A Review on Recent Developments in Positron Emission Tomography Technology

Newer high-performance time-of-flight (TOF) positron emission tomography (PET) systems have the capability to preserve diagnostic image quality with low count density, while maintaining a high raw photon detection sensitivity that would allow for a reduction in injected dose or rapid data acquisition. To assess this, we performed quantitative and visual assessments of the PET images acquired using a highly sensitive (23.3cps/kBq) large field of view (25-cm axial) silicon photomultiplier (SiPM)-based TOF PET (400-ps timing resolution) integrated with 3T-MRI in comparison to PET images acquired on non-TOF PET/x-ray computed tomography (CT) systems. Whole-body 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) PET/CT was acquired for 15 patients followed by whole body PET/magnetic resonance imaging (MRI) with an average injected dose of 325±84MBq. The PET list mode data from PET/MRI were reconstructed using full datasets (4min/bed) and reduced datasets (2, 1, 0.5, and 0.25min/bed). Qualitative assessment between PET/CT and PET/MR images were made. A Likert-type scale between 1 and 5, 1 for non-diagnostic, 3 equivalent to PET/CT, and 5 superior quality, was used. Maximum and mean standardized uptake values (SUVmax and SUVmean) of normal tissues and lesions detected were measured and compared. Mean visual assessment scores were 3.54±0.32, 3.62±0.38, and 3.69±0.35 for the brain and 3.05±0.49, 3.71±0.45, and 4.14±0.44 for the whole-body maximum intensity projections (MIPs) for 1, 2, and 4min/bed PET/MR images, respectively. The SUVmean values for normal tissues were lower and statistically significant for images acquired at 4, 2, 1, 0.5, and 0.25min/bed on the PET/MR, with values of -18±28% (p < 0.001), - 16±29% (p = 0.001), - 16±31% (p = 0.002), - 14±35% (p < 0.001), and - 13±34% (p = 0.002), respectively. SUVmax and SUVpeak values of all lesions were higher and statistically significant (p < 0.05) for 4, 2, 1, 0.50, and 0.25min/bed PET/MR datasets. High-sensitivity TOF PET showed comparable but still better visual image quality even at a much reduced activity in comparison to lower-sensitivity non-TOF PET. Our data translates to a seven times reduction in either injection dose for the same time or total scan time for the same injected dose. This "ultra-sensitivity" PET system provides a path to clinically acceptable extremely low-dose FDG PET studies (e.g., sub 1mCi injection or sub-mSv effective dose) or PET studies as short as 1min/bed (e.g., 6min of total scan time) to cover whole body without compromising diagnostic performance.

During particle therapy irradiation, positron emitters with half-lives ranging from 2 to 20 min are generated from nuclear processes. The half-lives are such that it is possible either to detect the positron signal in the treatment room using an in-beam positron emission tomography (PET) system, right after the irradiation, or to quickly transfer the patient to a close PET/CT scanner. Since the activity distribution is spatially correlated with the dose, it is possible to use PET imaging as an indirect method to assure the quality of the dose delivery. In this work, we present a new dedicated PET system able to operate in-beam. The PET apparatus consists in two 10 cm × 10 cm detector heads. Each detector is composed of four scintillating matrices of 23 × 23 LYSO crystals. The crystal size is 1.9 mm × 1.9 mm × 16 mm. Each scintillation matrix is read out independently with a modularized acquisition system. The distance between the two opposing detector heads was set to 20 cm. The system has very low dead time per detector area and a 3 ns coincidence window, which is capable to sustain high single count rates and to keep the random counts relatively low. This allows a new full-beam monitoring modality that includes data acquisition also while the beam is on. The PET system was tested during the irradiation at the CATANA (INFN, Catania, Italy) cyclotron-based proton therapy facility. Four acquisitions with different doses and dose rates were analysed. In all cases the random to total coincidences ratio was equal or less than 25%. For each measurement we estimated the accuracy and precision of the activity range on a set of voxel lines within an irradiated PMMA phantom. Results show that the inclusion of data acquired during the irradiation, referred to as beam-on data, improves both the precision and accuracy of the range measurement with respect to data acquired only after irradiation. Beam-on data alone are enough to give precisions better than 1 mm when at least 5 Gy are delivered.

