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Simon R. Cherry, PhD
Members > Simon R. Cherry, PhD
Dr. Cherry is Professor in the Department of Biomedical Engineering and Director of the Center for Molecular and Genomic Imaging at the University of California, Davis. Dr. Cherry's research interests center around biomedical imaging and in particular the development and application of in vivo molecular imaging technology and systems, with specific expertise in positron emission tomography (PET) and optical imaging and their application in preclinical research. The technologies developed by his laboratory have been broadly applied in biomedical science to study disease processes and measure the effects of novel therapeutic interventions. Dr. Cherry is an elected fellow of five professional societies, including the Institute for Electronic and Electrical Engineers (IEEE) and the Biomedical Engineering Society (BMES). He is Editor-in-Chief of the journal Physics in Medicine and Biology. Dr. Cherry is the author of more than 200 peer-reviewed journal articles, review articles and book chapters in the field of biomedical imaging.
Discipline: Imaging and Fundus Evaluation
H2RSPET: a 0.5 mm resolution high-sensitivity small-animal PET scanner, a simulation study.
Phys Med Biol. 2021 Feb 11;:
Authors: Lai Y, Wang Q, Zhou S, Xie Z, Qi J, Cherry SR, Jin M, Chi Y, Du J
With the goal of developing a total-body small-animal PET system with a high spatial resolution of ~ 0.5 mm and a high sensitivity > 10% for mouse/rat studies, we simulated four scanners using the graphical processing unit (GPU)-based Monte Carlo simulation package (gPET) and compared their performance in terms of spatial resolution and sensitivity. We also investigated the effect of depth-of-interaction (DOI) resolution on the spatial resolution. All the scanners are built upon 128 DOI encoding dual-ended readout detectors with lutetium yttrium oxyorthosilicate (LYSO) arrays arranged in 8 detector rings. The solid angle coverage of the four scanners are all ~0.85 steradians. Each LYSO element has a cross-section of 0.44 × 0.44 mm2and the pitch size of the LYSO arrays are all 0.5 mm. The four scanners can be divided into two groups: (1) H2RS110-C10 and H2RS110-C20 with 40 × 40 LYSO arrays, a ring diameter of 110 mm and axial length of 167 mm, and (2) H2RS160-C10 and H2RS160-C20 with 60 × 60 LYSO arrays, a diameter of 160 mm and axial length of 254 mm. C10 and C20 denote the crystal thickness of 10 and 20 mm, respectively. The simulation results show that all scanners have a spatial resolution better than 0.5 mm at the center of the field-of-view (FOV). The radial resolution strongly depends on the DOI resolution and radial offset, but not the axial resolution and tangential resolution. Comparing the C10 and C20 designs, the former provides better resolution, especially at positions away from the center of the FOV, whereas the latter has 2x higher sensitivity (~10% vs. ~20%). This simulation study provides evidence that the 110 mm systems are a good choice for total-body mouse studies at a lower cost, whereas the 160 mm systems are suited for both total-body mouse and rat studies.
PMID: 33571980 [PubMed - as supplied by publisher]
Farewell from the outgoing Editor-in-Chief.
Phys Med Biol. 2020 Dec 15;65(24):240301
Authors: Cherry SR
Quantitative PET in the 2020s: A Roadmap.
Phys Med Biol. 2020 Dec 18;:
Authors: Meikle SR, Sossi V, Roncali E, Cherry SR, Banati R, Mankoff DA, Jones T, James ML, Sutcliffe J, Ouyang J, Petibon Y, Ma C, El Fakhri G, Surti S, Karp JS, Badawi RD, Yamaya T, Akamatsu G, Schramm G, Rezaei A, Nuyts J, Fulton RR, Kyme AZ, Lois C, Sari H, Price J, Boellaard R, Jeraj R, Bailey DL, Eslick EM, Willowson KP, Dutta J
Positron emission tomography (PET) plays an increasingly important role in research and clinical applications, catalysed by remarkable technical advances and a growing appreciation of the need for reliable, sensitive biomarkers of human function in health and disease. Over the last 30 years a large amount of the physics and engineering effort in PET has been motivated by the dominant clinical application during that period, oncology. This has led to important developments such as PET/CT, whole-body PET, 3D PET, accelerated statistical image reconstruction, and time-of-flight PET. Despite impressive improvements in image quality as a result of these advances, the emphasis on static, semi-quantitative "hot spot" imaging for oncologic applications has meant that the capability of PET for quantifying biologically relevant parameters based on tracer kinetics has not been fully exploited. More recent advances, such as PET/MR and total body PET, have opened up the ability to address a vast range of new research questions from which a future expansion of applications and radiotracers appears highly likely. Many of these new applications and tracers will, at least initially, require quantitative analyses that more fully exploit the exquisite sensitivity of PET and the tracer principle on which it is based. It is also expected that they will require more sophisticated quantitative analysis methods than those that are currently available. At the same time, artificial intelligence is revolutionizing data analysis and impacting the relationship between the statistical quality of the acquired data and the information we can extract from the data. In this roadmap, leaders of the key sub-disciplines of the field identify the challenges and opportunities to be addressed over the next 10 years that will enable PET to realise its full quantitative potential, initially in research laboratories and, ultimately, in clinical practice.
Scanner Design Considerations for Long Axial Field-of-View PET Systems.
PET Clin. 2020 Nov 04;:
Authors: Daube-Witherspoon ME, Cherry SR
This article describes aspects of PET scanner design for long axial field-of-view systems and how these choices have an impact on scanner performance.
Performance evaluation of the uEXPLORER Total-body PET/CT scanner based on NEMA NU 2-2018 with additional tests to characterize long axial field-of-view PET scanners.
J Nucl Med. 2020 Oct 02;:
Authors: Spencer BA, Berg E, Schmall JP, Omidvari N, Leung EK, Abdelhafez YG, Tang S, Deng Z, Dong Y, Lv Y, Bao J, Liu W, Li H, Jones T, Badawi RD, Cherry SR
The world's first total-body PET scanner with an axial field-of-view (AFOV) of 194 cm is now in clinical and research use at our institution. The uEXPLORER PET/CT scanner, developed through a collaboration between the University of California, Davis (UC Davis) and United Imaging Healthcare (UIH), is the first commercially available total-body PET scanner. Here we present a detailed physical characterization of the uEXPLORER PET scanner based on NEMA NU-2-2018 along with a new set of measurements devised to appropriately characterize the total-body scanner. Methods: Sensitivity, count-rate performance, time-of-flight resolution, spatial resolution, and image quality were evaluated following the NEMA NU-2-2018 protocol. Additional measurements of sensitivity and count-rate capabilities more representative of total-body imaging were performed using extended geometry phantoms based on the world average human height (~165 cm). Lastly, image quality throughout the long AFOV was assessed with the NEMA image quality (IQ) phantom imaged at five axial positions and over a range of expected total-body PET imaging conditions (low dose, delayed imaging, short scan duration). Results: Our performance evaluation of the uEXPLORER PET system demonstrates that the scanner provides a very high sensitivity of 174 kcps/MBq, count-rate performance with a peak noise equivalent count-rate (NECR) of approximately 2 Mcps for total-body imaging, coupled with good spatial resolution capabilities for human imaging (≤ 3.0 mm FWHM near the center of the AFOV). Excellent image quality, contrast recovery, and low noise properties were illustrated across the AFOV in both NEMA IQ phantom evaluations and human imaging examples. Conclusion: In addition to standard NEMA NU-2-2018 characterization, a new set of measurements based on extending NEMA NU-2-2018 phantoms and experiments were devised to characterize the physical performance of the first total-body PET system. Rationale for these extended measurements was evident from differences in sensitivity, count-rate - activity relationships, and NECR limits imposed by differences in deadtime and randoms fraction between the NEMA NU-2 70 cm phantoms and the more representative total-body imaging phantoms. Overall, the total-body uEXPLORER PET system provides ultra-high sensitivity that supports excellent spatial resolution and image quality throughout the FOV in both phantom and human imaging.
Performance comparison of dual-ended readout depth-encoding PET detectors based on BGO and LYSO crystals.
Phys Med Biol. 2020 Oct 21;:
Authors: Du J, Ariño-Estrada G, Bai X, Cherry SR
The performance of dual-ended readout depth-encoding PET detectors based on bismuth germanate (BGO) coupled to silicon photomultipliers (SiPM) arrays was measured for the first time and compared to lutetium-yttrium oxyorthosilicate (LYSO) based detectors using the same readout. The BGO and LYSO crystal arrays all had a crystal pitch of 2.2 mm and were coupled to 8 × 8 SiPM arrays with a matching pitch of 2.2 mm, using a one-to-one coupling configuration. Three types of crystals with Toray reflector were used: polished LYSO, polished BGO, and unpolished BGO, and for two different crystal thicknesses of 20 mm and 30 mm. All the crystal elements in the BGO arrays were clearly resolved in the flood histogram. Better flood histograms were obtained using the LYSO arrays for a selected crystal thickness, and better flood histograms were obtained using the 20 mm thick crystal arrays for a selected crystal type. The average crystal level energy resolution and timing resolution for 20 mm polished LYSO, polished BGO and unpolished BGO crystals at their optimal SiPM bias voltage were 18.6 ± 1.3 % and 1.19 ± 0.20 ns, 17.8 ± 0.8 % and 4.43 ± 0.47 ns, and 18.0 ± 1.0 % and 4.68 ± 1.0 ns, respectively. Depth-of-interaction (DOI) resolution of the 20 mm polished LYSO array was 2.31 ± 0.17 mm and for the 20 mm unpolished BGO array was 3.53 ± 0.25 mm. However, polished BGO arrays with Toray reflector did not provide DOI information. Our key conclusion is that dual-ended readout depth-encoding 20 mm thick unpolished BGO detectors are good candidates for low-activity PET systems with small field-of-view and low timing performance requirements, such as preclinical or compact organ-dedicated PET systems, with the advantage over LYSO of having no background radiation and significantly lower cost.
Total-Body Quantitative Parametric Imaging of Early Kinetics of FDG.
J Nucl Med. 2020 Sep 18;:
Authors: Feng T, Zhao Y, Shi H, Zhang X, Wang G, Badawi RD, Price PM, Cherry SR, Jones T
Parametric imaging has been shown to provide better quantitation physiologically compared with SUV imaging in PET. With the increased sensitivity from a recently developed total-body PET scanner, whole-body scans with higher temporal resolution become possible for dynamic analysis and parametric imaging. In this paper, we focus on deriving the parameter k1 using compartmental modeling, and on developing a method to acquire whole-body FDG-PET parametric images using only the first 90 seconds of the post-injection scan data with the total-body PET system. Dynamic projections were acquired with a time interval of 1 second for the first 30 seconds and 2 seconds for the following minute. Image-derived input functions were acquired from the reconstructed dynamic sequences in the ascending aorta. The one-tissue compartment model with the total of 4 parameters (k1, k2, blood fraction, delay time) was used. A maximum-likelihood based estimation method was developed with the 1-tissue compartment model solution. The accuracy of the acquired parameters was compared with the ones estimated using a 2-tissue irreversible model with 1-hour long data. All four parametric images were successfully calculated using data from two volunteers. By comparing the time-activity-curves acquired from the volume of interests, it was shown that the parameters estimated using our method were able to predict the time-activity curves of the early dynamics of FDG in different organs. The time delay effects for different organs were also clearly visible in the reconstructed time delay image with delay variations as large as 40 seconds. The estimated parameters using both 90 seconds data and 1-hour long data were in good agreement for k1 and blood fraction, while a large difference of k2 was found between the 90 seconds and 1-hour data, suggesting k2 can't be reliably estimated from the 90 second scan. We have shown that with the use of total-body PET and the increased sensitivity, it is possible to estimate parametric images based on the very early dynamics following FDG injection. The estimated k1 could potentially be used clinically as an indicator for identifying abnormalities.
Imaging Salt Uptake Dynamics in Plants Using PET.
Sci Rep. 2019 Dec 09;9(1):18626
Authors: Ariño-Estrada G, Mitchell GS, Saha P, Arzani A, Cherry SR, Blumwald E, Kyme AZ
Soil salinity is a global environmental challenge for crop production. Understanding the uptake and transport properties of salt in plants is crucial to evaluate their potential for growth in high salinity soils and as a basis for engineering varieties with increased salt tolerance. Positron emission tomography (PET), traditionally used in medical and animal imaging applications for assessing and quantifying the dynamic bio-distribution of molecular species, has the potential to provide useful measurements of salt transport dynamics in an intact plant. Here we report on the feasibility of studying the dynamic transport of 22Na in millet using PET. Twenty-four green foxtail (Setaria viridis L. Beauv.) plants, 12 of each of two different accessions, were incubated in a growth solution containing 22Na+ ions and imaged at 5 time points over a 2-week period using a high-resolution small animal PET scanner. The reconstructed PET images showed clear evidence of sodium transport throughout the whole plant over time. Quantitative region-of-interest analysis of the PET data confirmed a strong correlation between total 22Na activity in the plants and time. Our results showed consistent salt transport dynamics within plants of the same variety and important differences between the accessions. These differences were corroborated by independent measurement of Na+ content and expression of the NHX transcript, a gene implicated in sodium transport. Our results demonstrate that PET can be used to quantitatively evaluate the transport of sodium in plants over time and, potentially, to discern differing salt-tolerance properties between plant varieties. In this paper, we also address the practical radiation safety aspects of working with 22Na in the context of plant imaging and describe a robust pipeline for handling and incubating plants. We conclude that PET is a promising and practical candidate technology to complement more traditional salt analysis methods and provide insights into systems-level salt transport mechanisms in intact plants.
