- Email: [email protected]
Quantification of the radionuclide image
Quantification of the Radionuclide Image D. W. Brown, D. L. Kireh, R, S. Trow, M. keFree, and P. P. Steele The clinical value of radionuclide images can be increased by using quantification. The earliest radionuc|ide images were digital or quantitative in nature, but they were soon replaced by analog photoscans. Now, with the introduction of computers, quantitative digital scanning is again becoming widely used. Interfacing either rectilinear scanners or Anger-type scintillation cameras to a c o m p u t e r is no longer a difficult problem. Relatively l o w costs, insignificant dead times, and dependability are easy to achieve, The selection of an appropriate sampling interval is an important problem in quantitative scanning. If the interval is too large, resolution is degraded; if it is too small, costs increase rapidly, and counts recorded during each interval become so small that they lack statistical validity. This is true for both spatial (the static image) and temporal (dynamic function) analysis. Using sampling theory, a basis for interval selection is developed. With an Anger-type scintillation camera, a 128 x 128 recording results in negligible degradation of resolution, a 64 x 64 array introduces detectable but acceptable loss, and a 32 x 32 array results in serious loss. The computer/camera system at the Denver
VA Hospital has been designed for maximum flexibility and ease of use by the clinician and technician. N e w developments for this system allow display in different shades of gray with variable contrast, selective intensification of levels or regions of interest, framing rates of 20/sec, input of remote analog signals via telephone, resolution enhancement, and a sophisticated curve-analysis program with functions such as curve fitting, integration, differentiation, Fourier transformation, and deconvolution. Resolution enhancement of static images is carried out in the frequency domain through a new adaptive method of filtering and deconvolution with empirically selected logarithmic functions. Use of the system for dynamic studies is illustrated using radionuclide angiocardiography. Ventricular end systolic and diastolic volume, ejection fractions, and forward and backward (regurgitant) stroke volumes through all four cardiac valves can be determined quantitatively. Computed radioisotopic end diastolic volumes and ejection fractions correlate well with similar measurements determined by left cine ventriculography.
VALUE of radionuclide images can be increased by quantificaT HEtion.CLINICAL Precise quantification requires recording and manipulating the image data in digital, as opposed to analog, form. Each radioisotopic disintegration is a discrete event, and each photon will ordinarily produce a single scintillation or impulse in the imaging device. The first isotope images of human organs were recorded digitally when Dr. Herb Allen, using one of the first focus-collimated scintillation crystals developed in 1950 by Dr. Benjamin Casson, produced an image of the thyroid gland) After 100 to 200/JCi of ~3~I were injected intravenously, Dr. Allen performed point-by-point From the Nuclear Medicine Service, Denver Veterans Administration Hospital, and the Division o f Nuclear Medicine, University of" Colorado Medical Center, Denver, Colo. D. W. Brown, M.D.: Head o f the Division o f Nuclear Medicine, University o f Colorado Medical Center, Chief o f the Radioisotope Service, Denver Veterans Administration Hospital, D. L. Kirch, M.S.: Engineer, Assistant Professor o f Radiology, University o f Colorado Medical Center. R. S. Trow, M.S.: Radiation Chemist, University o f Colorado Medical Center. M. LeFree, R.T.: Computer Operator, Denver Veterans Administration Hospital. P. P. Steele, M.D.: Cardiologist, Denver Veterans Administration Hospital. Reprints from D. W. Brown, M.D., Drawer 114, 4200 East Ninth A re., Denver, Colo. 80220. 9 by Grune & Stratton, Inc. Seminars in Nuclear Medicine, Vol. 3, No. 4 (October), 1973
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counting in a grid over the thyroid gland in 400 positions. These early scans took 1 to 1~ hr to produce. Scans remained digital and quantitative during the following years as Dr. Casson improved and automated the radioisotope scanner that he had invented, 2'3 but when Kuhl 4 introduced photoscanning, this nonquantitative analog method was quickly and almost universally adopted. A few investigators, s however, continued to use point counting in an attempt to quantitate the localization of radioisotopes. In the early 1960s, when computers were becoming available in medical institutions, Kawin, 6'7 Winkler, 8 Brown, 9 and Tauxe 1~ more or less independently described the use of systems designed to record the radioisotope scan digitally in a form that would allow computer processing. The first successful application of these techniques to patients was published by Brown in 1964. 9 From the beginning, a primary reason for quantifying the radioisotope scan was a desire to improve resolution through the application of various types of digital filtering. Additional goals were the ability to store and rapidly recall studies for objective comparison, to subtract one scan from another, to apply various statistical tests for significance of supposed lesions, and to allow the utilization of a number of new display devices, such as three-dimensional scans produced on X - Y plotters. Early examples of the use of this quantitative information were Winkler's ~l subtraction of the liver from a pancreas scan, Brown's 12-~4 quantitative comparison of concentration of radioactivity over selected areas of interest in the kidneys, and Gorton's is analysis of scans quantitating experimental myocardial infarction. Another noteworthy application was Dr. David Kuhl's use of a computer of his own design and manufacture to facilitate tomographic scanning.~6 The now-famous computer system IDA at the Johns Hopkins Institute 17 has played an important role in many new clinical radioisotope scanning applications. Interfacing the Anger-type scintillation camera to computers by investigators such as Drs. Merle Loken and Edward Smith ~8 and organized meetings sponsored by the Oak Ridge Associated Universities through tire chairmanship of A.B. Brill ~9 have been important in bringing computer applications to the point where nearly all large medical center nuclear medicine laboratories have a computer system interfaced to an Anger scintillation camera to allow them to quantitate, analyze, and display digital radionuclide images. Q U A N T I T A T I V E RECORDING
The mechanics of quantification of radionulcide images are simpler in rectilinear scanning than they are when a scintillation camera is used. In the former case, a simple recording system consists of a counter that accumulates each pulse passing out of the pulse-height analyzer. Shaft-angle encoders generate digital numbers corresponding to X and Y locations of the scanning head. At preset space intervals, as the collimated crystal traverses the patient, the accumulated count and digital codes on the X and Y encoders are transferred to storage through an interface, the accumulator is reset to zero, and a new count begins. A computer is not necessary for this recording. The data can be transferred to paper or magnetic tape for later computer processing. Obvious problems are introduced by variable speeds of the scanner, e.g., more counts are accumulated per increment at slow than at high speeds. An alternative method is to use a timer to dump counts at preset time instead of space intervals. A computer may be used to correct the distortions in spatial distribution caused by failure of the count intervals to coincide with memory locations and the introduction of ~-space
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interval scalloping caused by reversal of direction. Using timed intervals and X - Y shaft encoder signals , the computer also can be programmed to correct for variations in speed of the traversing collimator. A serious problem in the past has been the dead time between cessation of one count and resumption of another. During this pause, the data triplet must be transferred to a buffer so that it may be read into storage while the next count is being accumulated. With modern equipment, dead times less than 1 /asec can be achieved easily. Since the dead time of a NaI crystal is nominally about 3/lsec, it is obvious that thi s no longer need be a problem. 2~ Interfacing an Anger-type scintillation camera can also be relatively simple. Output can be recorded on tape by recording the analog or digital signals for X and Y positioning produced for the CRT tube with each pulse that passes the pulse-height analyzer, and the tape can be processed later. This is commonly called list-mode recording. If, instead, an on-line computer is used, A-D converters generate digital X and Y positioning signals, and these direct the corresponding memory location to be incremented by one. This method of recording is referred to a s histogram-mode recording. SAMPLING-INTERVAL SELECTION
Whatever the imaging device, an obvious and important problem is the selection of an appropriate sampling interval-one that does not degrade resolution. Decreasing the interval improves resolution at first, but also results in increasing the size of the recorded array, increasing memory size requirement and cost, and decreasing the statistical validity of the count recorded at each location, so that a practical limit is soon reached. In rectilinear scanning, the Y interval is determined by the spacing selected in recording the scan for each line. An Anger scintillation camera is usually divided into a square array with equal horizontal and vertical space intervals. With the latter, we are interested not only in spatial resolution but also temporal resolution in recording dynamic function studies. The degrading effect on either spatial or temporal resolution imposed by too large a sampling interval may be illustrated by considering sampling theory superficially. Digitizing a static image is a process whereby an array of discrete elements is used to represent a continuously varying distribution of isotope within the patient. Similarly, the accumulation of sequential images in the study of temporal movement of a radioisotope tracer through an orga n is also a sampling process in that a continuously time-varying process is discretized into frames that are integrated over brief increments of time. In the case of an image, the quantitative analysis is two-dimensional (X and Y location). In the case of a dynamic curve (e.g., a renogram curve), it is one-dimensional (time). Otherwise, the processes may be considered with similar mathematics. Let f(x) represent the continuous temporal or spatial function (isotope distribution) prior to sampling, f*(x) represent the function after sampling, and F(co) and F*(co) represent the Fourier transforms of these respective functions;f*(x) takes on a form depicted in Fig. 1, in which T is a sampling interval (space or time) and P the on time of the recording device [in the theory of digital signal analysis i f ( x ) is said to be a zero-order hold approximation of f(x)]. The effect of the point-spread function on image data is ignored here so that sampling effects alone can be emphasized.
