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Chapter 1
Introduction and Summary

Recent advances in imaging technology allow evaluation of biologic processes and events as they occur in vivo. For example, new magnetic resonance and radioisotope imaging methods reflect anatomy and dynamic body functions heretofore discerned only from textbook illustrations. These new methods give functional images of blood flow and metabolism essential to diagnoses and to research on the brain, heart, liver, kidneys, bone, and other organs of the human body.

Studies of such phenomena as brain atrophy during normal and abnormal aging (Figure 1.1) have been aided by advances in the resolution of magnetic resonance imaging (MRI), while advanced biomedical imaging techniques have improved care procedures in difficult medical situations such as brain surgery (Plate 1.1; plates appear after p. 12). In cancer research the new methods have enabled studies of the efficacy of therapy without the need for biopsy or the anguish of waiting for morbid signs of recurrence (Plate 1.2 and Figure 1.2).

Emerging x-ray and MRI methods applied to the skeletal system (Plate 1.3) and tissue microscopy of, for example, the eye (Plate 1.4) allow diagnoses to be made conveniently and efficiently. The emergence of MRI methods and improvements in acquisition techniques for x-ray computed tomography (CT) have also led to safe and convenient ways of visualizing blood vessels within the body (Figure 1.3). The capabilities of fast x-ray CT (spiral CT) to detect arterial wall calcifications and flows in vessels and kidneys, and of fast MRI to similarly detect vessel, kidney, and ureter flows, are illustrated on the cover. Even more detailed dynamic imaging of kidney function is shown by the sequence of 2.8 second abdominal MRI images of Plate 1.5, which is an example of the emerging methods of functional MRI.



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Page 1 Chapter 1 Introduction and Summary Recent advances in imaging technology allow evaluation of biologic processes and events as they occur in vivo. For example, new magnetic resonance and radioisotope imaging methods reflect anatomy and dynamic body functions heretofore discerned only from textbook illustrations. These new methods give functional images of blood flow and metabolism essential to diagnoses and to research on the brain, heart, liver, kidneys, bone, and other organs of the human body. Studies of such phenomena as brain atrophy during normal and abnormal aging (Figure 1.1) have been aided by advances in the resolution of magnetic resonance imaging (MRI), while advanced biomedical imaging techniques have improved care procedures in difficult medical situations such as brain surgery (Plate 1.1; plates appear after p. 12). In cancer research the new methods have enabled studies of the efficacy of therapy without the need for biopsy or the anguish of waiting for morbid signs of recurrence (Plate 1.2 and Figure 1.2). Emerging x-ray and MRI methods applied to the skeletal system (Plate 1.3) and tissue microscopy of, for example, the eye (Plate 1.4) allow diagnoses to be made conveniently and efficiently. The emergence of MRI methods and improvements in acquisition techniques for x-ray computed tomography (CT) have also led to safe and convenient ways of visualizing blood vessels within the body (Figure 1.3). The capabilities of fast x-ray CT (spiral CT) to detect arterial wall calcifications and flows in vessels and kidneys, and of fast MRI to similarly detect vessel, kidney, and ureter flows, are illustrated on the cover. Even more detailed dynamic imaging of kidney function is shown by the sequence of 2.8 second abdominal MRI images of Plate 1.5, which is an example of the emerging methods of functional MRI.

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Page 2 Figure 1.1. Magnetic resonance images of the aging brains of living subjects that show different degrees of atrophy of the hippocampal regions known to be involved in memory processes. The images at the top and on the bottom left are from a 73-year-old person with Alzheimer's disease, while that on the bottom right is from an 86-year-old athlete. (Illustration courtesy of Thomas Budinger, Lawrence Berkeley National Laboratory.)

