Performance of the Tachyon Time-of-Flight PET Camera.

We have constructed and characterized a time-of-flight Positron Emission Tomography (TOF PET) camera called the Tachyon. The Tachyon is a single-ring Lutetium Oxyorthosilicate (LSO) based camera designed to obtain significantly better timing resolution than the ~ 550 ps found in present commercial TOF cameras, in order to quantify the benefit of improved TOF resolution for clinically relevant tasks. The Tachyon's detector module is optimized for timing by coupling the 6.15 × 25 mm2 side of 6.15 × 6.15 × 25 mm3 LSO scintillator crystals onto a 1-inch diameter Hamamatsu R-9800 PMT with a super-bialkali photocathode. We characterized the camera according to the NEMA NU 2-2012 standard, measuring the energy resolution, timing resolution, spatial resolution, noise equivalent count rates and sensitivity. The Tachyon achieved a coincidence timing resolution of 314 ps +/- ps FWHM over all crystal-crystal combinations. Experiments were performed with the NEMA body phantom to assess the imaging performance improvement over non-TOF PET. The results show that at a matched contrast, incorporating 314 ps TOF reduces the standard deviation of the contrast by a factor of about 2.3.

A detector response function design in pinhole SPECT including geometrical calibration.

Clinical single photon emission computed tomography (SPECT) equipped with pinhole collimators have a magnification factor that results in high spatial resolution images for small animal imaging. Using Monte Carlo simulations to model the acquisition process and the propagation of the photons from their point of emission to their detection point then integrating the model into an iterative reconstruction algorithm improves the signal-to-noise ratio, the contrast and the spatial resolution in the reconstructed images. However, pinhole SPECT systems are known to be very sensitive to geometrical misalignments. Geometrical misalignments are defined as the radial or axial shift of the collimator pinhole and/or twist and tilt of the detector heads and are introduced in the system each time the collimation device is changed (pinhole to parallel holes or vice versa). In this work, we present a flexible detector response function table (DRFT) design that takes into account the geometrical misalignments and avoids performing new Monte Carlo simulations for each exam in order to calculate a geometrical study-dependent system matrix. The utilization of the DRFT for the calculation of the system matrix speeds up its computation time by two orders of magnitude making it acceptable for preclinical and clinical applications.

Effects of temporal modelling on the statistical uncertainty of spatiotemporal distributions estimated directly from dynamic SPECT projections.

Artefacts can result when reconstructing a dynamic image sequence from inconsistent single photon emission computed tomography (SPECT) projection data acquired by a slowly rotating gantry. The artefacts can lead to biases in kinetic parameters estimated from time-activity curves generated by overlaying volumes of interest on the images. Insufficient sampling and truncation of projections by cone-beam collimators can cause additional artefacts. To overcome these sources of bias in conventional image based dynamic data analysis, we have been investigating the estimation of time-activity curves and kinetic model parameters directly from dynamic SPECT projection data by modelling the spatial and temporal distribution of the radiopharmaceutical throughout the projected field of view. In the present work, we perform Monte Carlo simulations to study the effects of the temporal modelling on the statistical variability of the reconstructed spatiotemporal distributions. The simulations utilize fast methods for fully four-dimensional (4D) direct estimation of spatiotemporal distributions and their statistical uncertainties, using a spatial segmentation and temporal B-splines. The simulation results suggest that there is benefit in modelling higher orders of temporal spline continuity. In addition, the accuracy of the time modelling can be increased substantially without unduly increasing the statistical uncertainty, by using relatively fine initial time sampling to capture rapidly changing activity distributions.

Theoretical study of lesion detectability of MAP reconstruction using computer observers.

The low signal-to-noise ratio (SNR) in emission data has stimulated the development of statistical image reconstruction methods based on the maximum a posteriori (MAP) principle. Experimental examples have shown that statistical methods improve image quality compared to the conventional filtered backprojection (FBP) method. However, these results depend on isolated data sets. Here we study the lesion detectability of MAP reconstruction theoretically, using computer observers. These theoretical results can be applied to different object structures. They show that for a quadratic smoothing prior, the lesion detectability using the prewhitening observer is independent of the smoothing parameter and the neighborhood of the prior, while the nonprewhitening observer exhibits an optimum smoothing point. We also compare the results to those of FBP reconstruction. The comparison shows that for ideal positron emission tomography (PET) systems (where data are true line integrals of the tracer distribution) the MAP reconstruction has a higher SNR for lesion detection than FBP reconstruction due to the modeling of the Poisson noise. For realistic systems, MAP reconstruction further benefits from accurately modeling the physical photon detection process in PET.

