The Nobel Prize in Medicine for Magnetic ... - ACS Publications

Chemical Education Today

Report

The Nobel Prize in Medicine for Magnetic Resonance Imaging by Charles G. Fry

The Nobel Prize in Medicine awarded in December 2003 to chemist Paul C. Lauterbur and physicist Peter Mansfield for the development of magnetic resonance imaging (MRI) constituted a long overdue recognition of the huge impact MRI has had in medical diagnostics and research. The use of MRI for the diagnosis of brain and spinal ailments, for the pre- and post-operative studies of cancerous tumors, and for the investigation of ligament damage—four notable examples, there are many others—has made MRI nearly ubiquitous in modern society. What is often not realized in scientific circles is the fact that MRI was derived from, and remains an extension of nuclear magnetic resonance (NMR).1 MRI is a fine example of a completely unexpected spin-off from a research tool, developed primarily to solve the structures of organic molecules, into an enormously valuable medical tool. It could be argued, in fact, that had the chemical community not generated the funds to develop molecular NMR instrumentation, the leap to MRI could not have been made. NMR has had a long and proud Nobel history, starting with the Physics prize awarded to Isidor Isaac Rabi in 1944 “for his resonance method for recording the magnetic properties of atomic nuclei”.2 Felix Bloch and Edward M. Purcell followed with the award in Physics in 1952. More recently, Chemistry Nobel Prizes were awarded to Richard Ernst in 1991 and Kurt Wüthrich in 2002. While Mansfield becomes the first physicist receiving a Nobel award in NMR-related work in more than 50 years, Lauterbur is the third chemist to receive the Nobel Prize for research in the area of NMR since 1991. Both of the 2003 Nobel Laureates were pursuing research in NMR that led them to their seminal studies in the development of MRI. Lauterbur had more than a decade’s worth of research with multinuclear NMR ongoing (1–3),3 whereas Mansfield was more than six years into his investigations of solid-state NMR by the time their primary work began in the early 1970s, leading to the creation of MRI as we know it. Lauterbur was first to publish his initial discovery—a discovery that still strongly impacts chemical research today (4). He showed how variations in the strength of a magnetic field could be used to provide spatial information. Up until this discovery, variations, or gradients, in the strength of the magnetic field was the demon of NMR, an undesirable feature to be obliterated at all cost. Lauterbur managed to turn magnetic field gradients—one of the most problematic issues in NMR—on their head, to the good fortune and better health of us all.

ists everywhere—has as a goal the adjustment of a set of welldefined magnetic field gradients5 such that the static magnetic field across the observed region of a sample is very homogeneous. A homogeneous magnetic field leads to NMR peaks that are limited only by the relaxation time of the nuclei being observed, thus producing NMR spectra having optimal resolution. A review of some theory is needed at this point. The basis of all NMR observations lies with the Larmor equation: ν0 = γ B 0

where the resonant frequency of a nucleus ν0 is proportional to the gyromagnetic ratio (an intrinsic property of the observed nucleus), γ = γ/2π, and the applied static magnetic field, B0. If the magnetic field, B0, is identical, or homogeneous, everywhere across the sample, then ν0 is identical for all nuclei in the sample (ignoring for the moment variations caused by molecular effects such as the chemical shift and scalar couplings). Peaks of zero width are not observed. Their linewidth is limited by the relaxation (loss of phase-coherence) of the nuclear magnetization in the plane transverse to B0. This transverse relaxation is also called, and characterized by, the spin-spin relaxation time, T2. In liquids containing small molecules, such as H2O, the spin–spin relaxation time is typically equal to the longitudinal, or spin–lattice, relaxation time, T1, of the nuclei being observed (e.g., 1H for H2O). The observed peaks in a perfectly homogeneous static magnetic field will then have widths ∆ν1/2 = 1/πT2. Since relaxation times of common nuclei are typically of the order of seconds, NMR can provide sub-Hz linewidths, but only if B0 is homogeneous. Molecular features are what interest chemists: to resolve scalar couplings of 1 Hz or smaller, the inhomogeneity in B0 across the sample region must be 10᎑7 or smaller.6 Building magnets that attain these levels of homogeneity7 requires an extensive and carefully designed set of shims.8 Sub-part-per-million (ppm) homogeneity in strong magnetic fields is disturbed by the slightest changes in magnetic susceptibility in the sample region: minor changes in glass tube thickness, or in the height of the solvent meniscus, for example, can significantly degrade the homogeneity. Spectrometer designers took a Taylor series approach when building equipment to compensate for these disturbances. Any function in space can be described by a Taylor series expansion: ϒ (x , y , z ) = a1z + a2 x + a3 y + a 4 z 2 + a5x 2 + a6 y 2 + … + ai zx + ai +1z y

