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Item does not contain fulltext INTRODUCTION: (188)Rhenium-HEDP is an effective bone-targeting therapeutic radiopharmaceutical, for treatment of osteoblastic bone metastases. It is known that the presence of carrier (non-radioactive rhenium as ammonium perrhenate) in the reaction mixture during labeling is a prerequisite for adequate bone affinity, but little is known about the optimal carrier concentration. METHODS: We investigated the influence of carrier concentration in the formulation on the radiochemical purity, in-vitro hydroxyapatite affinity and the in-vivo bone accumulation of (188)Rhenium-HEDP in mice. RESULTS: The carrier concentration influenced hydroxyapatite binding in-vitro as well as bone accumulation in-vivo. Variation in hydroxyapatite binding with various carrier concentrations seemed to be mainly driven by variation in radiochemical purity. The in-vivo bone accumulation appeared to be more complex: satisfactory radiochemical purity and hydroxyapatite affinity did not necessarily predict acceptable bio-distribution of (188)Rhenium-HEDP. CONCLUSIONS: For development of new bisphosphonate-based radiopharmaceuticals for clinical use, human administration should not be performed without previous animal bio-distribution experiments. Furthermore, our clinical formulation of (188)Rhenium-HEDP, containing 10 mumol carrier, showed excellent bone accumulation that was comparable to other bisphosphonate-based radiopharmaceuticals, with no apparent uptake in other organs. ADVANCES IN KNOWLEDGE: Radiochemical purity and in-vitro hydroxyapatite binding are not necessarily predictive of bone accumulation of (188)Rhenium-HEDP in-vivo. IMPLICATIONS FOR PATIENT CARE: The formulation for (188)Rhenium-HEDP as developed by us for clinical use exhibits excellent bone uptake and variation in carrier concentration during preparation of this radiopharmaceutical should be avoided.

PET imaging of rodents is increasingly used in preclinical research, but its utility is limited by spatial resolution and signal-to-noise ratio of the images. A recently developed preclinical PET system uses a clustered-pinhole collimator, enabling high-resolution, simultaneous imaging of PET and SPECT tracers. Pinhole collimation strongly departs from traditional electronic collimation achieved via coincidence detection in PET. We investigated the potential of such a design by direct comparison to a traditional PET scanner.Two small-animal PET scanners, 1 with electronic collimation and 1 with physical collimation using clustered pinholes, were used to acquire data from Jaszczak (hot rod) and uniform phantoms. Mouse brain imaging using (18)F-FDG PET was performed on each system and compared with quantitative ex vivo autoradiography as a gold standard. Bone imaging using (18)F-NaF allowed comparison of imaging in the mouse body. Images were visually and quantitatively compared using measures of contrast and noise.Pinhole PET resolved the smallest rods (diameter, 0.85 mm) in the Jaszczak phantom, whereas the coincidence system resolved 1.1-mm-diameter rods. Contrast-to-noise ratios were better for pinhole PET when imaging small rods (1.1 mm) for a wide range of activity levels, but this reversed for larger rods. Image uniformity on the coincidence system (3%) was superior to that on the pinhole system (5%). The high (18)F-FDG uptake in the striatum of the mouse brain was fully resolved using the pinhole system, with contrast to nearby regions equaling that from autoradiography; a lower contrast was found using the coincidence PET system. For short-duration images (low-count), the coincidence system was superior.In the cases for which small regions need to be resolved in scans with reasonably high activity or reasonably long scan times, a first-generation clustered-pinhole system can provide image quality in terms of resolution, contrast, and the contrast-to-noise ratio superior to a traditional PET system.

Scintillation gamma cameras based on low-noise electron multiplication (EM-)CCDs can reach high spatial resolutions. For further improvement of these gamma cameras, more insight is needed into how various parameters that characterize these devices influence their performance. Here, we use the Cramer-Rao lower bound (CRLB) to investigate the sensitivity of the energy and spatial resolution of an EM-CCD-based gamma camera to several parameters. The gamma camera setup consists of a 3 mm thick CsI(Tl) scintillator optically coupled by a fiber optic plate to the E2V CCD97 EM-CCD. For this setup, the position and energy of incoming gamma photons are determined with a maximum-likelihood detection algorithm. To serve as the basis for the CRLB calculations, accurate models for the depth-dependent scintillation light distribution are derived and combined with a previously validated statistical response model for the EM-CCD. The sensitivity of the lower bounds for energy and spatial resolution to the EM gain and the depth-of-interaction (DOI) are calculated and compared to experimentally obtained values. Furthermore, calculations of the influence of the number of detected optical photons and noise sources in the image area on the energy and spatial resolution are presented. Trends predicted by CRLB calculations agree with experiments, although experimental values for spatial and energy resolution are typically a factor of 1.5 above the calculated lower bounds. Calculations and experiments both show that an intermediate EM gain setting results in the best possible spatial or energy resolution and that the spatial resolution of the gamma camera degrades rapidly as a function of the DOI. Furthermore, calculations suggest that a large improvement in gamma camera performance is achieved by an increase in the number of detected photons or a reduction of noise in the image area. A large noise reduction, as is possible with a new generation of EM-CCD electronics, may improve the energy and spatial resolution by a factor of 1.5.

Understanding how nanoparticle properties such as size, morphology and rigidity influence their circulation time and biodistribution is essential for the development of nanomedicine therapies. Herein we assess the influence of morphology on cellular internalization, in vivo biodistribution and circulation time of nanocarriers using polystyrene-b-poly(ethylene oxide) micelles of spherical or elongated morphology. The glassy nature of polystyrene guarantees the morphological stability of the carriers in vivo and by encapsulating Indium-111 in their core, an assessment of the longitudinal in vivo biodistribution of the particles in healthy mice is performed with single photon emission computed tomography imaging. Our results show prolonged blood circulation, longer than 24 hours, for all micelle morphologies studied. Dynamics of micelle accumulation in the liver and other organs of the reticuloendothelial system show a size-dependent nature and late stage liver clearance is observed for the elongated morphology. Apparent contradictions between recent similar studies can be resolved by considering the effects of flexibility and degradation of the elongated micelles on their circulation time and biodistribution.

The recently developed versatile emission computed tomography (VECTor) technology enables high-energy SPECT and simultaneous SPECT and PET of small animals at sub-mm resolutions. VECTor uses dedicated clustered pinhole collimators mounted in a scanner with three stationary large-area NaI(Tl) gamma detectors. Here, we develop and validate dedicated image reconstruction methods that compensate for image degradation by incorporating accurate models for the transport of high-energy annihilation gamma photons. Ray tracing software was used to calculate photon transport through the collimator structures and into the gamma detector. Input to this code are several geometric parameters estimated from system calibration with a scanning 99mTc point source. Effects on reconstructed images of (i) modelling variable depth-of-interaction (DOI) in the detector, (ii) incorporating photon paths that go through multiple pinholes ('multiple-pinhole paths' (MPP)), and (iii) including various amounts of point spread function (PSF) tail were evaluated. Imaging 18F in resolution and uniformity phantoms showed that including large parts of PSFs is essential to obtain good contrast-noise characteristics and that DOI modelling is highly effective in removing deformations of small structures, together leading to 0.75 mm resolution PET images of a hot-rod Derenzo phantom. Moreover, MPP modelling reduced the level of background noise. These improvements were also clearly visible in mouse images. Performance of VECTor can thus be significantly improved by accurately modelling annihilation gamma photon transport.

