which spreads the resulting signals into a spectrum, much as visible light is spread by passing through a prism--is the basis for radio frequency spectroscopy, which would revolutionize chemical analysis and prove a vital component in the development of magnetic resonance scanning as a tool for medical diagnosis.
A DIFFERENT KIND OF RESONANCE
The outbreak of World War II interrupted work on nuclear magnetic resonance, but the postwar years saw an explosion of progress. In the United States, two groups of physicists independently set out to develop a simpler method for observing the magnetic resonance in the nuclei of molecules in liquids and solids instead of the isolated molecules of Rabi’s experiments. At Harvard University, Edward Purcell, whose group included Henry Torrey and Robert Pound, led the research. At Stanford University, Felix Bloch led a team that included William Hansen and Martin Packard.
Both Purcell and Bloch chose to study the proton --the nucleus of the hydrogen atom (H). Because the hydrogen nucleus is composed of a single proton, it has a significant magnetic moment. Hydrogen would turn out to be the most important element for MRI because of its favorable nuclear properties, nearly universal presence, and abundance in the human body as part of water (H2O). Purcell's group used a two-pound block of paraffin wax as their hydrogen source; Bloch's group used a few drops of water contained in a glass sphere. The two research groups placed the samples in a magnetic field and waited for their nuclei to reach thermal and magnetic equilibrium, a magnetized state in which slightly more of the nuclei are aligned parallel to the external field than antiparallel to it. Then, as Rabi's team had done, the research teams applied radio waves in an effort to get the magnetic moments of the nuclei in the samples to flip. Purcell and Bloch hoped to detect magnetic resonance by observing the energy that precessing nuclei absorbed or gave to the radio frequency field when the resonance condition was satisfied.
In 1945, within three weeks of each other, both groups managed to create the conditions necessary to observe the phenomenon. Their experiments demonstrated what is technically known as nuclear magnetic resonance in condensed matter (now shortened to NMR) as distinguished from Rabi's discovery, molecular beam magnetic resonance. In 1952, Bloch and Purcell shared the Nobel Prize in physics for these experiments.
Research in NMR now leaped ahead. The researchers who surrounded the Purcell and Bloch labs quickly began using NMR spectroscopy to investigate the chemical composition and physical structure of matter. One of the first advances in the course of this work was measuring quantities called relaxation times, T1 and T2. T1 is the time it takes the nuclei in test samples to return to their natural alignment; T2 is the duration of the magnetic signal from the sample. One of Purcell's first graduate students, Nicolaas Bloembergen, who had arrived at Harvard from the Netherlands in 1946, played a key role with Pound and Purcell in this research. Bloembergen was the first researcher to measure relaxation times accurately and, along with Purcell and Pound, also measured how they changed in a variety of liquids and solids. Fortunately for future research and applications, relaxation times could be measured in seconds or fractions of seconds, making NMR a practical research tool.
Bloembergen, Purcell, and Pound published a paper in 1948 that became extremely influential in several branches of physics. The manipulation of relaxation times has provided a powerful method in chemistry and biology for analyzing the structure of molecules--and as other researchers would learn later, is essential for producing the contrast needed to image useful images of tissues in the human body.
LISTENING FOR ECHOES
In the late 1940s, Henry Torrey at Rutgers University and, independently, Erwin Hahn at the University of Illinois took a new step forward in NMR by applying pulses of strong radio waves to the sample instead of a single continuous wave. They first observed transient NMR signals during the application of long pulses. Following Hahn's later observations that transient NMR signals could be measured after the application of short pulses, the pulse technique became an important method for physicists and chemists investigating atoms and molecules.
Additionally, Hahn discovered a phenomenon known as "spin echo," which proved important for measuring relaxation times. At first he attributed these seemingly spurious signals to a misfiring of his electronics. After more study he recognized that they were caused by the speeding up and slowing down of the spinning nuclei due to variations in the local magnetic fields. By applying two or three short radio pulses and then listening for the echoes, Hahn found that he could obtain even more detailed information about nuclear spin relaxation than he could with a single pulse.