Kinetic analysis of 125I-iodorotenone as a deposited myocardial flow tracer: comparison with 99mTc-sestamibi.

UNLABELLED: The goal of this investigation was to assess the accuracy of 7'-Z-[125I]iodorotenone (125I-iodorotenone) as a new deposited myocardial flow tracer and compare the results with those for 99mTc-sestamibi. METHODS: The kinetics of these two flow tracers were evaluated in 25 isolated, erythrocyte- and albumin-perfused rabbit hearts over a flow range relevant to patients. The two flow tracers and a vascular reference tracer (131I-albumin) were introduced simultaneously as a compact bolus through a port just above the aortic cannula in the absence of tracer recirculation. Myocardial extraction, retention, washout, and uptake parameters were computed from the venous outflow curves using the multiple-indicator dilution technique and spectral analysis. RESULTS: The extraction of 125I-iodorotenone was much higher than the extraction of 99mTc-sestamibi (0.84 +/- 0.05 vs. 0.48 +/- 0.10, respectively, P < 0.001). 125I-iodorotenone extraction was also less affected by flow than was 99mTc-sestamibi (P < 0.001). Net retention of 125I-iodorotenone was significantly greater than 99mTc-sestamibi net retention at 1 min (0.77 +/- 0.08 vs. 0.41 +/- 0.11, respectively, P < 0.001) and 26 min (0.46 +/- 0.13 vs. 0.27 +/- 0.11, respectively, P < 0.001) after tracer injection. Flow had less effect on 125I-iodorotenone net retention than on 99mTc-sestamibi net retention 1 min after tracer injection (P < 0.04). However, at 26 min, flow had an equivalent effect on the retention of both flow tracers (P < 0.4). The relationship between 125I-iodorotenone and 99mTc-sestamibi washout was complex and depended on elapsed time after isotope introduction and perfusion rate. Reflecting the favorable extraction and retention characteristics of 125I-iodorotenone, both its maximum myocardial uptake and its 26-min uptake were more closely related to flow than were those of 99mTc-sestamibi (P < 0.001 for both comparisons). CONCLUSION: The extraction and retention of 125I-iodorotenone were greater than those of 99mTc-sestamibi, making 125I-iodorotenone the superior flow tracer in the isolated rabbit heart.

Direct least-squares estimation of spatiotemporal distributions from dynamic SPECT projections using a spatial segmentation and temporal B-splines.

Artifacts can result when reconstructing a dynamic image sequence from inconsistent, as well as insufficient and truncated, cone beam single photon emission computed tomography (SPECT) projection data acquired by a slowly rotating gantry. The artifacts can lead to biases in kinetic model parameters estimated from time-activity curves generated by overlaying volumes of interest on the images. However, the biases in time-activity curve estimates and subsequent kinetic parameter estimates can be reduced significantly by first modeling the spatial and temporal distribution of the radiopharmaceutical throughout the projected field of view, and then estimating the time-activity curves directly from the projections. This approach is potentially useful for clinical SPECT studies involving slowly rotating gantries, particularly those using a single-detector system or body contouring orbits with a multidetector system. We have implemented computationally efficient methods for fully four-dimensional (4-D) direct estimation of spatiotemporal distributions from dynamic SPECT projection data. Temporal B-splines providing various orders of temporal continuity, as well as various time samplings, were used to model the time-activity curves for segmented blood pool and tissue volumes in simulated cone beam and parallel beam cardiac data acquisitions. Least-squares estimates of time-activity curves were obtained quickly using a workstation. Given faithful spatial modeling, accurate curve estimates were obtained using cubic, quadratic, or linear B-splines and a relatively rapid time sampling during initial tracer uptake. From these curves, kinetic parameters were estimated accurately for noiseless data and with some bias for noisy data. A preliminary study of spatial segmentation errors showed that spatial model mismatch adversely affected quantitative accuracy, but also resulted in structured errors (projected model versus raw data) that were easily detected in our simulations. This suggests iterative refinement of the spatial model to reduce structured errors as an area of future research.