Introduction High-resolution pre-clinical 131 I SPECT can facilitate development of new radioiodine therapies for cancer. To this end, it is important to limit resolution-degrading effects of pinhole edge penetration by the high-energy γ-photons of iodine. Here we introduce, optimize and validate 131 I SPECT performed with a dedicated high-energy clustered multi-pinhole collimator. Methods A SPECT–CT system (VECTor/CT) with stationary gamma-detectors was equipped with a tungsten collimator with clustered pinholes. Images were reconstructed with pixel-based OSEM, using a dedicated 131 I system matrix that models the distance- and energy-dependent resolution and sensitivity of each pinhole, as well as the intrinsic detector blurring and variable depth of interaction in the detector. The system performance was characterized with phantoms and in vivo static and dynamic 131 I-NaI scans of mice. Results Reconstructed image resolution reached 0.6mm, while quantitative accuracy measured with a 131 I filled syringe reaches an accuracy of +3.6±3.5% of the gold standard value. In vivo mice scans illustrated a clear shape of the thyroid and biodistribution of 131 I within the animal. Pharmacokinetics of 131 I was assessed with 15-s time frames from the sequence of dynamic images and time–activity curves of 131 I-NaI. Conclusions High-resolution quantitative and fast dynamic 131 I SPECT in mice is possible by means of a high-energy collimator and optimized system modeling. This enables analysis of 131 I uptake even within small organs in mice, which can be highly valuable for development and optimization of targeted cancer therapies.

Optimal biodistribution and prolonged circulation of nanocarriers improve diagnostic and therapeutic effects of enhanced permeability and retention-based nanomedicines. Despite extensive use of Pluronics in polymer-based pharmaceuticals, the influence of different poly(ethylene oxide) (PEO) block length and aggregation state on the biodistribution of the carriers is rather unexplored. In this work, we studied these effects by evaluating the biodistribution of Pluronic unimers and cross-linked micelles with different PEO block size. In vivo biodistribution of 111In-radiolabeled Pluronic nanocarriers was investigated in healthy mice using single photon emission computed tomography. All carriers show fast uptake in the organs from the reticuloendothelial system followed by a steady elimination through the hepatobiliary tract and renal filtration. The PEO block length affects the initial renal clearance of the compounds and the overall liver uptake. The aggregation state influences the long-term accumulation of the nanocarriers in the liver. We showed that the circulation time and elimination pathways can be tuned by varying the physicochemical properties of Pluronic copolymers. Our results can be beneficial for the design of future Pluronic-based nanomedicines.

High spatial resolution γ-imaging can be achieved with scintillator readout by low-noise, fast, electron-multiplying charge-coupled devices (EMCCDs). Previously we have shown that false-positive events due to EMCCD noise can be rejected by using the sum signal from silicon photomultipliers (SiPMs) mounted on the sides of the scintillator. Here we launch a next generation hybrid CCD-SiPM camera that utilizes the individual SiPM signals and maximum likelihood estimation (MLE) pre-localization of events to discriminate between true and false events in CCD frames. In addition, SiPM signals are utilized for improved energy discrimination. The performance of this hybrid detector was tested for a continuous CsI:Tl crystal at 140 keV. With a pre-localization accuracy of 1.06 mm (full-width-at-half-maximum) attained with MLE the signal-to-background ratio (SBR) was improved by a factor of 5.9, 4.0 or 2.2 compared to the EMCCD-only readout, at the cost of rejecting, respectively, 47%, 9% or 4% of the events. Combining the pre-localization and SiPM energy estimation improved the energy resolution from 50% to (19 ± 3)% while maintaining the spatial resolution at 180 µm.

Detection of x-rays and gamma rays with high spatial resolution can be achieved with scintillators that are optically coupled to electron-multiplying charge-coupled devices (EMCCDs). These can be operated at typical frame rates of 50 Hz with low noise. In such a set-up, scintillation light within each frame is integrated after which the frame is analyzed for the presence of scintillation events. This method allows for the use of scintillator materials with relatively long decay times of a few milliseconds, not previously considered for use in photon-counting gamma cameras, opening up an unexplored range of dense scintillators. In this paper, we test CdWO₄ and transparent polycrystalline ceramics of Lu₂O₃:Eu and (Gd,Lu)₂O₃:Eu as alternatives to currently used CsI:Tl in order to improve the performance of EMCCD-based gamma cameras. The tested scintillators were selected for their significantly larger cross-sections at 140 keV ((99m)Tc) compared to CsI:Tl combined with moderate to good light yield. A performance comparison based on gamma camera spatial and energy resolution was done with all tested scintillators having equal (66%) interaction probability at 140 keV. CdWO₄, Lu₂O₃:Eu and (Gd,Lu)₂O₃:Eu all result in a significantly improved spatial resolution over CsI:Tl, albeit at the cost of reduced energy resolution. Lu₂O₃:Eu transparent ceramic gives the best spatial resolution: 65 µm full-width-at-half-maximum (FWHM) compared to 147 µm FWHM for CsI:Tl. In conclusion, these 'slow' dense scintillators open up new possibilities for improving the spatial resolution of EMCCD-based scintillation cameras.

Small-animal SPECT systems with stationary detectors and focusing multiple pinholes can achieve excellent resolution-sensitivity trade-offs. These systems are able to perform fast total-body scans by shifting the animal bed through the collimator using an automated xyz stage. However, so far, a large number of highly overlapping central fields of view have been used, at the cost of overhead time needed for animal repositioning and long image reconstruction times due to high numbers of projection views.To improve temporal resolution and reduce image reconstruction time for such scans, we have developed and tested spiral trajectories (STs) of the animal bed requiring fewer steps. In addition, we tested multiplane trajectories (MPTs) of the animal bed, which is the standard acquisition method of the U-SPECT-II system that is used in this study. Neither MPTs nor STs require rotation of the animal. Computer simulations and physical phantom experiments were performed for a wide range of numbers of bed positions. Furthermore, we tested STs in vivo for fast dynamic mouse scans.We found that STs require less than half the number of bed positions of MPTs to achieve sufficient sampling. The reduced number of bed positions made it possible to perform a dynamic total-body bone scan and a dynamic hepatobiliary scan with time resolutions of 60 s and 15 s, respectively.STs open up new possibilities for high throughput and fast dynamic radio-molecular imaging.

Ultra-high-resolution SPECT images can be obtained with focused multipinhole collimators. Here we investigate the influence of unwanted high tracer uptake outside the scan volume on reconstructed tracer distributions inside the scan volume, for (99m)Tc-tetrofosmin myocardial perfusion scanning in mice. Simulated projections of a digital mouse phantom (MOBY) in a focusing multipinhole SPECT system (U-SPECT-II, MILabs, The Netherlands) were generated. With this system differently sized user-defined scan volumes can be selected, by translating the animal in 3D through the focusing collimators. Scan volume selections were set to (i) a minimal volume containing just the heart, acquired without translating the animal during scanning, (ii) a slightly larger scan volume as is typically applied for the heart, requiring only small XYZ translations during scanning, (iii) same as (ii), but extended further transaxially, and (iv) same as (ii), but extended transaxially to cover the full thorax width (gold standard). Despite an overall negative bias that is significant for the minimal scan volume, all selected volumes resulted in visually similar images. Quantitative differences in the reconstructed myocardium between gold standard and the results from the smaller scan volume selections were small; the 17 standardized myocardial segments of a bull's eye plot, normalized to the myocardial mean of the gold standard, deviated on average 6.0%, 2.5% and 1.9% for respectively the minimal, the typical and the extended scan volume, while maximum absolute deviations were respectively 18.6%, 9.0% and 5.2%. Averaged over ten low-count noisy simulations, the mean absolute deviations were respectively 7.9%, 3.2% and 1.9%. In low-count noisy simulations, the mean and maximum absolute deviations for the minimal scan volume could be reduced to respectively 4.2% and 12.5% by performing a short survey scan of the exterior activity and focusing the remaining scan time at the organ of interest. We conclude that reconstructed tracer distribution in the myocardium can be influenced by activity in surrounding organs when a too narrow scan volume is used. With slightly larger scan volumes this problem is adequately suppressed. This approach produced a smaller mean deviation and may be more effective than employing a narrow scan volume with an additional survey scan.