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A second manifestation of sampling degradatio n is due to the term C(~o) in Eqs. (1) and (2), which acts as a low-pass filter tending to diminish the magnitude of F(~+n~s) as 6o increases. At co = cos/2,F(~o)is reduced by 2/7r, but with small sampling intervals, F is near zero at this point, and the function is not greatly affected. Dr. charles Metz and his associates at the University of Chicago Pritzker School of Medicine 22 have addressed the problem of sampling-interval selection on both theoretical and experimental grounds. Their work was with sampled representations of radiographic screen film modulation transfer functions (MTFs), but the results are applicable to radionuclide imaging devices as well. They computed the MTF (similar to F(6o) above with p = 0) of lihe-spread functions (LSF) observed with Varying sampling intervals. Errors due to spectral foldover in the computed MTFs were found to be less than 0.5% of the true MTF at the folding frequency for an assumed gaussian MTF if the sampling distance was less than 0.8 of the LSF half-width at half maximum (HWHM). Depending somewhat on the particular LSF, it would appear that accuracy suitable f o r scintigraphic imaging can be achieved by sampling intervals 80% of the LSF HWHM. Assuming a HWHM of 5.0 mm, this would indicate that recording one Sample per 4-mm interval would provide satisfactory resolution. For a 25- by 25-cm Anger-camera image, this means a 62.5 • 62.5 element array. In static imaging, our experience, as well as that of Metz, 23 has confirmed the fact that an image recorded using an 11.5-in. Nal crystal* in a 128,X 128 array results in negligible degradation of resolution, a 64 • 64 array will introduce detectable but usually acceptable loss of resolution, and a 32 X 32 array results in serious loss of resolution. The small, statistically less valid counts recorded in each array element that result from smaller sampling intervals often necessitate larger than ideal intervals in recording very rapid dynamic function studies (e.g., radionuclide angiocardiograms). In temporal as opposed to spatial studies, essentially the same principles hold. Temporal sampling-interval selection is important and will be illustrated by examination of a cardiac flow study such as those to be discussed later. Intracardiac radioactivity is recorded sample by sample in the histogram mode after a bolus injection and a sinusoidal pattern superimposed on an exponential decay curve is observed. The recording system is not perfect, and as the frequency (heart rate) increases, apparent ventricular ejection fraction is measured less and less accurately, appearing to decrease even though it is kept constant. This reduced sensitivity at higher frequencies may be plotted I and it forms a temporal MTF that is analytically expressed by C(w) in Eq. (2). When measured or computed for a specific recording device, this temporal MTF can be used to correct approximately a cardiac flow study for increasing heart rate by a simple linear operation once the flow study has been transformed to the frequency d~main. We do not use this correction at heart rates less than 120 beats/min. A QUANTIFICATION
SYSTEM
After selection of the desired sampling intervals, both spatial and temporal, a computer/imaging device that will achieve this result may be designed, and many such systems have been developed for use in nuclear medicine. Most feature a minicomputer operating on-line with an Anger-type scintillation camera. ~6-18'24 In general these systems feature the capability of accumulation, storage, and display of dynamic *Nuclear-Chicago Pho-Gamma HP Anger camera.
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scintigraphic data, but provide limited ability for more than the simplest mathematical manipulation of the recorded image. In the nuclear medicine laboratory at the Denver Veterans Administration Hospital, we have developed a system that we feel has advantages over most systems previously described. ~5 The system is outlined in Fig. 3. Hardware consists of a 12K core PDP-I 2* computer interfaced with a Nuclear-Chicago Pho-Gamma HP Anger camera. The PDP-12 uses 12-bit words, which we have found to be satisfactory in general, although it has precluded ease of adaptation of some advanced non-nuclear medical programs we feel could be very useful. Disregarding the cost, a 16-bit machine would be more desirable. The fundamental feature of a minicomputer needed for a nuclear medicine system is the databreak facility, which allows interruption with access to core memory on a priority basis. In our system, priorities are controlled by a channel DM-04* multiplexer that gives the disk the highest priority, the Anger-camera interface the next highest, and the display scope the lowest priority. In the static mode, images are recorded on LINC* tape or magnetic disk (RK08*) in 64 • 64 element arrays. For processing, a scan is transferred from tape to magnetic disk where it can be recalled automatically for display, resolution-enhancement processing, or comparison with other scans by a variety of simple commands entered through a keyboard (TTY). Two cathode-ray tubes (CRT) are used, one primarily for graphics and the other for image display. The image display scope was developed by Mr. Dennis Kirch and associates at a cost of about $3,500 (Fig. 4). It allows display in different shades of gray and with variable contrast, the range of each being continuously changed by simply rotating potentiometers. The image display scope has direct memory access so that it leaves the central processing unit (CPU) free to perform other computations, such as resolution enhancement at the same time images are being displayed. Another feature
*Digital Equipment Corp., Maynard, Mass.
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317
D
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Fig. 4. Lateral brain scan after resolution enhancement displayed on the CRT system (note the contrast and varying shades of gray): (A) raw data; (B) after linear enhancement and smoothing; (C) after adaptive smoothing and enhancement (note the small simulated hot lesion in the midparietal region); (D) horizontal cross sections through A on top and C on bottom (note improved contrast).
of this display system is that it permits selective intensification of those elements of the image that fall within a specified count range (selected by switches on the display control panel), thus allowing the viewer to amplify image count differences that otherwise would be too small to be visually discernible. Regions of interes'~ are selected visually by turning knobs on the computer panel to control a cursor dot and observing corresponding intensified areas on tile CRT. In the dynamic imaging, mode images are accumulated in 32 X 32 or 64 • 64
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element matrices, depending on the requirements of the study being p~rformed. If temporal resolution is of primary importance (such as in flow studies of the heart and lungs), then the 32 X 32 mode is selected. Frame rates up to 20 frames/sec for a total of up to 512 frames can be recorded in this mode. If spatial resolution is important, then the 64 X 64 mode is utilized with frame rates up to 8 frames/sec for a total of 128 frames. Dynamic studies are stored on the magnetic disk until tile analysis of the data is complete and then transferred to magnetic tape for permanent storage. A new feature of the dynamic recording system that is proving extremely useful is the ability to record physiological data such as EKG, pressure, flow, temperature, and ultrasonic transducer outputs along with dynamic scintigraphic studies. Up to eight channels of data are digitized and stored in the corner elements of the image array, which are normally unused due to the circular configuration of the Anger-camera detector. Three Schmidt trigger channels are also available for tagging the frames of the study that correspond to discrete events (such as the EKG R-wave or tile activation of automatic injection equipment). This ability to record analog data is now used frequently at our institution in nonimaging studies. Data from a single radioisotope probe can now be transmitted remotely by telephone and recorded in the computer. Renograms and cardiac flow studies from the bedsides of critically ill patients who cannot be brought to the nuclear medicine laboratory for study are recorded by this means. 26 This function is facilitated by the use of a general data-acquisition program that allows up to eight analog curves to be recorded on LINC tape at sampling frequencies up to 10(3/ sec.