Total-body PET and highly stable chelators together enable meaningful 89Zr-antibody-PET studies up to 30 days post-injection.
Authors: Berg E, Gill H, Marik J, Ogasawara A, Williams SP, van Dongen GAMS, Vugts DJ, Cherry SR, Tarantal AF
Rationale: The use of 89Zr-antibody-PET imaging to measure antibody biodistribution and tissue pharmacokinetics is well established, but current PET imaging systems lack the sensitivity needed to study 89Zr-labeled antibodies beyond two to three isotope half-lives (7-10 days), after which poor signal-to-noise is problematic. However, studies across many weeks are desirable to better match antibody circulation half-life in human and nonhuman primates. These studies investigated the technical feasibility of using the primate mini-EXPLORER PET scanner, making use of its high sensitivity and 45 cm axial field-of-view (FOV), for total-body imaging of 89Zr-labeled antibodies in rhesus monkeys up to 30-days post-injection. Methods: A humanized monoclonal IgG antibody against the herpes simplex viral protein gD was radiolabeled with 89Zr via one of four chelator-linker combinations (DFO-Bz-NCS, DFO-squaramide, DFO*-Bz-NCS, and DFO*-squaramide). The pharmacokinetics associated with these chelator-linker combinations were compared in 12 healthy young male rhesus monkeys (~1-2 years of age, ~3 ±1 kg). Each animal was initially injected intravenously with unlabeled antibody (10 mg/kg providing therapeutic-level antibody concentrations; right), which was then immediately followed by ~40 MBq of one of the 89Zr-labeled antibodies injected intravenously at a contralateral site (left). All animals were imaged six times over a period of 30 days, with an initial 60-minute dynamic scan on day 0 (day of injection), followed by static scans of 30-45 minutes on approximately days 3, 7, 14, 21, and 30, with all acquired using a single bed position and images reconstructed using a time-of-flight listmode OSEM algorithm. Activity concentrations in various organs were extracted from the PET images using manually defined regions-of-interest (ROIs). Results: Excellent image quality was obtained, capturing the initial distribution phase in the whole-body scan, later time points showed residual 89Zr mainly in the liver. Even at 30 days post-injection, representing approximately 9 half-lives of 89Zr and with a total residual activity in the animal of only 20-40 kBq, the image quality was sufficient to readily identify activity in the liver, kidneys, and bone joints. Significant differences were noted in late time-point liver uptake, bone uptake, and whole-body clearance between chelator-linker types, while little variation (±10%) was observed within each type. Conclusion: These studies demonstrate the ability to image 89Zr radiolabeled antibodies up to 30 days post-injection while maintaining satisfactory image quality provided by the primate mini-EXPLORER with high sensitivity and long axial FOV. Quantification demonstrated potentially important differences in the behavior of the four chelators, which supports further investigation.
FIRST HUMAN IMAGING STUDIES WITH THE EXPLORER TOTAL-BODY PET SCANNER.
J Nucl Med. 2019 Feb 07;:
Authors: Badawi RD, Shi H, Hu P, Chen S, Xu T, Price PM, Ding Y, Spencer BA, Nardo L, Liu W, Bao J, Jones T, Li H, Cherry SR
Within the EXPLORER consortium, the construction of the world's first total-body PET/CT scanner has recently been completed. The 194 cm axial field of view of the EXPLORER PET/CT scanner is sufficient to cover for the first time, the entire human adult body in a single acquisition in more than 99% of the population and allows total-body pharmacokinetic studies with frame durations as short as 1 second. The large increase in sensitivity arising from total-body coverage as well as increased solid angle for detection at any point within the body allows whole-body 18F-fluorodeoxyglucose (FDG) PET studies to be acquired with unprecedented count density, improving the signal-to-noise ratio of the resulting images. Alternatively, the sensitivity gain can be used to acquire state-of-the-art diagnostic PET images with very small amounts of activity in the field of view (< 1 mCi), with very short acquisition times (< 2 mins) or at later time points after the tracer's administration. We report here on the first human imaging studies on the EXPLORER scanner using a range of different protocols provide initial evidence in support of these claims. These case studies provide the foundation for future carefully controlled trials to quantitatively evaluate the improvements possible through total-body PET imaging.
Mini EXPLORER II: a prototype high-sensitivity PET/CT scanner for companion animal whole body and human brain scanning.
Phys Med Biol. 2019 Jan 08;:
Authors: Lyu Y, Lv X, Liu W, Judenhofer MS, Zwingenberger A, Wisner ER, Berg E, McKenney SE, Leung EK, Spencer BA, Cherry SR, Badawi RD
As part of the EXPLORER total-body positron emission tomography (PET) project, we have designed and built a high-resolution, high-sensitivity PET/CT scanner which is expected to have excellent performance for companion animal whole body and human brain imaging. The PET component has a ring diameter of 52 cm and an axial field of view of 48.3 cm. The detector modules are composed of arrays of lutetium (yttrium) oxyorthosilicate (LYSO) crystals of dimensions 2.76x2.76x18.1 mm coupled to silicon photomultipliers (SiPMs) for read-out. The CT component is a 24 detector row CT scanner with a 50 kW X-ray tube. PET system time-of-flight resolution was measured to be 409±39 ps and average system energy resolution was 11.7%±1.5% at 511 keV. The NEMA NU2-2012 system sensitivity was found to be 52-54 kcps/MBq. Spatial resolution was 2.6 mm at 10mm from the center of the FOV and 2.0 mm rods were clearly resolved on a mini-Derenzo phantom. Peak noise-equivalent count (NEC) rate, using the NEMA NU 2-2012 phantom, was measured to be 314 kcps at 9.2 kBq/cc. The CT scanner passed the technical components of the American College of Radiology (ACR) accreditation tests. We have also performed scans of a Hoffman brain phantom and we show images from the first canine patient imaged on this device.
Optimization of a depth of interaction encoding PET block detector for a PET/MRI insert.
Authors: Selfridge AR, Cherry SR, Judenhofer MS
Preclinical positron emission tomography, combined with magnetic resonance imaging (PET/MRI), is increasingly used as a tool to simultaneously characterize functional processes in vivo. Many emerging preclinical applications, however, are limited by PET detection sensitivity, especially when generating short imaging frames for quantitative studies. One such application is dynamic multifunctional imaging, which probes multiple aspects of a biological process, using relationships between the datasets to quantify interactions. These studies have limited accuracy due to the relatively low sensitivity of modern preclinical PET/MRI systems. The goal of this project is to develop a preclinical PET/MRI insert with detection sensitivity above 15% (250-750 keV) to improve quantitation in dynamic PET imaging. To achieve this sensitivity, we have developed a detector module incorporating a 2 cm thick crystal block, which will be arranged into a system with 8 cm axial FOV, targeting mice and rats. To maintain homogenous spatial resolution, the detector will incorporate dual-ended depth-of-interaction (DOI) encoding with silicon photomultiplier (SiPM) based photodetector arrays. The specific aim of this work is to identify a detector configuration with adequate performance for the proposed system. We have optimized the SiPM array geometry and tested two crystal array materials with pitch ranging from 0.8 to 1.2 mm and various surface treatments and reflectors. From these configurations, we have identified the best balance between crystal separation, energy resolution, and DOI resolution. The final detector module uses two rectangular SiPM arrays with 5 × 6 and 5 × 4 elements. The photodetector arrays are coupled to a 19 × 19 array of 1 mm pitch LYSO crystals with polished surfaces and a diffuse reflector. The prototype design has 14.3% ± 2.9% energy resolution, 3.57 ± 0.88 mm DOI resolution, and resolves all elements in the crystal array, giving it sufficient performance to serve as the basis for the proposed high sensitivity PET/MRI insert.
A depth-of-interaction encoding PET detector module with dual-ended readout using large-area silicon photomultiplier arrays.
Phys Med Biol. 2018 Nov 05;:
Authors: Du J, Bai X, Cherry SR
The performance of a depth-of-interaction (DOI) encoding PET detector module with dual-ended readout of LYSO scintillator arrays using large-area SiPM arrays was evaluated. Each SiPM array, with a surface area 50.2 mm x 50.2 mm, consists of 12 x 12 C-series SiPMs from SensL (SensL, Inc). The LYSO array, with a total size of 46 mm x 46 mm and a pitch size of 1.0 mm, consists of a 46 x 46 array of 0.945 mm x 0.945 mm x 20 mm polished LYSO crystals, separated by Toray reflector. Custom front-end electronics were designed to reduce the 288 SiPM signals of one detector module to 9 signals, 8 for position information and 1 for timing information. Schottky diodes were used to block noise from SiPMs that did not detect a significant number of scintillation photons following a gamma interaction. Measurements of noise, signal, signal-to-noise ratio, energy resolution and flood histogram quality were obtained at different bias voltages (26.0 to 31.0 V in 0.5 V intervals) and at two temperatures (5 °C and 20 °C). Clear acrylic plates, 2.0 mm thick, were used as light guides to spread the scintillation photons. Timing resolution, depth of interaction resolution, and the effect of event rate on detector performance were measured at the bias voltage determined to be optimal for the flood histograms. Performance obtained with and without the noise-blocking Shottky diodes was also compared. The results showed that all crystals in the LYSO array can be clearly resolved, and performance improved when using diodes to block noise, and at the lower temperature. The average energy resolution, flood histogram quality, timing resolution and DOI resolution were 23.8 ± 2.0 %, 1.54 ± 0.17, 1.78 ± 0.09 ns and 2.81 ± 0.13 mm respectively, obtained at a bias voltage of 30.0 V and a temperature of 5 °C using the diode readout method. The event rate experiments showed that the flood histogram and energy resolution of the detector were not significantly degraded for an event rate of up to 150 000 counts/s.
Development of TlBr detectors for PET imaging.
Phys Med Biol. 2018 May 04;:
Authors: Ariño-Estrada G, Du J, Kim H, Cirignano LJ, Shah KS, Cherry SR, Mitchell GS
Thallium bromide (TlBr) is a promising semiconductor detector material for positron emission tomography (PET) because it can offer very good energy resolution and 3-D segmentation capabilities, and it also provides detection efficiency surpassing that of commonly used scintillators. Energy, timing, and spatial resolution were measured for thin (<1 mm) TlBr detectors. The energy and timing resolution were measured simultaneously for the same planar 0.87 mm-thick TlBr device. An energy resolution of (6.41.3)% at 511 keV was achieved at -400 V bias voltage and at room temperature. A timing resolution of (27.84.1) ns FWHM was achieved for the same operating conditions when appropriate energy gating was applied. The intrinsic spatial resolution was measured to be 0.9 mm FWHM for a TlBr detector with metallic strip contacts of 0.5 mm pitch. As material properties improve, higher bias voltage should improve timing performance. A stack of thin detectors with finely segmented readout can create a modular detector with excellent energy and spatial resolution for PET applications.&#13.
Improving Edge Crystal Identification in Flood Histograms Using Triangular Shape Crystals.
Biomed Phys Eng Express. 2018 Mar;4(2):
Authors: Peng P, Liu CC, Du J, Bai X, Cherry SR
This work presents a method to improve the separation of edge crystals in PET block detectors. As an alternative to square-shaped crystal arrays, we used an array of triangular-shaped crystals. This increases the distance between the crystal centres at the detector edges potentially improving the separation of edge crystals. To test this design, we have compared the flood histograms of two 4×4 scintillator arrays in both square and triangular configurations. The quality of the flood histogram was quantified using the fraction of events positioned in the correct crystal based on a 2D Gaussian fit of the segmented flood histograms. In the first study, the two crystal arrays were coupled with the SiPM directly using optical grease, and the flood histogram quality for the edge and corner crystals in the triangular-shaped array were much better than that for those crystals in the square-shaped array. The average light collection efficiency for the triangular-shaped array was 5.9% higher than that for the square-shaped array. The average energy resolution for the triangular and square shape array were 11.6% and 13.2% respectively. In the second study, two light guides with thickness 1 mm and 2 mm were used between the crystal arrays and the SiPM. The thicker lightguide degraded the light collection efficiency and energy resolution due to the light loss introduced by the light guide. However, in the 2-mm thick lightguide case, the flood histogram quality for the edge and corner crystals in the square-shaped array were improved due to better separation of those crystals in the flood histogram. Comparing the performance of the two crystal arrays with three different light guides, the triangular-shaped crystal array with no lightguide gave the best performance.
TOTAL-BODY PET: MAXIMIZING SENSITIVITY TO CREATE NEW OPPORTUNITIES FOR CLINICAL RESEARCH AND PATIENT CARE.