Introduction: Ex vivo storage phosphor imaging rat studies reported increased brain dopamine D-2/3 receptor (DRD2/3) availability following treatment with varenicline, a nicotinergic drug. However, ex vivo studies can only be performed using cross-sectional designs. Small-animal imaging offers the opportunity to perform serial assessments. We evaluated whether high-resolution pinhole single photon emission computed tomography (SPECT) imaging in rats was able to reproduce previous ex vivo findings. Methods: Rats were imaged for baseline striatal DRD2/3 availability using ultra-high-resolution pinhole SPECT (U-SPECT-II) and [I-123] IBZM as a radiotracer, and randomized to varenicline (n=7; 2 mg/kg) or saline (n=7). Following 2 weeks of treatment, a second scan was acquired. Results: Significantly increased striatal DRD2/3 availability was found following varenicline treatment compared to saline (time*treatment effect): posttreatment difference in binding potential between groups corrected for initial baseline differences was 2.039 (P=.022), indicating a large effect size (d=1.48). Conclusions: Ultra-high-resolution pinhole SPECT can be used to assess varenicline-induced changes in DRD2/3 availability in small laboratory animals over time. Future small-animal studies should include imaging techniques to enable repeated within-subjects measurements and reduce the amount of animals. (C) 2012 Elsevier Inc. All rights reserved

At present, generally accepted standards to characterize small-animal single photon emission tomographs (SPECT) do not exist. Whereas for small-animal positron emission tomography (PET), the NEMA NU 4-2008 guidelines are available, such standards are still lacking for small-animal SPECT. More specifically, a dedicated image quality (IQ) phantom and corresponding IQ parameters are absent. The structures of the existing PET IQ phantom are too large to fully characterize the sub-millimeter spatial resolution of modern multi-pinhole SPECT scanners, and its diameter will not fit into all scanners when operating in high spatial resolution mode. We therefore designed and constructed an adapted IQ phantom with smaller internal structures and external diameter, and a facility to guarantee complete filling of the smallest rods. The associated IQ parameters were adapted from NEMA NU 4. An additional parameter, effective whole-body sensitivity, was defined since this was considered relevant in view of the variable size of the field of view and the use of multiple bed positions as encountered in modern small-animal SPECT scanners. The usefulness of the phantom was demonstrated for 99m Tc in a USPECT-II

Gamma cameras based on charge-coupled devices (CCDs) coupled to continuous scintillation crystals can combine a good detection efficiency with high spatial resolutions with the aid of advanced scintillation detection algorithms. A previously developed analytical multi-scale algorithm (MSA) models the depth-dependent light distribution but does not take statistics into account. Here we present and validate a novel statistical maximum-likelihood algorithm (MLA) that combines a realistic light distribution model with an experimentally validated statistical model. The MLA was tested for an electron multiplying CCD optically coupled to CsI(Tl) scintillators of different thicknesses. For (99m)Tc imaging, the spatial resolution (for perpendicular and oblique incidence), energy resolution and signal-to-background counts ratio (SBR) obtained with the MLA were compared with those of the MSA. Compared to the MSA, the MLA improves the energy resolution by more than a factor of 1.6 and the SBR is enhanced by more than a factor of 1.3. For oblique incidence (approximately 45°), the depth-of-interaction corrected spatial resolution is improved by a factor of at least 1.1, while for perpendicular incidence the MLA resolution does not consistently differ significantly from the MSA result for all tested scintillator thicknesses. For the thickest scintillator (3 mm, interaction probability 66% at 141 keV) a spatial resolution (perpendicular incidence) of 147 µm full width at half maximum (FWHM) was obtained with an energy resolution of 35.2% FWHM. These results of the MLA were achieved without prior calibration of scintillations as is needed for many statistical scintillation detection algorithms. We conclude that the MLA significantly improves the gamma camera performance compared to the MSA.

Several new methods for determining the depth of interaction (DOI) of annihilation photons in monolithic scintillator detectors with single-sided, multi-pixel readout are investigated. The aim is to develop a DOI decoding method that allows for practical implementation in a positron emission tomography system. Specifically, calibration data, obtained with perpendicularly incident gamma photons only, are being used. Furthermore, neither detector modifications nor a priori knowledge of the light transport and/or signal variances is required. For this purpose, a clustering approach is utilized in combination with different parameters correlated with the DOI, such as the degree of similarity to a set of reference light distributions, the measured intensity on the sensor pixel(s) closest to the interaction position and the peak intensity of the measured light distribution. The proposed methods were tested experimentally on a detector comprised of a 20 mm x 20 mm x 12 mm polished LYSO: Ce crystal coupled to a 4 x 4 multi-anode photomultiplier. The method based on the linearly interpolated measured intensities on the sensor pixels closest to the estimated (x, y)-coordinate outperformed the other methods, yielding DOI resolutions between similar to 1 and similar to 4.5 mm FWHM depending on the DOI, the (x, y) resolution and the amount of reference data used.

Pinhole SPECT often provides an excellent resolution sensitivity trade-off for radionuclide imaging compared to SPECT with parallel holes, particularly when imaging small experimental animals like rodents. High absorption pinhole materials are often chosen because of their low edge penetration and therefore good system resolution. Capturing more photons in the edges however results in decreased system sensitivity if the pinhole diameter remains the same, which may partly undo the beneficial effect on the resolution. In the search for an optimal trade-off we have compared pinhole projection data and reconstructed images of different materials with pinhole aperture diameters adjusted to obtain equal sensitivity. Monte Carlo calculations modeling the transmission, penetration and scattering of gamma radiation in single pinholes of uranium, gold, tungsten and lead were performed for a range of pinhole opening angles, diameters and gamma ray energies. In addition, reconstructed images of a hot rod phantom were determined for a multipinhole SPECT system and for a system that can image the 511 keV annihilation photons of positron emitting tracers with clustered pinholes. Our results indicate that, under the condition of equal sensitivity, tungsten and for SPECT also lead pinholes perform just as well as gold and uranium ones, indicating that a significant cost reduction can be achieved in pinhole collimator manufacturing while the use of rare or impractical materials can be avoided.

Purpose: Small-animal single photon emission computed tomography (SPECT) with focused multi-pinhole collimation geometries allows scanning modes in which large amounts of photons can be collected from specific volumes of interest. Here we present new tools that improve targeted imaging of specific organs and tumours, and validate the effects of improved targeting of the pinhole focus. Methods: A SPECT system with 75 pinholes and stationary detectors was used (U-SPECT-II). An XYZ stage automatically translates the animal bed with a specific sequence in order to scan a selected volume of interest. Prior to stepping the animal through the collimator, integrated webcams acquire images of the animal. Using sliders, the user designates the desired volume to be scanned (e.g. a xenograft or specific organ) on these optical images. Optionally projections of an atlas are overlaid semiautomatically to locate specific organs. In order to assess the effects of more targeted imaging, scans of a resolution phantom and a mouse myocardial phantom, as well as in vivo mouse cardiac and tumour scans, were acquired with increased levels of targeting. Differences were evaluated in terms of count yield, hot rod visibility and contrast-to-noise ratio. Results: By restricting focused SPECT scans to a 1.13-ml resolution phantom, count yield was increased by a factor 3.6, and visibility of small structures was significantly enhanced. At equal noise levels, the small-lesion contrast measured in the myocardial phantom was increased by 42%. Noise in in vivo images of a tumour and the mouse heart was significantly reduced. Conclusion: Targeted pinhole SPECT improves images and can be used to shorten scan times. Scan planning with optical cameras provides an effective tool to exploit this principle without the necessity for additional X-ray CT imaging.