Shimming and Magnetic Field Gradients A good way to better understand Lauterbur’s idea is to review what happens when an NMR spectrometer is shimmed.4 This procedure—one of the least favorite of chem922

Journal of Chemical Education

•

(1)

+ ai + 2 x y + ai + 3 z 2 x + …

(2)

It was found that the lower order terms were most important for compensation of magnetic field inhomogeneities.

Vol. 81 No. 7 July 2004

•

www.JCE.DivCHED.org


Report

Figure 1. (A) Five pie-shaped disks having thickness ∆z are shown in an NMR sample. The linear gradient in the magnetic field along the z-axis (parallel to B0) equaling Gz will produce frequency shifts as shown. (B) When the thickness ∆z → 0, a realistic NMR spectrum is produced having a z-profile as shown; a profile is a onedimensional image where the spin density is integrated normal to the gradient direction. (C) If a gradient of size -Gz is applied to the sample (for example, by the roomtemperature Z-shim coil on a spectrometer), the magnetic field inhomogeneity is canceled, leaving a homogenous field and a well-resolved peak. If Gz was the only inhomogeneity present, cancellation by -Gz will leave a linewidth (full-width at half-maximum) = 1/πT2. (D) If a Kel-f pie-shaped disk is inserted into the sample as shown, the 1H z-profile will show that Kel-f region as the portion of the spectrum having no 1H intensity. Such phantoms can be used to calibrate the size and zero position of a magnetic field gradient.

Magnetic field gradient coils that would replicate the form of the linear terms were relatively easy to build, as were gradients replicating the forms of the other low-order terms.9 Suppose a linear magnetic field inhomogeneity is present along the tube direction—the z-direction for superconducting magnets—in a sample. The effect of this linear gradient can be viewed as partitioning the sample into circular disks normal to the gradient direction, as shown in Figure 1A, with each disk i contributing intensity at a modified Larmor frequency: (3)

νi = γ ( B0 + Gz ∆ zi )

∆zi is the distance of the slice from the B0 position along the gradient direction, and Gz is the gradient strength (in units of Tesla per meter; γ Gz would have units of Hz/m). Each circular disk will contribute spectroscopically as shown in Figure 1A. Overall, the NMR line shape is broadened into something looking rectangular,10 as shown in Figure 1B. At this

Glossary of Acronyms MRI NMR NMRI FT 2D 3D EPI MRM PFG NOE

924

magnetic resonance imaging nuclear magnetic resonance nuclear magnetic resonance imaging Fourier transform two-dimensional three-dimensional echo–planar imaging magnetic resonance microscopy pulsed-field gradient nuclear Overhauser effect


•

point, if the Z-shim on the NMR spectrometer is adjusted such that it produces a linear magnetic field gradient exactly opposite to the linear gradient originally present in the sample, the combined gradients cancel, and good line shape and resolution are achieved (Figure 1C). Lauterbur’s Contribution Although magnetic field inhomogeneities are an undesirable, unwanted aspect of NMR, a strictly linear inhomogeneity in the magnetic field turns out to have a very useful property, one that is nearly screaming its presence in eq 3 as the variable ∆zi. One might not distort history too much in ascribing the emphasis on eradicating magnetic field gradients that so dominated NMR technological development during its first 20 years as a formidable barrier to Lauterbur’s discovery. Other effects were present at the time to assist Lauterbur, however, as noted below. But to review again the utility of eq 3 in providing spatial information, imagine (or make!) a liquid NMR sample having a solid circular disk (made, for example, of Kel-f ) inserted into it (see Figure 1D). The spectrum of this sample acquired in the presence of a linear magnetic field gradient will show the disk as an absence of spectral intensity, as shown in Figure 1D. The disk’s exact position along the z axis can be easily determined from the NMR spectrum, or more commonly for samples of this type (called a phantom), the disk can be used to calibrate the gradient strength (from the thickness of the disk) and the zero position for z (i.e., where the magnetic field strength in the sample equals B0 and thus Gz = 0).10 More precisely, Paul Lauterbur was first to publish NMR methods by which linear gradients could be used for mapping spectral information into spatial dimensions (4).11 Lauterbur rotated the linear gradients, creating one-dimensional information along the gradient directions as shown