The idea of a very sensitive positron emission tomography (PET) system covering a large portion of the body of a patient already dates back to the early 1990s. In the period 2000–2010, only some prototypes with long axial field of view (FOV) have been built, which never resulted in systems used for clinical research. One of the reasons was the limitations in the available detector technology, which did not yet have sufficient energy resolution, timing resolution or countrate capabilities for fully exploiting the benefits of a long axial FOV design. PET was also not yet as widespread as it is today: the growth in oncology, which has become the major application of PET, appeared only after the introduction of PET-CT (early 2000).The detector technology used in most clinical PET systems today has a combination of good energy and timing resolution with higher countrate capabilities and has now been used since more than a decade to build time-of-flight (TOF) PET systems with fully 3D acquisitions. Based on this technology, one can construct total body PET systems and the remaining challenges (data handling, fast image reconstruction, detector cooling) are mostly related to engineering. The direct benefits of long axial FOV systems are mostly related to the higher sensitivity. For single organ imaging, the gain is close to the point source sensitivity which increases linearly with the axial length until it is limited by solid angle and attenuation of the body. The gains for single organ (compared to a fully 3D PET 20-cm axial FOV) are limited to a factor 3–4. But for long objects (like body scans), it increases quadratically with scanner length and factors of 10–40 × higher sensitivity are predicted for the long axial FOV scanner. This application of PET has seen a major increase (mostly in oncology) during the last 2 decades and is now the main type of study in a PET centre. As the technology is available and the full body concept also seems to match with existing applications, the old concept of a total body PET scanner is seeing a clear revival. Several research groups are working on this concept and after showing the potential via extensive simulations; construction of these systems has started about 2 years ago. In the first phase, two PET systems with long axial FOV suitable for large animal imaging were constructed to explore the potential in more experimental settings. Recently, the first completed total body PET systems for human use, a 70-cm-long system, called PennPET Explorer, and a 2-m-long system, called uExplorer, have become reality and first clinical studies have been shown. These results illustrate the large potential of this concept with regard to low-dose imaging, faster scanning, whole-body dynamic imaging and follow-up of tracers over longer periods. This large range of possible technical improvements seems to have the potential to change the current clinical routine and to expand the number of clinical applications of molecular imaging. The J-PET prototype is a prototype system with a long axial FOV built from axially arranged plastic scintillator strips.This paper gives an overview of the recent technical developments with regard to PET scanners with a long axial FOV covering at least the majority of the body (so called total body PET systems). After explaining the benefits and challenges of total body PET systems, the different total body PET system designs proposed for large animal and clinical imaging are described in detail. The axial length is one of the major factors determining the total cost of the system, but there are also other options in detector technology, design and processing for reducing the cost these systems. The limitations and advantages of different designs for research and clinical use are discussed taking into account potential applications and the increased cost of these systems.

Small-animal positron emission tomography as a tool for neuropharmacology

The first time-of-flight positron emission tomography (TOF-PET) scanners were developed as early as in the 1980s. However, the poor light output and low detection efficiency of TOF-capable detectors available at the time limited any gain in image quality achieved with these TOF-PET scanners over the traditional non-TOF PET scanners. The discovery of LSO and other Lu-based scintillators revived interest in TOF-PET and led to the development of a second generation of scanners with high sensitivity and spatial resolution in the mid-2000s. The introduction of the silicon photomultiplier (SiPM) has recently yielded a third generation of TOF-PET systems with unprecedented imaging performance. Parallel to these instrumentation developments, much progress has been made in the development of image reconstruction algorithms that better utilize the additional information provided by TOF. Overall, the benefits range from a reduction in image variance (SNR increase), through allowing joint estimation of activity and attenuation, to better reconstructing data from limited angle systems. In this work, we review these developments, focusing on three broad areas: 1) timing theory and factors affecting the time resolution of a TOF-PET system; 2) utilization of TOF information for improved image reconstruction; and 3) quantification of the benefits of TOF compared to non-TOF PET. Finally, we offer a brief outlook on the TOF-PET developments anticipated in the short and longer term. Throughout this work, we aim to maintain a clinically driven perspective, treating TOF as one of multiple (and sometimes competitive) factors that can aid in the optimization of PET imaging performance.