PURPOSE: Previously, we demonstrated the potential of positron emission tomography detectors consisting of monolithic scintillation crystals read out by arrays of solid-state light sensors. We reported detector spatial resolutions of 1.1-1.3 mm full width at half maximum (FWHM) with no degradation for angles of incidence up to 30 degrees, energy resolutions of approximately 11% FWHM, and timing resolutions of approximately 2 ns FWHM, using monolithic LYSO:Ce3+ crystals coupled to avalanche photodiode (APD) arrays. Here we develop, validate, and demonstrate a simple model of the detector point spread function (PSF) of such monolithic scintillator detectors. METHODS: A PSF model was developed that essentially consists of two convolved components, one accounting for the spatial distribution of the energy deposited by annihilation photons within the crystal, and the other for the influences of statistical signal fluctuations and electronic noise. The model was validated through comparison with spatial resolution measurements on a detector consisting of an LYSO:Ce3+ crystal read out by two APD arrays. RESULTS: The model is shown to describe the measured detector spatial response well at the noise levels found in the experiments. In addition, it is demonstrated how the model can be used to correct the measured spatial response for the influence of the finite diameter of the annihilation photon beam used in the experiments, thus obtaining an estimate of the intrinsic detector PSF. CONCLUSIONS: Despite its simplicity, the proposed model is an accurate tool for analyzing the detector PSF of monolithic scintillator detectors and can be used to estimate the intrinsic detector PSF from the measured one.

Block-iterative image reconstruction methods, such as ordered subset expectation maximization (OSEM), are commonly used to accelerate image reconstruction. In OSEM, the speed-up factor over maximum likelihood expectation maximization (MLEM) is approximately equal to the number of subsets in which the projection data are divided. Traditionally, each subset consists of a couple of projection views, and the more subsets are used, the more the solution deviates from MLEM solutions. We found for multi-pinhole single photon emission computed tomography (SPECT) that even moderate acceleration factors in OSEM lead to inaccurate reconstructions. Therefore, we introduce pixel-based ordered subset expectation maximization (POSEM), which is based on an alternative subset choice. Pixels in each subset are spread out regularly over projections and are spatially separated as much as possible. We validated POSEM for data acquired with a focusing multi-pinhole SPECT system. Performance was compared with traditional OSEM and MLEM for a rat total body bone scan, a gated mouse myocardial perfusion scan and a Defrise phantom scan. We found that POSEM can be operated at acceleration factors that are often an order of magnitude higher than in traditional OSEM.

Preclinical cardiovascular research using noninvasive radionuclide and hybrid imaging systems has been extensively developed in recent years. Single photon emission computed tomography (SPECT) is based on the molecular tracer principle and is an established tool in noninvasive imaging. SPECT uses gamma cameras and collimators to form projection data that are used to estimate (dynamic) 3-D tracer distributions in vivo. Recent developments in multipinhole collimation and advanced image reconstruction have led to sub-millimetre and sub-half-millimetre resolution SPECT in rats and mice, respectively. In this article we review applications of microSPECT in cardiovascular research in which information about the function and pathology of the myocardium, vessels and neurons is obtained. We give examples on how diagnostic tracers, new therapeutic interventions, pre- and postcardiovascular event prognosis, and functional and pathophysiological heart conditions can be explored by microSPECT, using small-animal models of cardiovascular disease.

Item does not contain fulltext Much research is being conducted on position-sensitive scintillation detectors for medical imaging, particularly for emission tomography. Monte Carlo simulations play an essential role in many of these research activities. As the scintillation process, the transport of scintillation photons through the crystal(s), and the conversion of these photons into electronic signals each have a major influence on the detector performance; all of these processes may need to be incorporated in the model to obtain accurate results. In this work the optical and scintillation models of the GEANT4 simulation toolkit are validated by comparing simulations and measurements on monolithic scintillator detectors for high-resolution positron emission tomography (PET). We have furthermore made the GEANT4 optical models available within the user-friendly GATE simulation platform (as of version 3.0). It is shown how the necessary optical input parameters can be determined with sufficient accuracy. The results show that the optical physics models of GATE/GEANT4 enable accurate prediction of the spatial and energy resolution of monolithic scintillator PET detectors.

With the steadily improving resolution of novel small-animal single photon emission computed tomography (SPECT) and positron emission tomography devices, highly detailed phantoms are required for testing and optimizing these systems. We present a three-dimensional (3-D) digital and physical phantom pair to represent, e. g., cerebral blood flow, glucose metabolism, or neuroreceptor binding in small regions of the rat brain. The anatomical structures are based on digital photographs of the uncut part of a rat brain cryosection block. The photographs have been segmented into ventricles and gray and white matter and have been stacked afterwards. In the resulting voxelized digital phantom, tracer concentration in gray and white matter can be scaled independently. This is of relevance since, e. g., cerebral blood flow or metabolism are much higher in gray than in white matter. The physical phantom is based on the digital phantom and has been manufactured out of hardened polymer using rapid prototyping, a process in which complicated 3-D objects can be built up layer by layer. X-ray computed tomography and high-resolution SPECT images of the physical phantom are compared with the digital phantom. The detailed physical phantom can be filled bubble-free. Excellent correspondence is shown between details in the digital and physical phantom. Therefore, this newly developed brain phantom will enable the optimization of high-resolution imaging for recovery of complex shaped molecular distributions

We have investigated the timing performance of Hamamatsu Multi-Pixel Photon Counter (MPPC) photosensors in light of their use in time-of-flight (TOF) positron emission tomography detectors. Measurements using picosecond laser pulses show a single photo-electron root-mean-square (RMS) timing resolution down to about 100ps. In coincidences of 511 keV photons detected with an LYSO crystal coupled to a MPPC and a BaF(2) detector, an optimum FWHM timing resolution of 600ps was obtained with leading edge time pickoff at the 1-1.5 photo-electron level. By optimizing the LYSO/MPPC coupling, this can be improved by a factor of 2. We further conclude that the use of stored digitized pulses allows great flexibility and efficiency in developing data analysis algorithms. (C) 2009 Elsevier B.V. All rights reserved.

We present a new rodent SPECT system (U-SPECT-II) that enables molecular imaging of murine organs down to resolutions of less than half a millimeter and high-resolution total-body imaging. Methods: The U-SPECT-II is based on a triangular stationary detector set-up, an XYZ stage that moves the animal during scanning, and interchangeable cylindric collimators (each containing 75 pinhole apertures) for both mouse and rat imaging. A novel graphical user interface incorporating preselection of the field of view with the aid of optical images of the animal focuses the pinholes to the area of interest, thereby maximizing sensitivity for the task at hand. Images are obtained from list mode data using statistical reconstruction that takes system blurring into account to increase resolution. Results: For 99mTc, resolutions determined with capillary phantoms were smaller than 0.35 and 0.45 mm using the mouse collimator with 0.35- and 0.6-mm pinholes, respectively, and less than 0.8mm using the rat collimator with 1.0-mm pinholes. Peak geometric sensitivity is 0.07% and 0.18% for the mouse collimator with 0.35- and 0.6-mm pinholes, respectively, and 0.09% for the rat collimator. Resolution with 111In, compared with that with 99mTc, was barely degraded, and resolution with 125I was degraded by about 10%, with some additional distortion. In vivo, kidney, tumor, and bone images illustrated that U-SPECT-II could be used for novel applications in the study of dynamic biologic systems and radiopharmaceuticals at the suborgan level. Conclusion: Images and movies obtained with U-SPECT-II provide high-resolution radiomolecule visualization in rodents. Discrimination of molecule concentrations between adjacent volumes of about 0.04 µL in mice and 0.5 µL in rats with U-SPECT-II is readily possible.