Vol. 81 No. 7 July 2004

•

www.JCE.DivCHED.org


Report

Figure 2. Paul Lauterbur’s use of projection– reconstruction methods for producing twodimensional NMR images is shown in the schematic on the left. Gradients are applied within the x,y plane at various angles; projections are shown head-on at 30°, faceon at 300°, and at two intermediate angles. The resulting projections can be reconstructed into a two-dimensional image having intensities proportional to the proton density. On the right are 72 spectra taken at every 5° on a sample consisting of two water-filled capillaries inserted into an otherwise empty 5-mm tube. A 3-mm slice was taken along the z axis, and the x and y gradients were changed to give a constant gradient of size 20 G/cm along an angle θ in the x,y plane: Gx = a × cos θ, Gy = a × sin θ with a = 10000 DAC units; the data were acquired on an INOVA-600.

in Figure 2.12 Using back-projections algorithms already in use for X-ray tomography, Lauterbur was able to construct a two-dimensional image of two test tubes filled with H2O inside an NMR spectrometer. As simple as this idea appears to be today, it is the basis of all MRI images currently acquired, and is a primary factor in Lauterbur’s being awarded the Nobel Prize. Naysayers Beware Scientists must take risks in research, and Lauterbur and Mansfield’s foresight and enthusiasm about the potential of NMR for imaging tumors and other features in humans is an incredibly rich example of risk taking that has had tremendously positive impacts for the health of the human race. The idea in the early 1970s that MRI might (possibly) contest, or even complement, X-ray tomography’s pre-eminence as a medical diagnostic tool appeared to more than a few scientists as impossibly optimistic.13 The most obvious problem, as all practicing synthetic chemists know, is how insensitive a technique NMR is, requiring orders of magnitude more sample than other analytical techniques such as mass spectrometry and X-ray spectroscopy. The sensitivity issue had been shown to be, perhaps, not as problematic as first impressions might suggest. Two years prior to Lauterbur’s publication, R. Damadian had shown that water in normal tissues had substantially different NMR proton relaxation times than that for water in tumorous tissues (5). Water in tumors had T1 values at least 50% (and often >100%) larger than water in normal tissue. Normal tissue provides much more structure to the intracellular water than tumorous tissue, explaining the change in T1. With this work, Damadian first showed that NMR had significant potential toward the diagnosis and study of cancer, and gen926


•

erated much of the early impetus for the development of MRI.14 The tumorous tissue is said to have good NMR or MRI contrast compared to the normal tissue. Contrast is the essence of the clinical and research utility of MRI. Although X-rays are inherently much “brighter” than the radio wave radiation detected in MRI, there is very little difference in the absorbance of X-rays between the different tissues. The large differences in intensities (generated by the differences in relaxation times), or high contrast, provided by NMR gives MRI great specificity in observing differences in tissues. If a tumor is present, a good MRI image will show it! It is necessary, however, to first obtain, in a practicable period of time, spatially resolved MRI data that are not dominated by noise. Earlier projections of the required experimental times to overcome noise were not promising. Lauterbur used one linear gradient in his 1973 paper (4), and acquired sets of data by rotating the gradient about a single axis with respect to the sample, as illustrated above with regard to Figure 2. Later researchers applied two orthogonal gradients during the NMR experiment, and incremented the size of one gradient for different data sets—the spin warp method (6, 7). Standard 2D NMR methods and Fourier transform (FT) algorithms could then be used to construct the image. Although both projection–reconstruction and FT methods could be extended to three dimensions—by rotation about a second axis, or inclusion of a third orthogonal gradient— both had serious drawbacks. Each data set could be taken only within some sizable fraction of the nuclei’s spin–lattice relaxation time. Even with the injection into the sample (eventually a human!) of paramagnetic relaxation agents, the acquisition of a usable image of a human organ would take much too long to be useful as a clinical tool.

Vol. 81 No. 7 July 2004

•

www.JCE.DivCHED.org


Report

Figure 3. (A) Gradient spin-echo sequence, starting with a 90°x rf pulse, followed by a static gradient, G. A 180° pulse is inserted midway, as magnetization will refocus at τ after this pulse. (B) Gradient-echo sequence, identical to (A) but with the 180° pulse replaced by inversion in the sign of the gradient. (C) Nuclei at different z-positions in the sample will experience different magnetic field strengths while the gradient is being applied, changing the phases of the magnetization in a spatially dependent manner.