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Page 3 Figure 1.2. Whole-body studies with positron emission tomography (PET) of the accumulation of a radiolabeled analog of the sugar fluorodeoxyglucose (FDG) can detect tumor metastases from breast cancer. Shown here is the sequential evaluation of the effectiveness of therapy. (Illustration courtesy of Thomas Budinger, Lawrence Berkeley National Laboratory.)  Data processing methods applied to conventional electrical recordings allow display of the spatial patterns of an electroencephalograph of the brain (Figure 1.4), and this engineering accomplishment does not entail major new equipment investments. The major topics of recent interest in the area of functional imaging involve the use of MRI and positron emission tomography (PET) to explore the activity of the brain when it is challenged with sensory stimulation or mental processing tasks (Plate 1.6), and the use of PET to investigate the physiological basis of societal health problems such as drug abuse and craving (Plate 1.7). As we begin to apply modern biology in gene therapy trials,

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Page 4 Figure 1.3. Applications of critical importance include evaluation of the vascular tree using magnetic resonance imaging without the need for injected contrast materials, which must be used in conventional angiography with x-rays. (Illustration courtesy of G. Wright, University of Toronto, and D. Nishirura and A. Macovski, Stanford University.) dynamic and functional imaging methods are being called on to aid in evaluating the appropriateness and efficacy of therapies, as has been done for Parkinson's disease and is proposed for Alzheimer's disease. The emerging imaging methods have the potential to help unravel major medical and societal problems, including the mental disorders of depression, schizophrenia, and Alzheimer's disease and metabolic disorders such as osteoporosis and atherosclerosis. An example of an entirely new development is the integration of real-time MRI as a means for monitoring interventional procedures (''interventional MRI"), a capability that would be particularly appealing for use in conjunction with the emerging methods of minimally invasive surgery such as ablative procedures using lasers, cryoprobes, or focused ultrasound. Ultrasound in fact could be a completely noninvasive technique; applying it does not involve surgery. While ultrasound has been used in the past as a

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Page 5 Figure 1.4. The computerized electroencephalogram provides a means of mapping the spatial distribution of brain wave power by frequency bands. Only the alpha (10 to 13 Hz) and slow-wave delta bands are shown. Note the differences in the frequency components of brain waves between normal subjects and Alzheimer's patients. Drawing from data of Mody, C.K., McIntyre, H.B., Miller, B.L., Altman, K., and Read, S., Computerized EEG frequency analysis and topographic brain mapping in Alzheimer's disease, Ann. N. Y. Acad. Sci. 620 (1991), 45-56. source for heat destruction, its full potential cannot be realized without a capability for remote sensing of temperature. Fortunately, MRI is uniquely suited for on-line monitoring of focused ultrasound because of the temperature sensitivity of the signal. Interventional MRI systems incorporating new technology such as superconducting magnets that allow physicians to have access to their patients during a scan are already undergoing trials and are predicted to radically alter the ways surgical procedures will be performed in the 21st century. Some of the research challenges that could contribute to realization of this vision are described in Chapters 4 and 12 of this report. Many of the envisioned innovations in medical imaging are fundamentally dependent on the mathematical sciences. Equations that link imaging measurements to quantities of interest must be sufficiently complex to be realistic and accurate and yet simple enough to be capable of solution, either

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Page 6 Figure 1.5. Algorithms for single photon emission computed tomography (SPECT) of blood flow in the heart give erroneous results unless attenuation by intervening tissues of the radiation from the radionuclide is taken into account. The image on the left—a transaxial SPECT reconstruction of radionuclide in the heart muscle using backprojection of filtered projections—has not been corrected and would lead to a misdiagnosis of septal wall infarction. The image on the right, a transaxial SPECT reconstruction of the same heart but using the iterative maximum likelihood-expectation maximization algorithm with attenuation and scatter compensation, shows normal flow. (Illustration courtesy of Benjamin Tsui, University of North Carolina.)  by a direct "inversion formula" or by an appropriate iterative algorithm. In the early 1970s computer methods and algorithms became powerful enough to allow some equations to be solved for practical situations. But there is invariably noise in the measurements, and errors also arise because of the impossibility of giving an exact inversion solution to the equations, either because the equations are only approximate or because the solution technique involves approximation. The development of mathematical methods for producing images from projections thus also requires a capability for overcoming errors or artifacts of the reconstruction method that arise from different sources, and much remains to be done. The result is the need for approximate reconstruction strategies or the incorporation of prior or side information (Figure 1.5). In addition, computer simulation of imaging methods plays an essential role in separating errors of noise from errors in the design of the mathematical methods, and simulation allows the mathematician and physicist to critically evaluate new ideas in the emerging field of