The categorization of nuclear medicine procedures into static and dynamic modalities is arbitrary. Static imaging serves primarily to observe structure, dynamic imaging to observe function. At this time, a few procedures that are static in nature are conducted on a sequential basis for the purpose of visualizing, very slowly, changing phenomena. Cisternography delayed brain scans and gallium scans are examples of these. In order to use the computer capabilities to make quantitative determinations from these studies, precision in positioning of the patient is required. This is obtained in our system by the use of a marker dot attached to some appropriate point on the patient. Using the computer, successive images may easily be shifted until their marker dots visually correspond, correcting for patient motion. Playback of dynamic function is accomplished frame by frame in real time or at slower and slower rates selected on a variable potentiometer. Display can be stopped on a single frame for photography. Graphic infortnation is displayed on the graphics CRT. Curves of counts per frame or combinations of frames over multiple regions of interest are developed automatically. With a single keyboard instruction, a curve may be transferred from the CRT to the X - Y plotter for permanence. The clinical usefulness of a computer/Anger-camera system can be enhanced greatly by development of a flexible curve-analysis program. In addition to the rather extensive set of 'computer programs needed for the storage and playback functions described above, several additional computer programs have been developed or adapted for our system to facilitate curve analysis. Some of these are described in detail elsewhere. 2s Essentially, this program makes it possible to derive quantitative diagnostic information from these curves with minimal effort on the part of the clinician. The curve-analysis program used in our system has been adapted from the spectral-
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analysis system (called RUFUS) written by David Stern of the Laboratory for Atmospheric and Space Physics, University of Colorado, Boulder, Colo. as Up to six curves, with 512 data points each, may be stored in core. These curves may be added, subtracted, multiplied or divided, integrated or differentiated, smoothed, edited, shifted, correlated and fitted with exponentials or straight lines, plotted or Fourier-transformed, and deconvolved. All of these functions are carried out with simple instructions. After analysis, the results may be transferred by a single command to CRT, teletype, plotter, disk, or tape. Up to 256 of these curves can be stored on a single LINC tape. Instructions to the system are in the form of commands from the teletype. Commands are interpreted in three modes: (1) manually-commands are executed as they are typed; (2) automatically-commands are stored in a 1024-character buffer and executed under program control with variables, loops, etc.; (3) storage m o d e commands are stored in the program buffer as they are entered from the TTY and normally executed. (This is similar to FOCAL.*) Programs may be written using the text-editing features of the DIAL* system and loaded by the curve-analysis program from either a named DIAL file or from the working storage area. Also, programs can be saved on previously existing DIAL source files. These programs are completely compatible with the DIAL text editor. Every effort has been made to make the display as interactive and informative as possible. One or two curves may be displayed at once, selected directly by the operator or automatically as the result of a program command. The X axis can be expanded from 512 points to 2 points across the entire screen. The vertical separation between the two displayed curves or the position of one curve can be controlled by a knob on the computer. This allows easy superposition of curves for comparison. A cursor option is available, also set by a control knob. This cursor intensifies a single point along the X axis of each curve for visual identification quantification. To expand a portion of a curve, two vertical dash lines are displayed in the positions where they cross the X axis, selected by control knob. If sense switch 1 on the computer is off, the full curve is displayed; if on, the curve between the two vertical lines is expanded to fill the screen horizontally. In summary, the important features of this system are: (1) the great flexibility and speed with which the operator can analyze, manipulate, and display his data and (2) the ease with which programmed functions can be modified or built into segments of the program. R ESU LTS
The system of computer and Anger scintillation camera and the extensive set of programs described above greatly facilitate the development of new and clinically useful computer applications in medicine. Two developments from our institution will be used to illustrate this point. The first is a method of improving resolution of static images by what we call adaptive filtering. This method was developed primarily by Kirch and has been described in detail elsewhere, as'aT The second example is a method of quantitation of dynamic function studies, in particular quantifying the degree of cardiac valvular insufficiency by radioisotope angiocardiography. *Digital Equipment Corp., Maynard, Mass.
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STATIC IMAGE ENHANCEMENT
Our resolution-enhancement work began with a belief that since a recorded image O(s) is the result of an unknown spatial isotope distribution A(s) acted upon by a known response function of the recording system, primarily the collimator C(s), the image could be corrected explicitly to determine the true isotope distribution, z7 Mathematically, O(s) is said to be the result of the convolution of A(s) with C(s), and the process of solving for A(s) is called a deconvotution. Deconvolutions may be carried out in many ways, but the fastest available to us is to use the computer to take the Fourier transforms of C(s) and O(s). Division of one transform by the other and inverse transformation of the result accomplishes the deconvolution, although there are practical limits on the precision with whidr this can be performed. We concluded from our early studies that resolution could be improved somewhat by this linear form of filtering. Several factors tended to defeat the method, however. The most important was that this approach tended to amplify statistical fluctuations (noise) in the recorded scan. The noise in a scan, however, has a relatively high distribution of frequencies, and since the Fourier transform displays the image as intensities of increasing frequency, it seemed logical to simply set the high frequencies to zero, thus eliminating noise. Unfortunately, a sharp discontinuity in the transform of an image will result in severe undulations of the inverse transform, so rather than sharply dropping the transform to zero, an exponential function was used to taper it oft" gradually. There still remains the problem of where the noise ends and the true image begins. If low frequencies are attenuated, resolution is destroyed. For these reasons, what might be called classic or logical means of resolution enhancement were abandoned, and instead an empirical method (adaptive filtering) was developed. First, an average random noise level is computed by averaging the coefficients (actually magnitudes) of the transform at all frequencies above the intrinsic resolution of the collimator. The transform coefficients are then tested against this noise level (or a higher factored value of this level if greater statistical significance despite some loss of resolution is desired), and coefficients are set to zero if they are lower, or retained if they are higher. The resulting smoothing function formed in the transform (in the frequency plane) is very irregular and noncircular in shape because it is adapted to the Fourier transform of each individual image. Our results, however, show that this departure from previously used smooth filter functions makes this adaptive technique less susceptible to the production of artifacts. Since the transform of the image is adaptively smoothed, it would previously have been divided by the transform of the recording system, C(s). Surprisingly, however, more improvement in resolution results from applying an arbitrarily selected logarithmic function (which rises to a value of 3.0 at 0.4 cycles/cm) with no direct relationship to physical reality. An example of the results of this type of adaptive Cfltering is illustrated in Fig. 5. In one of many test situations, but perhaps an average one, an approximately 50% increase in non-lesion to lesion count ratio was achieved for a mock cold lesion 1.25 cm in diameter (see reference 25 for details) and artifactual undulations were significantly reduced. The computer system (hardware and software) described earlier makes it relatively simple to record a static image digitally, apply adaptive filtering, and display the enhanced image. At present this filtering process requires 10 min of PDP-12 time. De-
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D