List-mode maximum-likelihood reconstruction applied to positron emission mammography (PEM) with irregular sampling.

We present a preliminary study of list-mode likelihood reconstruction of images for a rectangular positron emission tomograph (PET) specifically designed to image the human breast. The prospective device consists of small arrays of scintillation crystals for which depth of interaction is estimated. Except in very rare instances, the number of annihilation events detected is expected to be far less than the number of distinguishable events. If one were to histogram the acquired data, most histogram bins would remain vacant. Therefore, it seems natural to investigate the efficacy of processing events one at a time rather than processing the data in histogram format. From a reconstruction perspective, the new tomograph presents a challenge in that the rectangular geometry leads to irregular radial and angular sampling, and the field of view extends completely to the detector faces. Simulations are presented that indicate that the proposed tomograph can detect 8-mm-diameter spherical tumors with a tumor-to-background tracer density ratio of 3:1 using realistic image acquisition parameters. Spherical tumors of 4-mm diameter are near the limit of detectability with the image acquisition parameters used. Expressions are presented to estimate the loss of image contrast due to Compton scattering.

Analytical propagation of errors in dynamic SPECT: estimators, degrading factors, bias and noise.

Dynamic SPECT is a relatively new technique that may potentially benefit many imaging applications. Though similar to dynamic PET, the accuracy and precision of dynamic SPECT parameter estimates are degraded by factors that differ from those encountered in PET. In this work we formulate a methodology for analytically studying the propagation of errors from dynamic projection data to kinetic parameter estimates. This methodology is used to study the relationships between reconstruction estimators, image degrading factors, bias and statistical noise for the application of dynamic cardiac imaging with 99mTc-teboroxime. Dynamic data were simulated for a torso phantom, and the effects of attenuation, detector response and scatter were successively included to produce several data sets. The data were reconstructed to obtain both weighted and unweighted least squares solutions, and the kinetic rate parameters for a two-compartment model were estimated. The expected values and standard deviations describing the statistical distribution of parameters that would be estimated from noisy data were calculated analytically. The results of this analysis present several interesting implications for dynamic SPECT. Statistically weighted estimators performed only marginally better than unweighted ones, implying that more computationally efficient unweighted estimators may be appropriate. This also suggests that it may be beneficial to focus future research efforts upon regularization methods with beneficial bias-variance trade-offs. Other aspects of the study describe the fundamental limits of the bias variance trade-off regarding physical degrading factors and their compensation. The results characterize the effects of attenuation, detector response and scatter, and they are intended to guide future research into dynamic SPECT reconstruction and compensation methods.

Estimating glucose metabolism using glucose analogs and two tracer kinetic models in isolated rabbit heart.

The purpose of this investigation was to 1) evaluate the relative accuracy of the Sokoloff and Patlak tracer kinetic models in estimating glucose metabolic rate (GMR) in the presence and absence of insulin; 2) evaluate the effect of nutritional state on the lumped constant (LC); and 3) compare the kinetics of 2-fluoro-2-deoxy-D-[14C]glucose (FDG) and 2-deoxy-D-[3H]glucose (DG) membrane transport and phosphorylation. The experimental preparation was the isolated, red blood cell-albumin-perfused rabbit heart. Our results showed that both tracer kinetic models provided GMR estimates that correlated well with the Fick method (for FDG, R = 0. 84 and 0.91 for the Sokoloff and Patlak models, respectively); nutritional state did not affect the LC; and FDG and DG have different transport and/or phosphorylation parameters. We also observed that 1) the addition of a fourth compartment to the Sokoloff model reduced the mean squared error between measured and modeled data by a factor of 7.4; 2) a longer time (21.8 min) was required to obtain a linear phase of the Patlak plot than is allowed in clinical studies; and 3) accurate GMR estimates were obtained only by using different LCs reflecting insulin's presence or absence. Our results indicate potential sources of error in the use of FDG and positron emission tomography to quantify GMR in patients.

Kinetic parameter estimation from SPECT cone-beam projection measurements.