Quantitative estimation of the radionuclide activity concentration in positron emission tomography (PET) requires precise modeling of PET physics. The authors are focused on designing unconventional PET geometries for specific applications. This work reports the creation of a generalized reconstruction framework, capable of reconstructing tomographic PET data for systems that use right cuboidal detector elements positioned at arbitrary geometry using a regular Cartesian grid of image voxels. The authors report on a variety of design choices and optimization for the creation of the generalized framework. The image reconstruction algorithm is maximum likelihood-expectation-maximization. System geometry can be specified using a simple script. Given the geometry, a symmetry seeking algorithm finds existing symmetry in the geometry with respect to the image grid to improve the memory usage/speed. Normalization is approached from a geometry independent perspective. The system matrix is computed using the Siddon's algorithm and subcrystal approach. The program is parallelized through open multiprocessing and message passing interface libraries. A wide variety of systems can be modeled using the framework. This is made possible by modeling the underlying physics and data correction, while generalizing the geometry dependent features. Application of the framework for three novel PET systems, each designed for a specific application, is presented to demonstrate the robustness of the framework in modeling PET systems of unconventional geometry. Three PET systems of unconventional geometry are studied. (1) Virtual-pinhole half-ring insert integrated into Biograph-40: although the insert device improves image quality over conventional whole-body scanner, the image quality varies depending on the position of the insert and the object. (2) Virtual-pinhole flat-panel insert integrated into Biograph-40: preliminary results from an investigation into a modular flat-panel insert are presented. (3) Plant PET system: a reconfigurable PET system for imaging plants, with resolution of greater than 3.3 mm, is shown. Using the automated symmetry seeking algorithm, the authors achieved a compression ratio of the storage and memory requirement by a factor of approximately 50 for the half-ring and flat-panel systems. For plant PET system, the compression ratio is approximately five. The ratio depends on the level of symmetry that exists in different geometries. This work brings the field closer to arbitrary geometry reconstruction. A generalized reconstruction framework can be used to validate multiple hypotheses and the effort required to investigate each system is reduced. Memory usage/speed can be improved with certain optimizations.

Positron emission tomography (PET) has now gained a place in the management of patients with cancer, including those with Hodgkin's disease and non-Hodgkin's lymphoma. Restaging studies and those addressing the monitoring of response to treatment are especially in focus. Most of the knowledge gained has been achieved with dedicated BGO-based PET technology, but there are a number of developments that will impact on the use of this metabolic imaging technique in the investigation of patients with lymphoma. The challenges ahead are determined by the need for high-quality whole-body imaging associated with increased patient throughput and the need to investigate the role of new labelled ligands. The latter are likely to yield new insights into tumour cell characterisation, tumour behaviour and tumour outcome assessment. The study of new radiolabelled ligands will impose further demands for rapid dynamic data acquisition and accurate tracer quantification. Current and future developments in PET technology range from the use of new detector materials to different detector geometries and data acquisition modes. The search for alternatives to BGO scintillation materials for PET has led to the development of PET instruments utilising new crystals such as LSO and GSO. The use of these new detectors and the increased sensitivity achieved with 3D data acquisitions represent the most significant current developments in the field. With the increasing demands imposed on the clinical utilisation of PET, issues such as study cost and patient throughput will emerge as significant future factors. As a consequence, low-cost units are being offered by the manufacturers through the utilisation of gamma camera-based SPET systems for PET coincidence imaging. Unfortunately, clinical studies in lymphoma and other cancers have already demonstrated the limitations of this technology, with 20% of lesions <15 mm in size escaping detection. On the other hand, the recent development of combined PET/CT devices attempts to address the lack of anatomical information inherent with PET images, taking advantage of further improvement in patient throughput and hence cost-effectiveness. Preliminary studies using this multimodality imaging approach have already demonstrated the potential of the technique. Although the potential exists, certain technical issues with PET/CT require refinement of the methodology. Such issues include organ movement (such as respiratory motion), which strongly influences the image fusion of a rapidly acquired CT scan with the slower acquisition of a PET dataset, and the derivation of CT-based attenuation coefficients in the presence of contrast agents or metallic implants. The application of the technology for radiotherapy planning also poses a number of associated challenges. Finally, the development of dedicated PET systems based on planar detector arrangements with new detector components has the potential to improve clinical throughput by over 100%, but clinical trials using such systems have still to be carried out in order to establish the associated whole-body image quality.

