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Chapter 11
Medical Optical Imaging

11.1 Introduction

The past few years have seen considerable advances in devices and algorithms designed to give useful clinical information through the use of a laser beam as a probe into human tissue. The two main areas of interest are tissue spectroscopy—for establishing the presence and if possible the concentration of certain quantities of interest—and imaging, that is, producing an image of these substances as they are localized in different parts of the tissue. The mathematical model is presented in section 14.1.4.

The term laser optical tomography has sometimes been used, because data are collected by applying a laser source at one or different locations around the object of interest and then detecting the light emitted in one or several locations to determine certain characteristics of the medium transversed by the beam. The method is thus analogous to x-ray computed tomography (CT).

Light in the near-infrared range (wavelength from 700 to 1200 nm) penetrates tissue and interacts with it in complicated ways; the predominant effects are absorption and scattering. Many of the substances of interest, such as hemoglobin and cytochromes, exhibit characteristic absorption spectra that depend on whether the molecule is in its oxidized or reduced state. Other substances of great importance, such as NAD/NADH (nicotinamide adenosine diphosphate), exhibit fluorescence properties that allow for their detection after excitation by light. As these substances play crucial roles in metabolic processes at the cell level, the ability to discern them through indirect measurements would have important medical implications.



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Page 157 Chapter 11 Medical Optical Imaging 11.1 Introduction The past few years have seen considerable advances in devices and algorithms designed to give useful clinical information through the use of a laser beam as a probe into human tissue. The two main areas of interest are tissue spectroscopy—for establishing the presence and if possible the concentration of certain quantities of interest—and imaging, that is, producing an image of these substances as they are localized in different parts of the tissue. The mathematical model is presented in section 14.1.4. The term laser optical tomography has sometimes been used, because data are collected by applying a laser source at one or different locations around the object of interest and then detecting the light emitted in one or several locations to determine certain characteristics of the medium transversed by the beam. The method is thus analogous to x-ray computed tomography (CT). Light in the near-infrared range (wavelength from 700 to 1200 nm) penetrates tissue and interacts with it in complicated ways; the predominant effects are absorption and scattering. Many of the substances of interest, such as hemoglobin and cytochromes, exhibit characteristic absorption spectra that depend on whether the molecule is in its oxidized or reduced state. Other substances of great importance, such as NAD/NADH (nicotinamide adenosine diphosphate), exhibit fluorescence properties that allow for their detection after excitation by light. As these substances play crucial roles in metabolic processes at the cell level, the ability to discern them through indirect measurements would have important medical implications.

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Page 158 An early tool of medical optical imaging was the "oximeter," devised in the 1930s to detect the amount of oxygen in blood by measuring the ratio of the light absorbed at two wavelengths. Great improvements to this concept came in the 1970s with the advent of microprocessors and light-emitting diodes that permitted the use of many more wavelengths, thus allowing measurement of the absolute amount of oxygen and elimination of background effects. Assessment of the oxygen content of arterial blood through such methods has become a major diagnostic tool for studying acutely ill patients. The potential of imaging with light was reinforced with the successful application of optical tools to determine the levels of oxygen in the brain of a cat. Later, this concept was used in monitoring brain and muscle oxygenation in humans, as well as in other applications. Optical imaging devices are now used in the neonatal clinic at the Stanford University Medical Center, the University Hospital in London, and possibly elsewhere, and Hamamatsu Corp., in Japan, produces an infrared spectrometer for bedside monitoring of oxygenation in the brains of babies. 11.2   Data Acquisition Strategies Objects have been illuminated for medical imaging by the continuous beam, time-resolved beam, and phase-modulated beam methods. The last method has the advantage of allowing measurement of the mean optical pathlength without the size and cost problems associated with ultrashort light pulses and a fast optical detector. The phase-modulated beam as a measure of optical length has proved to be very useful in quantifying absorption and scattering coefficient measurements. Data collection methods can be divided into two broad classes: (1) those that try to isolate photons undergoing no or very little scattering from source to detector and that thus may be able to use simpler reconstruction algorithms because the path of each photon is considered known; and (2) those that collect light over a longer period, with or without taking into account photon arrival times. Preliminary mathematical analysis indicates that the preferred approach is to sort photon counts by arrival time and then proceed to solve the complex nonlinear inversion problem.