To define the physical and clinical reproducibility of (201)Tl myocardial perfusion SPECT (MPS), this study assesses the variation between two repeated rest (201)Tl MPS with repositioning only, with a two-hour time interval and with phantom measurements as a reference.Three anthropomorphic thorax phantoms were filled with (201)Tl. For each phantom five repeated (201)Tl MPS were obtained. In addition, in 20 patients repeated (201)Tl rest-MPS and in 26 patients early and delayed (201)Tl rest-MPS were performed. Quantitative analysis was done using MunichHeart. Statistical methods were used to calculate variability. Visual analysis was performed by 2 independent observers.The average variation between repeated phantom MPS was 0.5% (95% confidence interval (CI): -0.4% to 1.4%). For patient scans this was -5.0% (95% CI: -2.5% to -7.5%) and between early and delayed (201)Tl MPS -15.5% (95% CI: -11.7% to -19.3%). Visual assessment revealed no clinical significant differences between rest (201)Tl and repeated or delayed (201)Tl MPS.Repositioning in phantom (201)Tl MPS does not cause significant variation. Repeated (201)Tl MPS in patients shows 5.0% decrease of (201)Tl in 30 minutes, which increases to 15% during a two-hour time interval without quantitative or visual regional differences. This decrease indicates a time-related washout of (201)Tl, but does not change clinical diagnosis.

Gamma cameras based on charge-coupled devices (CCDs) and micro-columnar CsI scintillators can reach high spatial resolutions. However, the gamma interaction probability of these scintillators is low (typically30% at 141 keV) due to the limited thickness of presently available micro-columnar scintillators. Continuous scintillators can improve the interaction probability but suffer from increased light spread compared to columnar scintillators. In addition, for both types of scintillators, gamma photons incident at an oblique angle reduce the spatial resolution due to the variable depth of interaction (DOI). To improve the spatial resolution and spectral characteristics of these detectors, we have developed a fast analytic scintillation detection algorithm that makes use of a depth-dependent light spread model and as a result is able to estimate the DOI in the scintillator. This algorithm, performing multi-scale frame analysis, was tested for an electron multiplying CCD (EM-CCD) optically coupled to CsI(Tl) scintillators of different thicknesses. For the thickest scintillator (2.6 mm) a spatial resolution of 148 microm full width half maximum (FWHM) was obtained with an energy resolution of 46% FWHM for perpendicularly incident gamma photons (interaction probability 61% at 141 keV). The multi-scale algorithm improves the spatial resolution up to 11%, the energy resolution up to 36% and the signal-to-background counts ratio up to 46% compared to a previously implemented algorithm that did not model the depth-dependent light spread. In addition, the multi-scale algorithm can accurately estimate DOI. As a result, degradation of the spatial resolution due to the variable DOI for gamma photons incident at a 45 degrees angle was improved from 2.0 10(3) to 448 microm FWHM. We conclude that the multi-scale algorithm significantly improves CCD-based gamma cameras as can be applied in future SPECT systems.

Purpose The dopamine D-2 receptor (D2R) is important in the mediation of addiction. [I-123]iodobenzamide (IBZM), a SPECT ligand for the D2R, has been used for in vivo studies of D2R availability in humans, monkeys, and rats. Although mouse models are important in the study of addiction, [I-123]IBZM has not been used in mice SPECT studies. This study evaluates the use of [I-123]IBZM for measuring D2R availability in mice. Methods Pharmacokinetics of [I-123]IBZM in mice were studied with pinhole SPECT imaging after intravenous (i.v.) injection of [I-123]IBZM (20, 40, and 70 MBq). In addition, the ability to measure the release of endogenous dopamine after amphetamine administration with [I-123]IBZM SPECT was investigated. Thirdly, i.v. administration, the standard route of administration, and intraperitoneal (i.p.) administration of [I-123]IBZM were compared. Results Specific binding of [I-123]IBZM within the mouse striatum could be clearly visualized with SPECT. Peak specific striatal binding ratios were reached around 90 min post-injection. After amphetamine administration, the specific binding ratios of [I-123]IBZM decreased significantly (-27.2%; n = 6; p = 0.046). Intravenous administration of [I-123]IBZM led to significantly higher specific binding than i.p. administration of the same dose. However, we found that i.v. administration of a dose of 70 MBq [I-123]IBZM might result in acute ethanol intoxication because ethanol is used as a preparative aid for the routine production of [I-123]IBZM. Conclusions Imaging of D2R availability and endogenous dopamine release in mice is feasible using [I-123]IBZM single pinhole SPECT. Using commercially produced [I-123]IBZM, a dose of 40 MBq injected i.v. can be recommended

Accurately registered images of complementary biomedicalimaging devices, for example images representing tissuefunction (PET or SPECT) registered with structural/anatomical images obtained with CT or MRI, are of crucialimportance for research, diagnosis and patient treatment.Several multi-modal tomography approaches have alreadyproven to significantly enhance accuracy of diagnosis andpatient management. The main reason for this is thatmolecular processes that show up at the site of (for example)atumourorinfectionprocesscanbeaccuratelylocalisedinananatomical framework and attributed to a specific tissue ororgan. Such combination of modalities presents addeddiagnosticinformationcomparedwitheitheroftheemployedmodalitiesusedinisolation.Furthermore,thereispotentialtoenhance reconstruction and improve quantification utilisingthe combined information from multiple modalities.Until recently, pure software-based methods based oneither rigid body or non-rigid algorithms were used forimage registration. There are several comprehensivereviews available covering both intra-modality and inter-modality registration [1–3]. In general, however, whenapplied to multi-modal studies involving emission tomog-raphy, these methods have been unable to deliver suffi-ciently robust registration for general clinical imagingpractice. For many parts of the body the registration iscomplicated, for instance because changes in the patient’sposition cause organs and tissues to shift relative to eachother, necessitating computationally slow, sometimes ill-defined, non-rigid approaches. More importantly forSPECT, some of the applications where registration hasmost clinical potential involve the localisation of specificuptake where there often is insufficient information outsidethe target tissue to permit accurate multi-modal registration.In addition, the logistics of retrieving data from multiplesites is seldom straightforward.The recognition of this problem led to the introduction ofcombined molecular and structural imaging devices: PET/CT [4, 5] and SPECT/CT [6, 7]. SPECT/CT, originallysuggested by Hasegawa and co-workers, predated PET/CTas an attempt to improve on the low-cost transmissionscanning that was developed for cardiac attenuationcorrection (whose commercial implementation proved tobe problematic [see 8]). Both PET/CT and SPECT/CT canbe very successful in eliminating the organ shift problem.In 2000, the modern PET/CT scanner, as proposed byTownsend and Nutt, was named by TIME Magazine as themedical invention of the year, and indeed it has maintaineda significant impact on clinical practice. Today, sales inPET involve almost exclusively PET/CT systems. This isnot the case yet with SPECT/CT scanners although theinstalled base is rapidly growing. One reason for the sloweracceptance of SPECT/CT is the relative cost of CT andSPECT, especially considering the relatively low percent-age of studies where SPECT/CT imaging is indicated. Asa consequence there was an initial trend to offer slow

(201)Tl-Chloride ((201)Tl) is a myocardial perfusion SPECT agent with excellent biochemical properties commonly used for assessing tissue viability. However, cardiac (201)Tl SPECT images are severely degraded by photons scattered in the thorax. Accurate correction for this scatter is complicated by the nonuniform density and varied sizes of thoraxes, by the additional attenuation and scatter caused by female patients' breasts, and by the energy spectrum of (201)Tl. Monte Carlo simulation is a general and accurate method well suited to modeling this scatter. METHODS: Statistical reconstruction that includes Monte Carlo modeling of scatter was compared with statistical reconstruction algorithms not corrected for scatter. In the ADS method, corrections for attenuation, detector response, and scatter (Monte Carlo-based) were implemented simultaneously via the dual-matrix ordered-subset expectation maximization algorithm with a Monte Carlo simulator as part of the forward projector. The ADS method was compared with the A method (ordered-subset expectation maximization with attenuation correction) and with the AD method (a method like the A method but with detector response modeling added). A dual-head SPECT system equipped with two (153)Gd scanning line sources was used for simultaneously acquiring transmission and emission data. Four clinically realistic phantom configurations (a large thorax and a small thorax, each with and without breasts) with a cardiac insert containing 2 cold defects were used to evaluate the proposed reconstruction algorithms. We compared the performance of the different algorithms in terms of noise properties, contrast-to-noise ratios, the contrast separability of perfusion defects, uniformity, and robustness to anatomic variations. RESULTS: The ADS method provided images with clearly better visual defect contrast than did the other methods. The contrasts achieved with the ADS method were 10%-24% higher than those achieved with the AD method and 11%-37% higher than those achieved with the A method. For a typical contrast level, the ADS method exhibited noise levels around 27% lower than the AD method and 34% lower than the A method. Compared with the other 2 algorithms, the ADS reconstructions were less sensitive to anatomic variations and had better image uniformity in the homogeneously perfused myocardium. Finally, we found that the improvements that can be achieved with Monte Carlo-based scatter correction are stronger for (201)Tl than for (99m)Tc imaging. CONCLUSION: Our results indicate that Monte Carlo-based scatter correction is suitable for (201)Tl cardiac imaging and that such correction simultaneously improves several image-quality metrics