Spin and Gradient Echoes Some discussion of how magnetization is echoed in NMR experiments is needed to understand how sensitivity issues in MRI were solved. The application of a magnetic field gradient will take the phase coherence of an ensemble of nuclear spins, initially along the y-axis as shown in Figure 3C, and warp them into a helix along the gradient direction. The application of a 180° rf pulse during application of a constant gradient will reverse the effect of the gradient, and create a spin echo (8, 9); see Figure 3A. Spin echoes will also echo any other linear Iz interactions such as the chemical shift. If instead of using a 180° rf pulse, the gradient amplitude is reversed at a time τ into the experiment, the effect of the first gradient is un-warped, creating a gradient echo at 2τ, as shown in Figure 3B. Now only the effects from the gradients themselves are echoed. Mansfield’s Contribution Sir Peter Mansfield’s first publication on NMR imaging followed Lauterbur’s in the same year (10). One year later, he and coworkers published the next important set of ideas (11), showing that application of selective excitation in the presence of a gradient provides a simple method of adding another spatial dimension to an image. This idea is illustrated in Figure 4, where the rf pulse is modified in such a way as to cause excitation only for a narrow, controllable band of 928


•

frequencies. Normally in NMR, a short (typically 10–40 µs) rectangular pulse of rf is used, as shown in Figure 3, producing broadband excitation; all protons are affected by these pulses. The longer (typically 1–200 ms) shaped rf used for selective excitation affect only protons having a Larmor frequency in a narrow band. An example would be to use a shaped rf pulse selectively exciting protons within 3 kHz of the carrier (or primary) frequency of the rf.15 If the carrier frequency is +4 kHz away from νo (see eq. 1), and γ G = 10 kHz/cm, protons will be excited only from that part of the sample ±3 mm from a center position 4 mm above the G = 0 spot. Thus the selective excitation of a nearly rectangular disk of nuclei is achieved by a shaped rf pulse in the presence of a z-gradient, as shown in Figure 4. This pulse sequence has a second gradient along the x-axis. If this x-gradient is rotated, similar to that shown in Figure 2, projection-reconstruction will now provide a 2D image of the nuclei only within the selected disk normal to the z-axis. Fourier transform methods of constructing the 2D image of the disk can also be performed, where the y-gradient is incremented in size for each data set, and the x-gradient provides a direct readout of the density of nuclei along the x-axis—in this example, the xgradient is commonly referred to as the read-gradient. If the selective excitation is stepped across the full z-dimension (only an appropriate shift in the center frequency of the shaped pulse is needed to change the position of the selected disk), a 3D image results from either method.

Vol. 81 No. 7 July 2004

•

www.JCE.DivCHED.org


Figure 4. Shaped rf pulses applied concurrent with a magnetic field gradient will select a spatial region of the sample determined by the shape and center frequency of the rf. A 3-lobe sinc pulse will select a rectangular region normal to the gradient direction, here along the z-axis. Detection of the resulting NMR signal during application of another gradient, in this case along the x-axis, will generate a projection of the nuclear spin density of that slice along the x-axis.

A major benefit of the selective excitation method is that only those nuclei within the selected region are driven away from equilibrium during the experiment. Another experiment selecting a new unperturbed region of the sample can be performed immediately after the first, with no delay for the T1 relaxation times. Consequently, a complete set of zselections can be performed within a single relaxation delay. A complete set of experiments with a single y-gradient size could be acquired within a short period of time (a fraction of T1). Even with this advantage, the insensitivity of NMR was still preventing usable data from being acquired on living, moving (breathing) subjects. Mansfield provided the final leap in overcoming these problems in 1977 when he published a method called echo-planar imaging (EPI) (14). This remarkable technique takes advantage of the long relaxation times of protons and gradient echo methods as discussed in the previous section. Mansfield realized that gradient echoes could be repeated over and over again—hundreds of times—in the course of a single experiment. Reforming spin echoes in a single experiment was not new to NMR (9), but Mansfield was the first to apply the idea to imaging experiments with gradient echoes. He also saw that one of the gradients (the y-gradient in Figure 3B) could encode spatial information during each switch of the read (x-) gradient amplitudes. In EPI, three-dimensional images are obtained as follows: (i)

one dimension (along x) is acquired directly in the presence of the read (x-) gradient;

(ii)

a second dimension (along y) is now determined by application of a (y-) gradient inserted between read gradient amplitude changes;

(iii)

the third dimension is acquired using selective excitation in the presence of the final (z-) gradient.