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spite this inconveniently long time, we find frequent clinical situations that justify this amount of computer time. Faster methods are under development. A blind comparison of the Kirch-Brown linear filtering technique for image enhancement and smoothing by this nonlinear frequency approach was recently provided by the cooperative project on evaluation of computer techniques for processing scintigraphic images being conducted by the International Atomic Energy Agency (IAEA). Two of the authors (Kirch and Brown) are participants in this project. Recently, 24 simulated phantom scans were generated and sent to the participants in the IAEA project for computer processing, following which the results were returned to the IAEA for evaluation. In our case, we returned two independent sets of results. The first set was processed using the linear filter developed by Kirch and Brown) 7 The Second was processed using the nonlinear frequency-domain technique described above. The improvement in the detection capabilities afforded by the nonlinear frequency-domain technique was dramatic. Measured in terms of probability of true detection Pt and probability of false detection PC"the results of the IAEA evaluation of these techniques were: Pt = 0.63 and PC"= 0.32 for the linear Kirch-Brown technique Pt = 0.80 and p f = 0.18 for the nonlinear technique. While a valid criticism of the IAEA project has concerned the variability in results, which is introduced by the display technique independently of the various computer
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processing techniques, the two sets of results compared above were displayed and scored on an identical basis. Results obtained to date indicate that improved detectability of simulated lesions is achieved by computer processing. The IAEA is currently preparing a more extensive quantitative comparison of image processing techniques. DYNAMIC FUNCTION ANALYSIS
A second example of the usefulness of quantification using a computer/camera system such as ours will be illustrated by describing its use in the analysis of a dynamic function test-the radioisotope angiocardiogram. This project resulted from cooperation between Dennis L. Kirch, M.S.E.E.; Charles Metz, Ph.D.;* Peter P. Steele, M.D., cardiologist at the Denver Veterans Administration Hospital; and Donald Van Dyke, M.D.r (More detailed reports of their investigations have been submitted for publication. 2s-3~ With the patient in the RAO position, a bolus of 8 mCi of 99mTc pertechnetate is flushed through a Swan-Ganz catheter 3~ wedged in a pulmonary artery branch for left-heart studies or placed in the superior vena cava for the right heart. This catheter is soft and has a small balloon near its tip that makes placement simple in most instances. The 32 • 32 element images of the heart and major vessels are recorded at 20 frames/sec for 25 sec on the magnetic disk using the computer/camera system. Cardiac output is determined by thermal dilution, indocyanine green dye (the Fick principle), or ll3mln cl. EKG is recorded to determine heart rate and premature beats. Using a cine-fashion computer playback, the cardiac flow is studied visually on the CRT, and the valve plane separating the atrium and ventricle is identified. Next, a summed image over many frames is developed, and four areas of interest are selected. Th@se correspond to the atrium, the ventricle, and an associated background for each of these chambers. Van Dyke 26'32 has demonstrated the necessity of correcting the time-activity curves for these chambers for background, and our selection of these areas follows his method with the modification that our backgrounds are semiannular rings surrounding the chamber to be corrected and excluding as much as possible the grea t vessels and adjacent chamber of the heart (Fig. 6). Using a system of recursion relationships, a set of finite-difference equations has been generated and solved by Ztransformation methods. These equations define the change in the amount of isotope in the atrium and ventricle on a beat-by-beat basis. After subtraction of the chamber background, and by using parameters such as time constants determined by the singleexponential least-squares fit to the later portions of the atrial and ventricular washout curves, the heart rate, the cardiac output, the beat-by-beat total ejection fraction, and the derived equations, the computer determines average end diastolic volume (EDV), end systolic volume, and forward and backward regurgitant ejection fraction for both the atrium and ventricle on the side being studied. 28-3~ More than 150 patients have been studied by Dr. Steele to date, without ill effect. Similar tests in animals did not produce significant damage at the site of injection. In the first 100 patients studied, a sharp enough bolus into the left heart to allow analysis was obtained in 89 cases. Most failures were due to lack of adequate wedging of the catheter into a distal posterior pulmonary artery. Twenty-nine of these 89
*Department of Radiology, University of Chicago Pritzker School of Medicine and the Franklin McClean Memorial Institute. 1"Donner Laboratories, University of California, Berkeley, Calif.
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Fig. 6. (A) Normal dynamic cardiac flow study following pulmonary wedge injection ofg~)mTc bolus. Image obtained by summing data during a 5-sec interval. (B) The background area used to correct the left-ventricular time-activity curve has been flagged. (C, D) Washout curves before and after correction. (E, F) Similar curves from a patient with rnitral insufficiency.
patients had adequate cine-angiograms, which allowed determination of ejection fraction bv classic contrast angiographic methods. 3s'36 Left-ventricular ejection fractions determined radioisotopically correlated well with those determined using contrast (r = 0.84). Correlation for left-ventricular end diastolic volumes by the two methods was even better (r = 0.95). When valvular regurgitation is present, this is quantitated with the same system of equations used in the nonregurgitant case. Preliminary evaluation of the regurgitant model in patients with mitral and aortic disease has been encouraging, particularly when correlated with contrast angiographic techniques. Details are being published elsewhere.28'3~
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ACKNOWLEDGMENT We are grateful to Ms. Corinne Schoener and Ms. Barbara Jannotti for their assistance. This work was made possible by U.S. Veterans Administration research grant 1103-01.
REFERENCES 1. Allen H, Libby R, Cassen B: The scintillation counter in clinical studies of human thyroid physiology using 1311. J Clin Endocrinol Metab 11:492, 1951 2. Cassen B, Curtis, L. Reed C, Libby R: Instrumentation of 1131 used in medical studies. Nucleonics 9:46, 1951 3. Cassen B: Theory of scanning and imaging of radioisotope distributions, in: Medical Radioisotope Scanning, vol. I. Proceedings of the Symposium on Medical Radioisotope Scanning, Athens, Apr. 20-24, 1964. Vienna, IAEA, 1964, p77 4. Kuhl DE, Chamberlain RH, Gorson RO: A high-contrast photographic recorder for scintillation counter scanning. Radiology 66:730, 1956 5. Bauer GCH, Wendeberg B: External counting of Ca-47 and Sr-85 in studies of localized skeletal lesions in man. J Bone Joint Surg 41B: 558, 1959 6. Kawin B, Huston FV: Dataphone/compurer system for radioisotope scan display, in: Proceedings of the 16th Annual Conference on Engineering in Medicine and Biology, Baltimore, Md., 1963. p 120 7. Kawin B, Huston FV, Cope CB: Digital processing/display system for radioisotope Scanning. J Nucl Med 5:500, 1964 8. Schepars H, Winkler C: An automatic scanning system using a tape perforator and computer techniques, in: Proceedings of the Symposium on Medical Radioisotope Scanning, Athens, Apr. 20-24, 1964. Vienna, IAEA, 1964, p 321 9. Brown DW: Digital computer analysis and display of the radioisotope scan. J Nucl Med 5:802, 1964 10. Tauxe WN, Chappel DW: Contrast enhancement of scanning procedures by highspeed computer. J Nucl Med 6:326, 1965 11. Winkler C: Datenverarbeitung in der Nuklearmedizin (auflage 2). Niirnberg, Siemens Aktiengesellschaft. 12. Brown DW: Digital computer analysis and display of the radionuclide scan. J Nucl Med 7:740, 1966 13. Brown DW, Groome DS: The role of the digital computer in nuclear medicine. JAMA 203:153, 1968 14. Brown DW, Groome DS, Cleaveland JD,