Authors: Cherry SR, Jones T, Karp JS, Qi J, Moses W, Badawi R
Positron emission tomography (PET) is widely considered as the most sensitive technique available for non-invasively studying physiology, metabolism and molecular pathways in the living human being. However, the utility of PET, being a photon deficient modality, remains constrained by factors including low signal-to-noise ratio (SNR), long imaging times and concerns regarding radiation dose. Two developments offer the potential to dramatically increase the effective sensitivity of PET. First by increasing the geometric coverage to encompass the entire body, sensitivity can be increased by a factor of ~40 for total-body imaging or a factor of ~4-5 for imaging a single organ such as the brain or heart. The world's first total-body PET/computerized tomography (CT) scanner is currently under construction to demonstrate how this step change in sensitivity impacts the way PET is utilized both in clinical research and patient care. Second, there is the future prospect of significant improvements in timing resolution that could lead to further effective sensitivity gains. When combined with total-body PET, this could produce overall sensitivity gains of more than two orders of magnitude compared to existing state-of-the-art systems. In this article we discuss the benefits of increasing body coverage, describe our efforts to develop a first-generation total-body PET/CT scanner, discuss selected application areas for total-body PET and project the impact of further improvements in time-of-flight (TOF) PET.
Performance Comparison of Different Readouts for Position-Sensitive Solid-State Photomultiplier Arrays.
Biomed Phys Eng Express. 2017 Aug;3(4):
Authors: Du J, Schmall JP, Di K, Yang Y, Dokhale PA, Shah KS, Cherry SR
A thorough comparison of five different readouts for reading out a 2 × 2 array of 5 mm × 5 mm position-sensitive solid-state photomultipliers (PS-SSPM) was undertaken. The five readouts include reading out the 20 signals (16 position and 4 timing) individually, two signal multiplexing readouts, and two position decoding readouts. Flood histogram quality, signal-to-noise ratio (SNR) and energy resolution were compared at different bias voltage (27.0 V to 32.0 V, at 0.5 V intervals) and at a fixed temperature of 0 °C by coupling a 6 × 6 array of 1.3 mm × 1.3 mm × 20 mm polished LSO crystals to the center of the PS-SSPM array. The timing resolution was measured at a bias voltage of 31.0 V (optimal bias voltage in terms of flood histogram quality). The best flood histogram quality value and signal-to-noise were 7.3 ± 1.6 and 33.5 ± 3.1, respectively, and were obtained by shaping and digitizing the 16 position signals individually. The capacitive charge-division readout is the simplest readout among the five evaluated but still resulted in good performance with a flood histogram quality value of 3.3 ± 0.4 and a SNR of 18.3 ± 1.3. The average energy resolution and the average timing resolution were 15.2 ± 1.2 % and 8.4 ± 1.6 ns for individual signal readout and 15.9 ± 1.2 % and 8.8 ± 1.3 ns by using the capacitive charge-division readout method. These studies show that for an ultra-high spatial resolution applications using the 2 × 2 PS-SSPM array, reading out the 20 signals individually is necessary; whilst the capacitive charge-division readout is a cost-effective readout for less demanding applications.
Open-field mouse brain PET: design optimisation and detector characterisation.
Phys Med Biol. 2017 Jul 13;62(15):6207-6225
Authors: Kyme AZ, Judenhofer MS, Gong K, Bec J, Selfridge A, Du J, Qi J, Cherry SR, Meikle SR
'Open-field' PET, in which an animal is free to move within an enclosed space during imaging, is a very promising advance for neuroscientific research. It provides a key advantage over conventional imaging under anesthesia by enabling functional changes in the brain to be correlated with an animal's behavioural response to environmental or pharmacologic stimuli. Previously we have demonstrated the feasibility of open-field imaging of rats using motion compensation techniques applied to a commercially available PET scanner. However, this approach of 'retro-fitting' motion compensation techniques to an existing system is limited by the inherent geometric and performance constraints of the system. The goal of this project is to develop a purpose-built PET scanner with geometry, motion tracking and imaging performance tailored and optimised for open-field imaging of the mouse brain. The design concept is a rail-based sliding tomograph which moves according to the animal's motion. Our specific aim in this work was to evaluate candidate scanner designs and characterise the performance of a depth-of-interaction detector module for the open-field system. We performed Monte Carlo simulations to estimate and compare the sensitivity and spatial resolution performance of four scanner geometries: a ring, parallel plate, and two box variants. Each system was based on a detector block consisting of a 23 × 23 array of 0.785 × 0.785 × 20 mm3 LSO crystals (overall dim. 19.6 × 19.6 × 20 mm). We found that a DoI resolution capability of 3 mm was necessary to achieve approximately uniform sub-millimetre spatial resolution throughout the FoV for all scanners except the parallel-plate geometry. With this DoI performance, the sensitivity advantage afforded by the box geometry with overlapping panels (16% peak absolute sensitivity, a 36% improvement over the ring design) suggests this unconventional design is best suited for imaging the mouse brain. We also built and characterised the block detector modelled in the simulations, including a dual-ended readout based on 6 × 6 arrays of through-silicon-via silicon photomultipliers (active area 84%) for DoI estimation. Identification of individual crystals in the flood map was excellent, energy resolution varied from 12.4% ± 0.6% near the centre to 24.4% ± 3.4% at the ends of the crystal, and the average DoI resolution was 2.8 mm ± 0.35 mm near the central depth (10 mm) and 3.5 mm ± 1.0 mm near the ends. Timing resolution was 1.4 ± 0.14 ns. Therefore, the DoI detector module meets the target specifications for the application and will be used as the basis for a prototype open-field mouse PET scanner.
PMID: 28475491 [PubMed - indexed for MEDLINE]
Advanced optical simulation of scintillation detectors in GATE V8.0: first implementation of a reflectance model based on measured data.
Phys Med Biol. 2017 Jun 21;62(12):L1-L8
Authors: Stockhoff M, Jan S, Dubois A, Cherry SR, Roncali E
Typical PET detectors are composed of a scintillator coupled to a photodetector that detects scintillation photons produced when high energy gamma photons interact with the crystal. A critical performance factor is the collection efficiency of these scintillation photons, which can be optimized through simulation. Accurate modelling of photon interactions with crystal surfaces is essential in optical simulations, but the existing UNIFIED model in GATE is often inaccurate, especially for rough surfaces. Previously a new approach for modelling surface reflections based on measured surfaces was validated using custom Monte Carlo code. In this work, the LUT Davis model is implemented and validated in GATE and GEANT4, and is made accessible for all users in the nuclear imaging research community. Look-up-tables (LUTs) from various crystal surfaces are calculated based on measured surfaces obtained by atomic force microscopy. The LUTs include photon reflection probabilities and directions depending on incidence angle. We provide LUTs for rough and polished surfaces with different reflectors and coupling media. Validation parameters include light output measured at different depths of interaction in the crystal and photon track lengths, as both parameters are strongly dependent on reflector characteristics and distinguish between models. Results from the GATE/GEANT4 beta version are compared to those from our custom code and experimental data, as well as the UNIFIED model. GATE simulations with the LUT Davis model show average variations in light output of <2% from the custom code and excellent agreement for track lengths with R (2) > 0.99. Experimental data agree within 9% for relative light output. The new model also simplifies surface definition, as no complex input parameters are needed. The LUT Davis model makes optical simulations for nuclear imaging detectors much more precise, especially for studies with rough crystal surfaces. It will be available in GATE V8.0.
An integrated model of scintillator-reflector properties for advanced simulations of optical transport.
Phys Med Biol. 2017 Jun 21;62(12):4811-4830
Authors: Roncali E, Stockhoff M, Cherry SR
Accurately modeling the light transport in scintillation detectors is essential to design new detectors for nuclear medicine or high energy physics. Optical models implemented in software such as Geant4 and GATE suffer from important limitations that we addressed by implementing a new approach in which the crystal reflectance was computed from 3D surface measurements. The reflectance was saved in a look-up-table (LUT) then used in Monte Carlo simulation to determine the fate of optical photons. Our previous work using this approach demonstrated excellent agreement with experimental characterization of crystal light output in a limited configuration, i.e. when using no reflector. As scintillators are generally encapsulated in a reflector, it is essential to include the crystal-reflector interface in the LUT. Here we develop a new LUT computation and apply it to several reflector types. A second LUT that contains transmittance data is also saved to enable modeling of optical crosstalk. LUTs have been computed for rough and polished crystals coupled to a Lambertian (e.g. Teflon tape) or a specular reflector (e.g. ESR) using air or optical grease, and the light output was computed using a custom Monte Carlo code. 3 × 3 × 20 mm(3) lutetium oxyorthosilicate crystals were prepared using these combinations, and the light output was measured experimentally at different irradiation depths. For all reflector and surface finish combinations, the measured and simulated light output showed very good agreement. The behavior of optical photons at the interface crystal-reflector was studied using these simulations, and results highlighted the large difference in optical properties between rough and polished crystals, and Lambertian and specular reflectors. These simulations also showed how the travel path of individual scintillation photons was affected by the reflector and surface finish. The ultimate goal of this work is to implement this model in Geant4 and GATE, and provide a database of scintillators combined with a variety of reflectors.
Quantitative assessment of Cerenkov luminescence for radioguided brain tumor resection surgery.
Phys Med Biol. 2017 May 21;62(10):4183-4201
Authors: Klein JS, Mitchell GS, Cherry SR
Cerenkov luminescence imaging (CLI) is a developing imaging modality that detects radiolabeled molecules via visible light emitted during the radioactive decay process. We used a Monte Carlo based computer simulation to quantitatively investigate CLI compared to direct detection of the ionizing radiation itself as an intraoperative imaging tool for assessment of brain tumor margins. Our brain tumor model consisted of a 1 mm spherical tumor remnant embedded up to 5 mm in depth below the surface of normal brain tissue. Tumor to background contrast ranging from 2:1 to 10:1 were considered. We quantified all decay signals (e(±), gamma photon, Cerenkov photons) reaching the brain volume surface. CLI proved to be the most sensitive method for detecting the tumor volume in both imaging and non-imaging strategies as assessed by contrast-to-noise ratio and by receiver operating characteristic output of a channelized Hotelling observer.
Quantitative image reconstruction for total-body PET imaging using the 2-meter long EXPLORER scanner.
Phys Med Biol. 2017 Mar 21;62(6):2465-2485
Authors: Zhang X, Zhou J, Cherry SR, Badawi RD, Qi J
The EXPLORER project aims to build a 2 meter long total-body PET scanner, which will provide extremely high sensitivity for imaging the entire human body. It will possess a range of capabilities currently unavailable to state-of-the-art clinical PET scanners with a limited axial field-of-view. The huge number of lines-of-response (LORs) of the EXPLORER poses a challenge to the data handling and image reconstruction. The objective of this study is to develop a quantitative image reconstruction method for the EXPLORER and compare its performance with current whole-body scanners. Fully 3D image reconstruction was performed using time-of-flight list-mode data with parallel computation. To recover the resolution loss caused by the parallax error between crystal pairs at a large axial ring difference or transaxial radial offset, we applied an image domain resolution model estimated from point source data. To evaluate the image quality, we conducted computer simulations using the SimSET Monte-Carlo toolkit and XCAT 2.0 anthropomorphic phantom to mimic a 20 min whole-body PET scan with an injection of 25 MBq (18)F-FDG. We compare the performance of the EXPLORER with a current clinical scanner that has an axial FOV of 22 cm. The comparison results demonstrated superior image quality from the EXPLORER with a 6.9-fold reduction in noise standard deviation comparing with multi-bed imaging using the clinical scanner.
IPEM codes of practice and topical report series.
Phys Med Biol. 2016 Dec 07;61(23):E5-E6
Authors: Castellano EA, Eaton DJ, MacDougall ND, Cherry SR
Improving Depth, Energy and Timing Estimation in PET Detectors with Deconvolution and Maximum Likelihood Pulse Shape Discrimination.
IEEE Trans Med Imaging. 2016 Nov;35(11):2436-2446
Authors: Berg E, Roncali E, Hutchcroft W, Qi J, Cherry SR
In a scintillation detector, the light generated in the scintillator by a gamma interaction is converted to photoelectrons by a photodetector and produces a time-dependent waveform, the shape of which depends on the scintillator properties and the photodetector response. Several depth-of-interaction (DOI) encoding strategies have been developed that manipulate the scintillator's temporal response along the crystal length and therefore require pulse shape discrimination techniques to differentiate waveform shapes. In this work, we demonstrate how maximum likelihood (ML) estimation methods can be applied to pulse shape discrimination to better estimate deposited energy, DOI and interaction time (for time-of-flight (TOF) PET) of a gamma ray in a scintillation detector. We developed likelihood models based on either the estimated detection times of individual photoelectrons or the number of photoelectrons in discrete time bins, and applied to two phosphor-coated crystals (LFS and LYSO) used in a previously developed TOF-DOI detector concept. Compared with conventional analytical methods, ML pulse shape discrimination improved DOI encoding by 27% for both crystals. Using the ML DOI estimate, we were able to counter depth-dependent changes in light collection inherent to long scintillator crystals and recover the energy resolution measured with fixed depth irradiation (~11.5% for both crystals). Lastly, we demonstrated how the Richardson-Lucy algorithm, an iterative, ML-based deconvolution technique, can be applied to the digitized waveforms to deconvolve the photodetector's single photoelectron response and produce waveforms with a faster rising edge. After deconvolution and applying DOI and time-walk corrections, we demonstrated a 13% improvement in coincidence timing resolution (from 290 to 254 ps) with the LFS crystal and an 8% improvement (323 to 297 ps) with the LYSO crystal.