This single experiment—comprised of hundreds of gradient echoes, each nearly equal in sensitivity to one acquisition prior to EPI—could be repeated immediately for new (z-) slices. www.JCE.DivCHED.org

•

Full 3D images using EPI could now be acquired up to 10,000× faster than with earlier methods (15)! EPI techniques improved sensitivity so enormously that MRI quickly advanced into new realms: real-time movies of heart function, for example, were now possible. More importantly, time spans for diagnostic images became sufficiently short to allow MRI to become practical as a clinical technique. Breathing artifacts could be reduced, allowing detailed studies of all portions of the human anatomy. In addition, EPI techniques allowed for additional discrimination (or contrast) in MRI images due to chemical shift, relaxation (T1 or T2), flow, or diffusion. The sensitivity of NMR/MRI to these many features provides a primary utility to the technique, as discussed above; a proper combination of these factors allows, as a simple example, for suppression of signals from fat or water. MRI for Chemists It is apparent to all how valuable MRI is for the medical community. What may not be as apparent is how strongly MRI has impacted its parent technique, NMR, and thereby how strongly it is impacting chemical research. Many chemists may not realize that any pulsed-field gradient (PFG)5-capable NMR spectrometer16 can perform NMR imaging of small samples. Of most immediate interest in this respect is the specialized area of magnetic resonance microscopy (MRM). Probably best known for the publication of an image of a single cell which made the cover of Nature in the 10 July 1986 issue (16), MRM encompasses imaging experiments taken on small samples with relatively high spatial resolution. Mansfield suggests, in a good review of the limitations of MRM (17), that the technique be renamed “magnetic resonance mini-scopy,” since 1 µm resolutions are the current (and in a practical sense, perhaps ultimate) spatial resolution limit. In common organic liquid samples, diffusion limits resolutions in MRM to ~7 µm. Various other aspects of MRM limit usable resolutions to 10–100 µm; a common example is magnetic susceptibility

Vol. 81 No. 7 July 2004

•


929


Report gradients arising from bulk changes in the sample itself. MRM utilizes all the sensitivity to molecular mobility, diffusion, flow, chemical shift, etc. that make NMR and MRI such valuable techniques. An NMR probe and console equipped with triple-axis PFG are needed to generate three-dimensional information (unless the sample can be physically rotated);17 even so, onedimensional spatial information can be obtained on singleaxis PFG probes that are now common on new spectrometers. The ability to obtain chemical shift information in spatially resolved images (18) provides significant utility for the chemist. One simple method for generating such spatially-selective information is to use the selective excitation scheme shown previously in Figure 4. The excitation is performed in the presence of a strong gradient, and the data are then acquired with the gradient off. A normal NMR spectrum is obtained, but only from the portion of the sample selected. Additional spectra can be obtained immediately from other slices of the sample. 31P or 13C spatiallyresolved spectra can be obtained in a similar manner. Diffusion (19) and flow (20) determinations having spatial information can also be obtained via MRM. These techniques have proven useful for studies of mixing, porosity, self-diffusion, blending, etc., in a wide variety of studies (21). By far the largest impact of MRI on chemical research has occurred by transfer of PFG technology back into NMR. Although Lauterbur and Mansfield did not directly contribute to these issues, the success of MRI provided the economic driving force behind these developments, in much the same way that molecular NMR initially provided the economic driving force for the development of the magnetic and electronic capabilities that enabled MRI. PFGcapable spectrometers, as one example, can provide automated shimming that is faster and less dependent on sample quality than older automated shimming methodologies. PFGshimming is now the standard technique for automated line-shape optimization used in the NMR community, especially for samples in H2O.18 Even as seemingly useful as automated shimming appears to be,19 a primary utility of PFG in NMR is the ability of magnetic field gradients in performing coherence selection (22). Many modern two- and multi-dimensional NMR experiments make use of this technique. A simple description of coherence selection is the following: magnetization of a magnetically active nucleus, X, is varied by application of a gradient. Since gradients do no more than (spatially) vary the intensity of B0, X has a large, spatially dependent offset (similar to a large chemical shift) imposed during application of the gradient of length τX: ∆νX = γ X G X z τ X The phases of the X magnetization will warp similar to what is shown in Figure 3C. The magnetization is then transferred to another nucleus S, typically protons, via a J-coupling (in a manner completely analogous to INEPT or DEPT) or NOE. If detection is attempted at this point, the phases of the S magnetization will still be warped, and nothing will be observed. If, however, another gradient is imposed in a spin– 930


