A versatile imaging system for in vivo small animal research

In vivo small animal imaging has become an essential technique for molecular biology studies. However, requirements of spatial resolution, sensitivity and image quality are quite challenging for the development of small-animal imaging systems. The capabilities of the system are also significant for carrying out small animal imaging in a wide range of biological studies. The goal of this dissertation is to develop a high-performance imaging system that can readily meet a wide range of requirements for a variety of small animal imaging applications. Several achievements have been made in order to fulfill this goal.;To supplement our system for parallel-hole single photon emission computed tomography (SPECT) based upon a 110 mm diameter circular detector, we have developed novel compact gamma cameras suitable for imaging an entire mouse. These gamma cameras facilitate multi-head (\u3e2) parallel-hole SPECT with the mouse in close proximity to the detector face in order to preserve spatial resolution. Each compact gamma cameras incorporates pixellated Nal(Tl) scintillators and a pair of Hamamatsu H8500 position sensitive photomultiplier tubes (PSPMTs). Two types of copper-beryllium parallel-hole collimators have been designed. These provide high-sensitivity imaging of I-125 or excellent spatial resolution over a range of object-detector distances. Both phantom and animal studies have demonstrated that these gamma cameras perform well for planar scintigraphy and parallel-hole SPECT of mice.;To further address the resolution limitations in parallel-hole SPECT and the sensitivity and limited field of view of single-pinhole SPECT, we have developed novel multipinhole helical SPECT based upon a 110 mm diameter circular detector equipped with a pixellated Nal(Tl) scintillator array. A brass collimator has been designed and produced containing five 1 mm diameter pinholes. Results obtained in SPECT studies of various phantoms show an enlarged field of view, very good resolution and improved sensitivity using this new imaging technique.;These studies in small-animal imaging have been applied to in vivo biological studies related to human health issues including studies of the thyroid and breast cancer. A re-evaluation study of potassium iodide blocking efficiency in radioiodine uptake in mice suggests that the FDA-recommended human dose of stable potassium iodide may not be sufficient to effectively protect the thyroid from radioiodine contamination. Another recent study has demonstrated that multipinhole helical SPECT can resolve the fine structure of the mouse thyroid using a relatively low dose (200 muCi). Another preclinical study has focused on breast tumor imaging using a compact gamma camera and an endogenous reporter gene. In that ongoing study, mammary tumors are imaged at different stages. Preliminary results indicate different functional patterns in the uptake of radiotracers and their potential relationship with other tumor parameters such as tumor size.;In summary, we have developed a versatile imaging system suitable for in vivo small animal research as evidenced by a variety of applications. The modular construction of this system will allow expansion and further development as new needs and new opportunities arise

Effects of patient motion on absolute quantification of glucose metabolism in cardiac positron emission tomography (PET)

Die Positronen-Emissions-Tomographie (PET) stellt eine der leistungsfähigsten Methoden zur Bestimmung myokardialer Vitalität dar, deren Bestimmung für die Prognose und Therapie von Patienten mit koronarer Herzerkrankung elementar ist. Ziel der vorliegenden Arbeit war es, das Auftreten und die Einflüsse von Patientenbewegung anhand von klinischen und simulierten Daten zu untersuchen. Ein numerisches Herzmodell wurde neu entwickelt, die Einflüsse von künstlichen Bewegungen auf das Modell und klinische Daten untersucht und diese Ergebnisse mit bewegungskontaminierten klinischen Daten verglichen. Es wurde festgestellt, dass Patientenbewegung in mehr als einem Drittel der PET-Untersuchungen auftritt. Die simulierten Bewegungsartefakte zeigten gleiche Ergebnisse für das Modell und die klinischen Daten. Der Vergleich mit klinischen Bewegungsartefakten bestätigt diese Ergebnisse. Positron-Emission-Tomography (PET) is one of the most efficient methods for the assessment of myocardial vitality, the assessment of which is fundamental for prognosis and therapy of coronary artery disease. Aim of this work was to determine the occurence and influence of patient motion by means of clinical and simulated data. A numerical model of the heart was newly developed. The influences of artificial motion on the model and clinical data was investigated and compared with clinical data. It was shown that patient motion occurs in more than a third of the PET-investigations. Simulated effects of motion were similar in the model and the clinical data. These results are comparable to those of clinical motion-biased data

Simulation of Clinical PET Studies for the Assessment of Quantification Methods

On this PhD thesis we developed a methodology for evaluating the robustness of SUV measurements based on MC simulations and the generation of novel databases of simulated studies based on digital anthropomorphic phantoms. This methodology has been applied to different problems related to quantification that were not previously addressed. Two methods for estimating the extravasated dose were proposed andvalidated in different scenarios using MC simulations. We studied the impact of noise and low counting in the accuracy and repeatability of three commonly used SUV metrics (SUVmax, SUVmean and SUV50). The same model was used to study the effect of physiological muscular uptake variations on the quantification of FDG-PET studies. Finally, our MC models were applied to simulate 18F-fluorocholine (FCH) studies. The aim was to study the effect of spill-in counts from neighbouring regions on the quantification of small regions close to high activity extended sources