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Page 159 11.3 Comparisons with Other Imaging Modalities Comparisons between optical imaging and more established modalities of medical imaging such as CT, positron emission tomography (PET), single photon emission computed tomography (SPECT), and magnetic resonance imaging (MRI) are both inevitable and pedagogically useful. It is quite possible that medical optical imaging's eventual role will be as a complement to standard techniques rather than as a replacement for them, or perhaps as a complement to other modalities that are under development and have not yet reached maturity (e.g., electrical impedance tomography or magnetic source imaging). In a broader sense it appears likely that the effective use of optical imaging technology will require advances in understanding how low-energy photons interact with complex media like human tissue, particularly as the energy of the photons involved is decreased. Increased understanding of energy-tissue interaction could be applied in some of the more established imaging modalities, many of which do not model for scattering events and strive to throw out this ''noise." One result might be the development of good ways of dealing with "scatter correction" in other imaging modalities. In thinking about the possibilities and difficulties associated with optical imaging, it is necessary to realize that energy in the infrared range interacts with tissue in ways that are dominated by scattering, a phenomenon that is to a large extent absent when higher-energy portions of the electromagnetic spectrum are used. Although the scattering in optical imaging is at times confined to the forward direction, scattering effects accumulate over any thick specimen—because the scattering coefficients in tissue are rather large—and the directional beam of laser light is quickly converted into a diffuse flux. In fact the situation is more complicated: large particles with diameters much larger than that of the wavelength act as mostly forward scatterers, while cell nuclei and mitochondria within the cell scatter light almost uniformly in all directions. In the case of CT one always assumes that a reading connected to a given source-detector pair reflects an absorption event that took place along the straight line joining the two. Mathematically this assumption allows reduction of the problem to one of reconstructing an unknown attenuation distribution function from its straight line integrals. Nothing like that can

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Page 160 be assumed when the photons travel according to the local and varying characteristics of the medium. In fact the photon counts for any source-detector pair result from many absorption and scattering events that happen over the entire medium. It is fortunate that in the near-infrared range, the absorption coefficient of water, fat, and the other chromophores is relatively low. The physically derived mathematical models of the interaction of light and any complex media, such as human tissue, usually take the form of (1) a Boltzmann-type linear transport equation or (2) some of its approximations, such as the diffusion equation with a diffusion coefficient and an absorption coefficient that model the (unknown) local characteristics of the medium (cf. section 14.1.4). The problem of interest in imaging is then that of determining these functions from the data. A more complete and realistic model allows for an anisotropic diffusivity, which makes the inversion problem even more complex. The mathematical problem of solving simultaneously for an unknown pair of spatially varying diffusion and absorption coefficients given data collected under a variety of imaging conditions has only recently started to attract attention. More work is required—both to obtain mathematical formulations of complicated scattering environments and to assess the numerical stability of possible inversion algorithms for these highly nonlinear problems. Existing mathematical theory makes it likely that any reconstruction algorithms that emerge could be seriously ill-conditioned or sensitive to noise in the data. Comparison with the corresponding mathematical problem in CT is likely to lead to pessimism about the prospects for handling the complexities of optical imaging. CT involves a linear inversion problem, for which a well-developed theory was available, although the pioneers of the field had to develop practical implementation schemes. Questions about the degree of ill-conditioning of this problem were answered, and an effective, fast, and accurate way of implementing the inversion was found rather swiftly, so that CT became a great success story. The fact that even the simpler model of optical imaging involves two functions (attenuation and scatter) makes the present problem akin to that encountered in SPECT and PET. Thus one can ask the question, Is laser optical tomography ever going to yield pictures of the "visual" quality of CT scans? The answer is most likely not. The question then is, What role could this emerging technique play? This issue is addressed below with full knowledge of the fact that, in the past, many such predictions have been incorrect or shortsighted.