et al: An on-line computer system for the nuclear medicine laboratory. J Nucl Med 11: 203, 1970 15. Gorton RJ: various papers presented at the annual meetings of the Society of Nuclear Medicine between 1965 and 1972 and abstracted in J Nucl Med 16. Manlio FL, Masland WS, Kuhl DE, Staum MM: Prognostic significance of a deep-wedge pattern in transverse section scanning of cerebral infarctions. Radiology 103: 135, 1972 17. Moses DC, Natarojan TK, Previosi TJ, et al: Quantitative cerebral circulation studies with sodium pertechnetate. J Nucl Med 14:142, 1973 18. Kenny PJ, Smith EM (eds): Quantitative Organ Visualization in Nuclear Medicine. Coral Gables, University of Miami Press, 1971 19. Proceedings of 2nd Symposium on Sharing of Computer Programs and Technology in Nuclear Medicine, Oak Ridge, Tenn., Apr. 21, 1972, CONF-720430. Springfield, Va., U.S. Department of Commerce, 1972 20. Wolff JR: Detection, acquisition and storage devices: A summary. J Nucl Med 14: 15-30, 1973 21. Kuo BC: Analysis and Synthesis of Sampled-Data Control Systems. Englewood ~21iffs, N.J., Preritice Hall, 1963, pp 39--49 22. Metz CE, Strubler KA, Rossman K: Choice of line spread function sampling distance for computing the MTF of radiographic screenfilm systems. Phys Med Biol 17:638-647, 1972 23. Metz CE: personal communication of unpublished data. 24. Series 50/50 Nuclear Medicine Software I Description. Apr. 1971, Nuclear Data Inc., P.O. Box 451, Palatine, II1., 60067. 25. Kirch DL, Brown DW: Recent advances in digital processing static and dynamic data, in: Proceedings of the 2nd Symposium on Sharing of Computer Programs and Technology in Nuclear Medicine, Oak Ridge, Tenn., Apr. 21, 1972, CONF-720430. Springfield, Va., U.S. Department of Commerce, 1972, pp 27-54 26. Steele PP, Van Dyke D, Trow RS, et al: A simple and safe bedside method for serial measurement of left ventricular ejection fraction, cardiac output and pulmonary blood volume. (submitted for publication)
QUANTIFICATION
27. Brown DW, Kirch DL, Ryerson TW, et al: Computer processing of scans using Fourier and other transformations. J Nucl Med 12:287, 1971 28. Kirch DL, Metz CE, Steele PP: An atrial-ventricular heart model for quantitation of valvular insufficiency by radioisotope angiography. (submitted for publication) 29. Steele PP, Kirch DL, Mathews M, Davies H: Quantitation of left heart function by a computerized scintigraphic technique using a wedged pulmonary artery catheter. (submitted for publication) 30. Metz CE, Kirch DL, Steele PP: A mathematical model for determination of cardiac regurgitant and ejection fractions from radioisotope angiocardiograms. (submitted for publication) 31. Swan HJC, Ganz W, Forrester T, et al:
325
Catheterization of the heart in man with the use of a flow-directed balloon-tipped catheter. N Engl J Med 283:447, 1970 32. Van Dyke D, Anger HO, Sullivan RW, et al: Cardiac evaluation from radioisotope dynamics. J Nucl Med 13:589, 1972 33. Donato L: Basic concepts of radiocardiography. Semin Nucl Med 3:111, 1973 34. Ashburn WL, Kostuk WJ, Karliner JS, et al: Left ventricular volume and ejection fraction determination by radionuclide angiography. Semin Nucl Med 3:165, 1973 35. Arvidsson H: Angiocardiographic determination of left ventricular volume during angiography. Am J Cardiol 27:460, 1971 36. Carleton RA: Change in left ventricular volume during angiography. Am J Cardiol 27: 460, 1971
VA Hospital has been designed for maximum flexibility and ease of use by the clinician and technician. N e w developments for this system allow display in different shades of gray with variable contrast, selective intensification of levels or regions of interest, framing rates of 20/sec, input of remote analog signals via telephone, resolution enhancement, and a sophisticated curve-analysis program with functions such as curve fitting, integration, differentiation, Fourier transformation, and deconvolution. Resolution enhancement of static images is carried out in the frequency domain through a new adaptive method of filtering and deconvolution with empirically selected logarithmic functions. Use of the system for dynamic studies is illustrated using radionuclide angiocardiography. Ventricular end systolic and diastolic volume, ejection fractions, and forward and backward (regurgitant) stroke volumes through all four cardiac valves can be determined quantitatively. Computed radioisotopic end diastolic volumes and ejection fractions correlate well with similar measurements determined by left cine ventriculography.
VALUE of radionuclide images can be increased by quantificaT HEtion.CLINICAL Precise quantification requires recording and manipulating the image data in digital, as opposed to analog, form. Each radioisotopic disintegration is a discrete event, and each photon will ordinarily produce a single scintillation or impulse in the imaging device. The first isotope images of human organs were recorded digitally when Dr. Herb Allen, using one of the first focus-collimated scintillation crystals developed in 1950 by Dr. Benjamin Casson, produced an image of the thyroid gland) After 100 to 200/JCi of ~3~I were injected intravenously, Dr. Allen performed point-by-point From the Nuclear Medicine Service, Denver Veterans Administration Hospital, and the Division o f Nuclear Medicine, University of" Colorado Medical Center, Denver, Colo. D. W. Brown, M.D.: Head o f the Division o f Nuclear Medicine, University o f Colorado Medical Center, Chief o f the Radioisotope Service, Denver Veterans Administration Hospital, D. L. Kirch, M.S.: Engineer, Assistant Professor o f Radiology, University o f Colorado Medical Center. R. S. Trow, M.S.: Radiation Chemist, University o f Colorado Medical Center. M. LeFree, R.T.: Computer Operator, Denver Veterans Administration Hospital. P. P. Steele, M.D.: Cardiologist, Denver Veterans Administration Hospital. Reprints from D. W. Brown, M.D., Drawer 114, 4200 East Ninth A re., Denver, Colo. 80220. 9 by Grune & Stratton, Inc. Seminars in Nuclear Medicine, Vol. 3, No. 4 (October), 1973
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counting in a grid over the thyroid gland in 400 positions. These early scans took 1 to 1~ hr to produce. Scans remained digital and quantitative during the following years as Dr. Casson improved and automated the radioisotope scanner that he had invented, 2'3 but when Kuhl 4 introduced photoscanning, this nonquantitative analog method was quickly and almost universally adopted. A few investigators, s however, continued to use point counting in an attempt to quantitate the localization of radioisotopes. In the early 1960s, when computers were becoming available in medical institutions, Kawin, 6'7 Winkler, 8 Brown, 9 and Tauxe 1~ more or less independently described the use of systems designed to record the radioisotope scan digitally in a form that would allow computer processing. The first successful application of these techniques to patients was published by Brown in 1964. 9 From the beginning, a primary reason for quantifying the radioisotope scan was a desire to improve resolution through the application of various types of digital filtering. Additional goals were the ability to store and rapidly recall studies for objective comparison, to subtract one scan from another, to apply various statistical tests for significance of supposed lesions, and to allow the utilization of a number of new display devices, such as three-dimensional scans produced on X - Y plotters. Early examples of the use of this quantitative information were Winkler's ~l subtraction of the liver from a pancreas scan, Brown's 12-~4 quantitative comparison of concentration of radioactivity over selected areas of interest in the kidneys, and Gorton's is analysis of scans quantitating experimental myocardial infarction. Another noteworthy application was Dr. David Kuhl's use of a computer of his own design and manufacture to facilitate tomographic scanning.~6 The now-famous computer system IDA at the Johns Hopkins Institute 17 has played an important role in many new clinical radioisotope scanning applications. Interfacing the Anger-type scintillation camera to computers by investigators such as Drs. Merle Loken and Edward Smith ~8 and organized meetings sponsored by the Oak Ridge Associated Universities through tire chairmanship of A.B. Brill ~9 have been important in bringing computer applications to the point where nearly all large medical center nuclear medicine laboratories have a computer system interfaced to an Anger scintillation camera to allow them to quantitate, analyze, and display digital radionuclide images. Q U A N T I T A T I V E RECORDING
The mechanics of quantification of radionulcide images are simpler in rectilinear scanning than they are when a scintillation camera is used. In the former case, a simple recording system consists of a counter that accumulates each pulse passing out of the pulse-height analyzer. Shaft-angle encoders generate digital numbers corresponding to X and Y locations of the scanning head. At preset space intervals, as the collimated crystal traverses the patient, the accumulated count and digital codes on the X and Y encoders are transferred to storage through an interface, the accumulator is reset to zero, and a new count begins. A computer is not necessary for this recording. The data can be transferred to paper or magnetic tape for later computer processing. Obvious problems are introduced by variable speeds of the scanner, e.g., more counts are accumulated per increment at slow than at high speeds. An alternative method is to use a timer to dump counts at preset time instead of space intervals. A computer may be used to correct the distortions in spatial distribution caused by failure of the count intervals to coincide with memory locations and the introduction of ~-space
QUANTI F ICATION