Pulsed NMR and spin echoes would play a crucial role in the development of magnetic resonance imaging two decades later. At the time, however, the idea of using NMR to make images simply did not occur to scientists using NMR spectra in physics and chemistry. In any event, before NMR could become a practical imaging tool, some further steps were needed. One important aid was a new pulse method called Fourier transform NMR, first proposed by Russell Varian of Varian Associates in the late 1950s. At about the same time, Richard E. Norberg and Irving Lowe at Washington University in St. Louis showed experimentally and theoretically how one could get all the results available from continuous wave experiments by mathematical manipulation of the signals produced in a pulse experiment. However, at that time the mathematical step needed to analyze the pulse data (a technique called Fourier transformation) was impractical because of the limitations of the computers available.
In the late 1960s, Richard Ernst and Weston Anderson, while working at Varian Associates, were studying the complex many-line NMR spectra of interest to chemists. It was a slow process searching by trial and error for the frequencies to produce all the many lines of the spectra. They realized that simultaneously broadcasting a range of radio frequencies at the atoms in the sample and then performing Fourier analysis of the resulting pulse signal could give all the results of the continuous wave method. This technique was thousands of times faster than the old method, and it also allowed researchers to observe signals only one-tenth as strong. By then advances in computers had made Fourier transformation practical. It now became possible to use NMR to analyze very small samples of a material or to identify very rare atoms in larger samples. In 1991, Ernst won the Nobel Prize in chemistry for his contributions to the development of high-resolution NMR spectroscopy.
THE SCIENCE OF IMAGING
Critical to making MRI a reality was the advent of the high speed computers needed to handle the enormous quantity and complexity of the computations involved in imaging. In addition to the necessary computing power, three other developments contributed to the birth of MRI. One was the work of British electronics engineer Godfrey Hounsfield, who in 1971 built an instrument that combined an x-ray machine and a computer and used certain principles of algebraic reconstruction to scan the body from many directions--manipulating the images to produce a kind of cutaway view of the interior. Unknown to Hounsfield, South African nuclear physicist Allan Cormack had published essentially the same idea in 1963, using a reconstruction technique called the Radon transform. Although Cormack's work was not widely circulated, in 1979 he and Hounsfield shared the Nobel Prize in physiology or medicine for the development of computerized tomography, or CT. The principles underlying CT are the foundation of many sophisticated imaging methods in use today.
The other two developments essential to MRI were related to nuclear magnetic resonance. One was the conceptualization of NMR as a medical diagnostic tool; the other was the invention of a practical method for producing useful images from NMR data.
As early as 1959, J. R. Singer at the University of California, Berkeley, proposed that NMR could be used as a non-invasive tool to measure in vivo blood flow. Then in 1969, Raymond Damadian, a physician at Downstate Medical Center in Brooklyn, New York, began to think of a way to use the technique to probe the body for early signs of cancer. In a 1970 experiment he surgically removed fast-growing tumors that had been implanted in lab rats and showed that the tumors' NMR signals differed from those of normal tissue. Damadian published the results of his experiments in 1971 in the journal Science.
An essential technical advance that opened up the ensuing widespread application of NMR to produce useful images was due to chemist Paul Lauterbur, who was then at the State University of New York at Stony Brook. In 1971, he watched a chemist named Leon Saryan repeat Damadian's experiments with tumors and healthy tissues from rats. Lauterbur concluded that the technique was insufficiently informative for locating and diagnosing tumors and went on to devise a practical way to use NMR to make images.
Lauterbur's groundbreaking idea was to superimpose on the spatially uniform static magnetic field a second weaker magnetic field that varied with position in a controlled fashion, creating what is know as a magnetic field gradient. At one end of a sample the graduated magnetic field would be strong, becoming weaker in a precisely calibrated way down to the other end. Because the resonance frequency of nuclei in an external magnetic field is proportional to the strength of the field, different parts of the sample would have different resonance frequencies. Thus, a given resonance frequency could be associated with a given position. Moreover, the strength of the resonance signal at each frequency would indicate the relative size of volumes containing nuclei at different frequencies and thus at the corresponding position. Subtle variations in the signals could then be used to map the positions of the molecules and construct an image. (Today's magnetic resonance imaging devices impose three sets of electromagnetic gradient coils on the subject to encode the three spatial coordinates of the signals.)