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Page 161 11.4 Possible Applications of Optical Tomography The purpose of any new medical imaging technology is to help the clinician reach a decision. This decision is based on both an assessment of the tissue structure and knowledge about the functioning state of the tissue. There is wide consensus that the emerging technology of optical tomography could be useful in providing both kinds of information. In neonatal imaging, optical tomography has been used to assess tissue structure in ongoing trials to monitor the location and onset of hemorrhage (using both time-resolved and continuous-beam systems); in efforts to monitor strokes, it has been used to gain knowledge about functioning tissue, a task that does not require the high spatial image resolution needed for hemorrhage detection. Developers of optical technology must maintain a clear understanding of which of these two kinds of information is the goal of their particular application. Applications in which optical tomography in its present state has started to yield useful results, and where high spatial resolution is not required, include the measurement of tissue oxygenation for the study of muscular dystrophy, assessment of tissue perfusion in the extremities of diabetics, and the study of brain activity during specific tasks. Some topics that have been or could be studied as part of this effort include the following: · Changes in the concentration of glucose modify the indexes of refraction of both the intra- and extracellular medium, which alters the scattering properties of those media. Recently, such changes in scattering have been monitored separately from photon absorption in clinical measurements, and a very good correlation has been observed between a reduced scattering coefficient and the concentration of glucose determined from a blood test, suggesting the possible use of optical methods for glucose monitoring. · In certain situations it is possible to identify most of the received photons with the blood in the smaller blood vessels. This possibility could be useful since it is only in the capillary beds that oxygen exchange with tissue occurs. Measurement of the levels of hemoglobin saturation in these vessels is important in the monitoring of metabolic function. · Although blood vessels and capillaries occupy only a very small portion of brain tissue, any hemorrhage results in a relatively high local concentration of hemoglobin. Thus cranial bleeds could be detected

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Page 162 by the asymmetry of absorption with a simple device usable in the emergency room or intensive care unit. · Contrast agents such as indocyanine green, which absorbs at 800 nm and fluoresces at a slightly shorter wavelength, can be detected in very small amounts. This property has been used to observe regions with high differential absorbance in the human breast, suggesting the possibility of optical mammography. · The fluorescence properties of certain dyes depend on the intensity of the excitation and biological parameters such as oxygenation state and local electric potential. Certain dyes are sensitive to the drop in potential that exists across many cell walls. Optical scattering experiments could help in the study of these potentials across an array of cells. The results could in turn be important in the study of wound healing, fetal development, and other organ processes including brain function. · A combination of coherent imaging and spectroscopic measurements could have applications in the study and monitoring of thin tissues, such as the skin and many parts of the eye, where the effects of scattering are not severe. The living cornea, lens, and retina could be visualized in detail and their functions studied through careful optical scattering investigations. 11.5 Research Opportunities The central question in investigations of medical optical imaging is, How do human tissues and other complex media propagate light, and what can be learned about those media through such study? Specific examples of this line of research are given in the preceding section. Important general directions are as follows: · Development of mathematical tools for the mapping of parameters such as absorption and scattering coefficients that play a crucial role in the propagation of light in human tissues, · Investigations to determine the biophysical basis for diffusion of light in tissue, and · Investigations of excited fluorochromes that target specific tissues.

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Page 163 11.6 Suggested Reading 1. Arridge, S.R., Cope, M., and Delpy, D.T., The theoretical basis for the determination of optical pathlengths in tissue-Temporal and frequency analysis, Phys. Med. Bio. 37 (1992), 1531-1560. 2. Arridge, S.R., Schweiger, M., Hiraoka, M., and Delpy, D.T., A finite element approach for modeling photon transport in tissue, Med. Phys. 20 (1993), 299-309. 3. Benaron, D.A., Optical biopsy and imaging advance medical care, Laser Focus World 30 (1994), 79. 4. Benaron, D.A., Benitz, W.E., Ariagno, R.L., and Stevenson, D.K., Noninvasive methods for estimating in vivo oxygenation, Clin. Pediatr. 31 (1992), 258-273. 5. Benaron, D.A., and Stevenson, D.K., Optical time-of-flight and absorbance imaging of biologic media, Science 259 (1993), 1463-1466. 6. Boas, D.A., O'Leary, M.A., Chance, B., and Yodh, A.G., Scattering and wavelength transduction of diffuse photon density waves, Phys. Rev. E 47 (1993), R2999-R3002. 7. Chance, B., Kang, K., He, L., Weng, J., and Sevick, E., Highly sensitive object location in tissue models with linear in-phase and anti-phase multi-element optical arrays in one and two dimensions, Proc. Natl. Acad. Sci. USA 90 (1993), 3423-3427. 8. Chance, B., Leigh, J.S., and Gratton, E., New image, Nature 349, (1991), 660. 9. Chance, B., Zhuang, Z., Unah, C., Alter, C., et al., Cognition-activated low-frequency modulation of light absorption in human brain, Proc. Natl. Acad. Sci. USA 90 (1993), 3770-3774. 10. Fantini, S., Franceschini, M.A., Fishkin, J.B., Barbieri, B., et al., Quantitative determination of the absorption spectra of chromophores in strongly scattering media-A light-emitting-diode based technique, Appl. Opt. 33 (1994), 5204-5213.

