FPGA-Based Pulse Pile-Up Correction With Energy and Timing Recovery.

Modern field programmable gate arrays (FPGAs) are capable of performing complex discrete signal processing algorithms with clock rates well above 100 MHz. This, combined with FPGA's low expense, ease of use, and selected dedicated hardware make them an ideal technology for a data acquisition system for a positron emission tomography (PET) scanner. The University of Washington is producing a high-resolution, small-animal PET scanner that utilizes FPGAs as the core of the front-end electronics. For this scanner, functions that are typically performed in dedicated circuits, or offline, are being migrated to the FPGA. This will not only simplify the electronics, but the features of modern FPGAs can be utilized to add significant signal processing power to produce higher quality images. In this paper we report on an all-digital pulse pile-up correction algorithm that has been developed for the FPGA. The pile-up mitigation algorithm will allow the scanner to run at higher count rates without incurring large data losses due to the overlapping of scintillation signals. This correction technique utilizes a reference pulse to extract timing and energy information for most pile-up events. Using pulses acquired from a Zecotech Photonics MAPD-N with an LFS-3 scintillator, we show that good timing and energy information can be achieved in the presence of pile-up utilizing a moderate amount of FPGA resources.

Parametric positioning of a continuous crystal PET detector with depth of interaction decoding.

Here we demonstrate a parametric positioning method on a continuous crystal detector. Three different models for the light distribution were tested. Diagnosis of the residues showed that the parametric model fits the experimental data better than Gaussian and Cauchy models in our particular experimental setup. Based on the correlation between the spread and the peak value of the light distribution model with the depth of interaction (DOI), we were able to estimate the three-dimensional position of a scintillation event. On our continuous miniature crystal element (cMiCE) detector module with 8 mm thick LYSO crystal, the intrinsic spatial resolution is 1.06 mm at the center and 1.27 mm at the corner using a maximum-likelihood estimation (MLE) method and the parametric model. The DOI resolution (full width at half maximum) is estimated to be approximately 3.24 mm. The positioning method using the parametric model outperformed the Gaussian and Cauchy models, in both MLE and weighted least-squares (WLS) fitting methods. The key feature of this technique is that it requires very little calibration of the detector, but still retains high resolution and high sensitivity.

Measured count-rate performance of the Discovery STE PET/CT scanner in 2D, 3D and partial collimation acquisition modes.

We measured count rates and scatter fraction on the Discovery STE PET/CT scanner in conventional 2D and 3D acquisition modes, and in a partial collimation mode between 2D and 3D. As part of the evaluation of using partial collimation, we estimated global count rates using a scanner model that combined computer simulations with an empirical live-time function. Our measurements followed the NEMA NU2 count rate and scatter-fraction protocol to obtain true, scattered and random coincidence events, from which noise equivalent count (NEC) rates were calculated. The effect of patient size was considered by using 27 cm and 35 cm diameter phantoms, in addition to the standard 20 cm diameter cylindrical count-rate phantom. Using the scanner model, we evaluated two partial collimation cases: removing half of the septa (2.5D) and removing two-thirds of the septa (2.7D). Based on predictions of the model, a 2.7D collimator was constructed. Count rates and scatter fractions were then measured in 2D, 2.7D and 3D. The scanner model predicted relative NEC variation with activity, as confirmed by measurements. The measured 2.7D NEC was equal or greater than 3D NEC for all activity levels in the 27 cm and 35 cm phantoms. In the 20 cm phantom, 3D NEC was somewhat higher ( approximately 15%) than 2.7D NEC at 100 MBq. For all higher activity concentrations, 2.7D NEC was greater and peaked 26% above the 3D peak NEC. The peak NEC in 2.7D mode occurred at approximately 425 MBq, and was 26-50% greater than the peak 3D NEC, depending on object size. NEC in 2D was considerably lower, except at relatively high activity concentrations. Partial collimation shows promise for improved noise equivalent count rates in clinical imaging without altering other detector parameters.

Depth of interaction decoding of a continuous crystal detector module.