•

echo type of experiment, such that ∆νS = γS G S z τ S = ∆νX or

G τ γX = S S γS GX τ X

the spin warp is reversed and only magnetization that started on X and connected to S via scalar coupling or NOE will be detected.20 A very common example in the chemical NMR lab is the following. Magnetization is transferred from protons to carbon-13 nuclei using an INEPT. During chemical shift evolution of the 13C, a gradient γCGCτC is applied. The warped 13C magnetization is then transferred back to protons (using an inverse INEPT). Another gradient γHGHτH = γCGCτC is applied to the protons, and detection is performed. This 2D experiment—a gradient HSQC for 1-bond 1H–13C chemical shift correlation, or a gradient HMBC for longrange 1H–13C chemical shift correlation—comprises a major advance for modern NMR. The two coherence-transfer gradients provide the following, crucial (especially for the HMBC) criterion: only protons having J-coupling to a 13C nucleus will be observed; protons having 12C nearby are eliminated to better than 1 in 105! Further discussion of these techniques, from inverse heterocorrelation to selective one-dimensional NOE methods, lies outside the scope of this article. Even so, chemists working in the modern NMR laboratory have much reason to thank Paul Lauterbur and Sir Peter Mansfield for their contributions. Not only have they significantly advanced the state of modern health care and research, but their contributions have added significantly to modern chemical research within all areas of MRI and NMR. Notes 1. The initial acronym for MRI was NMRI, short for Nuclear Magnetic Resonance Imaging. Patients became worried about the “Nuclear”, thinking the technique might be radioactive. After some time fighting this misperception, the medical and scientific community finally dropped the N from the acronym. 2. Brief biographies and discussions of Nobel awards can be found at http://www.nobel.se/index.html (accessed Apr 2004). 3. Student researchers should be motivated by the fact that Lauterbur was one of the early investigators of 13C, 29Si, and 31P NMR. His early publications (1–3) were performed well in advance of his obtaining a Ph.D. at the University of Pittsburgh in 1962. Students should also note that in ref 1, Lauterbur is the sole author. 4. Shimming is not just a historical term to a chemist like Lauterbur. Early permanent and electromagnets used for NMR had to be adjusted by a set of wooden shims—identical to those used to shim a wooden floor—to assist in getting the magnet poles parallel to each other. 5. The terms “magnetic field gradients” and “pulsed-field gradients” (used later in this review) are in common use in the NMR and MRI research communities. They are, of course, a shorthand form of the more correct English phrases “gradients of a magnetic field” and “gradients of pulsed magnetic fields”.