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Page 164 11. Fantini, S., Franceschini, M.A., and Gratton, E., Semi-infinite-geometry boundary problem for light migration in highly scattering media-A frequency-domain study in the diffusion approximation, J. Opt. Soc. Am. B 11 (1994), 2128-2138. 12. Firbank, M., Hiraoka, M., Essenpreis, M., and Delpy, D.T., Measurement of the optical properties of the skull in the wavelength range 650-690 nm, Phys. Med. Biol. 38 (1993), 503-510. 13. Fishkin, J.B., and Gratton, E., Propagation of photon-density waves in strongly scattering media containing an absorbing semi-infinite plane bounded by a straight edge, J. Opt. Soc. Am. A 10 (1993), 127-140. 14. Gopinath, S.P., Robertson, C.S., Grossman, R.G., and Chance, B., Near-infrared spectroscopic localization of intracranial hematomas, J. Neurosurg. 79 (1993), 43-47. 15. Gratton, G., Maier, J.S., Fabiani, M., Mantulin, W.W., et al., Feasibility of intracranial near-infrared optical scanning, Psychophysiology 31 (1994), 211-215. 16. Griinbaum, F.A., and Patch, S.K., Simplification of a general model in diffuse tomography, in Proc. Photon Migration and Imaging in Random Media and Tissues, Britton Chance and Robert R. Alfano, eds., SPIE Proc. 1888 (1993), 387-401. 17. Haselgrove, J.C., Wang, N.G., and Chance, B., Investigation of the nonlinear aspects of imaging through a highly scattering medium, Med. Phys. 19 (1992), 17-23. 18. Hebden, J., Delpy, D., and Arridge, S., Infrared lasers muscle in on medical imaging, Physics World 6 (1993), 23-24. 19. Hiraoka, M., Firbank, M., Essenpreis, M., Cope, M., et al., A MonteCarlo investigation of optical pathlength in inhomogeneous tissue and its application to near-infrared spectroscopy, Phys. Med. Biol. 38 (1993), 1859-1876. 20. Kantar, A., Giorgi, P.L., Gratton, E., and Fiorini, R., Probing the interaction of PAF with human platelet membrane using the fluorescent probe laurdan, Platelets 5 (1994), 145-148.

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Page 165 21. Klibanov, M.V., Gutman, S., Barbour, R.L., Chang, J., Malinsky, J., and Alfano, R.R., Consideration of solutions to the inverse scattering problem for biomedical applications, in Proc. Physiological Imaging, Spectroscopy, and Early-Detection Diagnostic Methods, Randall L. Barbour and Mark J. Carvlin, eds., SPIE Proc. 1887 (1993), 77-97. 22. Kurth, C.D., Steven, J.M., Benaron, D., and Chance, B., Near-infrared monitoring of the cerebral circulation, J. Clin. Monitoring 9 (1993), 163-170. 23. O'Leary, M.A., Boas, D.A., Chance, B., and Yodh, A.G., Reradiation and images of diffuse photon density waves using fluorescent inhomogeneities, J. Lumin. 60 (1994), 281-286. 24. Peebles, D.M., Edwards, A.D., Wyatt, J.S., Bishop, A.P., et al., Changes in human fetal cerebral hemoglobin concentration and oxygenation during labor measured by near-infrared spectroscopy, Am. J. Obst. Gynecol. 166 (1992), 1369-1373. 25. Schweiger, M., Arridge, S.R., and Delpy, D.T., Application of the finite element method for the forward and inverse problems in optical tomography, J. Mathematical Imaging and Vision 3 (1993), 263-283. 26. Sevick, E.M., Chance, B., Leigh, J., Nioka, S., et al., Quantization of time-resolved and frequency-resolved optical spectra for the determination of tissue oxygenation, Anal. Biochem. 195 (1991), 330-351. 27. Singer, J., Griinbaum, F.A., Kohn, P.D., and Zubelli, J.P., Image reconstruction of the interior of bodies that diffuse radiation, Science 248 (1990), 990-993. 28. Wang, L., and Jacques, S.L., Hybrid model of Monte-Carlo simulation and diffusion theory for light reflectance in turbid media, J. Opt. Soc. Am. 10 (1993), 1746-1752. 29. Wilson, B.C., Sevick, E.M., Patterson, M.S., and Chance, B., Timedependent optical spectroscopy and imaging for biomedical applications, Proc. IEEE 80 (1993), 918-930.

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