Kinetic parameters are commonly estimated from dynamically acquired nuclear medicine data by first reconstructing a dynamic sequence of images and subsequently fitting the parameters to time-activity curves generated from regions of interest overlaid upon the image sequence. Biased estimates can result from images reconstructed using inconsistent projections of a time-varying distribution of radiopharmaceutical acquired by a rotating SPECT system. If the SPECT data are acquired using cone-beam collimators wherein the gantry rotates so that the focal point of the collimators always remains in a plane, additional biases can arise from images reconstructed using insufficient, as well as truncated, projection samples. To overcome these problems we have investigated the estimation of kinetic parameters directly from SPECT cone-beam projection data by modelling the data acquisition process. To accomplish this it was necessary to parametrize the spatial and temporal distribution of the radiopharmaceutical within the SPECT field of view. In a simulated chest image volume, kinetic parameters were estimated for simple one-compartment models for four myocardial regions of interest. Myocardial uptake and washout parameters estimated by conventional analysis of noiseless simulated cone-beam data had biases ranging between 3-26% and 0-28%, respectively. Parameters estimated directly from the noiseless projection data were unbiased as expected, since the model used for fitting was faithful to the simulation. Statistical uncertainties of parameter estimates for 10,000,000 events ranged between 0.2-9% for the uptake parameters and between 0.3-6% for the washout parameters.

An investigation into the effect of input function shape and image acquisition interval on estimates of washin for dynamic cardiac SPECT.

Dynamic cardiac SPECT and PET can be used to measure myocardial perfusion by estimating the kinetic rate constant describing the washing of radioactive-labelled tracers from the blood to the extravascular myocardial tissue. Because of differences in photon statistics and data acquisition techniques, protocols which produce optimal estimates of the washin for dynamic cardiac PET may give suboptimal estimates if applied in dynamic cardiac SPECT. Two important factors in the estimation of washin are the shape of the tracer input function and the image acquisition interval. This study uses computer simulations to investigate the effect of varying the tracer infusion length and image acquisition interval on the bias and variance of estimates of washin obtained with dynamic cardiac SPECT and 99mTc-labelled teboroxime. Bias in parameter estimates can be introduced by aliasing, integration of the time-varying radioactivity by the detector, and detector motion. This bias can be reduced by decreasing the acquisition interval and using a longer-duration input function. However, this results in poor photon statistics, which generate large variance, and can also introduce bias in the estimates of the washin. Our studies indicate that better estimates of the washin are obtained by using an acquisition interval that is of sufficient duration to obtain adequate photon statistics even if this is at the expense of temporal resolution. The increase in bias caused by using a 10 or 20 s acquisition interval instead of a 5 s acquisition interval is minimal when compared with the reduction in variance. Variance in estimates is also reduced by using a sharp input function, resulting in higher peak counts during washin. It is also shown that the variance of estimates of the washin increases generally when faster kinetics are observed. This variance can, however, be reduced by using longer acquisition intervals.

Consolidation of common parameters from multiple fits in dynamic PET data analysis.

In dynamic positron emission tomography (PET) data analysis, regions of interest (ROI's) are analyzed by fitting a parametric model to the time-activity curve acquired after a radio-labeled tracer has been introduced into the patient's bloodstream. This procedure can be carried out for multiple ROI's and/or multiple injections of the same or a different radiopharmaceutical. The approach presented here takes advantage of prior knowledge that some of the parameters of those multiple fits are the same. Reduction of the total number of parameters to be estimated results in smaller statistical uncertainty for all parameter estimates, especially those common to multiple fits.

A methodology for specifying PET VOI's using multimodality techniques.

Volume-of-interest (VOI) extraction for radionuclide and anatomical measurements requires correct identification and delineation of the anatomical feature being studied. We have developed a toolset for specifying three-dimensional (3-D) VOI's on a multislice positron emission tomography (PET) dataset. The software is particularly suited for specifying cerebral cortex VOI's which represent a particular gyrus or deep brain structure. A registered 3-D magnetic resonance image (MRI) dataset is used to provide high-resolution anatomical information, both as oblique two-dimensional (2-D) sections and as volume renderings of a segmented cortical surface. VOI's are specified indirectly in two dimensions by drawing a stack of 2-D regions on the MRI data. The regions are tiled together to form closed triangular mesh surface models, which are subsequently transformed into the observation space of the PET scanner. Quantification by this method allows calculation of radionuclide activity in the VOI's, as well as their statistical uncertainties and correlations. The methodology for this type of analysis and validation results are presented.