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interval scalloping caused by reversal of direction. Using timed intervals and X - Y shaft encoder signals , the computer also can be programmed to correct for variations in speed of the traversing collimator. A serious problem in the past has been the dead time between cessation of one count and resumption of another. During this pause, the data triplet must be transferred to a buffer so that it may be read into storage while the next count is being accumulated. With modern equipment, dead times less than 1 /asec can be achieved easily. Since the dead time of a NaI crystal is nominally about 3/lsec, it is obvious that thi s no longer need be a problem. 2~ Interfacing an Anger-type scintillation camera can also be relatively simple. Output can be recorded on tape by recording the analog or digital signals for X and Y positioning produced for the CRT tube with each pulse that passes the pulse-height analyzer, and the tape can be processed later. This is commonly called list-mode recording. If, instead, an on-line computer is used, A-D converters generate digital X and Y positioning signals, and these direct the corresponding memory location to be incremented by one. This method of recording is referred to a s histogram-mode recording. SAMPLING-INTERVAL SELECTION
Whatever the imaging device, an obvious and important problem is the selection of an appropriate sampling interval-one that does not degrade resolution. Decreasing the interval improves resolution at first, but also results in increasing the size of the recorded array, increasing memory size requirement and cost, and decreasing the statistical validity of the count recorded at each location, so that a practical limit is soon reached. In rectilinear scanning, the Y interval is determined by the spacing selected in recording the scan for each line. An Anger scintillation camera is usually divided into a square array with equal horizontal and vertical space intervals. With the latter, we are interested not only in spatial resolution but also temporal resolution in recording dynamic function studies. The degrading effect on either spatial or temporal resolution imposed by too large a sampling interval may be illustrated by considering sampling theory superficially. Digitizing a static image is a process whereby an array of discrete elements is used to represent a continuously varying distribution of isotope within the patient. Similarly, the accumulation of sequential images in the study of temporal movement of a radioisotope tracer through an orga n is also a sampling process in that a continuously time-varying process is discretized into frames that are integrated over brief increments of time. In the case of an image, the quantitative analysis is two-dimensional (X and Y location). In the case of a dynamic curve (e.g., a renogram curve), it is one-dimensional (time). Otherwise, the processes may be considered with similar mathematics. Let f(x) represent the continuous temporal or spatial function (isotope distribution) prior to sampling, f*(x) represent the function after sampling, and F(co) and F*(co) represent the Fourier transforms of these respective functions;f*(x) takes on a form depicted in Fig. 1, in which T is a sampling interval (space or time) and P the on time of the recording device [in the theory of digital signal analysis i f ( x ) is said to be a zero-order hold approximation of f(x)]. The effect of the point-spread function on image data is ignored here so that sampling effects alone can be emphasized.
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ET AL.
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QUANTI F ICATION
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A second manifestation of sampling degradatio n is due to the term C(~o) in Eqs. (1) and (2), which acts as a low-pass filter tending to diminish the magnitude of F(~+n~s) as 6o increases. At co = cos/2,F(~o)is reduced by 2/7r, but with small sampling intervals, F is near zero at this point, and the function is not greatly affected. Dr. charles Metz and his associates at the University of Chicago Pritzker School of Medicine 22 have addressed the problem of sampling-interval selection on both theoretical and experimental grounds. Their work was with sampled representations of radiographic screen film modulation transfer functions (MTFs), but the results are applicable to radionuclide imaging devices as well. They computed the MTF (similar to F(6o) above with p = 0) of lihe-spread functions (LSF) observed with Varying sampling intervals. Errors due to spectral foldover in the computed MTFs were found to be less than 0.5% of the true MTF at the folding frequency for an assumed gaussian MTF if the sampling distance was less than 0.8 of the LSF half-width at half maximum (HWHM). Depending somewhat on the particular LSF, it would appear that accuracy suitable f o r scintigraphic imaging can be achieved by sampling intervals 80% of the LSF HWHM. Assuming a HWHM of 5.0 mm, this would indicate that recording one Sample per 4-mm interval would provide satisfactory resolution. For a 25- by 25-cm Anger-camera image, this means a 62.5 • 62.5 element array. In static imaging, our experience, as well as that of Metz, 23 has confirmed the fact that an image recorded using an 11.5-in. Nal crystal* in a 128,X 128 array results in negligible degradation of resolution, a 64 • 64 array will introduce detectable but usually acceptable loss of resolution, and a 32 X 32 array results in serious loss of resolution. The small, statistically less valid counts recorded in each array element that result from smaller sampling intervals often necessitate larger than ideal intervals in recording very rapid dynamic function studies (e.g., radionuclide angiocardiograms). In temporal as opposed to spatial studies, essentially the same principles hold. Temporal sampling-interval selection is important and will be illustrated by examination of a cardiac flow study such as those to be discussed later. Intracardiac radioactivity is recorded sample by sample in the histogram mode after a bolus injection and a sinusoidal pattern superimposed on an exponential decay curve is observed. The recording system is not perfect, and as the frequency (heart rate) increases, apparent ventricular ejection fraction is measured less and less accurately, appearing to decrease even though it is kept constant. This reduced sensitivity at higher frequencies may be plotted I and it forms a temporal MTF that is analytically expressed by C(w) in Eq. (2). When measured or computed for a specific recording device, this temporal MTF can be used to correct approximately a cardiac flow study for increasing heart rate by a simple linear operation once the flow study has been transformed to the frequency d~main. We do not use this correction at heart rates less than 120 beats/min. A QUANTIFICATION
SYSTEM
After selection of the desired sampling intervals, both spatial and temporal, a computer/imaging device that will achieve this result may be designed, and many such systems have been developed for use in nuclear medicine. Most feature a minicomputer operating on-line with an Anger-type scintillation camera. ~6-18'24 In general these systems feature the capability of accumulation, storage, and display of dynamic *Nuclear-Chicago Pho-Gamma HP Anger camera.
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scintigraphic data, but provide limited ability for more than the simplest mathematical manipulation of the recorded image. In the nuclear medicine laboratory at the Denver Veterans Administration Hospital, we have developed a system that we feel has advantages over most systems previously described. ~5 The system is outlined in Fig. 3. Hardware consists of a 12K core PDP-I 2* computer interfaced with a Nuclear-Chicago Pho-Gamma HP Anger camera. The PDP-12 uses 12-bit words, which we have found to be satisfactory in general, although it has precluded ease of adaptation of some advanced non-nuclear medical programs we feel could be very useful. Disregarding the cost, a 16-bit machine would be more desirable. The fundamental feature of a minicomputer needed for a nuclear medicine system is the databreak facility, which allows interruption with access to core memory on a priority basis. In our system, priorities are controlled by a channel DM-04* multiplexer that gives the disk the highest priority, the Anger-camera interface the next highest, and the display scope the lowest priority. In the static mode, images are recorded on LINC* tape or magnetic disk (RK08*) in 64 • 64 element arrays. For processing, a scan is transferred from tape to magnetic disk where it can be recalled automatically for display, resolution-enhancement processing, or comparison with other scans by a variety of simple commands entered through a keyboard (TTY). Two cathode-ray tubes (CRT) are used, one primarily for graphics and the other for image display. The image display scope was developed by Mr. Dennis Kirch and associates at a cost of about $3,500 (Fig. 4). It allows display in different shades of gray and with variable contrast, the range of each being continuously changed by simply rotating potentiometers. The image display scope has direct memory access so that it leaves the central processing unit (CPU) free to perform other computations, such as resolution enhancement at the same time images are being displayed. Another feature
*Digital Equipment Corp., Maynard, Mass.