Charge-coupled devices (CCDs) coupled to scintillation crystals can be used for high-resolution imaging with x-rays and gamma rays. When the CCD images can be read out fast enough, the energy and interaction position of individual gamma quanta can be estimated by a real-time image analysis of the scintillation light flashes ('photon-counting mode'). The electron-multiplying CCD (EMCCD) is well suited for fast read out, since even at high frame rates it has extremely low read-out noise. Back-illuminated (BI) EMCCDs have much higher quantum efficiency than front-illuminated (FI) EMCCDs. Here we compare the spatial and energy resolution of gamma cameras based on FI and BI EMCCDs. The CCDs are coupled to a 1000 microm thick columnar CsI(Tl) crystal for the purpose of Tc-99m and I-125 imaging. Intrinsic spatial resolutions of 44 microm for I-125 and 49 microm for Tc-99m were obtained when using a BI EMCCD, which is an improvement by a factor of about 1.2-2 over the FI EMCCD. Furthermore, in the energy spectrum of the BI EMCCD, the I-125 signal could be clearly separated from the background noise, which was not the case for the FI EMCCD. The energy resolution of a BI EMCCD for Tc-99m was estimated to be approximately 36 keV, full width at half maximum, at 141 keV. The excellent results for the BI EMCCD encouraged us to investigate the cooling requirements for our setup. We have found that for the BI EMCCD, the spatial and energy resolution, as well as image noise, remained stable over a range of temperatures from -50 degrees C to -15 degrees C. This is a significant advantage over the FI EMCCD, which suffered from loss of spatial and especially energy resolution at temperatures as low as -40 degrees C. We conclude that the use of BI EMCCDs may significantly improve the imaging capabilities and the cost efficiency of CCD-based high-resolution gamma cameras.

A pivotal question in neuropharmacology is how the function of neurotransmitter systems relates to psychiatric diseases. In experimental neuropharmacology, we have dreamt about a looking glass that would allow us to see neurotransmitter systems in action, and about animals that would faithfully serve us as models for human psychiatric disease. Analysis of animal models has been limited by the availability of methods to study in vivo neurotransmitter dynamics. Now, a single photon emission computed tomography system called U-SPECT can localize dopamine transporters in sub-compartments of the mouse brain during a range of points in time. Applied to the midbrain dopamine system of different models of disease, this will aid the understanding of dynamic processes of this neurotransmitter that underlie brain functions and human brain pathology.

Single photon emission computed tomography (SPECT) images are degraded by the detection of scattered photons and photons that penetrate the collimator septa. In this paper, a previously proposed Monte Carlo software that employs fast object scatter simulation using convolution-based forced detection (CFD) is extended towards a wide range of medium and high energy isotopes measured using various collimators. To this end, a fast method was developed for incorporating effects of septal penetrating (SP) photons. The SP contributions are obtained by calculating the object attenuation along the path from primary emission to detection followed by sampling a pre-simulated and scalable septal penetration point spread function (SP-PSF). We found that with only a very slight reduction in accuracy, we could accelerate the SP simulation by four orders of magnitude. To achieve this, we combined: (i) coarse sampling of the activity and attenuation distribution; (ii) simulation of the penetration only for a coarse grid of detector pixels followed by interpolation and (iii) neglection of SP-PSF elements below a certain threshold. By inclusion of this SP-PSF-based simulation it became possible to model both primary and septal penetrated photons while only 10% extra computation time was added to the CFD-based Monte Carlo simulator. As a result, a SPECT simulation of a patient-like distribution including SP now takes less than 5 s per projection angle on a dual processor PC. Therefore, the simulator is well-suited as an efficient projector for fully 3D model-based reconstruction or as a fast data-set generator for applications such as image processing optimization or observer studies.

In trauma and orthopedic surgery, infection of implants has a major impact on the outcome for patients. Infections may develop either during the initial implantation or during the lifetime of an implant. Both infections, as well as aseptic loosening of the implant, are reasons for revision of the implants. Therefore, discrimination between aseptic-mechanical-loosening and septic-bacterial-loosening of implants is critical during selection of a patient-tailored treatment policy. Specific detection and visualization of infections is a challenge because it is difficult to discriminate infections from inflammation. An imaging tracer that facilitates bacterial identification in a pre- and intraoperative setting may aid the workup for patients suspicious of bacterial infections. In this study we evaluated an antimicrobial peptide conjugated to a hybrid label, which contains both a radioisotope and a fluorescent dye. After synthesis of DTPA-Cy5-UBI29-41 and-when necessary-radiolabeling with (111)In (yield 96.3 ± 2.7%), in vitro binding to various bacterial strains was evaluated using radioactivity counting and confocal fluorescence microscopy. Intramuscular bacterial infections (S. aureus or K. pneumoniae) were also visualized in vivo using a combined nuclear and fluorescence imaging system. The indium-111 was chosen as label as it has a well-defined coordination chemistry, and in pilot studies labeling DTPA-Cy5-UBI29-41 with technetium-99m, we encountered damage to the Cy5 dye after the reduction with SnCl2. As a reference, we used the validated tracer (99m)Tc-UBI29-41. Fast renal excretion of (111)In-DTPA-Cy5-UBI29-41 was observed. Target to nontarget (T/NT) ratios were highest at 2 h post injection: radioactivity counting yielded T/NT ratios of 2.82 ± 0.32 for S. aureus and 2.37 ± 0.05 for K. pneumoniae. Comparable T/NT ratios with fluorescence imaging of 2.38 ± 0.09 for S. aureus and 3.55 ± 0.31 for K. pneumoniae were calculated. Ex vivo confocal microscopy of excised infected tissues showed specific binding of the tracer to bacteria. Using a combination of nuclear and fluorescence imaging techniques, the hybrid antimicrobial peptide conjugate DTPA-Cy5-UBI29-41 was shown to specifically accumulate in bacterial infections. This hybrid tracer may facilitate integration of noninvasive identification of infections and their extent as well as real-time fluorescence guidance during surgical resection of infected areas.

We validated the Monte Carlo package, GATE, for multi-pinhole gamma-ray imaging simulations using calculations and measurements. For these studies requiring large amount of photon histories, the newly designed cluster version of GATE was used. Accordingly that validated simulator allowed us then to evaluate design parameters for 123 I-experiments on a prototype multi-pinhole SPECT camera for which analytical calculations were failing due to scatter of high-energy photons.

X-ray CT images obtained with iterative reconstruction (IR) can be hampered by the so-called edge and aliasing artefacts, which appear as interference patterns and severe overshoots in the areas of sharp intensity transitions. Previously, we have demonstrated that these artefacts are caused by discretization errors during the projection simulation step in IR. Although these errors are inherent to IR, they can be adequately suppressed by reconstruction on an image grid that is finer than that typically used for analytical methods such as filtered back-projection. Two other methods that may prevent edge artefacts are: (i) smoothing the projections prior to reconstruction or (ii) using an image representation different from voxels; spherically symmetric Kaiser-Bessel functions are a frequently employed example of such a representation. In this paper, we compare reconstruction on a fine grid with the two above-mentioned alternative strategies for edge artefact reduction. We show that the use of a fine grid results in a more adequate suppression of artefacts than the smoothing of projections or using the Kaiser-Bessel image representation.