Quantification Methods for Clinical Studies in Nuclear Medicine - Applications in AMS, PET/CT and SPECT/CT

An essential part of the development of new radiopharmaceuticals for use in diagnostic nuclear medicine is the determination of its biokinetic properties. The uptake and turn-over of the radiopharmaceutical in the source organs is of great interest since this could determine whether the radiopharmaceutical would be suitable for clinical use or not. It is also important that the biokinetics and dosimetry of the radiopharmaceuticals is thoroughly investigated in order to determine the radiation absorbed doses to various organs and tissues and the effective dose. This is done to evaluate the radiation risks, which is one of the risks factors that have to be compared, with the benefits of their use. Modern imaging systems such as single photon emission computed tomography (SPECT) and positron emission tomography (PET) have limitations that complicate the accurate estimation of the activity content in source organs, and thus also the estimation of the radiation absorbed dose, to organs and tissues of the human body. As an example, the partial volume effect poses significant problems with the reliability of the activity values when imaging small volumes. Drawing regions of interest smaller than the actual structure could influence the results. With large ROIs, the activity concentration has been shown to be underestimated by 70 % for a 0.5-ml sphere and 31 % for a 20-ml sphere. With small ROIs the underestimation ranges from 66 to 16 % (Paper II). PET is becoming more common in radiotherapy treatment planning and also used to monitor treatment response. In these cases, as well as in planning of surgery, it is important that the volume of the structure of interest is estimated accurately. Using phantoms with fillable, hollow, plastic spheres in an active background for estimation of the volume reproducing threshold would lead to overestimation of the tumour volume. The background dependence seen when using plastic phantoms is not present when using gelatin phantoms without walls (Paper III). As new imaging modalities are introduced, the measurement procedures and outline of clinical studies have to be adjusted to make use of the full potential of these new techniques. Biokinetic studies have commonly been performed using planar gamma camera images and the use of the conjugate view technique. As SPECT is very common at nuclear medicine clinics today, the use of this new and supposedly more accurate technique for determination of the biokinetics of radiopharmaceuticals is a natural step in the development process. It was shown that the organ dose estimations differed significantly when using complementary SPECT/CT measurements to quantify activity in the organs (i.e. to conduct dosimetry measurements) than when using planar images alone (Paper I). In drug development, accelerator mass spectrometry (AMS) has become an important tool for quantifying the content of 14C-labelled drug molecules in biological samples and to determine the pharmacokinetics of promising new drugs. PET or SPECT can be used simultaneously with AMS for analysis of the behaviour of the same compound labelled with positron (PET) or photon (SPECT) emitting radionuclides. The information acquired from the different modalities is complementary i.e. AMS gives information about the pharmacokinetic profile in blood and urine and PET and SPECT gives information about the pharmacokinetic behaviour in organs and tissues. The human microdosing concept is aiming to speed up drug development and reducing the costs by improved candidate selection in early drug development. In order to promote the use of AMS for analysis of biomedical samples, a fast and easily implemented sample preparation method is needed, which converts the biological samples to solid graphite. The precision of such a method, which is developed in Paper IV, is lower that earlier more time-consuming methods, but it is well suited for this type of application. In order to facilitate the implementation of the AMS technique closer to the clinics, the development of smaller AMS systems is a constantly ongoing process. When comparing high-voltage AMS with low-voltage AMS it is shown that the AMS instruments themselves were comparable and that low voltage AMS provides a good alternative to the larger and more expensive high-voltage tandem AMS systems (Paper V)