Vol. 81 No. 7 July 2004

•

www.JCE.DivCHED.org


6. This discussion is appropriate for observation of gross 1H chemical shifts in a magnetic field strength ≥0.23 T ( ν 0 1H ≥10 MHz). Homogeneity of 10᎑8 is a more common standard for lower field NMR magnets. Higher field magnets are designed similarly: resolutions of 0.2 Hz are typical for protons resonating at 500 MHz, or a homogeneity of 10᎑9. 7. The homogeneity design criteria of high field NMR magnets are so difficult to achieve that they comprise a major factor in the $5,000,000+ cost of today’s commercially available highest field strength NMR magnets, where protons resonate at 900 MHz. 8. Magnetic field inhomogeneities from one laboratory to another arise from differences in metal structures close to the magnet. A set of superconducting shims provides the primary cancellation of these inhomogeneities. The differences in each NMR probe’s metal structure also significantly degrades magnetic field homogeneity, and newer spectrometers often have 40 or more room-temperature shims, enabling nearly complete compensation for probe differences. Sample-to-sample changes can usually be compensated for with adjustments in only a few of the low-order shims. 9. Although true, the quality of shims (and magnets) has improved dramatically over the last decade due to the advent of twodimensional NMR, where sample spinning should not be used. This restriction forced significant improvements in the non-spinning shim sets, and increased “purity” (e.g., having the z4 shim not have x and y impurities) of all the shims. For these reasons, it is often productive to upgrade shim sets as older spectrometers (but typically not their magnets) are replaced. 10. For a liquid 5-mm NMR sample, a perfectly rectangular shape might be expected from a sample observed while a linear zgradient is present; we should observe nothing—zero intensity— outside the detection region, and constant proton density along the z direction within the detection region. The volume detected is not, however, perfectly cylindrical. All rf coils—which detect the proton magnetization—have a region of decreasing rf intensity (proportional to the detected signal) as the sample extends outside the coil. The rf intensity inside the coil is not perfectly homogeneous either, leading to a shape seen on modern spectrometers similar to the schematic shown in Figure 1B. Readers can discover the shape of their detection region by adjusting the Z1 shim well away from the correctly-shimmed value—producing a linear z gradient—and acquiring a “normal” 1H NMR spectrum (the sweep width may have to be increased from that normally used). The sample should be concentrated, e.g., 50% H2O in D2O. The observed spectrum should have an appearance similar to that shown in Figure 1B, being a z-profile of the proton density as a function of the z-dimension (along the length of the tube). If a cylindrical disk is wedged into the sample within the detection region, an intensity “hole” will be observed, similar to that shown in Figure 1D. From the width of the disk, ∆z, in cm, and the width of the hole, ∆ν, in Hz, the strength of the gradient can be calculated as: γ Gz = ∆z/∆ν in Hz/cm. By referencing the water signal when well shimmed to 0 Hz, Gz = 0 occurs at the 0 Hz position in the resulting z-profile spectrum. 11. Lauterbur was not the first to show how magnetic field gradients can be used as a research tool. It was understood early on in the development of NMR that magnetic field gradients affect the intensity of spin echoes, because of incomplete formation of the echoes due to diffusion. Gradients were therefore used to measure

www.JCE.DivCHED.org

•

diffusion of the nuclear spins. A. Abragam provides a good introductory discussion of this effect in Chap. III, Section III. A of his (still excellent) book The Principles of Nuclear Magnetism (Oxford University Press, 1961, ISBN 198512368; reprinted in 1983 in paperback by Oxford Science Publications, 1983, ISBN 019852014X). 12. The left side of Figure 2 is a near-reproduction of Lauterbur’s original Figure 1. On the right are spectra obtained by the author on an INOVA-600 equipped for normal liquids work, using a standard 5- mm, 3-axis PFG inverse probe. 13. The author has the embarrassing memory of reading Lauterbur’s work in the late 1970s as a young graduate student and deciding (obviously without studying the area in close to enough detail) that the idea of NMRI having practical clinical utility was ridiculous. 14. The Nobel committee’s exclusion of Damadian for the 2003 Nobel Prize in Medicine has generated considerable controversy; of particular relevance is publication (5). 15. Other excitation shapes are used, depending on the application. Two good reviews of shaped rf excitation used in NMR are given in (12, 13); ref 12 provides a relatively brief introduction to the field, whereas ref 13 is more complete. 16. Most new NMR spectrometers have pulsed-field gradient (PFG) capability installed on them. The examples in this article provide strong reasons why all new NMR spectrometers should be purchased with, at the least, z-axis PFG capability. 17. Other probes could generate three dimensional images: e.g., a probe equipped with radio-frequency gradients. The statement in the text applies to commonly available commercial probes. 18. Automated PFG-shimming of samples in deuterated solvents is also available, and works well, on properly equipped commercial NMR spectrometers. 2H has a much larger variation in relaxation properties, however, as a function of solvent, temperature and solute than 1H. This variability in 2H relaxation makes 2 H PFG shimming easily adaptable to only constant temperature use. The technique is excellent in shimming samples in variable temperature experiments, but only if the spectroscopist knows how to properly adjust the experimental parameters to match the changes in the 2H relaxation. 19. Many students “love” PFG shimming, and will stridently state that they cannot manage without it (a common refrain from those who end up with experimental setups where it cannot be used). But the reality is that their predecessors did just fine without it, and so can they if required! 20. The previous discussion applies only to single quantum evolution; gradients affect coherences of quantum order p as ∆νS = γ S G S z τS p .

Literature Cited 1. Lauterbur, Paul C. Carbon-13 Nuclear Magnetic Resonance Spectra. J. Chem. Phys. 1957, 26, 217–218. 2. Muller, Norbert; Lauterbur, Paul C.; Goldenson, Jerome Nuclear Magnetic Resonance Spectra of Phosphorous Compounds. J. Am. Chem. Soc. 1956, 78, 3557–3561. 3. Holzman, G. R.; Lauterbur, P. C.; Anderson, John H.; Koth, W. Nuclear Magnetic Resonance Field Shifts of Silicon-29 in Various Materials. J. Chem. Phys. 1956, 25, 172–173.