Quantitative accuracy of single-photon-emission computed tomography (SPECT) images is highly dependent on the photon scatter model used for image reconstruction. Monte Carlo simulation (MCS) is the most general tool for accurate modeling and correction of scatter, but calculations are notoriously slow. Recently, we proposed an efficient strategy for fully three-dimensional (3-D) statistical reconstruction using highly accelerated MCS as a forward projector. We use convolution forced detection (CFD) which accelerates convergence of reprojection by about two orders of magnitude. Here, we investigate how many photon histories during CFD-based MCS need to be calculated to: i) ensure that the noise in the reconstructed image does not increase markedly because of the stochastic nature of MCS reprojections; and ii) to determine the reconstruction time needed. To this end, phantom studies representing Tc-99m cardiac perfusion SPECT, were carried out. We generated reconstructions with different numbers of photon histories during MCS forward projection. Images and profiles were compared for reconstructions with a different number of photon tracks, for reconstructions from different noise realizations using a repeat measurement and for reconstructions with different random seeds for MCS reprojection. We found that 10/sup 5/ photon histories per subset is sufficient to produce accurate images; more photons do not show visible improvement. This amount of photons corresponds to a typical reconstruction time below 5 min for a 64/sup 3/ volume image on a dual-cpu PC (2.66 GHz), which is sufficiently short to apply such highly accurate reconstruction in clinical routine.

We have developed a compact ultra-high-resolution gamma camera (UGC), based on an electron-multiplying charge-coupled device (EMCCD) coupled to a columnar CsI(Tl) scintillator. The EMCCD is suitable for photon-counting gamma-camera imaging, since it has an extremely low readout noise, even at high frame rates (

Statistical reconstruction methods offer possibilities of improving image quality as compared to analytical methods, but current reconstruction times prohibit routine clinical applications. To reduce reconstruction times we have parallelized a statistical reconstruction algorithm for cone-beam x-ray CT, the ordered subset convex algorithm (OSC), and evaluated it on a shared memory computer. Two different parallelization strategies were developed: one that employs parallelism by computing the work for all projections within a subset in parallel, and one that divides the total volume into parts and processes the work for each sub-volume in parallel. Both methods are used to reconstruct a three-dimensional mathematical phantom on two different grid densities. The reconstructed images are binary identical to the result of the serial (non-parallelized) algorithm. The speed-up factor equals approximately 30 when using 32 to 40 processors, and scales almost linearly with the number of cpus for both methods. The huge reduction in computation time allows us to apply statistical reconstruction to clinically relevant studies for the first time.

Statistical methods for image reconstruction such as maximum likelihood expectation maximization (ML-EM) are more robust and flexible than analytical inversion methods and allow for accurate modelling of the photon transport and noise. Statistical reconstruction is prohibitively slow when applied to clinical x-ray cone-beam CT due to the large data sets and the high number of iterations required for reconstructing high resolution images. One way to reduce the reconstruction time is to use ordered subsets of projections during the iterations, which has been successfully applied to fan-beam x-ray CT. In this paper, we quantitatively analyse the use of ordered subsets in concert with the convex algorithm for cone-beam x-ray CT reconstruction, for the case of circular acquisition orbits. We focus on the reconstructed image accuracy of a 3D head phantom. Acceleration factors larger than 300 were obtained with errors smaller than 1%, with the preservation of signal-to-noise ratio. Pushing the acceleration factor towards 600 by using an increasing number of subsets increases the reconstruction error up to 5% and significantly increases noise. The results indicate that the use of ordered subsets can be extremely useful for cone-beam x-ray CT.

Monte Carlo (MC) methods can accurately simulate scatter in X-ray imaging. However, when low noise scatter projections have to be simulated these MC simulations tend to be very time consuming. Rapid computation of scatter estimates is essential for several applications. The aim of the work presented in this paper is to speed up the estimation of noise-free scatter projections while maintaining their accuracy. Since X-ray scatter projections are often rather smooth, an approach is chosen whereby a short MC simulation is combined with a data fitting program that is robust to projection truncation and noise. This method allows us to estimate the smooth scatter projection rapidly. The speed-up and accuracy achieved by using the fitting algorithm were validated for the projection simulation of a small animal X-ray CT system. The acceleration that can be obtained over standard MC simulations is typically two orders of magnitude, depending on the accuracy required. The proposed approach may be useful for rapid simulation of patient and animal studies and for correction of the image-degrading effects of scatter in tomography.

Statistical reconstruction (SR) methods provide a general and flexible framework for obtaining tomographic images from projections. For several applications SR has been shown to outperform analytical algorithms in terms of resolution-noise trade-off achieved in the reconstructions. A disadvantage of SR is the long computational time required to obtain the reconstructions, in particular when large data sets characteristic for x-ray computer tomography (CT) are involved. As was shown recently, by combining statistical methods with block iterative acceleration schemes [e.g., like in the ordered subsets convex (OSC) algorithm], the reconstruction time for x-ray CT applications can be reduced by about two orders of magnitude. There are, however, some factors lengthening the reconstruction process that hamper both accelerated and standard statistical algorithms to similar degree. In this simulation study based on monoenergetic and scatter-free projection data, we demonstrate that one of these factors is the extremely high number of iterations needed to remove artifacts that can appear around high-contrast structures. We also show (using the OSC method) that these artifacts can be adequately suppressed if statistical reconstruction is initialized with images generated by means of Radon inversion algorithms like filtered back projection (FBP). This allows the reconstruction time to be shortened by even as much as one order of magnitude. Although the initialization of the statistical algorithm with FBP image introduces some additional noise into the first iteration of OSC reconstruction, the resolution-noise trade-off and the contrast-to-noise ratio of final images are not markedly compromised.

Molecular imaging can be defined as the characterization and measurement of biological processes in living animals, model systems and humans at the cellular and molecular level using remote imaging detectors. An example concerns the mapping of the distributions of radioactively labeled molecules in laboratory animals which is of crucial importance for life sciences. Tomographic methods like Single Photon Emission Computed Tomography (SPECT) offer a possibility to visualize distributions of radioactively labeled molecules in living animals. Miniature tomography systems, derived from their clinical counterparts, but with a much higher image resolution are under development in several institutes. An example is U-SPECT that will be discussed in the present paper. Such systems are expected to accelerate several biomedical research procedures, the understanding of gene and protein function, as well as pharmaceutical development.

Individualised dosage models are frequently applied for radioiodine therapy in patients with Graves' hyperthyroidism, especially in Europe. In these dosage schemes the thyroid volume is an important parameter. Thyroid volume determinations are usually made with ultrasonography or with thyroid scintigraphy, although the accuracy of planar scintigraphy for this purpose is not well established. The aim of this study was to compare the accuracy of three modalities for the determination of the thyroid volume in patients with Graves' disease: planar scintigraphy (PS), single-photon emission tomography (SPET) and ultrasonography (US). These three modalities were compared with magnetic resonance imaging (MRI) as the gold standard. Thyroid volume estimations were performed in 25 patients with Graves' disease. The PS images were subjected to filtering and thresholding, and a standard surface formula was used to calculate the thyroid volume. With SPET the iteratively reconstructed thyroid images were filtered, and after applying a threshold method an automatic segmentation algorithm was used for the volume determinations. Thyroid volumes were estimated from the US images using the ellipsoid volume model for multiple two-dimensional measurements. For MRI, thyroid segmentation was performed manually in gadolinium-enhanced T1-weighted images and a summation-of-areas technique was used for the volume measurements. The thyroid volumes calculated with MRI were 25.0+/-13.8 ml (mean+/-SD, range 7.0-56.3 ml). PS correlated poorly with MRI ( R(2)=0.61) and suffered from a considerable bias (-4.0+/-17.6 ml). The differences between PS and MRI volume estimations had a very large spread (33+/-58%). For SPET both the correlation with MRI ( R(2)=0.84) and the bias (1.8+/-11.9 ml) were better than for PS. US had by far the best correlation with MRI ( R(2)=0.97) and the best precision, but the bias (6.8+/-7.5 ml) was not negligible. In conclusion, SPET is preferred over PS for accurate measurements of thyroid volume. US is the most accurate of the three modalities, if a correction is made for bias.