Gamma-ray imaging detector for small animal research

A novel radiation imaging technology for in vivo molecular imaging in small mammals is described. The goal of this project is to develop a new type of imaging detector system suitable for real-time in vivo probe imaging studies in small animals. This technology takes advantage of the gamma-ray and x-ray emission properties of the radioisotope iodine 125 (125I) which is employed as the label for molecular probes. The radioisotope 125I is a gamma-ray emitting radioisotope that can be commercially obtained already attached to biomedically interesting molecules to be used as tracers for biomedical and molecular biology research.;The isotope 125I decays via electron capture consequently emitting a 35 keV gamma-ray followed by the near coincident emission of several 27--32 keV Kalpha and Kbeta shell x-rays. Because of these phenomena, a coincidence condition can be set to detect 125I thus enabling the reduction of any background radiation that could contaminate the image. The detector system is based on an array of CsI(Na) crystal scintillators coupled to a 125 mm diameter position sensitive photomultiplier tube. An additional standard 125 mm diameter photomultiplier tube coupled to a NaI(Tl) scintillator acts as the coincident detector. to achieve high resolution images the detector system utilizes a custom-built copper laminate high resolution collimator. The 125I detector system can achieve a spatial resolution of less than 2 mm FWHM for an object at a distance of 1.5 cm from the collimator. The measured total detector sensitivity while using the copper collimator was 68 cpm/muCi.;Results of in vivo mouse imaging studies of the biodistribution of iodine, melatonin, and a neurotransmitter analog (RTI-55) are presented. Many studies in molecular biology deal with following the expression and regulation of a gene at different stages of an organism\u27s development or under different physiological conditions. This detector system makes it possible for laboratories without access to standard nuclear medicine radiopharmaceuticals to perform in vivo imaging research on small a mammals using a whole range of 125I labeled markers that are obtainable from commercial sources

Organ-Dedicated Molecular Imaging Systems

[EN] In this review, we will cover both clinical and technical aspects of the advantages and disadvantages of organ specific (dedicated) molecular imaging (MI) systems, namely positron emission tomography (PET) and single photon emission computed tomography, including gamma cameras. This review will start with the introduction to the organ-dedicated MI systems. Thereafter, we will describe the differences and their advantages/disadvantages when compared with the standard large size scanners. We will review time evolution of dedicated systems, from first attempts to current scanners, and the ones that ended in clinical use. We will review later the state of the art of these systems for different organs, namely: breast, brain, heart, and prostate. We will also present the advantages offered by these systems as a function of the special application or field, such as in surgery, therapy assistance and assessment, etc. Their technological evolution will be introduced for each organ-based imager. Some of the advantages of dedicated devices are: higher sensitivity by placing the detectors closer to the organ, improved spatial resolution, better image contrast recovery (by reducing the noise from other organs), and also lower cost. Designing a complete ring-shaped dedicated PET scanner is sometimes difficult and limited angle tomography systems are preferable as they have more flexibility in placing the detectors around the body/organ. Examples of these geometries will be presented for breast, prostate and heart imaging. Recently achievable excellent time of flight capabilities below 300-ps full width at half of the maximum reduce significantly the impact of missing angles on the reconstructed images.This work was supported in part by the European Research Council through the European Union's Horizon 2020 Research and Innovation Program under Grant 695536, in part by the EU through the FP7 Program under Grant 603002, and in part by the Spanish Ministerio de Economia, Industria y Competitividad through PROSPET (DTS15/00152) funded by the Ministerio de Economia y Competitividad under Grant TEC2016-79884-C2-1-R.González Martínez, AJ.; Sánchez, F.; Benlloch Baviera, JM. (2018). Organ-Dedicated Molecular Imaging Systems. IEEE Transactions on Radiation and Plasma Medical Sciences. 2(5):388-403. https://doi.org/10.1109/TRPMS.2018.2846745S3884032