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Page 7 dynamic biomedical imaging. Although the mathematical sciences were used in a general way for image processing, they were of little importance in biomedical work until the development in the 1970s of computed tomography (CT) for the imaging of x-rays (leading to the computer-assisted tomography, or CAT, scan) and isotope emission tomography (leading to PET scans and single photon emission computed tomography (SPECT) scans). An example of SPECT imaging is shown in Figure 1.5. In the 1980s, MRI eclipsed the other modalities in many ways as the most informative medical imaging methodology. Besides these well-established techniques, computer-based mathematical methods are being explored in applications to other well-known methods, such as ultrasound and electroencephalography, as well as new techniques of optical imaging, impedance tomography, and :agnetic source imaging. It is worth pointing out that, while the final images of many of these techniques bear many similarities to each other, the technologies involved in each are completely different and the parameters represented in the images are very different in character as well as in medical usefulness. In each case, rather different mathematical or statistical models are used, with different equations. One common thread is the paradigm of reconstruction from indirect measurements-this is the unifying theme of this report. The imaging methods used in biomedical applications that this report discusses include: • X-ray projection imaging, • X-ray computed tomography (CT), • Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy, • Single photon emission computed tomography (SPECT), • Positron emission tomography (PET), • Ultrasonics, • Electrical source imaging (ESI), • Electrical impedance tomography (EIT), • Magnetic source imaging (MSI), and • Medical optical imaging.

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Page 8 Introductions to these modalities, and their frontiers, are given in Chapters 2 through 11. The physics, mathematical, and engineering challenges inherent in each of the methods are included in the discussions of each modality. While the emphasis is on research challenges, significant development opportunities are also pointed out where appropriate. Chapters 12 and 13 step back to present a vision of the emerging world of biomedical imaging, wherein imaging plays an expanded role in diagnosis and therapy, and sophisticated image processing gives medical personnel access to much greater insight into their patients' conditions. To emphasize the mathematical underpinnings of biomedical imaging, Chapter 14 takes a cross-cutting and more detailed look at mathematical models and algorithms and outlines the related research opportunities. Microwave imaging, infrared imaging, electron spin resonance, and interferometry are not discussed in this report because those methods at present are further from the forefront of development and applications. Also not covered in this report are the techniques of in vitro microscopy, such as confocal microscopy, atomic force microscopy, fluorescence microscopy, and methods of electron microscopy used to study biological systems. Although use of radioisotopes and contrast agents in x-ray computed tomography and MRI involves the chemical sciences, innovations in these areas are not critically evaluated in this report because they are too far afield of its focus. Although this report emphasizes methodologies for visualizing internal body anatomy and function, some mention is warranted of the importance of improving techniques for the evaluation of human biology and disease processes through visualization of external features and functions. For example, sequential image-based descriptions of skin texture or color, gait, flexibility, and so on would require the development of convenient observation systems, perhaps with greater sensitivities than the human eye, and mathematical methods (e.g., artificial intelligence) for identifying significant changes. This volume discusses each of the modalities listed above in some detail to give the reader a picture of the current state of development. It also points to aspects of these biomedical imaging technologies where a deeper understanding is needed and to frontiers where future advances are most likely. The reader is encouraged to imagine the horizons for new developments and to critically examine the recommendations offered for the further development of each imaging modality. Biomedical imaging has seen truly exciting advances in recent years. New imaging methods can now reflect internal anatomy and dynamic body functions heretofore only derived from textbook pictures, and applications