Roberts Prize for the best paper published in 2015.
Phys Med Biol. 2016 Nov 07;61(21):E3-E4
Authors: Cherry SR, Simmons M
Bismuth germanate coupled to near ultraviolet silicon photomultipliers for time-of-flight PET.
Phys Med Biol. 2016 Sep 21;61(18):L38-L47
Authors: Kwon SI, Gola A, Ferri A, Piemonte C, Cherry SR
Bismuth germanate (BGO) was a very attractive scintillator in early-generation positron emission tomography (PET) scanners. However, the major disadvantages of BGO are lower light yield and longer rise and decay time compared to currently popular scintillators such as LSO and LYSO. This results in poorer coincidence timing resolution and it has generally been assumed that BGO is not a suitable scintillator for time-of-flight (TOF) PET applications. However, when a 511 keV photon interacts in a scintillator, a number of Cerenkov photons are produced promptly by energetic electrons released by photoelectric or Compton interactions. If these prompt photons can be captured, they could provide a better timing trigger for PET. Since BGO has a high refractive index (increasing the Cerenkov light yield) and excellent optical transparency down to 320 nm (Cerenkov light yield is higher at shorter wavelengths), we hypothesized that the coincidence timing resolution of BGO can be significantly improved by efficient detection of the Cerenkov photons. However, since the number of Cerenkov photons is far less than the number of scintillation photons, and they are more abundant in the UV and blue part of the spectrum, photosensors need to have high UV/blue sensitivity, fast temporal response, and very low noise in order to trigger on the faint Cerenkov signal. In this respect, NUV-HD silicon photomultipliers (SiPMs) (FBK, Trento, Italy) are an excellent fit for our approach. In this study, coincidence events were measured using BGO crystals coupled with NUV-HD SiPMs. The existence and influence of Cerenkov photons on the timing measurements were studied using different configurations to exploit the directionality of the Cerenkov emissions. Coincidence resolving time values (FWHM) of ~270 ps from 2 × 3 × 2 mm(3) BGO crystals and ~560 ps from 3 × 3 × 20 mm(3) BGO crystals were obtained. To our knowledge, these are the best coincidence resolving time values reported for BGO to date. With these values, BGO can be considered as a relevant scintillator for TOF PET scanners, especially if photodetectors with even better near UV/blue response can be developed to further improve the efficiency of Cerenkov light detection.
Developing a Nanoparticle-Delivered High-Efficacy Treatment for Infantile Hemangiomas Using a Mouse Hemangioendothelioma Model.
Plast Reconstr Surg. 2016 Aug;138(2):410-7
Authors: Orbay H, Li Y, Xiao W, Cherry SR, Lam K, Sahar DE
BACKGROUND: Current treatments for infantile hemangiomas have unpredictable outcomes. The authors' aim was to develop a nanoporphyrin-delivered, high-efficacy treatment for infantile hemangiomas using a mouse hemangioendothelioma model.
METHODS: The authors injected mouse hemangioendothelioma cells intradermally to axillary regions of 5-week-old, female, nude mice (n = 19) to induce hemangioendothelioma growth. They documented nanoporphyrin accumulation in hemangioendotheliomas using positron emission tomography. For the treatment study, the authors randomized hemangioendothelioma-bearing nude mice (n = 9) into three groups (n = 3 each). Group I received only saline injections. Group II received only laser treatment after saline injection, and group III received laser treatment after nanoporphyrin injection through the tail vein. The authors followed up the treatment response with digital caliper measurements.
RESULTS: Hemangioendotheliomas started to grow approximately 1 week after inoculation and resembled infantile hemangiomas histologically. Nanoporphyrin uptake in hemangioendotheliomas was 19.7 ± 2.2, 16.7 ± 2.02, 8.4 ± 0.3, and 4.9 ± 0.6 percent injected dose per gram of tissue at 3, 6, 24, and 48 hours after injection, respectively. Nanoporphyrin uptake was significantly higher than in blood at 24 and 48 hours after injection (p < 0.05). Results of ex vivo biodistribution study were consistent with positron emission tomographic imaging. Hemangioendotheliomas in group III started to regress 1 day after the treatment and disappeared totally by day 21. The difference between tumor volumes in group III and other groups was significant on days 17 and 21 (p < 0.05).
CONCLUSIONS: Nanoporphyrin accumulated in hemangioendotheliomas at high concentrations, enabling a high-efficacy photodynamic therapy. Given the similarities between hemangioendotheliomas and infantile hemangiomas, this treatment potentially can be a high-efficacy treatment for infantile hemangiomas.
On the assessment of spatial resolution of PET systems with iterative image reconstruction.
Phys Med Biol. 2016 Mar 7;61(5):N193-202
Authors: Gong K, Cherry SR, Qi J
Spatial resolution is an important metric for performance characterization in PET systems. Measuring spatial resolution is straightforward with a linear reconstruction algorithm, such as filtered backprojection, and can be performed by reconstructing a point source scan and calculating the full-width-at-half-maximum (FWHM) along the principal directions. With the widespread adoption of iterative reconstruction methods, it is desirable to quantify the spatial resolution using an iterative reconstruction algorithm. However, the task can be difficult because the reconstruction algorithms are nonlinear and the non-negativity constraint can artificially enhance the apparent spatial resolution if a point source image is reconstructed without any background. Thus, it was recommended that a background should be added to the point source data before reconstruction for resolution measurement. However, there has been no detailed study on the effect of the point source contrast on the measured spatial resolution. Here we use point source scans from a preclinical PET scanner to investigate the relationship between measured spatial resolution and the point source contrast. We also evaluate whether the reconstruction of an isolated point source is predictive of the ability of the system to resolve two adjacent point sources. Our results indicate that when the point source contrast is below a certain threshold, the measured FWHM remains stable. Once the contrast is above the threshold, the measured FWHM monotonically decreases with increasing point source contrast. In addition, the measured FWHM also monotonically decreases with iteration number for maximum likelihood estimate. Therefore, when measuring system resolution with an iterative reconstruction algorithm, we recommend using a low-contrast point source and a fixed number of iterations.
Characterization of Large-Area SiPM Array for PET Applications.
IEEE Trans Nucl Sci. 2016 Feb;63(1):8-16
Authors: Du J, Yang Y, Bai X, Judenhofer MS, Berg E, Di K, Buckley S, Jackson C, Cherry SR
The performance of an 8 × 8 array of 6.0 × 6.0 mm(2) (active area) SiPMs was evaluated for PET applications using crystal arrays with different pitch sizes (3.4 mm, 1.5 mm, 1.35 mm and 1.2 mm) and custom designed five-channel front-end readout electronics (four channels for position information and one channel for timing information). The total area of this SiPM array is 57.4 × 57.4 mm(2), and the pitch size is 7.2 mm. It was fabricated using enhanced blue sensitivity SiPMs (MicroFB-60035-SMT) with peak spectral sensitivity at 420 nm. The performance of the SiPM array was characterized by measuring flood histogram decoding quality, energy resolution, timing resolution and saturation at several bias voltages (from 25.0 V to 30.0 V in 0.5 V intervals) and two different temperatures (5 °C and 20 °C). Results show that the best flood histogram was obtained at a bias voltage of 28.0 V and 5 °C and an array of polished LSO crystals with a pitch as small as 1.2 mm can be resolved. No saturation was observed up to a bias voltage of 29.5 V during the experiments, due to adequate light sharing between SiPMs. Energy resolution and timing resolution at 5 °C ranged from 12.7 ± 0.8% to 14.6 ± 1.4 % and 1.58 ± 0.13 ns to 2.50 ± 0.44 ns, for crystal array pitch sizes of 3.4 mm and 1.2 mm respectively. Superior flood histogram quality, energy resolution and timing resolution were obtained with larger crystal array pitch sizes and at lower temperature. Based on our findings, we conclude that this large-area SiPM array can serve as a suitable photodetector for high-resolution small-animal PET or dedicated human brain PET scanners.
A combined time-of-flight and depth-of-interaction detector for total-body positron emission tomography.
Med Phys. 2016 Feb;43(2):939
Authors: Berg E, Roncali E, Kapusta M, Du J, Cherry SR
PURPOSE: In support of a project to build a total-body PET scanner with an axial field-of-view of 2 m, the authors are developing simple, cost-effective block detectors with combined time-of-flight (TOF) and depth-of-interaction (DOI) capabilities.
METHODS: This work focuses on investigating the potential of phosphor-coated crystals with conventional PMT-based block detector readout to provide DOI information while preserving timing resolution. The authors explored a variety of phosphor-coating configurations with single crystals and crystal arrays. Several pulse shape discrimination techniques were investigated, including decay time, delayed charge integration (DCI), and average signal shapes.
RESULTS: Pulse shape discrimination based on DCI provided the lowest DOI positioning error: 2 mm DOI positioning error was obtained with single phosphor-coated crystals while 3-3.5 mm DOI error was measured with the block detector module. Minimal timing resolution degradation was observed with single phosphor-coated crystals compared to uncoated crystals, and a timing resolution of 442 ps was obtained with phosphor-coated crystals in the block detector compared to 404 ps without phosphor coating. Flood maps showed a slight degradation in crystal resolvability with phosphor-coated crystals; however, all crystals could be resolved. Energy resolution was degraded by 3%-7% with phosphor-coated crystals compared to uncoated crystals.
CONCLUSIONS: These results demonstrate the feasibility of obtaining TOF-DOI capabilities with simple block detector readout using phosphor-coated crystals.
Challenges to the Pair Bond: Neural and Hormonal Effects of Separation and Reunion in a Monogamous Primate.
Front Behav Neurosci. 2016;10:221
Authors: Hinde K, Muth C, Maninger N, Ragen BJ, Larke RH, Jarcho MR, Mendoza SP, Mason WA, Ferrer E, Cherry SR, Fisher-Phelps ML, Bales KL
Social monogamy at its most basic is a group structure in which two adults form a unit and share a territory. However, many socially monogamous pairs display attachment relationships known as pair bonds, in which there is a mutual preference for the partner and distress upon separation. The neural and hormonal basis of this response to separation from the adult pair mate is under-studied. In this project, we examined this response in male titi monkeys (Callicebus cupreus), a socially monogamous New World primate. Males underwent a baseline scan, a short separation (48 h), a long separation (approximately 2 weeks), a reunion with the female pair mate and an encounter with a female stranger (with nine males completing all five conditions). Regional cerebral glucose metabolism was measured via positron emission tomography (PET) imaging using [18F]-fluorodeoxyglucose (FDG) co-registered with structural magnetic resonance imaging (MRI), and region of interest (ROI) analysis was carried out. In addition, plasma was collected and assayed for cortisol, oxytocin (OT), vasopressin (AVP), glucose and insulin concentrations. Cerebrospinal fluid (CSF) was collected and assayed for OT and AVP. We used generalized estimating equations (GEE) to examine significant changes from baseline. Short separations were characterized by decreases in FDG uptake, in comparison to baseline, in the lateral septum (LS), ventral pallidum (VP), paraventricular nucleus of the hypothalamus (PVN), periaqueductal gray (PAG), and cerebellum, as well as increases in CSF OT, and plasma cortisol and insulin. Long separations differed from baseline in reduced FDG uptake in the central amygdala (CeA), reduced whole brain FDG uptake, increased CSF OT and increased plasma insulin. The response on encounter with a stranger female depended on whether or not the male had previously reproduced with his pair mate, suggesting that transitions to fatherhood contribute to the neurobiology underlying response to a novel female. Reunion with the partner appeared to stimulate coordinated release of central and peripheral OT. The observed changes suggest the involvement of OT and AVP systems, as well as limbic and striatal areas, during separation and reunion from the pair mate.
Activating Photodynamic Therapy in vitro with Cerenkov Radiation Generated from Yttrium-90.
J Environ Pathol Toxicol Oncol. 2016;35(2):185-92
Authors: Hartl BA, Hirschberg H, Marcu L, Cherry SR
The translation of photodynamic therapy (PDT) to the clinical setting has primarily been limited to easily accessible and/or superficial diseases, for which traditional light delivery can be performed noninvasively. Cerenkov radiation, as generated from medically relevant radionuclides, has been suggested as a means to deliver light to deeper tissues noninvasively to overcome this depth limitation. This article investigates the utility of Cerenkov radiation, as generated from the radionuclide yttrium-90, for activating the PDT process using clinically approved aminolevulinic acid at 1.0 mm and also the more efficient porphyrin-based photosensitizer mesotetraphenylporphine with two sulfonate groups on adjacent phenyl rings (TPPS2a) at 1.2 µm. Experiments were conducted with monolayer cultured glioma and breast tumor cell lines. Although aminolevulinic acid proved to be ineffective for generating a therapeutic effect at all but the highest activity levels, TPPS2a produced at least a 20% therapeutic effect at activities ranging from 6 to 60 µCi/well for the C6 glioma cell line. Importantly, these results demonstrate for the first time, to our knowledge, that Cerenkov radiation generated from a radionuclide can be used to activate PDT using clinically relevant photosensitizers. These results therefore provide evidence that it may be possible to generate a phototherapeutic effect in vivo using Cerenkov radiation and clinically relevant photosensitizers.