Acceleration of GATE Monte Carlo simulations

Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography are forms of medical imaging that produce functional images that reflect biological processes. They are based on the tracer principle. A biologically active substance, a pharmaceutical, is selected so that its spatial and temporal distribution in the body reflects a certain body function or metabolism. In order to form images of the distribution, the pharmaceutical is labeled with gamma-ray-emitting or positron-emitting radionuclides (radiopharmaceuticals or tracers). After administration of the tracer to a patient, an external position-sensitive gamma-ray camera can detect the emitted radiation to form a stack of images of the radionuclide distribution after a reconstruction process. Monte Carlo methods are numerical methods that use random numbers to compute quantities of interest. This is normally done by creating a random variable whose expected value is the desired quantity. One then simulates and tabulates the random variable and uses its sample mean and variance to construct probabilistic estimates. It represents an attempt to model nature through direct simulation of the essential dynamics of the system in question. Monte Carlo modeling is the method of choice for all applications where measurements are not feasible or where analytic models are not available due to the complex nature of the problem. In addition, such modeling is a practical approach in nuclear medical imaging in several important application fields: detector design, quantification, correction methods for image degradations, detection tasks etc. Several powerful dedicated Monte Carlo simulators for PET and/or SPECT are available. However, they are often not detailed nor flexible enough to enable realistic simulations of emission tomography detector geometries while also modeling time dependent processes such as decay, tracer kinetics, patient and bed motion, dead time or detector orbits. Our Monte Carlo simulator of choice, GEANT4 Application for Tomographic Emission (GATE), was specifically designed to address all these issues. The flexibility of GATE comes at a price however. The simulation of a simple prototype SPECT detector may be feasible within hours in GATE but an acquisition with a realistic phantom may take years to complete on a single CPU. In this dissertation we therefore focus on the Achilles’ heel of GATE: efficiency. Acceleration of GATE simulations can only be achieved through a combination of efficient data analysis, dedicated variance reduction techniques, fast navigation algorithms and parallelization. In the first part of this dissertation we consider the improvement of the analysis capabilities of GATE. The static analysis module in GATE is both inflexible and incapable of storing more detail without introducing a large computational overhead. However, the design and validation of the acceleration techniques in this dissertation requires a flexible, detailed and computationally efficient analysis module. To this end, we develop a new analysis framework capable of analyzing any process, from the decay of isotopes to particle interactions and detections in any detector element for any type of phantom. The evaluation of our framework consists of the assessment of spurious activity in 124I-Bexxar PET and of contamination in 131I-Bexxar SPECT. In the case of PET we describe how our framework can detect spurious coincidences generated by non-pure isotopes, even with realistic phantoms. We show that optimized energy thresholds, which can readily be applied in the clinic, can now be derived in order to minimize the contamination. We also show that the spurious activity itself is not spatially uniform. Therefore standard reconstruction and correction techniques are not adequate. In the case of SPECT we describe how it is now possible to classify detections into geometric detections, phantom scatter, penetration through the collimator, collimator scatter and backscatter in the end parts. We show that standard correction algorithms such as triple energy window correction cannot correct for septal penetration. We demonstrate that 124I PET with optimized energy thresholds offer better image quality than 131I SPECT when using standard reconstruction techniques. In the second part of this dissertation we focus on improving the efficiency of GATE with a variance reduction technique called Geometrical Importance Sampling (GIS). We describe how only 0.02% of all emitted photons can reach the crystal surface of a SPECT detector head with a low energy high resolution collimator. A lot of computing power is therefore wasted by tracking photons that will not contribute to the result. A twofold strategy is used to solve this problem: GIS employs Russian Roulette to discard those photons that will not likely contribute to the result. Photons in more important regions on the other hand are split into several photons with reduced weight to increase their survival chance. We show that this technique introduces branches into the particle history. We describe how this can be taken into account by a particle history tree that is used for the analysis of the results. The evaluation of GIS consists of energy spectra validation, spatial resolution and sensitivity for low and medium energy isotopes. We show that GIS reaches acceleration factors between 5 and 13 over analog GATE simulations for the isotopes in the study. It is a general acceleration technique that can be used for any isotope, phantom and detector combination. Although GIS is useful as a safe and accurate acceleration technique, it cannot deliver clinically acceptable simulation times. The main reason lies in its inability to force photons in a specific direction. In the third part of this dissertation we solve this problem for 99mTc SPECT simulations. Our approach is twofold. Firstly, we introduce two variance reduction techniques: forced detection (FD) and convolution-based forced detection (CFD) with multiple projection sampling (MPS). FD and CFD force copies of photons at decay and at every interaction point to be transported through the phantom in a direction sampled within a solid angle toward the SPECT detector head at all SPECT angles simultaneously. We describe how a weight must be assigned to each photon in order to compensate for the forced direction and non-absorption at emission and scatter. We show how the weights are calculated from the total and differential Compton and Rayleigh cross sections per electron with incorporation of Hubbell’s atomic form factor. In the case of FD all detector interactions are modeled by Monte Carlo, while in the case of CFD the detector is modeled analytically. Secondly, we describe the design of an FD and CFD specialized navigator to accelerate the slow tracking algorithms in GEANT4. The validation study shows that both FD and CFD closely match the analog GATE simulations and that we can obtain an acceleration factor between 3 (FD) and 6 (CFD) orders of magnitude over analog simulations. This allows for the simulation of a realistic acquisition with a torso phantom within 130 seconds. In the fourth part of this dissertation we exploit the intrinsic parallel nature of Monte Carlo simulations. We show how Monte Carlo simulations should scale linearly as a function of the number of processing nodes but that this is usually not achieved due to job setup time, output handling and cluster overhead. We describe how our approach is based on two steps: job distribution and output data handling. The job distribution is based on a time-domain partitioning scheme that retains all experimental parameters and that guarantees the statistical independence of each subsimulation. We also reduce the job setup time by the introduction of a parameterized collimator model for SPECT simulations. We reduce the data output handling time by a chain-based output merger. The scalability study is based on a set of simulations on a 70 CPU cluster and shows an acceleration factor of approximately 66 on 70 CPUs for both PET and SPECT.We also show that our method of parallelization does not introduce any approximations and that it can be readily combined with any of the previous acceleration techniques described above

Dynamic image data compression in spatial and temporal domains : theory and algorithm

Author name used in this publication: Dagan FengVersion of RecordPublishe