Positron emission tomography (PET) is one of the most promising techniques for hadron therapy monitoring. This method uses imaging of the annihilation photons resulting from positron emitting isotopes produced during patient irradiation in hadron therapy. In order to maximize the sensitivity, in-beam PET is the preferred option, which requires a partial ring configuration. The usage of partial ring PET systems causes image artefacts and low quality images due to incomplete data. The inclusion of Time-of-flight (TO F) information into the reconstruction algorithm provides better image quality for PET systems. Therefore, a PET system with very good time and spatial resolution is necessary for hadron therapy monitoring. The Resistive-Plate-Chambers (RPCs), providing very good time and spatial resolution might be used for the quality control of hadron therapy. However, they have lower sensitivity than crystal-based systems. The objective of this study is the comparison of the performance of two TOF-PET systems, a RPC-based PET system currently under investigation by the TERA group and a commercially available crystal-based PET system, with respect to their feasibility of being applied to monitor cancer treatment with ion- and proton-beams. Various Monte-Carlo simulations were performed using GATE to evaluate the performance of both systems following NEMA protocols. Furthermore, a set of sources emulating the annihilation photons from β+-emitters produced after proton pencil beam irradiation on a PMMA target were obtained. These sources were employed to study the capability to reproduce the proton beam path and the distal edge position. Finally, we calculated the activity distribution produced by carbon ions on the basis of one field of a real treatment plan. The results obtained indicate that a RPC-based system has five times lower sensitivity, similar spatial resolution and about two times higher scatter fraction compared to the crystal-based system. The low sensitivity obtained by the RPC-based system is not sufficient to determine range deviations.

The future of positron emission tomography (PET) is systems with ultra-precise coincidence time resolution (CTR) to advance time-of-flight PET (TOF-PET) performance. Current state-of-the-art commercial PET systems have 350-800 ps fullwidth-at-half-maximum (FWHM) timing performance, constraining annihilation events to lie somewhere within a 5–12 cm region along system detector response lines (LORs). This constraint is applied during the image reconstruction process to enhance image SNR for improved lesion detectability, increased accuracy and precision of lesion uptake measurements, less sensitivity to errors in data correction techniques (normalization, scatter, and attenuation corrections), lower injected dose, or shorter scan time. The effect of these improvements on image quality and accuracy scales with system CTR performance, and a long-standing milestone for the TOFPET community is to drive system CTR towards 100 ps FWHM (1.5 cm localization along LORs). At this level of performance, a factor of five improvement in SNR can be realized compared to non-TOF imaging, with a transformational impact on quantitative PET imaging in many count starved and contrast-limited scenarios. Traditional PET detector designs are not able to achieve this level of CTR performance, and thus new detector concepts and signal processing methods should be explored to advance system CTR

Ordered Subsets Expectation Maximization (OSEM) has been introduced to greatly reduce reconstruction time compared to Maximum Likelihood Expectation Maximization (MLEM) in Positron Emission Tomography (PET). In case of noise-free data, OSEM converges to a MLEM image, but in presence of noise this might not be true, and also OSEM might not converge at all but cycle between similar but distinct images. Assessing what are the limits of the OSEM in terms of reliable contrast recovery is particularly interesting in situation of very short acquisitions and very sparse data. In this work, we study the convergence value of the contrast recovery as a function of the count statistics (and therefore the noise level) in the PET data, using a NEMA image quality phantom. A comparison between Time-of-Flight (TOF) and non-TOF implementations is performed. The scope of the work is to assess how the count statistics affects the convergence value and the convergence rate for OSEM reconstruction, and then to compare the corresponding convergence rates in conventional PET and in TOF PET reconstructions, by analyzing both experimental and simulated data.