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Page 9 to a wide range of diagnostic and therapeutic procedures can be envisioned. Not only can technological advances create new and better ways to extract information about our bodies, but they also offer the promise of making some existing imaging tools more convenient and economical. While exponential improvements in computing power have contributed to the development of today's biomedical imaging capabilities, computing power alone does not account for the dramatic expansion of the field, nor will future improvements in computer hardware be a sufficient springboard to enable the development of the biomedical imaging tools described in this report. That development will require continued research in physics and the mathematical sciences, fields that have contributed greatly to biomedical imaging and will continue to do so.

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Page 11 PLATE CAPTIONS Plate 1.1. Three-dimensional magnetic resonance image processed mathematically to segment the blood vessels (red) from tumor tissues (green and yellow) and the corpus callosum (blue). Visualization of this information helps guide neurosurgery for individual patients. (Illustration courtesy of T. Peters, Montreal Neurological Institute.) Plate 1.2. Magnetic resonance spectroscopy is used to map the presence of an abnormally high concentration of choline relative to citrate (red) in the human prostate before cryosurgery. The disappearance of this high choline-to-citrate ratio shows the efficacy of cryosurgery and is a guide to deciding whether to give more or less treatment. (Illustration courtesy of J. Kurhanewitz and D. Vigneron, University of California at San Francisco.) Plate 1.3. The image on the left, showing bone structure of the knee, results from high-resolution x-ray computed tomography (CT) done with a spiral CT. The axial resolution is approximately 1.25 mm. The image on the right, of a different knee joint, was made with magnetic resonance imaging (MRI) and has a resolution of 200 4m. (Left image courtesy of Siemens Medical Engineering Group; right image courtesy of S. Majumdar, University of California at San Francisco.) Plate 1.4. Advances in engineering and in image processing mathematics have allowed practical microscopy of both superficial and internal tissues using hand-held ultrasound instruments. Shown here are a cyst (CY) in the human cornea and a localized tumor (M) in the tissues of the human eye, both detected through ultrasound with 50 yrm resolution. (Illustration courtesy of F. Foster and C. Pavlin, Sunnybrook Health Science Center, Toronto.) Plate 1.5. High-speed magnetic resonance imaging allows diagnosis of kidney functions through moment-to-moment visualization of uptake of the contrast agent gadolinium (DTPA), shown here at 2.8 s intervals. (Illustrations courtesy of Joop J. van Vaals, Philips Medical Systems.) Plate 1.6. The changes in brain physiology during mental tasks can be imaged by non-invasive techniques. A notable development is the non-invasive

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Page 12 use of magnetic resonance imaging (MRI) to show the position in the brain of increases in blood volume and blood oxygenation during brain activation. Positron emission tomography (PET) can also show quantitative changes in metabolism during verbal processing, as indicated by spots of increased activity superposed on the MRI anatomic image of the cortex in the same subject. (Illustration courtesy of U. Pietrzyk and D. Heiss, Max Planck Institut, Koln, Germany.) Plate 1.7. The concentrations of neurotransmitters and neuroreceptors in the brain are 1 million times lower than the concentration of amino acids, sugars, enzymes, and other constituents of the brain. However, these trace neurochemicals can be detected by positron emission tomography (PET). Depicted here are (left to right) the concentrations of dopamine receptors at three anatomic levels of the brain for two subjects, one with a normal number of receptors and one with a decreased number of receptors resulting from a cocaine addiction. (Illustration courtesy of N. Volkow and J. Fowler, Brookhaven National Laboratory.) Plate 1.1 Plate 1.2 Plate 1.3 Plate 1.4 Plate 1.5 Plate 1.6 Plate 1.7