Vol. 81 No. 7 July 2004

•


931


Report 4. Lauterbur, P. C. Image Formation by Induced Local Interactions: Examples Employing Nuclear Magnetic Resonance. Nature 1973, 242 (5394), 190–191. 5. Damadian, R. Tumor Detection by Nuclear Magnetic Resonance. Science 1971, 171 (976), 1151–1153. 6. Edelstein, W. A.; Hutchison, J. M. S.; Johnson, G.; Redpath, T. W. Spin Warp NMR Imaging and Applications to Human Whole-Body Imaging. Physics in Medicine and Biology 1980, 25 (4), 751–756. 7. Johnson, G.; Hutchison, J. M. S.; Redpath, T. W.; Eastwood, L. M. Improvements in Performance Time for Simultaneous 3-Dimensional NMR Imaging. J. Magn. Reson. 1983, 54 (3), 374–384. 8. Hahn, E. L. Spin Echoes. Phys. Rev. 1950, 80, 580–594. 9. Carr, H. Y.; Purcell, E. M. Effects of Diffusion on Free Precession in Nuclear Magnetic Resonance Experiments. Phys. Rev. 1954, 94, 630–638. 10. Mansfield, P.; Grannell, P. K. NMR Diffraction in Solids. J. Physics C: Solid State Physics 1973, 6 (22), L422–L426. 11. Garroway, A. N.; Grannell, P. K.; Mansfield, P. Image Formation in NMR by a Selective Irradiative Process. J. Physics C: Solid State Physics 1974, 7, L457–L462. 12. Warren, Warren S. Effects of Pulse Shaping in Laser Spectroscopy and Nuclear Magnetic Resonance. Science 1988, 242, 878–884. 13. Freeman, Ray Shaped Radiofrequency Pulses in High Resolution NMR. Prog. NMR Spec. 1988, 32 (1), 59–106. 14. Mansfield, P. Multi-Planar Image Formation Using NMR Spin Echoes. J. Physics C: Solid State Physics 1977, 10 (3), L55–L58.

932


•

15. A good review is given in Stehling, M. K.; Turner, R.; Mansfield, P. Echo-Planar Imaging: Magnetic Resonance Imaging in a Fraction of a Second. Science 1991, 254 (5028), 43–50. 16. Aguayo, J. B.; Blackband, S. J.; Schoeniger, J.; Mattingly, M. A.; Hinterman, M. Nuclear Magnetic Resonance Imaging of a Single Cell. Nature 1986, 322, 190–191. 17. Glover, Paul; Mansfield, Peter. Limits to magnetic resonance microscopy. Rep. Prog. Phys. 2002, 65, 1489–1511. 18. See, for example, Price, W. S. NMR Imaging. Ann. Reports on NMR Spec. 1998, 35, 139–216; Rumpel, Helmut; Pope, James. M. Chemical Shift Imaging in Nuclear Magnetic Resonance: A Comparison of Methods. Concepts Magn. Reson. 1993, 5 (1), 43–55. 19. See, for example, Callaghan, Paul. T. Principles of Nuclear Magnetic Resonance Microscopy; Clarendon Press: Oxford, 1991. 20. See, for example, Callaghan, P. T.; Jeffrey, K. R.; Xia, Y. Translational Motion Imaging with Pulsed Gradient Spin Echo Methods. Magn. Reson. Microsc. 1992, 327–347. 21. See, for example, ref 18 and Miller, J. B. NMR Imaging of Materials. Prog. NMR Spec. 1998, 33 (3,4), 273–308. 22. See, for example, the discussion in section 2.6.2.6 of Hull, William E. Experimental Aspects of Two-Dimensional NMR. TwoDimensional NMR Spectroscopy: Applications for Chemists and Biochemists, 2nd ed.; Croasmun W. R.; Carlson, R. M. K., Eds.; VCH Publishers: New York, 1994, Chapter 2, pp 246–252.

Charles G. Fry is Director, Magnetic Resonance Facility, Department of Chemistry, University of Wisconsin–Madison, 1101 University Avenue, Madison, WI 53706-1322.

Vol. 81 No. 7 July 2004

•

www.JCE.DivCHED.org

The Nobel Prize in Medicine for Magnetic ... - ACS Publications

Recommend Documents