Time resolution in time-of-flight positron emission tomography (TOF-PET) has improved significantly over the last decade due to advancements in scintillation materials, photodetectors, and readout electronics, which has increased the signal-to-noise ratio (SNR) compared to conventional PET. Silicon photomultipliers (SiPMs) in TOF-PET detectors are often operated at high bias voltage to improve the time performance at the expense of increasing signal noise. SiPM noise, both correlated and uncorrelated, can cause baseline fluctuations, leading to time-walk effects when a leading edge trigger strategy is used, and thus limiting timing performance. We examined the effect of SiPM baseline fluctuations using the FastIC ASIC, a scalable multichannel readout for fast timing applications. We flagged noisy events by using a comparator signal triggered by dark counts before the actual scintillation event. We tested different classification and correction methods with scintillating crystals and Cherenkov radiators, coupled to analog SiPMs from Broadcom (NUV-MT) and Hamamatsu Photonics. We reduced the coincidence time resolution (CTR) in bismuth germanate 2×2×3 mm3 (BGO) crystals from 410 ± 10 ps to 388 ± 10 ps FWHM (5 %) by correcting the time-walk on the noisy events. We measured an improvement from 107 ±2 ps to 93.5 ± 0.6 ps (11 %) for LYSO 2×2×3 mm3 crystals by filtering the noisy events. An improvement of 9 % on the CTR of the EJ232 plastic scintillator was also achieved by filtering noisy events, reducing it from 82.2 ± 0.5 ps to 75 ± 1 ps. This study presents a scalable method for flagging undesired events in a full TOF-PET system and discusses the impact of SiPM noise on the FastIC readout.

Developments in positron emission tomography (PET) technology have resulted in systems with finer detector elements designed to further improve spatial resolution. However, there is a limit to what extent reducing detector element size will improve spatial resolution in PET. The spatial resolution of PET imaging is limited by several other factors, such as annihilation photon non-collinearity, positron range, off-axis detector penetration, detector Compton scatter, undersampling of the signal in the linear or angular directions for the image reconstruction process, and patient motion. The overall spatial resolution of the systems is a convolution of these components. Of these other factors that contribute to resolution broadening, perhaps the most uncertain, poorly understood, and, for certain isotopes, the most dominant effect is from positron range. To study this latter effect we have developed a Monte Carlo simulation code that models positron trajectories and calculates the distribution of the end point coordinates in water for the most common PET isotopes used: F, N, C and O. In this work we present some results from these positron trajectory studies and calculate what effect positron range has on the overall PET system spatial resolution, and how this influences the choice of PET system design parameters such as detector element size and system diameter. We found that the fundamental PET system spatial resolution limit set from detector size, photon non-collinearity and positron range alone varied from nearly 1 mm FWHM (2 mm FWTM) for a 10-20 cm diameter system typical for animal studies with F to roughly 4 mm FWHM (7 mm FWTM) for an 80 cm diameter system typical for human imaging using O.

State of the art and challenges of time-of-flight PET

Recent developments in radiation detection technology have demonstrated the feasibility of simultaneous magnetic resonance imaging (MRI) and time-of-flight positron emission tomography (TOF-PET). In this paper we report on a compact detector module design for TOF-PET compatible with MR based on the FlexToT front-end application specific integrated circuit (ASIC), a fast, low-power front-end readout for silicon photomultiplier arrays. The module comprises scintillators, photosensors, ASICs, field-programmable gate arrays, and USB or Ethernet protocols for communication with data acquisition systems. The small footprint of the proposed design allows its use on positron emission tomography (PET) inserts for existing MRI equipment, both whole-body scanners, and dedicated organ systems. The main design features are presented together with results from the characterization of a proof-of-concept prototype in terms of radiation detection and measurements of radio frequency emission spectra from the electronic components. Ongoing work is focused on implementing and characterizing a full module inside MRI for ensuring electromagnetic compatibility, addressing proper shielding, and the possibility of simultaneous PET-MR acquisition using our compact detector module design.

Positron emission tomography (PET) images suffer from a noticeable amount of statistical noise. In order to reduce the noise, a post smoothing process is usually adopted in the conventional PET systems. However, its performance is limited because the process is mostly based on a Gaussian random noise which is quite distinct from the noise of PET images. It has been reported that noise variance of each voxel is proportional to the square of the mean value in a PET image reconstructed by expectation-maximization (EM). In addition, we also observe that the variance varies with the spatial sensitivity distribution in a PET system. Based on those properties, we determine a unique formula representing a relationship between the mean and variance for a given PET system. Meanwhile, a block matching 3D (or 4D) algorithm is known as the state of the art in Gaussian noise reduction. To effectively apply it for noise reduction of PET images, we first perform a noise characteristic conversion from the PET image noise to Gaussian random noise using a pre-determined relationship. We then apply a block matching 4D (BM4D) algorithm and reconvert the result. Using the Monte Carlo simulation, we demonstrate that proposed algorithm can effectively reduce the noise in the whole image region while minimizing the image resolution degradation.