We present a clustering method to extract the depth of interaction (DOI) information from an 8 mm thick crystal version of our continuous miniature crystal element (cMiCE) small animal PET detector. This clustering method, based on the maximum-likelihood (ML) method, can effectively build look-up tables (LUT) for different DOI regions. Combined with our statistics-based positioning (SBP) method, which uses a LUT searching algorithm based on the ML method and two-dimensional mean-variance LUTs of light responses from each photomultiplier channel with respect to different gamma ray interaction positions, the position of interaction and DOI can be estimated simultaneously. Data simulated using DETECT2000 were used to help validate our approach. An experiment using our cMiCE detector was designed to evaluate the performance. Two and four DOI region clustering were applied to the simulated data. Two DOI regions were used for the experimental data. The misclassification rate for simulated data is about 3.5% for two DOI regions and 10.2% for four DOI regions. For the experimental data, the rate is estimated to be approximately 25%. By using multi-DOI LUTs, we also observed improvement of the detector spatial resolution, especially for the corner region of the crystal. These results show that our ML clustering method is a consistent and reliable way to characterize DOI in a continuous crystal detector without requiring any modifications to the crystal or detector front end electronics. The ability to characterize the depth-dependent light response function from measured data is a major step forward in developing practical detectors with DOI positioning capability.

Evaluation of event position reconstruction in monolithic crystals that are optically coupled.

A PET detector featuring a pseudo-monolithic crystal is being developed as a more cost-effective alternative to a full monolithic crystal PET detector. This work evaluates different methods to localize the scintillation events in quartered monolithic crystals that are optically coupled. A semi-monolithic crystal assembly was formed using four 26 × 26 × 10 mm3 LYSO crystals optically coupled together using optical adhesive, to mimic a 52 × 52 × 10 mm3 monolithic crystal detector. The crystal assembly was coupled to a 64-channel multi-anode photomultiplier tube using silicon grease. The detector was calibrated using a 34 × 34 scan grid. Events were first filtered and depth separated using a multi-Lorentzian fit to the collected light distribution. Next, three different techniques were explored to generate the look up tables for the event positioning. The first technique was 'standard interpolation' across the interface. The second technique was 'central extrapolation', where a bin was placed at the midpoint of the interface and events positioned within the interface region were discarded. The third technique used a 'central overlap' method where an extended region was extrapolated at each interface. Events were then positioned using least-squares minimization and maximum likelihood methods. The least-squares minimization applied to the look up table generated with the standard interpolation technique had the best full width at half maximum (FWHM) intrinsic spatial resolution and the lowest bias. However, there were discontinuities in the event positioning that would most likely lead to artifacts in the reconstructed image. The central extrapolation technique also had discontinuities and a 30% sensitivity loss near the crystal-crystal interfaces. The central overlap technique had slightly degraded performance metrics, but it still provided ~2.1 mm intrinsic spatial resolution at the crystal-crystal interface and had a symmetric and continuously varying response function. Results using maximum likelihood positioning were similar to least-squares minimization for the central overlap data.

Quantitative autoradiographic evidence for insulin receptors in the choroid plexus of the rat brain.

Techniques of in vitro receptor autoradiography were used to visualize binding of 125I-insulin on slices of frozen rat brain. Slide-mounted sections of frozen rat brain were incubated in 0.05 nM porcine 125I-monoiodoinsulin, alone or mixed with 1 microM unlabeled porcine insulin, ribonuclease, or glucagon, for 2 h at 22 degrees C. The labeled brain slices were apposed to LKB Ultrofilm to generate autoradiograms. The method permitted equal access of labeled insulin to both sides of the blood-brain barrier and localization of insulin binding sites in small anatomic regions. Quantitative estimates of specific iodoinsulin binding were made by computer digital image densitometry of the autoradiographic film images. High concentrations of specific binding sites for iodoinsulin were present in the choroid plexus of the lateral (26.9 +/- 2.0 X 10(-3) fmol/mm2), fourth (18.3 +/- 3.0 X 10(-3) fmol/mm2), and third (13.2 +/- 1.5 X 10(-3) fmol/mm2) ventricles (insulin binding is expressed per unit area of autoradiographic image). Binding to the third ventricular choroid plexus was similar to the concentrations observed for liver slices and the external plexiform layer of the olfactory bulb. Specific binding of iodoinsulin in the cingulate cortex and other surrounding regions was less than in choroid plexus. Ribonuclease or glucagon had no measurable effect on binding when mixed with labeled insulin. The results support the hypothesis that the choroid plexus has a high density of receptors for insulin, and suggests that the choroid plexus may be a target of CSF insulin action and/or a site of insulin transport into the CSF.

Imaging of hypoxia in human tumors with [F-18]fluoromisonidazole.