QUANTI FICATION
317
D
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Fig. 4. Lateral brain scan after resolution enhancement displayed on the CRT system (note the contrast and varying shades of gray): (A) raw data; (B) after linear enhancement and smoothing; (C) after adaptive smoothing and enhancement (note the small simulated hot lesion in the midparietal region); (D) horizontal cross sections through A on top and C on bottom (note improved contrast).
of this display system is that it permits selective intensification of those elements of the image that fall within a specified count range (selected by switches on the display control panel), thus allowing the viewer to amplify image count differences that otherwise would be too small to be visually discernible. Regions of interes'~ are selected visually by turning knobs on the computer panel to control a cursor dot and observing corresponding intensified areas on tile CRT. In the dynamic imaging, mode images are accumulated in 32 X 32 or 64 • 64
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element matrices, depending on the requirements of the study being p~rformed. If temporal resolution is of primary importance (such as in flow studies of the heart and lungs), then the 32 X 32 mode is selected. Frame rates up to 20 frames/sec for a total of up to 512 frames can be recorded in this mode. If spatial resolution is important, then the 64 X 64 mode is utilized with frame rates up to 8 frames/sec for a total of 128 frames. Dynamic studies are stored on the magnetic disk until tile analysis of the data is complete and then transferred to magnetic tape for permanent storage. A new feature of the dynamic recording system that is proving extremely useful is the ability to record physiological data such as EKG, pressure, flow, temperature, and ultrasonic transducer outputs along with dynamic scintigraphic studies. Up to eight channels of data are digitized and stored in the corner elements of the image array, which are normally unused due to the circular configuration of the Anger-camera detector. Three Schmidt trigger channels are also available for tagging the frames of the study that correspond to discrete events (such as the EKG R-wave or tile activation of automatic injection equipment). This ability to record analog data is now used frequently at our institution in nonimaging studies. Data from a single radioisotope probe can now be transmitted remotely by telephone and recorded in the computer. Renograms and cardiac flow studies from the bedsides of critically ill patients who cannot be brought to the nuclear medicine laboratory for study are recorded by this means. 26 This function is facilitated by the use of a general data-acquisition program that allows up to eight analog curves to be recorded on LINC tape at sampling frequencies up to 10(3/ sec.
The categorization of nuclear medicine procedures into static and dynamic modalities is arbitrary. Static imaging serves primarily to observe structure, dynamic imaging to observe function. At this time, a few procedures that are static in nature are conducted on a sequential basis for the purpose of visualizing, very slowly, changing phenomena. Cisternography delayed brain scans and gallium scans are examples of these. In order to use the computer capabilities to make quantitative determinations from these studies, precision in positioning of the patient is required. This is obtained in our system by the use of a marker dot attached to some appropriate point on the patient. Using the computer, successive images may easily be shifted until their marker dots visually correspond, correcting for patient motion. Playback of dynamic function is accomplished frame by frame in real time or at slower and slower rates selected on a variable potentiometer. Display can be stopped on a single frame for photography. Graphic infortnation is displayed on the graphics CRT. Curves of counts per frame or combinations of frames over multiple regions of interest are developed automatically. With a single keyboard instruction, a curve may be transferred from the CRT to the X - Y plotter for permanence. The clinical usefulness of a computer/Anger-camera system can be enhanced greatly by development of a flexible curve-analysis program. In addition to the rather extensive set of 'computer programs needed for the storage and playback functions described above, several additional computer programs have been developed or adapted for our system to facilitate curve analysis. Some of these are described in detail elsewhere. 2s Essentially, this program makes it possible to derive quantitative diagnostic information from these curves with minimal effort on the part of the clinician. The curve-analysis program used in our system has been adapted from the spectral-
QUANTIFICATION
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analysis system (called RUFUS) written by David Stern of the Laboratory for Atmospheric and Space Physics, University of Colorado, Boulder, Colo. as Up to six curves, with 512 data points each, may be stored in core. These curves may be added, subtracted, multiplied or divided, integrated or differentiated, smoothed, edited, shifted, correlated and fitted with exponentials or straight lines, plotted or Fourier-transformed, and deconvolved. All of these functions are carried out with simple instructions. After analysis, the results may be transferred by a single command to CRT, teletype, plotter, disk, or tape. Up to 256 of these curves can be stored on a single LINC tape. Instructions to the system are in the form of commands from the teletype. Commands are interpreted in three modes: (1) manually-commands are executed as they are typed; (2) automatically-commands are stored in a 1024-character buffer and executed under program control with variables, loops, etc.; (3) storage m o d e commands are stored in the program buffer as they are entered from the TTY and normally executed. (This is similar to FOCAL.*) Programs may be written using the text-editing features of the DIAL* system and loaded by the curve-analysis program from either a named DIAL file or from the working storage area. Also, programs can be saved on previously existing DIAL source files. These programs are completely compatible with the DIAL text editor. Every effort has been made to make the display as interactive and informative as possible. One or two curves may be displayed at once, selected directly by the operator or automatically as the result of a program command. The X axis can be expanded from 512 points to 2 points across the entire screen. The vertical separation between the two displayed curves or the position of one curve can be controlled by a knob on the computer. This allows easy superposition of curves for comparison. A cursor option is available, also set by a control knob. This cursor intensifies a single point along the X axis of each curve for visual identification quantification. To expand a portion of a curve, two vertical dash lines are displayed in the positions where they cross the X axis, selected by control knob. If sense switch 1 on the computer is off, the full curve is displayed; if on, the curve between the two vertical lines is expanded to fill the screen horizontally. In summary, the important features of this system are: (1) the great flexibility and speed with which the operator can analyze, manipulate, and display his data and (2) the ease with which programmed functions can be modified or built into segments of the program. R ESU LTS
The system of computer and Anger scintillation camera and the extensive set of programs described above greatly facilitate the development of new and clinically useful computer applications in medicine. Two developments from our institution will be used to illustrate this point. The first is a method of improving resolution of static images by what we call adaptive filtering. This method was developed primarily by Kirch and has been described in detail elsewhere, as'aT The second example is a method of quantitation of dynamic function studies, in particular quantifying the degree of cardiac valvular insufficiency by radioisotope angiocardiography. *Digital Equipment Corp., Maynard, Mass.