Consequences of using a simplified kinetic model for dynamic PET data.

UNLABELLED: We compared a physiological model of 82Rb kinetics in the myocardium with two reduced-order models to determine their usefulness in assessing physiological parameters from dynamic PET data. METHODS: A three-compartment model of 82Rb in the myocardium was used to simulate kinetic PET ROI data. Simulations were generated for eight different blood-flow rates reflecting the physiological range of interest. Two reduced-order models commonly used with myocardial PET studies were fit to the simulated data, and parameters of the reduced-order models were compared with the physiological parameters. Then all three models were fit to the simulated data with noise added. Monte Carlo simulations were used to evaluate and compare the diagnostic utility of the reduced-order models. A description length criterion was used to assess goodness of fit for each model. Finally, fits to simulated data were compared with fits to actual dynamic PET data. RESULTS: Fits of the reduced-order models to the three-compartment model noise-free simulated data produced model misspecification artifacts, such as flow parameter bias and systematic variation with flow in estimates of nonflow parameters. Monte Carlo simulations showed some of the parameter estimates for the two-compartment model to be highly variable at PET noise levels. Fits to actual PET data showed similar variability. One-compartment model estimates of the flow parameter at high and low flow were separated by several s.d.s for both the simulated and the real data. With the two-compartment model, the separation was about one s.d., making it difficult to differentiate a high and a low flow in a single experiment. Fixing nonflow parameters reduced flow parameter variability in the two-compartment model and did not significantly affect variability in the one-compartment model. Goodness of fit indicated that, at realistic noise levels, both reduced-order models fit the simulated data at least as well as the three-compartment model that generated the data. CONCLUSION: The one-compartment reduced-order model of 82Rb dynamic PET data can be used effectively to compare myocardial blood-flow rates at rest and stress levels. The two-compartment model can differentiate flow only if a priori values are used for nonflow parameters.

Kinetic analysis of rubidium and thallium as deposited myocardial blood flow tracers in isolated rabbit heart.

Evaluation of myocardial perfusion with tracers such as thallium and rubidium is based on the assumption that tissue tracer content is proportional to flow. The purpose of this study was to evaluate the relationship between flow and tissue tracer content of 201Tl and 83Rb in the isolated perfused rabbit heart. 83Rb (86-day half-life), an isotope that is not used clinically, was used as a subsitute for 82Rb (76-s half-life) to improve the accuracy and precision of data acquisition. The multiple indicator-dilution technique was employed with two independent computational approaches. The first approach explicitly deconvolved 201Tl and 83Rb venous concentration curves by the intravascular reference tracer curve. The second approach used a conventional analysis. Both approaches showed that there was more early washout of 83Rb than 201Tl and that the heart retained 201Tl better than 83Rb within 2 min after isotope introduction. These data indicate that 201Tl is a better perfusion tracer than 83Rb in the isolated rabbit heart.

Equivalent methods to analyse dynamic experiments in which the input function is noisy.

A comparison is made between two methods of parameter estimation for analysis of dynamic experiments in which the input function is noisy. Noise in the input function leads to uncertainties in the calculated model-predicted values, and therefore the covariance matrix of the residuals is a function of the model parameters. Statistical uncertainties in the model-predicted values significantly change the nature of the fitting process and the quality of the results. The initial method uses a weighted least-squares criterion where the weighting matrix is the inverse of the full covariance matrix of the residuals, incorporating both the noise in the output data and the noise in the input function. The methodology was applied to dynamic emission tomography studies of the heart, where the blood (input) and tissue (output) tracer concentrations at each time are derived from two regions of interest in the same tomographic section. The second method introduces additional parameters to describe the input function, and adds terms to the weighted sum of squares which comprise the criterion. Instead of only summing the weighted terms to account for differences between the model and the output function, there is a second set of terms to account for the differences between the model and the input function. The two methods have different theoretical bases and appear to optimize different criteria, but it is shown here that they are equivalent to one another. The criterion which they minimize is the same under certain matrix invertibility constraints, which must be satisfied to ensure the stability of either method.

Strategies for extraction of quantitative data from volumetric dynamic cardiac positron emission tomography data.