Fluoromisonidazole (FMISO) has been shown to bind selectively to hypoxic cells in vitro and in vivo at radiobiologically significant oxygen levels. When labeled with the positron emitter fluorine-18 (F-18), its uptake in tissue can be detected quantitatively with high precision by positron emission transaxial tomography (PETT). This paper presents the first experiences with PETT imaging of [F-18]FMISO uptake in human malignancies, and describes the development of this technique as a tool for the non-invasive assessment of tumor hypoxia. Eight patients with selected cancers were imaged prior to primary radiotherapy, and 3 returned for follow-up scans, for a total of 11 imaging studies. Six of eight pre-radiotherapy studies revealed retention of [F-18]FMISO in tumors that significantly exceeded plasma concentrations by 2 hr after drug injection; all five patients with head and neck primaries had such "positive" scans. An analytic method for the interpretation of [F-18] FMISO PETT images is presented, defining hypoxic elements within a tumor volume as regions with a threshold regional tumor:plasma [F-18]FMISO ratio of greater than or equal to 1.4 by 2 or more hours after injection. Toward the end of a course of fractionated radiotherapy, three repeat studies in patients with initially positive scans showed no tumor accumulation of drug above the threshold ratio of 1.4, suggesting reoxygenation had occurred. Pharmacokinetic and dosimetry data support continued use of [F-18]FMISO as a safe hypoxia probe. Two imaging protocols have been developed for human studies; a long protocol allows for more complete biodistribution and dosimetry information, and a shorter protocol facilitates increased patient accrual by applying a simple, clinically expedient imaging procedure. When correlated with tumor outcome, [F-18]FMISO PETT imaging may be developed as a predictor of tumor response to conventional radiotherapy. The implications of this technique in addressing persistent questions of tumor hypoxia in human oncology is discussed.

Quantifying regional hypoxia in human tumors with positron emission tomography of [18F]fluoromisonidazole: a pretherapy study of 37 patients.

PURPOSE: To assess pretreatment hypoxia in a variety of tumors using positron emission tomography (PET) after injection of the hypoxia-binding radiopharmaceutical [18F]fluoromisonidazole ([18F]FMISO). METHODS AND MATERIALS: Tumor fractional hypoxic volume (FHV) was determined in 21 nonsmall cell lung cancer patients, 7 head and neck cancer patients, 4 prostate cancer patients, and 5 patients with other malignancies by quantitative PET imaging after injection of [18F]FMISO (0.1 mCi/kg). The FHV was defined as the proportion of pixels in the imaged tumor volume with a tissue:blood [18F] activity ratio > or = 1.4 at 120-160 min postinjection. A FHV > 0 was taken as evidence for tumor hypoxia. RESULTS: Hypoxia was observed in 36 of 37 tumors studied with FMISO PET imaging; FHVs ranged from 0 to 94.7%. In nonsmall cell lung cancers (n = 21), the median FHV was 47.6% and the range, 1.3 to 94.7%. There was no correlation between tumor size and FHV. In the seven head and neck carcinomas, the median FHV was 8.8%, with a range from 0.2 to 18.9%. In the group of four prostate cancers, the median and range were 18.2% and 0 to 93.9%, while in a group of five tumors of different types the median FHV was 55.2% (range: 21.4 to 85.8%). CONCLUSIONS: Hypoxia was present in 97% of the tumors studied and the extent of hypoxia varied markedly between tumors in the same site or of the same histology. Hypoxia also was distributed heterogeneously between regions within a single tumor. These results are consistent with O2 electrode measures with other types of human tumors. The intra- and intertumor variability indicate the importance of making oxygenation measures in individual tumors and the necessity to sample as much of the tumor volume as possible.

Evaluation of oxygenation status during fractionated radiotherapy in human nonsmall cell lung cancers using [F-18]fluoromisonidazole positron emission tomography.