Phys Med Biol. 2015 Sep 21;60(19):E1-2
Authors: Cherry SR, Ruffle J
Computed Cerenkov luminescence yields for radionuclides used in biology and medicine.
Authors: Gill RK, Mitchell GS, Cherry SR
Cerenkov luminescence imaging is an emerging biomedical imaging modality that takes advantage of the optical Cerenkov photons emitted following the decay of radionuclides in dielectric media such as tissue. Cerenkov radiation potentially allows many biomedically-relevant radionuclides, including all positron-emitting radionuclides, to be imaged in vivo using sensitive CCD cameras. Cerenkov luminescence may also provide a means to deliver light deep inside tissue over a sustained period of time using targeted radiotracers. This light could be used for photoactivation, including photorelease of therapeutics, photodynamic therapy and photochemical internalization. Essential to assessing the feasibility of these concepts, and the design of instrumentation designed for detecting Cerenkov radiation, is an understanding of the light yield of different radionuclides in tissue. This is complicated by the dependence of the light yield on refractive index and the volume of the sample being interrogated. Using Monte Carlo simulations, in conjunction with step-wise use of the Frank-Tamm equation, we studied forty-seven different radionuclides and show that Cerenkov light yields in tissue can be as high as a few tens of photons per nuclear decay for a wavelength range of 400-800 nm. The dependency on refractive index and source volume is explored, and an expression for the scaling factor necessary to compute the Cerenkov yield in any arbitrary spectral band is given. This data will be of broad utility in guiding the application of Cerenkov radiation emitted from biomedical radionuclides.
Characterizing low fluence thresholds for in vitro photodynamic therapy.
Biomed Opt Express. 2015 Mar 1;6(3):770-9
The translation of photodynamic therapy (PDT) to the clinic has mostly been limited to superficial diseases where traditional light delivery is noninvasive. To overcome this limitation, a variety of mechanisms have been suggested to noninvasively deliver light to deep tissues. This work explores the minimum amount of light required by these methods to produce a meaningful PDT effect in the in vitro setting under representative low fluence and wavelength conditions. This threshold was found to be around 192 mJ/cm(2) using the clinically approved photosensitizer aminolevulinic acid and 12 mJ/cm(2) for the more efficient, second generation photosensitizer TPPS2a.
Evaluation of Matrix9 silicon photomultiplier array for small-animal PET.
Authors: Du J, Schmall JP, Yang Y, Di K, Roncali E, Mitchell GS, Buckley S, Jackson C, Cherry SR
PURPOSE: The MatrixSL-9-30035-OEM (Matrix9) from SensL is a large-area silicon photomultiplier (SiPM) photodetector module consisting of a 3 × 3 array of 4 × 4 element SiPM arrays (total of 144 SiPM pixels) and incorporates SensL's front-end electronics board and coincidence board. Each SiPM pixel measures 3.16 × 3.16 mm(2) and the total size of the detector head is 47.8 × 46.3 mm(2). Using 8 × 8 polished LSO/LYSO arrays (pitch 1.5 mm) the performance of this detector system (SiPM array and readout electronics) was evaluated with a view for its eventual use in small-animal positron emission tomography (PET).
METHODS: Measurements of noise, signal, signal-to-noise ratio, energy resolution, flood histogram quality, timing resolution, and array trigger error were obtained at different bias voltages (28.0-32.5 V in 0.5 V intervals) and at different temperatures (5 °C-25 °C in 5 °C degree steps) to find the optimal operating conditions.
RESULTS: The best measured signal-to-noise ratio and flood histogram quality for 511 keV gamma photons were obtained at a bias voltage of 30.0 V and a temperature of 5 °C. The energy resolution and timing resolution under these conditions were 14.2% ± 0.1% and 4.2 ± 0.1 ns, respectively. The flood histograms show that all the crystals in the 1.5 mm pitch LSO array can be clearly identified and that smaller crystal pitches can also be resolved. Flood histogram quality was also calculated using different center of gravity based positioning algorithms. Improved and more robust results were achieved using the local 9 pixels for positioning along with an energy offset calibration. To evaluate the front-end detector readout, and multiplexing efficiency, an array trigger error metric is introduced and measured at different lower energy thresholds. Using a lower energy threshold greater than 150 keV effectively eliminates any mispositioning between SiPM arrays.
CONCLUSIONS: In summary, the Matrix9 detector system can resolve high-resolution scintillator arrays common in small-animal PET with adequate energy resolution and timing resolution over a large detector area. The modular design of the Matrix9 detector allows it to be used as a building block for simple, low channel-count, yet high performance, small animal PET or PET/MRI systems.
Validation of the SimSET simulation package for modeling the Siemens Biograph mCT PET scanner.
Phys Med Biol. 2015 Feb 7;60(3):N35-45
Authors: Poon JK, Dahlbom ML, Casey ME, Qi J, Cherry SR, Badawi RD
Monte Carlo simulation provides a valuable tool in performance assessment and optimization of system design parameters for PET scanners. SimSET is a popular Monte Carlo simulation toolkit that features fast simulation time, as well as variance reduction tools to further enhance computational efficiency. However, SimSET has lacked the ability to simulate block detectors until its most recent release. Our goal is to validate new features of SimSET by developing a simulation model of the Siemens Biograph mCT PET scanner and comparing the results to a simulation model developed in the GATE simulation suite and to experimental results. We used the NEMA NU-2 2007 scatter fraction, count rates, and spatial resolution protocols to validate the SimSET simulation model and its new features. The SimSET model overestimated the experimental results of the count rate tests by 11-23% and the spatial resolution test by 13-28%, which is comparable to previous validation studies of other PET scanners in the literature. The difference between the SimSET and GATE simulation was approximately 4-8% for the count rate test and approximately 3-11% for the spatial resolution test. In terms of computational time, SimSET performed simulations approximately 11 times faster than GATE simulations. The new block detector model in SimSET offers a fast and reasonably accurate simulation toolkit for PET imaging applications.
Un-collimated single-photon imaging system for high-sensitivity small animal and plant imaging.
Phys Med Biol. 2015 Jan 7;60(1):403-20
Authors: Walker KL, Judenhofer MS, Cherry SR, Mitchell GS
In preclinical single-photon emission computed tomography (SPECT) system development the primary objective has been to improve spatial resolution by using novel parallel-hole or multi-pinhole collimator geometries. However, such high-resolution systems have relatively poor sensitivity (typically 0.01-0.1%). In contrast, a system that does not use collimators can achieve very high-sensitivity. Here we present a high-sensitivity un-collimated detector single-photon imaging (UCD-SPI) system for the imaging of both small animals and plants. This scanner consists of two thin, closely spaced, pixelated scintillator detectors that use NaI(Tl), CsI(Na), or BGO. The performance of the system has been characterized by measuring sensitivity, spatial resolution, linearity, detection limits, and uniformity. With (99m)Tc (140 keV) at the center of the field of view (20 mm scintillator separation), the sensitivity was measured to be 31.8% using the NaI(Tl) detectors and 40.2% with CsI(Na). The best spatial resolution (FWHM when the image formed as the geometric mean of the two detector heads, 20 mm scintillator separation) was 19.0 mm for NaI(Tl) and 11.9 mm for CsI(Na) at 140 keV, and 19.5 mm for BGO at 1116 keV, which is somewhat degraded compared to the cm-scale resolution obtained with only one detector head and a close source. The quantitative accuracy of the system's linearity is better than 2% with detection down to activity levels of 100 nCi. Two in vivo animal studies (a renal scan using (99m)Tc MAG-3 and a thyroid scan with (123)I) and one plant study (a (99m)TcO4(-) xylem transport study) highlight the unique capabilities of this UCD-SPI system. From the renal scan, we observe approximately a one thousand-fold increase in sensitivity compared to the Siemens Inveon SPECT/CT scanner. UCD-SPI is useful for many imaging tasks that do not require excellent spatial resolution, such as high-throughput screening applications, simple radiotracer uptake studies in tumor xenografts, dynamic studies where very good temporal resolution is critical, or in planta imaging of radioisotopes at low concentrations.
Phys Med Biol. 2014 Oct 21;59(20):5971-2
Timing properties of phosphor-coated polished LSO crystals.
Phys Med Biol. 2014 Aug 7;59(15):N139-51
Authors: Schmall JP, Roncali E, Berg E, Viswanath V, Du J, Cherry SR
This study investigates a time-of-flight (TOF)-depth-of-interaction (DOI) detector design for positron emission tomography (PET), based on phosphor-coated lutetium oxyorthosilicate (LSO) scintillator crystals coupled to fast single channel photomultiplier tubes. Interaction of the scintillation light with the phosphor coating changes the pulse shape in a depth-dependent manner. 3 × 3 × 10 mm(3) LSO scintillation crystals with polished surfaces were characterized, with and without phosphor coating, to assess DOI capability and timing properties. Two different phosphor coating geometries were studied: coating of the top surface of the crystal, and the top plus half of the crystal sides. There was negligible depth dependency in the decay time when coating only the top surface, however there was a ∼10 ns difference in end-to-end decay time when coating the top plus half of the crystal sides, sufficient to support the use of three DOI bins (3.3 mm DOI bin width). The rise time of the half-coated phosphor crystal was slightly faster at all depths, compared to uncoated crystals, however the signal amplitude was lower. Phosphor coating resulted in depth-dependent photopeak positions with an energy resolution of 13.7%, at a depth of 1 mm, and 15.3%, at a depth of 9 mm, for the half-coated crystal. Uncoated LSO crystals showed no change in photopeak position as a function of depth, with an energy resolution of 10.4%. The head-on coincidence timing resolution (CTR) of two uncoated LSO crystals was 287 ps using constant fraction discrimination for time pick-off. With phosphor coating, the CTR of the top-coated crystal was 314 ps, compared to 384 ps for the half-coated crystal. We demonstrate that the trade-off between timing resolution and DOI resolution can be controlled by the phosphor coating geometry. Here we present preliminary results demonstrating that good DOI resolution can be achieved with only a modest 26% degradation in CTR.
Effects of reflector and crystal surface on the performance of a depth-encoding PET detector with dual-ended readout.
Med Phys. 2014 Jul;41(7):072503
Authors: Ren S, Yang Y, Cherry SR
PURPOSE: Depth encoding detectors are required to improve the spatial resolution and spatial resolution uniformity of small animal positron emission tomography (PET) scanners, as well as dedicated breast and brain scanners. Depth of interaction (DOI) can be measured by using dual-ended readout of lutetium oxyorthosilicate (LSO) scintillator arrays with position-sensitive avalanche photodiodes. Inter-crystal reflectors and crystal surface treatments play important roles in determining the performance of dual-ended detectors. In this paper, the authors evaluated five LSO arrays made with three different intercrystal reflectors and with either polished or unpolished crystal surfaces.
METHODS: The crystal size in all arrays was 1.5 mm, which is typical of the detector size used in small animal and dedicated breast scanners. The LSO arrays were measured with dual-ended readout and were compared in terms of flood histogram, energy resolution, and DOI resolution performance.
RESULTS: The four arrays using enhanced specular reflector (ESR) and Toray reflector provided similar quality flood histograms and the array using Crystal Wrap reflector gave the worst flood histogram. The two arrays using ESR reflector provided the best energy resolution and the array using Crystal Wrap reflector yielded the worst energy resolution. All arrays except the polished ESR array provided good DOI resolution ranging from 1.9 mm to 2.9 mm. DOI resolution improved as the gradient in light collection efficiency with depth (GLCED) increased. The geometric mean energies were also calculated for these dual-ended readout detectors as an alternative to the conventional summed total energy. It was shown that the geometric mean energy is advantageous in that it provides more uniform photopeak amplitude at different depths for arrays with high GLCED, and is beneficial in event selection by allowing a fixed energy window independent of depth. A new method of DOI calculation that improved the linearity of DOI ratio vs depth and simplifies the DOI calibration procedure also was developed and tested.
CONCLUSIONS: The results of these studies provide useful guidance in selecting the proper reflectors and crystal surface treatments when LSO arrays are used for high-resolution PET applications in small animal scanners or dedicated breast and brain scanners.
A Study of Position-Sensitive Solid-State Photomultiplier Signal Properties.