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STATIC IMAGE ENHANCEMENT
Our resolution-enhancement work began with a belief that since a recorded image O(s) is the result of an unknown spatial isotope distribution A(s) acted upon by a known response function of the recording system, primarily the collimator C(s), the image could be corrected explicitly to determine the true isotope distribution, z7 Mathematically, O(s) is said to be the result of the convolution of A(s) with C(s), and the process of solving for A(s) is called a deconvotution. Deconvolutions may be carried out in many ways, but the fastest available to us is to use the computer to take the Fourier transforms of C(s) and O(s). Division of one transform by the other and inverse transformation of the result accomplishes the deconvolution, although there are practical limits on the precision with whidr this can be performed. We concluded from our early studies that resolution could be improved somewhat by this linear form of filtering. Several factors tended to defeat the method, however. The most important was that this approach tended to amplify statistical fluctuations (noise) in the recorded scan. The noise in a scan, however, has a relatively high distribution of frequencies, and since the Fourier transform displays the image as intensities of increasing frequency, it seemed logical to simply set the high frequencies to zero, thus eliminating noise. Unfortunately, a sharp discontinuity in the transform of an image will result in severe undulations of the inverse transform, so rather than sharply dropping the transform to zero, an exponential function was used to taper it oft" gradually. There still remains the problem of where the noise ends and the true image begins. If low frequencies are attenuated, resolution is destroyed. For these reasons, what might be called classic or logical means of resolution enhancement were abandoned, and instead an empirical method (adaptive filtering) was developed. First, an average random noise level is computed by averaging the coefficients (actually magnitudes) of the transform at all frequencies above the intrinsic resolution of the collimator. The transform coefficients are then tested against this noise level (or a higher factored value of this level if greater statistical significance despite some loss of resolution is desired), and coefficients are set to zero if they are lower, or retained if they are higher. The resulting smoothing function formed in the transform (in the frequency plane) is very irregular and noncircular in shape because it is adapted to the Fourier transform of each individual image. Our results, however, show that this departure from previously used smooth filter functions makes this adaptive technique less susceptible to the production of artifacts. Since the transform of the image is adaptively smoothed, it would previously have been divided by the transform of the recording system, C(s). Surprisingly, however, more improvement in resolution results from applying an arbitrarily selected logarithmic function (which rises to a value of 3.0 at 0.4 cycles/cm) with no direct relationship to physical reality. An example of the results of this type of adaptive Cfltering is illustrated in Fig. 5. In one of many test situations, but perhaps an average one, an approximately 50% increase in non-lesion to lesion count ratio was achieved for a mock cold lesion 1.25 cm in diameter (see reference 25 for details) and artifactual undulations were significantly reduced. The computer system (hardware and software) described earlier makes it relatively simple to record a static image digitally, apply adaptive filtering, and display the enhanced image. At present this filtering process requires 10 min of PDP-12 time. De-
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_.. . ./..p.R.D~..L.=?..=.'..:~ ....... 9......................... Fig. 5. A resolution phantom before and after resolution enhancement using adaptive filtering to reduce noise and an empiric function to improve resolution; C displays a very narrow count range selected to outline significant structures in B.
spite this inconveniently long time, we find frequent clinical situations that justify this amount of computer time. Faster methods are under development. A blind comparison of the Kirch-Brown linear filtering technique for image enhancement and smoothing by this nonlinear frequency approach was recently provided by the cooperative project on evaluation of computer techniques for processing scintigraphic images being conducted by the International Atomic Energy Agency (IAEA). Two of the authors (Kirch and Brown) are participants in this project. Recently, 24 simulated phantom scans were generated and sent to the participants in the IAEA project for computer processing, following which the results were returned to the IAEA for evaluation. In our case, we returned two independent sets of results. The first set was processed using the linear filter developed by Kirch and Brown) 7 The Second was processed using the nonlinear frequency-domain technique described above. The improvement in the detection capabilities afforded by the nonlinear frequency-domain technique was dramatic. Measured in terms of probability of true detection Pt and probability of false detection PC"the results of the IAEA evaluation of these techniques were: Pt = 0.63 and PC"= 0.32 for the linear Kirch-Brown technique Pt = 0.80 and p f = 0.18 for the nonlinear technique. While a valid criticism of the IAEA project has concerned the variability in results, which is introduced by the display technique independently of the various computer
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processing techniques, the two sets of results compared above were displayed and scored on an identical basis. Results obtained to date indicate that improved detectability of simulated lesions is achieved by computer processing. The IAEA is currently preparing a more extensive quantitative comparison of image processing techniques. DYNAMIC FUNCTION ANALYSIS
A second example of the usefulness of quantification using a computer/camera system such as ours will be illustrated by describing its use in the analysis of a dynamic function test-the radioisotope angiocardiogram. This project resulted from cooperation between Dennis L. Kirch, M.S.E.E.; Charles Metz, Ph.D.;* Peter P. Steele, M.D., cardiologist at the Denver Veterans Administration Hospital; and Donald Van Dyke, M.D.r (More detailed reports of their investigations have been submitted for publication. 2s-3~ With the patient in the RAO position, a bolus of 8 mCi of 99mTc pertechnetate is flushed through a Swan-Ganz catheter 3~ wedged in a pulmonary artery branch for left-heart studies or placed in the superior vena cava for the right heart. This catheter is soft and has a small balloon near its tip that makes placement simple in most instances. The 32 • 32 element images of the heart and major vessels are recorded at 20 frames/sec for 25 sec on the magnetic disk using the computer/camera system. Cardiac output is determined by thermal dilution, indocyanine green dye (the Fick principle), or ll3mln cl. EKG is recorded to determine heart rate and premature beats. Using a cine-fashion computer playback, the cardiac flow is studied visually on the CRT, and the valve plane separating the atrium and ventricle is identified. Next, a summed image over many frames is developed, and four areas of interest are selected. Th@se correspond to the atrium, the ventricle, and an associated background for each of these chambers. Van Dyke 26'32 has demonstrated the necessity of correcting the time-activity curves for these chambers for background, and our selection of these areas follows his method with the modification that our backgrounds are semiannular rings surrounding the chamber to be corrected and excluding as much as possible the grea t vessels and adjacent chamber of the heart (Fig. 6). Using a system of recursion relationships, a set of finite-difference equations has been generated and solved by Ztransformation methods. These equations define the change in the amount of isotope in the atrium and ventricle on a beat-by-beat basis. After subtraction of the chamber background, and by using parameters such as time constants determined by the singleexponential least-squares fit to the later portions of the atrial and ventricular washout curves, the heart rate, the cardiac output, the beat-by-beat total ejection fraction, and the derived equations, the computer determines average end diastolic volume (EDV), end systolic volume, and forward and backward regurgitant ejection fraction for both the atrium and ventricle on the side being studied. 28-3~ More than 150 patients have been studied by Dr. Steele to date, without ill effect. Similar tests in animals did not produce significant damage at the site of injection. In the first 100 patients studied, a sharp enough bolus into the left heart to allow analysis was obtained in 89 cases. Most failures were due to lack of adequate wedging of the catheter into a distal posterior pulmonary artery. Twenty-nine of these 89
*Department of Radiology, University of Chicago Pritzker School of Medicine and the Franklin McClean Memorial Institute. 1"Donner Laboratories, University of California, Berkeley, Calif.
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Fig. 6. (A) Normal dynamic cardiac flow study following pulmonary wedge injection ofg~)mTc bolus. Image obtained by summing data during a 5-sec interval. (B) The background area used to correct the left-ventricular time-activity curve has been flagged. (C, D) Washout curves before and after correction. (E, F) Similar curves from a patient with rnitral insufficiency.
patients had adequate cine-angiograms, which allowed determination of ejection fraction bv classic contrast angiographic methods. 3s'36 Left-ventricular ejection fractions determined radioisotopically correlated well with those determined using contrast (r = 0.84). Correlation for left-ventricular end diastolic volumes by the two methods was even better (r = 0.95). When valvular regurgitation is present, this is quantitated with the same system of equations used in the nonregurgitant case. Preliminary evaluation of the regurgitant model in patients with mitral and aortic disease has been encouraging, particularly when correlated with contrast angiographic techniques. Details are being published elsewhere.28'3~
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ACKNOWLEDGMENT We are grateful to Ms. Corinne Schoener and Ms. Barbara Jannotti for their assistance. This work was made possible by U.S. Veterans Administration research grant 1103-01.
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