Pinhole collimation of gamma rays to image distributions of radiolabeled tracers is considered promising for use in small animal imaging. The recent availability of transgenic mice, coupled with the development of /sup 125/I and /sup 99m/Tc labeled tracers, has allowed the study of a range of human disease models while creating demand for ultrahigh resolution imaging devices. We have developed a compact gamma camera that, in combination with pinhole collimation, allows for accessible, ultrahigh resolution in vivo single photon emission computed tomography (SPECT) imaging of small animals. The system is based on a pixilated array of NaI(Tl) crystals coupled to an array of position sensitive photomultiplier tubes. Interchangeable tungsten pinholes with diameters ranging from 0.5 to 3 mm are available, allowing the camera to be optimized for a variety of imaging situations. We use a three dimensional maximum likelihood expectation maximization algorithm to reconstruct the images. Our evaluation indicates that high quality, submillimeter spatial resolution images can be achieved in living mice. Reconstructed axial spatial resolution was measured to be 0.53, 0.74, and 0.96 mm full width at half maximum (FWHM) for rotation radii of 1, 2, and 3 cm, respectively, using the 0.5-mm pinhole. In this configuration, sensitivity is comparable to that of a high-resolution parallel hole collimator. SPECT images of hot- and cold-rod phantoms and a highly structured monkey brain phantom illustrate that high quality images can be obtained with the system. Images of living mice demonstrate the ability of the system to obtain high-resolution images in vivo. The effect of object size on the quantitative assessment of isotope distributions in an image was also studied.

Pinhole collimation can provide both higher sensitivity and resolution than parallel hole collimation when used to image small objects. When objects are placed close to the pinhole, small pinhole diameters combined with high-magnification pinhole geometries yield ultra high resolution images. With Monte Carlo (MC) calculations it is possible to simulate accurately a wide range of features of pinhole imaging. The aim of the present work is to accelerate MC simulations of pinhole SPECT projections. To achieve speed-up, forced detection (FD), a commonly used acceleration technique, is replaced by a kernel-based forced detection (KFD) step. In KFD, instead of tracing individual photons from the source or last scatter position to the detector, a position dependent kernel (point spread function (PSF)) is projected on the detector. The PSFs for channel and knife edge pinhole apertures model the penetration effects through the aperture material. For simulations, the PSFs are pre-calculated and stored in tables. The speed-up and accuracy achieved by using KFD were validated by means of digital phantoms. MC simulations with FD and with KFD converge to almost identical images. However, KFD converges to an equal image noise level one to four orders of magnitude faster than FD, depending on the number of photons simulated. A simulator accelerated by KFD could serve as a practical tool to improve iterative image reconstruction.

Position-sensitive gamma-radiation detectors equipped with collimators have been used for in vivo im- aging of the distribution of radiolabelled molecules in laboratory animals and humans for several decades. To date, the best image resolution achieved in a rodent is on the order of 1 mm. Here we demonstrate how a basic and compact gamma camera can be constructed for in vivo radionuclide imaging in small animals, at much higher spatial resolution. Resolution improvements were ob- tained by combining dense, shaped, micro-pinhole aper- tures with iodine-125, an isotope with low energy emis- sions, ease of incorporation into a wide range of mole- cules, and straightforward translation into the clinic via other isotopes of iodine that are suitable for nuclear med- icine imaging. 125 I images of test distributions and a mouse thyroid have been obtained at a resolution of as high as 200 µm using this simple bench-top camera. Pos- sible future applications and extension to ultra-high-res- olution emission tomography are discussed.

A major image degrading factor in simultaneous Dual Isotope (DI) SPECT or simultaneous Emission-Transmission (ECT-TCT) imaging, is the detection of photons emitted by the higher energy isotope in the energy window used for imaging the lower energy isotope. In Tc-99m/Tl-201 DI-SPECT typically tens of percents of the total detected down-scatter is caused by lead x rays. In Tc-99m/Gd-153 ECT-TCT, a comparable fraction of the down-scatter originates from Tc-99m photons which only partly deposit their energy in the detector crystal (i.e., due to crystal interactions). Efficient simulation methods which model down-scatter can be used to optimize DI-SPECT or ECT-TCT imaging acquisition or reconstruction protocols. In this paper we adapt a previously proposed efficient down-scatter simulation method, to include the interactions of photons with the detector crystal and collimator lead. To this end, point spread function tables including crystal and lead interactions are precalculated. Subsequently, photons are traced through the patient body until their last scatter position, and the precalculated responses are used to project the photons onto the detector plane, while photon attenuation in the patient is taken into account. The approach is evaluated by comparing simulated Tc-99m down-scatter projections with measured projections. Incorporation of photon interaction with crystal and lead leads to significantly improved accuracy of the shape of down-scatter responses, while differences in total counts between simulated and measured projections typically decrease from tens of percents to a couple of percents. Calculating 60 down-scatter projections of an extended distribution on a 64 x 64 x 64 grid takes about three minutes on a PC with two 1.2 GHz processors. We conclude that accurate and efficient simulation of down-scatter is now possible including the major effects of the nonuniform mass density of the patient as well as photon interactions with the crystal and collimator lead.

In computer simulations of x-ray CT systems one can either use continuous geometrical descriptions for phantoms or a voxelized representation. The voxelized approach allows arbitrary phantoms to be defined without being confined to geometrical shapes. The disadvantage of the voxelized approach is that inherent errors are introduced due to the phantom voxelization. To study effects of phantom discretization, analytical CT simulations were run for a fan-beam geometry with phantom voxel sizes ranging from 0.0625 to 2 times the reconstructed pixel size and noise levels corresponding to 10 3 –10 7 photons per detector pixel prior to attenuation. The number of rays traced per detector element was varied from 1 to 16. Differences in the filtered backprojection images caused by changing the phantom matrix sizes and number of rays traced were assessed by calculating the difference between reconstructions based on the finest matrix and coarser matrix simulations. In noise free simulations, all phantom matrix sizes produced a measurable difference in comparison with the finest phantom matrix used. When even a small amount of noise was added to the projection data, the differences due to the phantom discretization were masked by the noise, and in all cases there was almost no improvement by using a phantom matrix that was more than twice as fine as the reconstruction matrix. No substantial improvement was achieved by tracing more than 4 rays per detector pixel.

Imaging of Tc-99m labelled tracers is gaining popularity for detecting breast tumours. Recently, we proposed a novel design for molecular breast tomosynthesis (MBT) based on two sliding focusing multi-pinhole collimators that scan a modestly compressed breast. Simulation studies indicate that MBT has the potential to improve the tumour-to-background contrast-to-noise ratio significantly over state-of-the-art planar molecular breast imaging. The aim of the present paper is to optimize the collimator-detector geometry of MBT. Using analytical models, we first optimized sensitivity at different fixed system resolutions (ranging from 5 to 12 mm) by tuning the pinhole diameters and the distance between breast and detector for a whole series of automatically generated multi-pinhole designs. We evaluated both MBT with a conventional continuous crystal detector with 3.2 mm intrinsic resolution and with a pixelated detector with 1.6 mm pixels. Subsequently, full system simulations of a breast phantom containing several lesions were performed for the optimized geometry at each system resolution for both types of detector. From these simulations, we found that tumour-to-background contrast-to-noise ratio was highest for systems in the 7 mm to 10 mm system resolution range over which it hardly varied. No significant differences between the two detector types were found.