Perelman School of Medicine at the University of Pennsylvania

Physics and Instrumentation Group

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Review Articles & Chapters

Roadmap toward the 10 ps time-of-flight PET challenge

Lecoq P, Morel C, Prior J, Visvikis D, Gundacker S, Auffray E, Krizan P, Martinez Turtos R, Thers D, Charbon E, Varela J, de La Taille C, Rivetti A, Breton D, Pratte J-F, Nuyts J, Surti S, Vandenberghe S, Marsden PK, Parodi K, Benlloch JM, Benoit M.

Physics in Medicine & Biology (2020).

Since the seventies, positron emission tomography (PET) has become an invaluable medical molecular imaging modality with an unprecedented sensitivity at the picomolar level, especially for cancer diagnosis and the monitoring of its response to therapy. More recently, its combination with X-ray computed tomography (CT) or magnetic resonance (MR) has added high precision anatomic information in fused PET/CT and PET/MR images, thus compensating for the modest intrinsic spatial resolution of PET. Nevertheless, a number of medical challenges call for further improvements in PET sensitivity. These concern in particular new treatment opportunities in the context personalized (also called precision) medicine, such as the need to dynamically track a small number of cells in cancer immunotherapy or stem cells for tissue repair procedures. A better signal-to-noise ratio (SNR) in the image would allow detecting smaller size tumours together with a better staging of the patients, thus increasing the chances of putting cancer in complete remission. Moreover, there is an increasing demand for reducing the radioactive doses injected to the patients without impairing image quality. There are three ways to improve PET scanner sensitivity: improving detector efficiency, increasing geometrical acceptance of the imaging device and pushing the timing performance of the detectors. Currently, some pre-localization of the electron-positron annihilation along a line-of-response (LOR) given by the detection of a pair of annihilation photons is provided by the detection of the time difference between the two photons, also known as the time-of-flight (TOF) difference of the photons, whose accuracy is given by the coincidence time resolution (CTR). A CTR of about 10 picoseconds FWHM will ultimately allow to obtain a direct 3D volume representation of the activity distribution of a positron emitting radiopharmaceutical, at the millimetre level, thus introducing a quantum leap in PET imaging and quantification and fostering more frequent use of 11C radiopharmaceuticals. The present roadmap article toward the advent of 10 ps TOF-PET addresses the status and current/future challenges along the development of TOF-PET with the objective to reach this mythic 10 ps frontier that will open the door to real-time volume imaging virtually without tomographic inversion. The medical impact and prospects to achieve this technological revolution from the detection and image reconstruction point-of-views, together with a few perspectives beyond the TOF-PET application are discussed.


Attenuation correction in emission tomography using the emission data -- A review.

Berker Y, Li Y.

Med Phys, vol. 43, pp. 807-832, 2016.

The problem of attenuation correction (AC) for quantitative positron emission tomography (PET) had been considered solved to a large extent after the commercial availability of devices combining PET with computed tomography (CT) in 2001; single photon emission computed tomography (SPECT) has seen a similar development. However stimulated in particular by technical advances toward clinical systems combining PET and magnetic resonance imaging (MRI), research interest in alternative approaches for PET AC has grown substantially in the last years. In this comprehensive literature review, the authors first present theoretical results with relevance to simultaneous reconstruction of attenuation and activity. The authors then look back at the early history of this research area especially in PET; since this history is closely interwoven with that of similar approaches in SPECT, these will also be covered. We then review algorithmic advances in PET, including analytic and iterative algorithms. The analytic approaches are either based on the Helgason-Ludwig data consistency conditions of the Radon transform, or generalizations of John's partial differential equation; with respect to iterative methods, we discuss maximum likelihood reconstruction of attenuation and activity (MLAA), the maximum likelihood attenuation correction factors (MLACF) algorithm, and their offspring. The description of methods is followed by a structured account of a0pp0lications for simultaneous reconstruction techniques: this discussion covers organ-specific applications, applications specific to PET/MRI, applications using supplemental information, and motion-aware applications. After briefly summarizing SPECT applications, we consider recent developments using emission data other than unscattered photons. In summary, developments using time-of-flight (TOF) PET emission data for AC have shown promising advances and open a wide range of applications. These techniques may both remedy deficiencies of purely MRI-based AC approaches in PET/MRI and improve standalone PET imaging.


System models for PET statistical iterative reconstruction: A review.

Iriarte A, Marabini R, Matej S, Sorzano COS, Lewitt RM.

Comput Med Imaging Graph, vol. 48, pp. 30-48, 2016.

Positron emission tomography (PET) is a nuclear imaging modality that provides in vivo quantitative measurements of the spatial and temporal distribution of compounds labeled with a positron emitting radionuclide. In the last decades, a tremendous effort has been put into the field of mathematical tomographic image reconstruction algorithms that transform the data registered by a PET camera into an image that represents slices through the scanned object. Iterative image reconstruction methods often provide higher quality images than conventional direct analytical methods. Aside from taking into account the statistical nature of the data, the key advantage of iterative reconstruction techniques is their ability to incorporate detailed models of the data acquisition process. This is mainly realized through the use of the so-called system matrix, that defines the mapping from the object space to the measurement space. The quality of the reconstructed images relies to a great extent on the accuracy with which the system matrix is estimated. Unfortunately, an accurate system matrix is often associated with high reconstruction times and huge storage requirements. Many attempts have been made to achieve realistic models without incurring excessive computational costs. As a result, a wide range of alternatives to the calculation of the system matrix exists. In this article we present a review of the different approaches used to address the problem of how to model, calculate and store the system matrix.