PURPOSE: Recent clinical investigations have shown a strong correlation between pretreatment tumor hypoxia and poor response to radiotherapy. These observations raise questions about standard assumptions of tumor reoxygenation during radiotherapy, which has been poorly studied in human cancers. Positron emission tomography (PET) imaging of [F-18]fluoromisonidazole (FMISO) uptake allows noninvasive assessment of tumor hypoxia, and is amenable for repeated studies during fractionated radiotherapy to systematically evaluate changes in tumor oxygenation. METHODS AND MATERIALS: Seven patients with locally advanced nonsmall cell lung cancers underwent sequential [F-18]FMISO PET imaging while receiving primary radiotherapy. Computed tomograms were used to calculate tumor volumes, define tumor extent for PET image analysis, and assist in PET image registration between serial studies. Fractional hypoxic volume (FHV) was calculated for each study as the percentage of pixels within the analyzed imaged tumor volume with a tumor:blood [F-18]FMISO ratio > or = 1.4 by 120 min after injection. Serial FHVs were compared for each patient. RESULTS: Pretreatment FHVs ranged from 20-84% (median 58%). Subsequent FHVs varied from 8-79% (median 29%) at midtreatment, and ranged from 3-65% (median 22%) by the end of radiotherapy. One patient had essentially no detectable residual tumor hypoxia by the end of radiation, while two others showed no apparent decrease in serial FHVs. There was no correlation between tumor size and pretreatment FHV. CONCLUSIONS: Although there is a general tendency toward improved oxygenation in human tumors during fractionated radiotherapy, these changes are unpredictable and may be insufficient in extent and timing to overcome the negative effects of existing pretreatment hypoxia. Selection of patients for clinical trials addressing radioresistant hypoxic cancers can be appropriately achieved through single pretreatment evaluations of tumor hypoxia.

A comparison of count rate parameters in gamma cameras.

Pulse pile-up is a fundamental problem that limits the ability of a gamma camera to produce high quality images at high count rates. Pulse pile-up results in loss of events and spatial distortions in the image. The question asked in this study is how well do some of the test procedures for measuring count rate performance in gamma cameras compare. In four gamma cameras we compared measurements of spectral fraction, count-rate curve, pulse-pair resolution, deadtime, maximum count rate, full width at half maximum of the line spread function, and misplaced event count rate. The results indicated that no one technique provides a complete description of the count-rate effects in gamma cameras. The misplaced-event measurements provided the most information.

A low-contrast phantom for daily quality control.

A simple phantom is proposed to provide a low-contrast test object for daily quality assurance. The phantom consists of four quarters and five dimes taped to a Plexiglas plate. For daily quality control, the phantom is used with 5 cm of Plexiglas as scattering material and a flood source. Examples of images are presented for several gamma cameras, illustrating some of the information that can be obtained. In particular, we present examples of cameras providing improper imaging performance with the coin phantom but with "normal" floods and bar-phantom images. The major conclusion is that daily quality-control images should include significant of scattering material and low-contrast objects.

Quantitative autoradiography using a personal computer.

A video digitizing system based on an Apple II personal computer has been developed for use in quantitative autoradiography. The selection process of an acceptable video camera, an illumination system, and the functions provided in the software are discussed. This system is in routine use and has been duplicated by several other laboratories.

A method for imaging therapeutic doses of iodine-131 with a clinical gamma camera.

Imaging therapeutic doses of 131I-labeled monoclonal antibody would provide valuable biodistribution data for dosimetry, but gamma cameras are unable to accurately handle the corresponding high counting rate. To image patients undergoing radioimmunotherapy, we attached 1.6- to 6.4-mm-thick Pb sheets to the front face of a high-energy parallel-hole collimator. With this method, we were able to acquire planar images of up to 700 mCi of radiolabeled antibody 1 hr after infusion. Monte Carlo simulations indicated that less than 7% of the events counted in the photopeak window were due to 364-keV photons that scattered in the Pb attenuator. Measurements indicated that the Pb sheets degraded system resolution by no more than 13%. A quantitative comparison of trace and therapy biodistribution data from planar images of the same patient was made using corrections for Pb sheet attenuation and camera deadtime.

Absolute measurement of total-body calcium by the Ar-37 method-preliminary results: concise communication.

Measurements of exhaled Ar-37 produced by total-body neutron irradiation of Ca-40, were used to determine total-body calcium in ten human subjects. There was a good correlation between the Ar-37 yield and total-body calcium determined by measurement of Ca-49.

A field procedure for the quantitative assessment of nuclear imaging cameras.

Techniques developed for the quantitative assessment of gamma cameras are described. The performance parameters discussed include energy resolution, intransic line spread function, uniformity, and extrinsic line spread function. In addition to describing the equipment used and indicating methods used in analyzing data, some of the potential problems in interfacing multichannel analyzers to gamma cameras are discussed.

Evaluation of a clinical scintillation camera with pulse tail extrapolation electronics.

The performance of a new scintillation camera, designed for high event rate capability, was evaluated. The system consisted of a 400 mm field-of-view Nal(T1) camera with 61 photomultiplier tubes and modified General Electric Starport electronics. A significant feature of the system was circuitry for performing pulse tail extrapolation and separation of individual pulses involved in pulse pile-up events. System deadtime, flood field uniformity, energy resolution, linearity, spatial resolution, and bar phantom image quality were evaluated for count rates up to 200 kcps in a 20% photopeak window. Our results indicate that this camera design does not compromise image quality at normal clinical count rates and at higher event rates can provide better image quality and increased sensitivity over many Anger cameras currently employed in nuclear medicine.