IEEE Trans Nucl Sci. 2014 Jun 12;61(3):1074-1083
Authors: Schmall JP, Du J, Judenhofer MS, Dokhale P, Christian J, McClish M, Shah KS, Cherry SR
We present an analysis of the signal properties of a position-sensitive solid-state photomultiplier (PS-SSPM) that has an integrated resistive network for position sensing. Attractive features of PS-SSPMs are their large area and ability to resolve small scintillator crystals. However, the large area leads to a high detector capacitance, and in order to achieve high spatial resolution a large network resistor value is required. These inevitably create a low-pass filter that drastically slows what would be a fast micro-cell discharge pulse. Significant changes in the signal shape of the PS-SSPM cathode output as a function of position are observed, which result in a position-dependent time delay when using traditional time pick-off methods such as leading edge discrimination and constant fraction discrimination. The timing resolution and time delay, as a function of position, were characterized for two different PS-SSPM designs, a continuous 10 mm × 10 mm PS-SSPM and a tiled 2 × 2 array of 5 mm × 5 mm PS-SSPMs. After time delay correction, the block timing resolution, measured with a 6 × 6 array of 1.3 × 1.3 × 20 mm(3) LSO crystals, was 8.6 ns and 8.5 ns, with the 10 mm PS-SSPM and 5 mm PS-SSPM respectively. The effect of crystal size on timing resolution was also studied, and contrary to expectation, a small improvement was measured when reducing the crystal size from 1.3 mm to 0.5 mm. Digital timing methods were studied and showed great promise for allowing accurate timing by implementation of a leading edge time pick-off. Position-dependent changes in signal shape on the anode side also are present, which complicates peak height data acquisition methods used for positioning. We studied the effect of trigger position on signal amplitude, flood histogram quality, and depth-of-interaction resolution in a dual-ended readout detector configuration. We conclude that detector timing and positioning can be significantly improved by implementation of digital timing methods and by accounting for changes in the shape of the signals from PS-SSPMs.
Evaluation of 2-[¹⁸F]fluoroacetate kinetics in rodent models of cerebral hypoxia-ischemia.
J Cereb Blood Flow Metab. 2014 May;34(5):836-44
Authors: Ouyang Y, Tinianow JN, Cherry SR, Marik J
Glia account for 90% of human brain cells and have a significant role in brain homeostasis. Thus, specific in vivo imaging markers of glial metabolism are potentially valuable. In the brain, 2-fluoroacetate is selectively taken up by glial cells and becomes metabolically trapped in the tricarboxylic acid cycle. Recent work in rodent brain injury models demonstrated elevated lesion uptake of 2-[(18)F]fluoroacetate ([(18)F]FACE), suggesting possible use for specifically imaging glial metabolism. To assess this hypothesis, we evaluated [(18)F]FACE kinetics in rodent models of cerebral hypoxia-ischemia at 3 and 24 hours post insult. Lesion uptake was significantly higher at 30 minutes post injection (P<0.05). An image-based method for input function estimation using cardiac blood was validated. Analysis of whole blood showed no significant metabolites and plasma activity concentrations of ∼50% that of whole blood. Kinetic models describing [(18)F]FACE uptake were developed and quantitatively compared. Elevated [(18)F]FACE uptake was found to be driven primarily by K₁/k₂ rather than k₃, but changes in the latter were detectable. The two-tissue irreversible uptake model (2T3k) was found to be necessary and sufficient for modeling [(18)F]FACE uptake. We conclude that kinetic modeling of [(18)F]FACE uptake represents a potentially useful tool for interrogation of glial metabolism.
Numerical simulation of x-ray luminescence optical tomography for small-animal imaging.
J Biomed Opt. 2014 Apr;19(4):046002
Authors: Li C, Martínez-Dávalos A, Cherry SR
X-ray luminescence optical tomography (XLOT) is an emerging hybrid imaging modality in which x-ray excitable particles (phosphor particles) emit optical photons when stimulated with a collimated x-ray beam. XLOT can potentially combine the high sensitivity of optical imaging with the high spatial resolution of x-ray imaging. For reconstruction of XLOT data, we compared two reconstruction algorithms, conventional filtered backprojection (FBP) and a new algorithm, x-ray luminescence optical tomography with excitation priors (XLOT-EP), in which photon propagation is modeled with the diffusion equation and the x-ray beam positions are used as reconstruction priors. Numerical simulations based on dose calculations were used to validate the proposed XLOT imaging system and the reconstruction algorithms. Simulation results showed nanoparticle concentrations reconstructed with XLOT-EP are much less dependent on scan depth than those obtained with FBP. Measurements at just two orthogonal projections are sufficient for XLOT-EP to reconstruct an XLOT image for simple source distributions. The heterogeneity of x-ray energy deposition is included in the XLOT-EP reconstruction and improves the reconstruction accuracy, suggesting that there is a need to calculate the x-ray energy distribution for experimental XLOT imaging.
Predicting the timing properties of phosphor-coated scintillators using Monte Carlo light transport simulation.
Phys Med Biol. 2014 Apr 21;59(8):2023-39
Authors: Roncali E, Schmall JP, Viswanath V, Berg E, Cherry SR
Current developments in positron emission tomography focus on improving timing performance for scanners with time-of-flight (TOF) capability, and incorporating depth-of-interaction (DOI) information. Recent studies have shown that incorporating DOI correction in TOF detectors can improve timing resolution, and that DOI also becomes more important in long axial field-of-view scanners. We have previously reported the development of DOI-encoding detectors using phosphor-coated scintillation crystals; here we study the timing properties of those crystals to assess the feasibility of providing some level of DOI information without significantly degrading the timing performance. We used Monte Carlo simulations to provide a detailed understanding of light transport in phosphor-coated crystals which cannot be fully characterized experimentally. Our simulations used a custom reflectance model based on 3D crystal surface measurements. Lutetium oxyorthosilicate crystals were simulated with a phosphor coating in contact with the scintillator surfaces and an external diffuse reflector (teflon). Light output, energy resolution, and pulse shape showed excellent agreement with experimental data obtained on 3 × 3 × 10 mm³ crystals coupled to a photomultiplier tube. Scintillator intrinsic timing resolution was simulated with head-on and side-on configurations, confirming the trends observed experimentally. These results indicate that the model may be used to predict timing properties in phosphor-coated crystals and guide the coating for optimal DOI resolution/timing performance trade-off for a given crystal geometry. Simulation data suggested that a time stamp generated from early photoelectrons minimizes degradation of the timing resolution, thus making this method potentially more useful for TOF-DOI detectors than our initial experiments suggested. Finally, this approach could easily be extended to the study of timing properties in other scintillation crystals, with a range of treatments and materials attached to the surface.
Ultra staging to unmask the prescribing of adjuvant therapy in cancer patients: the future opportunity to image micrometastases using total-body 18F-FDG PET scanning.
J Nucl Med. 2014 Apr;55(4):696-7
Authors: Price PM, Badawi RD, Cherry SR, Jones T
In vivo tracking of Th1 cells by PET reveals quantitative and temporal distribution and specific homing in lymphatic tissue.
J Nucl Med. 2014 Feb;55(2):301-7
Authors: Griessinger CM, Kehlbach R, Bukala D, Wiehr S, Bantleon R, Cay F, Schmid A, Braumüller H, Fehrenbacher B, Schaller M, Eichner M, Sutcliffe JL, Ehrlichmann W, Eibl O, Reischl G, Cherry SR, Röcken M, Pichler BJ, Kneilling M
UNLABELLED: Although T cells can be labeled for noninvasive in vivo imaging, little is known about the impact of such labeling on T-cell function, and most imaging methods do not provide holistic information about trafficking kinetics, homing sites, or quantification.
METHODS: We developed protocols that minimize the inhibitory effects of (64)Cu-pyruvaldehyde-bis(N4-methylthiosemicarbazone) ((64)Cu-PTSM) labeling on T-cell function and permit the homing patterns of T cells to be followed by PET. Thus, we labeled ovalbumin (OVA) T-cell receptor transgenic interferon (IFN)-γ-producing CD4(+) T (Th1) cells with 0.7-2.2 MBq of (64)Cu-PTSM and analyzed cell viability, IFN-γ production, proliferation, apoptosis, and DNA double-strand breaks and identified intracellular (64)Cu accumulation sites by energy dispersive x-ray analysis. To elucidate the fate of Th1 cell homing by PET, 10(7 64)Cu-OVA-Th1 cells were injected intraperitoneally or intravenously into healthy mice. To test the functional capacities of (64)Cu-OVA-Th1 cells during experimental OVA-induced airway hyperreactivity, we injected 10(7 64)Cu-OVA-Th1 cells intraperitoneally into OVA-immunized or nonimmunized healthy mice, which were challenged with OVA peptide or phosphate-buffered saline or remained untreated. In vivo PET investigations were followed by biodistribution, autoradiography, and fluorescence-activated cell sorting analysis.
RESULTS: PET revealed unexpected homing patterns depending on the mode of T-cell administration. Within 20 min after intraperitoneal administration, (64)Cu-OVA-Th1 cells homed to the perithymic lymph nodes (LNs) of naive mice. Interestingly, intravenously administered (64)Cu-OVA-Th1 cells homed predominantly into the lung and spleen but not into the perithymic LNs. The accumulation of (64)Cu-OVA-Th1 cells in the pulmonary LNs (6.8 ± 1.1 percentage injected dose per cubic centimeter [%ID/cm(3)]) 24 h after injection was highest in the OVA-immunized and OVA-challenged OVA airway hyperreactivity-diseased littermates 24 h after intraperitoneal administration and lowest in the untreated littermates (3.7 ± 0.4 %ID/cm(3)). As expected, (64)Cu-OVA-Th1 cells also accumulated significantly in the pulmonary LNs of nonimmunized OVA-challenged animals (6.1 ± 0.5 %ID/cm(3)) when compared with phosphate-buffered saline-challenged animals (4.6 ± 0.5 %ID/cm(3)).
CONCLUSION: Our protocol permits the detection of Th1 cells in single LNs and enables temporal in vivo monitoring of T-cell homing over 48 h. This work enables future applications for (64)Cu-PTSM-labeled T cells in clinical trials and novel therapy concepts focusing on T-cell-based immunotherapies of autoimmune diseases or cancer.
New shielding configurations for a simultaneous PET/MRI scanner at 7T.
J Magn Reson. 2014 Feb;239:50-6
Authors: Peng BJ, Wu Y, Cherry SR, Walton JH
Understanding sources of electromagnetic interference are important in designing any electronic system. This is especially true when combining positron emission tomography (PET) and magnetic resonance imaging (MRI) in a multimodality system as coupling between the subsystems can degrade the performance of either modality. For this reason, eliminating radio frequency (RF) interference and gradient-induced eddy currents have been major challenges in building simultaneous hybrid PET/MRI systems. MRI requires negligible RF interference at the Larmor resonance frequency, while RF interference at almost any frequency may corrupt PET data. Moreover, any scheme that minimizes these interactions would, ideally, not compromise the performance of either subsystem. This paper lays out a plan to resolve these problems. A carbon fiber composite material is found to be a good RF shield at the Larmor frequency (300MHz in this work) while introducing negligible gradient eddy currents. This carbon fiber composite also provides excellent structural support for the PET detector components. Low frequency electromagnetic radiation (81kHz here) from the switching power supplies of the gradient amplifiers was also found to interfere with the PET detector. Placing the PET detector module between two carbon fiber tubes and grounding the inner carbon fiber tube to the PET detector module ground reduced this interference. Further reductions were achieved by adding thin copper (Cu) foil on the outer carbon fiber case and electrically grounding the PET detector module so that all 3 components had a common ground, i.e. with the PET detector in an electrostatic cage. Finally, gradient switching typical in MRI sequences can result in count losses in the particular PET detector design studied. Moreover, the magnitude of this effect depends on the location of the detector within the magnet bore and which MRI gradient is being switched. These findings have a bearing on future designs of PET/MRI systems.
Performance and limitations of positron emission tomography (PET) scanners for imaging very low activity sources.
Phys Med. 2014 Feb;30(1):104-10
Authors: Freedenberg MI, Badawi RD, Tarantal AF, Cherry SR
Emerging applications for positron emission tomography (PET) may require the ability to image very low activity source distributions in the body. The performance of clinical PET scanners in the regime where activity in the field of view is <1 MBq has not previously been explored. In this study, we compared the counting rate performance of two clinical PET/CT scanners, the Siemens Biograph Reveal 16 scanner which is based on lutetium oxyorthosilicate (LSO) detectors and the GE Discovery-ST scanner which is based on bismuth germanate (BGO) detectors using a modified National Electrical Manufacturers Association (NEMA) NU 2-2007 protocol. Across the activity range studied (2-100 kBq/mL in a 5.5 mL line source in the NEMA scatter phantom), the BGO-based scanner significantly outperformed the LSO-based scanner. This was largely due to the effect of background counts emanating from naturally occurring but radioactive (176)Lu within the LSO detector material, which dominates the observed counting rate at the lowest activities. Increasing the lower energy threshold from 350 keV to 425 keV in an attempt to reduce this background did not significantly improve the measured NECR performance. The measured singles rate due to (176)Lu emissions within the scanner energy window was also found to be dependent on temperature, and to be affected by the operation of the CT component, making approaches to correct or compensate for the background more challenging. We conclude that for PET studies in a very low activity range, BGO-based scanners are likely to have better performance because of the lack of significant background.
A Monte Carlo investigation of the spatial resolution performance of a small-animal PET scanner designed for mouse brain imaging studies.