Advances in time-of-flight PET imaging.

Surti S, Karp JS.

Physica Medica, vol. 32, pp. 12-22, 2016.

This paper provides a review and an update on time-of-flight PET imaging with a focus on PET instrumentation, ranging from hardware design to software algorithms. We first present a short introduction to PET, followed by a description of TOF PET imaging and its history from the early days. Next, we introduce the current state-of-art in TOF PET technology and briefly summarize the benefits of TOF PET imaging. This is followed by a discussion of the various technological advancements in hardware (scintillators, photo-sensors, electronics) and software (image reconstruction) that have led to the current widespread use of TOF PET technology, and future developments that have the potential for further improvements in the TOF imaging performance. We conclude with a discussion of some new research areas that have opened up in PET imaging as a result of having good system timing resolution, ranging from new algorithms for attenuation correction, through efficient system calibration techniques, to potential for new PET system designs.


Time-of-flight PET: a review of different benefits and recent developments in time-of-flight PET.

Vandenberghe S, Mikhaylova E, D'Hoe E, Mollet P, Karp JS.

Eur J Nucl Med, vol. 3:3, 2016.

While the first time-of-flight (TOF)-positron emission tomography (PET) systems were already built in the early 1980s, limited clinical studies were acquired on these scanners. PET was still a research tool, and the available TOF-PET systems were experimental. Due to a combination of low stopping power and limited spatial resolution (caused by limited light output of the scintillators), these systems could not compete with bismuth germanate (BGO)-based PET scanners. Developments on TOF system were limited for about a decade but started again around 2000. The combination of fast photomultipliers, scintillators with high density, modern electronics, and faster computing power for image reconstruction have made it possible to introduce this principle in clinical TOF-PET systems. This paper reviews recent developments in system design, image reconstruction, corrections, and the potential in new applications for TOF-PET. After explaining the basic principles of time-of-flight, the difficulties in detector technology and electronics to obtain a good and stable timing resolution are shortly explained. The available clinical systems and prototypes under development are described in detail. The development of this type of PET scanner also requires modified image reconstruction with accurate modeling and correction methods. The additional dimension introduced by the time difference motivates a shift from sinogram- to listmode-based reconstruction. This reconstruction is however rather slow and therefore rebinning techniques specific for TOF data have been proposed. The main motivation for TOF-PET remains the large potential for image quality improvement and more accurate quantification for a given number of counts. The gain is related to the ratio of object size and spatial extent of the TOF kernel and is therefore particularly relevant for heavy patients, where image quality degrades significantly due to increased attenuation (low counts) and high scatter fractions. The original calculations for the gain were based on analytical methods. Recent publications for iterative reconstruction have shown that it is difficult to quantify TOF gain into one factor. The gain depends on the measured distribution, the location within the object, and the count rate. In a clinical situation, the gain can be used to either increase the standardized uptake value (SUV) or reduce the image acquisition time or administered dose. The localized nature of the TOF kernel makes it possible to utilize local tomography reconstruction or to separate emission from transmission data. The introduction of TOF also improves the joint estimation of transmission and emission images from emission data only. TOF is also interesting for new applications of PET-like isotopes with low branching ratio for positron fraction. The local nature also reduces the need for fine angular sampling, which makes TOF interesting for limited angle situations like breast PET and online dose imaging in proton or hadron therapy. The aim of this review is to introduce the reader in an educational way into the topic of TOF-PET and to give an overview of the benefits and new opportunities in using this additional information.


Update on time-of-flight PET imaging.

Surti S.

J Nucl Med, vol. 56, pp. 98-105, 2015.

Time-of-flight (TOF) PET was initially introduced in the early days of PET. The TOF PET scanners developed in the 1980s had limited sensitivity and spatial resolution, were operated in 2-dimensional mode with septa, and used analytic image reconstruction methods. The current generation of TOF PET scanners has the highest sensitivity and spatial resolution ever achieved in commercial whole-body PET, is operated in fully-3-dimensional mode, and uses iterative reconstruction with full system modeling. Previously, it was shown that TOF provides a gain in image signal-to-noise ratio that is proportional to the square root of the object size divided by the system timing resolution. With oncologic studies being the primary application of PET, more recent work has shown that in modern TOF PET scanners there is an improved tradeoff between lesion contrast, image noise, and total imaging time, leading to a combination of improved lesion detectability, reduced scan time or injected dose, and more accurate and precise lesion uptake measurement. Because the benefit of TOF PET is also higher for heavier patients, clinical performance is more uniform over all patient sizes.


Overview of methods for image reconstruction from projections in emission computed tomography.

Lewitt RM, Matej S.

Proc IEEE, vol. 91, pp. 1588–1611, 2003.

Emission computed tomography (ECT) is a technology for medical imaging whose importance is increasing rapidly. There is a growing appreciation for the value of the functional (as opposed to anatomical) information that is provided by ECT and there are significant advancements taking place, both in the instrumentation for data collection, and in the computer methods for generating images from the measured data. These computer methods are designed to solve the inverse problem known as "image reconstruction from projections". This paper uses the various models of the data collection process as the framework for presenting an overview of the wide variety of methods that have been developed for image reconstruction in the major subfields of ECT, which are positron emission tomography (PET) and single-photon emission computed tomography (SPECT). The overall sequence of the major sections in the paper, and the presentation within each major section, both proceed from the more realistic and general models to those that are idealized and application specific. For most of the topics, the description proceeds from the three-dimensional case to the two-dimensional case. The paper presents a broad overview of algorithms for PET and SPECT, giving references to the literature where these algorithms and their applications are described in more detail.