Across the Atlantic in Britain, Peter Mansfield at the University of Nottingham, England, had a similar idea. He was looking into using NMR to obtain structural details of crystalline materials. In work published in 1973, Mansfield and his colleagues also used a field gradient scheme. In 1976, Mansfield developed a MRI technique known as echo-planar imaging, which can rapidly scan a whole brain.
Meanwhile, Lauterbur's results, published in 1973, included an image of his test sample: a pair of small glass tubes immersed in a vial of water. Working with the small NMR scanner he had created (and using a technique called back projection borrowed from CT scanning), he continued to image small objects, including a tiny crab scavenged by his daughter from the Long Island beach near his home. By 1974, using a larger NMR device, he produced an image of the thoracic cavity of a living mouse. Mansfield, for his part, had imaged a number of plant stems and a dead turkey leg by 1975, and by the next year he had captured the first human NMR image--a finger. Damadian also was at work producing images. In 1977, he produced an image of the chest cavity of a live man.
By the early 1980s the flurry of activity around MRI had given rise to a burgeoning commercial enterprise. ("Nuclear" had been quietly dropped from the name in the meantime because of its unfavorable connotations.) Advances in high-speed computing and superconductive magnets allowed researchers to build larger MRI machines with enormously improved sensitivity and resolution and made possible many new applications.
FROM STRUCTURE TO FUNCTION
A phenomenal tool for imaging the anatomy and structure of living tissue, MRI was greatly enhanced in the 1980s and 1990s by the development of its ability to capture an organism in action--to study function. The breakthrough that led to functional MRI, fMRI as it is known, came in the early 1980s, when George Radda and colleagues at the University of Oxford, England, found that MRI could be used to register changes in the level of oxygen in the blood, which in turn could be used to track physiological activity. The principle behind BOLD (for blood oxygen level dependent) contrast imaging had been described some 40 years earlier by Linus Pauling. In 1936, Pauling and Charles D. Coryell, both then at the California Institute of Technology, published a paper describing the magnetism of hemoglobin, the oxygen-carrying pigment that gives red blood cells their color. Much earlier, in 1845, English physicist and chemist Michael Faraday, the discoverer of electromagnetic induction, investigated the magnetic properties of dried blood and made a note to himself: "Must try recent fluid blood." As it happened, Faraday never got around to it, leaving it to Pauling and Coryell more than 90 years later. The two chemists found that the magnetic susceptibility of fully oxygenated arterial blood differed by as much as 20 percent from that of fully deoxygenated venous blood.
In 1990, Seiji Ogawa of AT&T's Bell Laboratories reported that, in studies with animals, deoxygenated hemoglobin, when placed in a magnetic field, would increase the strength of the field in its vicinity, while oxygenated hemoglobin would not. Ogawa showed in animal studies that a region containing a lot of deoxygenated hemoglobin will slightly distort the magnetic field surrounding the blood vessel, a distortion that shows up in a magnetic resonance image.
At about the same time, other investigators also were studying these effects in humans. In 1992, for example, a number of researchers, including Ogawa, John W. Belliveau at Massachusetts General Hospital, and Peter Bandettini at the Medical College of Wisconsin, published results of studies of the brain's response to sensory stimulation using functional MRI techniques. Among other uses, fMRI currently can help guide brain surgeons away from critical areas of the brain, detect signs of stroke, and elucidate the workings of the brain.
Today what Rabi began has become a multibillion dollar industry. MRI scanning and spectroscopy are widely used diagnostic imaging technologies in medicine, and as new techniques and ever more powerful machines have come online in the past few years, the speed and precision of MRI and fMRI have increased dramatically.
None of this would have been possible without the nearly four decades of basic research following Rabi's first detection of nuclear magnetic resonance. Those decades included crucial discoveries by physicists and chemists interested in studying the magnetic properties of atoms and molecules, in seeing how they interact, and in elucidating their basic structures. As George Pake, Purcell's second graduate student, put it in 1993, "Without the basic research, magnetic resonance imaging was unimaginable."