The ability of positron emission tomography (PET) to serve as a useful myocardial perfusion indicator is well established. We describe a methodology for obtaining reliable quantitative kinetic parameters from dynamic cardiac PET data. Reconstructed images of the myocardium are subdivided into three-dimensional volumes of interest which are used to obtain quantitative measures of myocardial perfusion over physiologically meaningful anatomical regions. The quantitation technique rigorously models the uncertainty of estimated parameters while compensating for effects such as patient motion and partial volumes to arrive at model parameters with well-established confidence intervals.

Temporal lobe metabolic differences in medication-free outpatients with schizophrenia via the PET-600.

Regional cerebral glucose metabolic rates (rCMRglc) were compared in 18 unmedicated outpatients with schizophrenia and 11 normal controls using high resolution positron emission tomography (PET) and the tracer [F-18]-2-fluoro-2D-deoxyglucose (FDG). From previous work we expected to see abnormal hippocampal rCMRglc in the patients, but no striatal abnormalities. Trial-by-trial Stroop cognitive task, which has been shown to activate the anterior cingulate, was performed within a day of the PET study. As our patients performed abnormally on the Stroop we tested for a correlation between the anterior cingulate rCMRglc and Stroop performance. We found no whole slice cortical average glucose metabolic abnormalities. As, predicted we found abnormally decreased left hippocampal rCMRglc in the patients. No striatal or cingulate rCMRglc abnormalities were noted in patients, but they demonstrated a highly positive correlation between anterior and cingulate rCMRglc and Stroop facilitation. Patients with higher Stroop interference had more prominent hippocampal metabolic decreases. These localized temporal lobe abnormalities could account for some of the patient's positive symptoms and are consistent with recent findings in the literature.

Variability and reproducibility of rubidium-82 kinetic parameters in the myocardium of the anesthetized canine.

UNLABELLED: Kinetic analysis of 82Rb dynamic PET data produces quantitative measures which could be used to evaluate ischemic heart disease. These measures have the potential to generate objective comparisons of different patients or the same patient at different times. To achieve this potential, it is essential to determine the variability and reproducibility of the kinetic parameters. METHODS: A total of 48 82Rb dynamic PET datasets were acquired from two pure bred beagles. Each animal underwent eight 82Rb PET studies with essentially the same protocol for three successive weeks. Data were acquired with the Donner 600-Crystal Positron Tomograph (PET600). In each week, single-slice dynamic 82Rb PET datasets were collected with the animal at rest at three different gantry positions separated by 5 mm. Additional dataset were collected after dipyridamole infusion and after administration of aminophylline to induce a return to rest. A two-compartment kinetic model with correction for myocardial vasculature and spillover from the left ventricular blood pool was used to analyze the dynamic datasets. Model parameters for uptake (k1), washout (k2) and vascular fraction (fv) were estimated in 11-14 myocardial regions of interest (ROIs) using a weighted least-squares criterion. Statistical fluctuation due to the PET acquisition process was minimized by using a relatively high 82Rb dose (about 30 mCi) to take advantage of the high count rate capacity of the PET600. RESULTS: The variation in mean k1, where the mean is taken over the myocardial ROIs was 10%-20% (Dog 1) and 15%-50% (Dog 2) among the rest studies conducted on the same date. Similar variation was evident in comparing studies in the same animal for different weeks. CONCLUSION: Spatial and temporal variation in estimates of the uptake rate (k1) of 82Rb in the resting myocardium of the anesthetized canine are small in relation to the functional increase in k1 following dipyridamole infusion.

Mechanical inventiveness: a three-phase study.

This paper focuses on mechanical inventiveness, the conception and development of new devices which require use of mechanical principles. In Phase 1 of the three-phase investigation, we studied 34 inventors who received between three and 82 agricultural and industrial patents. These inventors formed the original criterion group of mechanical inventors. Phase 2 of the investigation was the development of an inventiveness measure. From the criterion group of adult mechanical inventors, the Iowa Inventiveness Inventory (III) was developed to measure attitudes and characteristics of inventors. Subjects for Phase 3 of the study were 90 young inventors (40 males, 50 females), students (grades five to eight) who won local and regional invention contests and reached the state convention of Invent Iowa. In Phase 3, Invent Iowa state finalists in grades five to eight (n = 90) were administered the III and the Mechanical Reasoning test of the Differential Aptitude Tests. Characteristics of the young inventors, as delineated by these assessments, are provided.