Phys Med. 2014 Feb;30(1):76-85
Authors: Rodríguez-Villafuerte M, Yang Y, Cherry SR
Our laboratory has developed PET detectors with depth-encoding accuracy of ∼2 mm based on finely pixelated crystals with a tapered geometry, readout at both ends with position-sensitive avalanche photodiodes (PSAPDs). These detectors are currently being used in our laboratory to build a one-ring high resolution PET scanner for mouse brain imaging studies. Due to the inactive areas around the PSAPDs, large gaps exist between the detector modules which can degrade the image spatial resolution obtained using analytical reconstruction with filtered backprojection (FBP). In this work, the Geant4-based GATE Monte Carlo package was used to assist in determining whether gantry rotation was necessary and to assess the expected spatial resolution of the system. The following factors were investigated: rotating vs. static gantry modes with and without compensation of missing data using the discrete cosine transform (DCT) method, two levels of depth-encoding, and positron annihilation effects for (18)F. Our results indicate that while the static scanner produces poor quality FBP images with streak and ring artifacts, the image quality was greatly improved after compensation of missing data. The simulation indicates that the expected FWHM system spatial resolution is 0.70 ± 0.05 mm, which approaches the predicted limit of 0.5 mm FWHM due to positron range, photon non-colinearity and physical detector element size effects. We conclude that excellent reconstructed resolution without gantry rotation is possible even using FBP if the gaps are appropriately handled and that this design can approach the resolution limits set by positron annihilation physics.
A smart and versatile theranostic nanomedicine platform based on nanoporphyrin.
Nat Commun. 2014;5:4712
Authors: Li Y, Lin TY, Luo Y, Liu Q, Xiao W, Guo W, Lac D, Zhang H, Feng C, Wachsmann-Hogiu S, Walton JH, Cherry SR, Rowland DJ, Kukis D, Pan C, Lam KS
Multifunctional nanoparticles with combined diagnostic and therapeutic functions show great promise towards personalized nanomedicine. However, attaining consistently high performance of these functions in vivo in one single nanoconstruct remains extremely challenging. Here we demonstrate the use of one single polymer to develop a smart 'all-in-one' nanoporphyrin platform that conveniently integrates a broad range of clinically relevant functions. Nanoporphyrins can be used as amplifiable multimodality nanoprobes for near-infrared fluorescence imaging (NIRFI), magnetic resonance imaging (MRI), positron emission tomography (PET) and dual modal PET-MRI. Nanoporphyrins greatly increase the imaging sensitivity for tumour detection through background suppression in blood, as well as preferential accumulation and signal amplification in tumours. Nanoporphyrins also function as multiphase nanotransducers that can efficiently convert light to heat inside tumours for photothermal therapy (PTT), and light to singlet oxygen for photodynamic therapy (PDT). Furthermore, nanoporphyrins act as programmable releasing nanocarriers for targeted delivery of drugs or therapeutic radio-metals into tumours.
A Simple Capacitive Charge-Division Readout for Position-Sensitive Solid-State Photomultiplier Arrays.
IEEE Trans Nucl Sci. 2013 Oct;60(5):3188-3197
Authors: Du J, Schmall JP, Yang Y, Di K, Dokhale PA, Shah KS, Cherry SR
A capacitive charge-division readout method for reading out a 2 × 2 array of 5 mm × 5 mm position-sensitive solid-state photomultipliers (PS-SSPM) was designed and evaluated. Using this analog multiplexing method, the 20 signals (16 position, 4 timing) from the PS-SSPM array are reduced to 5 signals (4 position, 1 timing), allowing the PS-SSPM array to be treated as an individual large-area PS-SSPM module. A global positioning approach can now be used, instead of individual positioning for each PS-SSPM in the array, ensuring that the entire light signal is utilized. The signal-to-noise ratio (SNR) and flood histogram quality at different bias voltages (27.5 V to 32.0 V at 0.5 V intervals) and a fixed temperature of 0 °C were evaluated by coupling a 6 × 6 array of 1.3 mm × 1.3 mm × 20 mm polished LSO crystals to the center of the PS-SSPM array. The timing resolution was measured at a fixed bias voltage of 31.0 V and a fixed temperature of 0 °C. All the measurements were evaluated and compared using capacitors with different values and tolerances. Capacitor values ranged from 0.051 nf to 10 nf, and the capacitance tolerance ranged from 1% to 20%. The results show that better performance was achieved using capacitors with smaller values and better capacitance tolerance. Using 0.2 nf capacitors, the SNR, energy resolution and timing resolution were 24.3, 18.2% and 8.8 ns at a bias voltage 31.0 V, respectively. The flood histogram quality was also evaluated by using a 10 × 10 array of 1 mm × 1 mm × 10 mm polished LSO crystals and a 10 × 10 array of 0.7 mm × 0.7 mm × 20 mm unpolished LSO crystals to determine the smallest crystal size resolvable. These studies showed that the high spatial resolution of the PS-SSPM was preserved allowing for 0.7 mm crystals to be identified. These results show that the capacitive charge-division analog signal processing method can significantly reduce the number of electronic channels, from 20 to 5, while retaining the excellent performance of the detector.
X-ray luminescence optical tomography imaging: experimental studies.
Opt Lett. 2013 Jul 1;38(13):2339-41
Authors: Li C, Di K, Bec J, Cherry SR
We present a hybrid imaging modality, x-ray luminescence optical tomography (XLOT), in which collimated x-ray beams are used to excite phosphor-based contrast agents. Images are reconstructed from the optical signals, using the known x-ray beam location and spatial extent as priors. We demonstrate XLOT using phantom experiments with deep targets and show that the reconstructed signal varies by <12% when the depth changes from 4.2 to 7.7 mm. For simple source distributions, we find as few as two orthogonal projection measurements are sufficient for XLOT reconstruction.
Simulation of light transport in scintillators based on 3D characterization of crystal surfaces.
Phys Med Biol. 2013 Apr 7;58(7):2185-98
Authors: Roncali E, Cherry SR
In the development of positron emission tomography (PET) detectors, understanding and optimizing scintillator light collection is critical for achieving high performance, particularly when the design incorporates depth-of-interaction (DOI) encoding or time-of-flight information. Monte-Carlo simulations play an important role in guiding research in detector designs and popular software such as GATE now include models of light transport in scintillators. Although current simulation toolkits are able to provide accurate models of perfectly polished surfaces, they do not successfully predict light output for other surface finishes, for example those often used in DOI-encoding detectors. The lack of accuracy of those models mainly originates from a simplified description of rough surfaces as an ensemble of micro-facets determined by the distribution of their normal, typically a gaussian distribution. The user can specify the standard deviation of this distribution, but this parameter does not provide a full description of the surface reflectance properties. We propose a different approach based on 3D measurements of the surface using atomic force microscopy. Polished and rough (unpolished) crystals were scanned to compute the surface reflectance properties. The angular distributions of reflectance and reflected rays were computed and stored in look-up tables (LUTs). The LUTs account for the effect of incidence angle and were integrated in a light transport model. Crystals of different sizes were simulated with and without reflector. The simulated maximum light output and the light output as a function of DOI showed very good agreement with experimental characterization of the crystals, indicating that our approach provides an accurate model of polished and rough surfaces and could be used to predict light collection in scintillators. This model is based on a true 3D representation of the surface, makes no assumption about the surface and provides insight on the optical behaviour of rough crystals that can play a critical role in optimizing the design of PET detectors. This approach is also compatible with existing simulation toolkits and next steps include the implementation in GATE.
Applications for preclinical PET/MRI.
Semin Nucl Med. 2013 Jan;43(1):19-29
Authors: Judenhofer MS, Cherry SR
Currently, the combination of positron emission tomography (PET) and magnetic resonance imaging (MRI) as a hybrid imaging modality is receiving great attention not only in its emerging clinical applications but also in the preclinical field. Several prototypes based on several different types of PET detector technology have been developed in recent years, some of which have been used for first preclinical studies. This article provides an overview of currently available PET systems and considerations for combined PET/MRI workflows, and summarizes the results of the first studies performed on dedicated preclinical PET/MRI systems. The article also highlights other research using PET and MRI in combination and highlights potential benefits for integrated systems.
Radiolabeling human peripheral blood stem cells for positron emission tomography (PET) imaging in young rhesus monkeys.
PLoS One. 2013;8(10):e77148
Authors: Tarantal AF, Lee CC, Kukis DL, Cherry SR
These studies focused on a new radiolabeling technique with copper ((64)Cu) and zirconium ((89)Zr) for positron emission tomography (PET) imaging using a CD45 antibody. Synthesis of (64)Cu-CD45 and (89)Zr-CD45 immunoconjugates was performed and the evaluation of the potential toxicity of radiolabeling human peripheral blood stem cells (hPBSC) was assessed in vitro (viability, population doubling times, colony forming units). hPBSC viability was maintained as the dose of (64)Cu-TETA-CD45 increased from 0 (92%) to 160 µCi/mL (76%, p>0.05). Radiolabeling efficiency was not significantly increased with concentrations of (64)Cu-TETA-CD45 >20 µCi/mL (p>0.50). Toxicity affecting both growth and colony formation was observed with hPBSC radiolabeled with ≥40 µCi/mL (p<0.05). For (89)Zr, there were no significant differences in viability (p>0.05), and a trend towards increased radiolabeling efficiency was noted as the dose of (89)Zr-Df-CD45 increased, with a greater level of radiolabeling with 160 µCi/mL compared to 0-40 µCi/mL (p<0.05). A greater than 2,000 fold-increase in the level of (89)Zr-Df-CD45 labeling efficiency was observed when compared to (64)Cu-TETA-CD45. Similar to (64)Cu-TETA-CD45, toxicity was noted when hPBSC were radiolabeled with ≥40 µCi/mL (p<0.05) (growth, colony formation). Taken together, 20 µCi/mL resulted in the highest level of radiolabeling efficiency without altering cell function. Young rhesus monkeys that had been transplanted prenatally with 25×10(6) hPBSC expressing firefly luciferase were assessed with bioluminescence imaging (BLI), then 0.3 mCi of (89)Zr-Df-CD45, which showed the best radiolabeling efficiency, was injected intravenously for PET imaging. Results suggest that (89)Zr-Df-CD45 was able to identify engrafted hPBSC in the same locations identified by BLI, although the background was high.
Comparison of large-area position-sensitive solid-state photomultipliers for small animal PET.
Phys Med Biol. 2012 Dec 21;57(24):8119-34
Authors: Schmall JP, Du J, Yang Y, Dokhale PA, McClish M, Christian J, Shah KS, Cherry SR
This paper evaluates the performance of two large-area position-sensitive solid-state photomultipliers (PS-SSPM) for use in small animal PET detector designs. Both PS-SSPM device designs are 1 cm² in area, the first being a 2 × 2 tiled array of 5 mm × 5 mm PS-SSPMs and the second being a 10 mm × 10 mm continuous PS-SSPM. Signal-to-noise measurements were performed to investigate the optimal operating parameters for each device and to compare the performance of the two PS-SSPM designs. A maximum signal-to-noise ratio of 29.3 was measured for the 5 mm PS-SSPM array and 15.1 for the 10 mm PS-SSPM, both measurements were made at 0 °C and at the optimal bias voltage. The best energy resolution measured with an array of 1.3 mm polished LSO crystals was 16% for the 5 mm PS-SSPM array and 18% for the 10 mm PS-SSPM. The timing properties of both devices were similar, with a best timing resolution (in coincidence with an LSO/PMT detector) of 6.8 ns (range 6.8-8.9 ns) and 7.1 ns (range 7.1-9.6 ns) for the 5 mm PS-SSPM and 10 mm PS-SSPM respectively. The 2 × 2 array of 5 mm PS-SSPMs was able to visually resolve the elements in an 0.5 × 0.5 × 20 mm LYSO scintillator array (unpolished, diffuse reflector) with an average peak-to-valley ratio in the flood histograms of ∼11 indicating clear separation of the crystals. Advantages and drawbacks of PET detector designs using PS-SSPM photodetectors are addressed and comparisons to other small-animal PET detector designs using position-sensitive avalanche photodiodes are made.
Pulse shape discrimination and classification methods for continuous depth of interaction encoding PET detectors.
Phys Med Biol. 2012 Oct 21;57(20):6571-85
Authors: Roncali E, Phipps JE, Marcu L, Cherry SR
In previous work we demonstrated the potential of positron emission tomography (PET) detectors with depth-of-interaction (DOI) encoding capability based on phosphor-coated crystals. A DOI resolution of 8 mm full-width at half-maximum was obtained for 20 mm long scintillator crystals using a delayed charge integration linear regression method (DCI-LR). Phosphor-coated crystals modify the pulse shape to allow continuous DOI information determination, but the relationship between pulse shape and DOI is complex. We are therefore interested in developing a sensitive and robust method to estimate the DOI. Here, linear discriminant analysis (LDA) was implemented to classify the events based on information extracted from the pulse shape. Pulses were acquired with 2×2×20 mm(3) phosphor-coated crystals at five irradiation depths and characterized by their DCI values or Laguerre coefficients. These coefficients were obtained by expanding the pulses on a Laguerre basis set and constituted a unique signature for each pulse. The DOI of individual events was predicted using LDA based on Laguerre coefficients (Laguerre-LDA) or DCI values (DCI-LDA) as discriminant features. Predicted DOIs were compared to true irradiation depths. Laguerre-LDA showed higher sensitivity and accuracy than DCI-LDA and DCI-LR and was also more robust to predict the DOI of pulses with higher statistical noise due to low light levels (interaction depths further from the photodetector face). This indicates that Laguerre-LDA may be more suitable to DOI estimation in smaller crystals where lower collected light levels are expected. This novel approach is promising for calculating DOI using pulse shape discrimination in single-ended readout depth-encoding PET detectors.