Considerations in the purchase of a nuclear medicine computer system.

Selection of a nuclear medicine computer system is a process that should be approached with care and forethought. The general scheme should be to define your needs and constraints, determine what is available, investigate the leading candidates, make a site visit, and, finally, submit an order. Through a series of discussions between members of the Computer Council of the Society of Nuclear Medicine and representatives from the manufacturers of computer systems, a set of important considerations emerged, which are reported in this paper. This paper is not intended to be a step-by-step guideline to the purchase of a computer system. Rather, it is a set of concepts and considerations with which the prospective purchaser should be familiar before undertaking such a purchase.

Energy-based scatter corrections for scintillation camera images of iodine-131.

UNLABELLED: The use of high-dose 131I antibody therapy requires accurate measurement of normal tissue uptake to optimize the therapeutic dose. One of the factors limiting the accuracy of such measurements is scatter and collimator septal penetration. This study evaluated two classes of energy-based scatter corrections for quantitative 131I imaging: window-based and spectrum-fitting. METHODS: The window-based approaches estimate scatter from data in two or three energy windows placed on either side of the 364-keV photopeak using empirical weighting factors. A set of images from spheres in an elliptical phantom were used to evaluate each of the window-based corrections. The spectrum-fitting technique estimates detected scatter at each pixel by fitting the observed energy spectrum with a function that models the photopeak and scatter, and which incorporates the response function of the camera. This technique was evaluated using a set of Rollo phantom images. RESULTS: All of the window-based methods performed significantly better than a single photopeak window (338-389 keV), but the weighting factors were found to depend on the object being imaged. For images contaminated with scatter, the spectrum-fitting method significantly improved quantitation over photopeak windowing. Little difference, however, between any of the methods was observed for images containing small amounts of scatter. CONCLUSION: Most clinical 131I imaging protocols will benefit from qualitative and quantitative improvements provided by the spectrum-fitting scatter correction. The technique offers the practical advantage that it does not require phantom-based calibrations. Finally, our results suggest that septal penetration and scatter in the collimator and other detector-head components are important sources of error in quantitative 131I images.

Preliminary observations on excretion of 37Ar from man following whole-body neutron activation--an indicator of total-body calcium.

Measurements of exhaled 37-Ar produced by total-body neutron irradiation of 40-Ca were used to determine total-body calcium in 16 human subjects. There was a good correlation between body calcium using the 30-min postirradiation breath sample of 37-Ar and body calcium determined by measurement of 49-Ca.

Noninvasive detection of hypoxic myocardium using fluorine-18-fluoromisonidazole and positron emission tomography.

Fluoromisonidazole (FMISO) is metabolically trapped in viable cells as a function of reduced cellular pO2. Therefore [18F]-FMISO is potentially useful for evaluating patients with hypoxic but viable myocardium. The goal of this study was to investigate [18F]FMISO uptake in ischemic myocardium non-invasively using positron emission tomography (PET). Studies were performed in 10 open-chest dogs subjected to either complete (Group 1, n = 5) or partial (Group 2, n = 5) occlusion of the left anterior descending coronary artery. The tracer was administered by intravenous bolus following the onset of ischemia and serial PET images were acquired for the next 4 hr. In Group 1, viability was assessed using histochemical staining (nitroblue tetrazolium, NBT) and 99mTc-pyrophosphate (Tc-PYP). In Group 2, viability was assessed using measurements of regional wall motion, histochemical staining and histology (two animals). In each study, PET images obtained at times between 2 and 4 hr postinjection showed specific enhancement of tracer activity in the distal anterior wall and apex of the left ventricle. At 4 hr, the tissue-to-blood pool count ratio was significantly higher in ischemic regions; 1.8 +/- 0.4 for Group 1 and 1.6 +/- 0.2 for Group 2 versus 1.0 +/- 0.1 in nonischemic regions. Postmortem tissue sampling of Group 1 hearts showed significant FMISO retention in samples without evidence for infarction, either by NBT or Tc-PYP deposition, as well as in more severely ischemic regions. In Group 2 animals, FMISO was retained in myocardial regions with reduced blood flow (microspheres), which exhibited improved contraction following reperfusion. We conclude that PET imaging of [18F]FMISO is a promising technique for the noninvasive identification of viable hypoxic myocardium.