Optimal whole-body PET scanner configurations for different volumes of LSO scintillator: a simulation study.
Phys Med Biol. 2012 Jul 7;57(13):4077-94
Authors: Poon JK, Dahlbom ML, Moses WW, Balakrishnan K, Wang W, Cherry SR, Badawi RD
The axial field of view (AFOV) of the current generation of clinical whole-body PET scanners range from 15-22 cm, which limits sensitivity and renders applications such as whole-body dynamic imaging or imaging of very low activities in whole-body cellular tracking studies, almost impossible. Generally, extending the AFOV significantly increases the sensitivity and count-rate performance. However, extending the AFOV while maintaining detector thickness has significant cost implications. In addition, random coincidences, detector dead time, and object attenuation may reduce scanner performance as the AFOV increases. In this paper, we use Monte Carlo simulations to find the optimal scanner geometry (i.e. AFOV, detector thickness and acceptance angle) based on count-rate performance for a range of scintillator volumes ranging from 10 to 93 l with detector thickness varying from 5 to 20 mm. We compare the results to the performance of a scanner based on the current Siemens Biograph mCT geometry and electronics. Our simulation models were developed based on individual components of the Siemens Biograph mCT and were validated against experimental data using the NEMA NU-2 2007 count-rate protocol. In the study, noise-equivalent count rate (NECR) was computed as a function of maximum ring difference (i.e. acceptance angle) and activity concentration using a 27 cm diameter, 200 cm uniformly filled cylindrical phantom for each scanner configuration. To reduce the effect of random coincidences, we implemented a variable coincidence time window based on the length of the lines of response, which increased NECR performance up to 10% compared to using a static coincidence time window for scanners with a large maximum ring difference values. For a given scintillator volume, the optimal configuration results in modest count-rate performance gains of up to 16% compared to the shortest AFOV scanner with the thickest detectors. However, the longest AFOV of approximately 2 m with 20 mm thick detectors resulted in performance gains of 25-31 times higher NECR relative to the current Siemens Biograph mCT scanner configuration.
Quantitative, simultaneous PET/MRI for intratumoral imaging with an MRI-compatible PET scanner.
J Nucl Med. 2012 Jul;53(7):1102-9
Authors: Ng TS, Bading JR, Park R, Sohi H, Procissi D, Colcher D, Conti PS, Cherry SR, Raubitschek AA, Jacobs RE
UNLABELLED: Noninvasive methods are needed to explore the heterogeneous tumor microenvironment and its modulation by therapy. Hybrid PET/MRI systems are being developed for small-animal and clinical use. The advantage of these integrated systems depends on their ability to provide MR images that are spatially coincident with simultaneously acquired PET images, allowing combined functional MRI and PET studies of intratissue heterogeneity. Although much effort has been devoted to developing this new technology, the issue of quantitative and spatial fidelity of PET images from hybrid PET/MRI systems to the tissues imaged has received little attention. Here, we evaluated the ability of a first-generation, small-animal MRI-compatible PET scanner to accurately depict heterogeneous patterns of radiotracer uptake in tumors.
METHODS: Quantitative imaging characteristics of the MRI-compatible PET (PET/MRI) scanner were evaluated with phantoms using calibration coefficients derived from a mouse-sized linearity phantom. PET performance was compared with a commercial small-animal PET system and autoradiography in tumor-bearing mice. Pixel and structure-based similarity metrics were used to evaluate image concordance among modalities. Feasibility of simultaneous PET/MRI functional imaging of tumors was explored by following (64)Cu-labeled antibody uptake in relation to diffusion MRI using cooccurrence matrix analysis.
RESULTS: The PET/MRI scanner showed stable and linear response. Activity concentration recovery values (measured and true activity concentration) calculated for 4-mm-diameter rods within linearity and uniform activity rod phantoms were near unity (0.97 ± 0.06 and 1.03 ± 0.03, respectively). Intratumoral uptake patterns for both (18)F-FDG and a (64)Cu-antibody acquired using the PET/MRI scanner and small-animal PET were highly correlated with autoradiography (r > 0.99) and with each other (r = 0.97 ± 0.01). On the basis of these data, we performed a preliminary study comparing diffusion MRI and radiolabeled antibody uptake patterns over time and visualized movement of antibodies from the vascular space into the tumor mass.
CONCLUSION: The MRI-compatible PET scanner provided tumor images that were quantitatively accurate and spatially concordant with autoradiography and the small-animal PET examination. Cooccurrence matrix approaches enabled effective analysis of multimodal image sets. These observations confirm the ability of the current simultaneous PET/MRI system to provide accurate observations of intratumoral function and serve as a benchmark for future evaluations of hybrid instrumentation.
Radiolabeling and in vivo imaging of transplanted renal lineages differentiated from human embryonic stem cells in fetal rhesus monkeys.
Mol Imaging Biol. 2012 Apr;14(2):197-204
Authors: Tarantal AF, Lee CC, Batchelder CA, Christensen JE, Prater D, Cherry SR
PURPOSE: The goals of this study were to optimize radiolabeling of renal lineages differentiated from human embryonic stem (hES) cells and use noninvasive imaging (positron emission tomography (PET) and bioluminescence imaging (BLI)) to detect the cells in fetal monkeys post-transplant.
PROCEDURES: hES cells expressing firefly luciferase (5 × 10(6)) were radiolabeled with the optimized concentration of 10 μCi/ml (64)Cu-PTSM then transplanted under ultrasound guidance into early second trimester fetal monkey kidneys. Fetuses were imaged in utero with PET and tissues collected for analysis 3 days post-transplant. Fetal kidneys were imaged ex vivo (PET and BLI) post-tissue harvest, and serial kidney sections were assessed by PCR for human-specific DNA sequences, fluorescent in situ hybridization (FISH) for human-specific centromere probes, and immunohistochemistry (IHC) to assess engrafted cells.
RESULTS: Transplanted cells were readily imaged in vivo and identified at the site of injection; tissue analyses confirmed the imaging findings. Using a semi-quantitative method, one in approximately 650 cells in the kidney was shown to be of human origin by PCR and FISH.
CONCLUSIONS: These studies suggest that hES cells differentiated toward renal lineages can be effectively radiolabeled, transplanted into fetal monkey kidneys under ultrasound guidance, monitored with PET post-transplant, and identified by PET, BLI, PCR, FISH, and IHC post-tissue harvest.
Joint L1 and total variation regularization for fluorescence molecular tomography.
Phys Med Biol. 2012 Mar 21;57(6):1459-76
Authors: Dutta J, Ahn S, Li C, Cherry SR, Leahy RM
Fluorescence molecular tomography (FMT) is an imaging modality that exploits the specificity of fluorescent biomarkers to enable 3D visualization of molecular targets and pathways in vivo in small animals. Owing to the high degree of absorption and scattering of light through tissue, the FMT inverse problem is inherently ill-conditioned making image reconstruction highly susceptible to the effects of noise and numerical errors. Appropriate priors or penalties are needed to facilitate reconstruction and to restrict the search space to a specific solution set. Typically, fluorescent probes are locally concentrated within specific areas of interest (e.g., inside tumors). The commonly used L(2) norm penalty generates the minimum energy solution, which tends to be spread out in space. Instead, we present here an approach involving a combination of the L(1) and total variation norm penalties, the former to suppress spurious background signals and enforce sparsity and the latter to preserve local smoothness and piecewise constancy in the reconstructed images. We have developed a surrogate-based optimization method for minimizing the joint penalties. The method was validated using both simulated and experimental data obtained from a mouse-shaped phantom mimicking tissue optical properties and containing two embedded fluorescent sources. Fluorescence data were collected using a 3D FMT setup that uses an EMCCD camera for image acquisition and a conical mirror for full-surface viewing. A range of performance metrics was utilized to evaluate our simulation results and to compare our method with the L(1), L(2) and total variation norm penalty-based approaches. The experimental results were assessed using the Dice similarity coefficients computed after co-registration with a CT image of the phantom.
Pharmacokinetics and biodistribution of a human monoclonal antibody to oxidized LDL in cynomolgus monkey using PET imaging.
PLoS One. 2012;7(9):e45116
Authors: Kamath AV, Williams SP, Bullens S, Cowan KJ, Stenberg Y, Cherry SR, Rendig S, Kukis DL, Griesemer C, Damico-Beyer LA, Bunting S
PURPOSE: Oxidized low-density lipoprotein (LDL) plays an essential role in the pathogenesis of atherosclerosis. The purpose of this study was to characterize the pharmacokinetics (PK) of a human recombinant IgG1 antibody to oxidized LDL (anti-oxLDL) in cynomolgus monkey. The tissue biodistribution of anti-oxLDL was also investigated using positron emission tomography (PET) imaging.
METHODS: Anti-oxLDL was conjugated with the N-hydroxysuccinimide ester of DOTA (1,4,7,10-tetraazacyclododecane 1,4,7,10-tetraacetic acid) and radiolabeled by chelation of radioactive copper-64 ((64)Cu) for detection by PET. Anti-oxLDL was administered as a single intravenous (IV) dose of 10 mg/kg (as a mixture of radiolabeled and non-labeled material) to two male and two female cynomolgus monkeys. Serum samples were collected over 29 days. Two ELISA methods were used to measure serum concentrations of anti-oxLDL; Assay A was a ligand binding assay that measured free anti-oxLDL (unbound and partially bound forms) and Assay B measured total anti-oxLDL. The biodistribution was observed over a 48-hour period following dose administration using PET imaging.
RESULTS: Anti-oxLDL serum concentration-time profiles showed a biphasic elimination pattern that could be best described by a two-compartment elimination model. The serum concentrations obtained using the two ELISA methods were comparable. Clearance values ranged from 8 to 17 ml/day/kg, while beta half-life ranged from 8 to 12 days. The initial volume of distribution and volume of distribution at steady state were approximately 55 mL/kg and 150 mL/kg, respectively. PET imaging showed distribution predominantly to the blood pool, visible as the heart and great vessels in the trunk and limbs, plus diffuse signals in the liver, kidney, spleen, and bone marrow.
CONCLUSIONS: The clearance of anti-oxLDL is slightly higher than typical IgG1 antibodies in cynomolgus monkeys. The biodistribution pattern appears to be consistent with an antibody that has no large, rapid antigen sink outside the blood space.
Establishment of clonal MIN-O transplant lines for molecular imaging via lentiviral transduction & in vitro culture.
Authors: Boucher DL, Chen JQ, Cherry SR, Borowsky AD
As the field of molecular imaging evolves and increasingly is asked to fill the discovery and validation space between basic science and clinical applications, careful consideration should be given to the models in which studies are conducted. The MIN-O mouse model series is an established in vivo model of human mammary precancer ductal carcinoma in situ with progression to invasive carcinoma. This series of transplant lines is propagated in vivo and experiments utilizing this model can be completed in non-engineered immune intact FVB/n wild type mice thereby modeling the tumor microenvironment with biological relevance superior to traditional tumor cell xenografts. Unfortunately, the same qualities that make this and many other transplant lines more biologically relevant than standard cell lines for molecular imaging studies present a significant obstacle as somatic genetic re-engineering modifications common to many imaging applications can be technically challenging. Here, we describe a protocol for the efficient lentiviral transduction of cell slurries derived from precancerous MIN-O lesions, in vitro culture of "MIN-O-spheres" derived from single cell clones, and the subsequent transplantation of these spheres to produce transduced sublines suitable for optical imaging applications. These lines retain the physiologic and pathologic properties, including multilineage differentiation, and complex microanatomic interaction with the host stroma characteristic of the MIN-O model. We also present the in vivo imaging and immunohistochemical analysis of serial transplantation of one such subline and detail the progressive multifocal loss of the transgene in successive generations.
Biodistribution and pharmacokinetics of a telodendrimer micellar paclitaxel nanoformulation in a mouse xenograft model of ovarian cancer.
Int J Nanomedicine. 2012;7:1587-97
Authors: Xiao W, Luo J, Jain T, Riggs JW, Tseng HP, Henderson PT, Cherry SR, Rowland D, Lam KS
BACKGROUND: A multifunctional telodendrimer-based micelle system was characterized for delivery of imaging and chemotherapy agents to mouse tumor xenografts. Previous optical imaging studies demonstrated qualitatively that these classes of nanoparticles, called nanomicelles, preferentially accumulate at tumor sites in mice. The research reported herein describes the detailed quantitative imaging and biodistribution profiling of nanomicelles loaded with a cargo of paclitaxel.
METHODS: The telodendrimer was covalently labeled with ¹²⁵I and the nanomicelles were loaded with ¹⁴C-paclitaxel, which allowed measurement of pharmacokinetics and biodistribution in the mice using microSPECT/CT imaging and liquid scintillation counting, respectively.
RESULTS: The radio imaging data showed preferential accumulation of nanomicelles at the tumor site along with a slower clearance rate than paclitaxel formulated in Cremophor EL (Taxol®). Liquid scintillation counting confirmed that ¹⁴C-labeled paclitaxel sequestered in nanomicelles had increased uptake by tumor tissue and slower pharmacokinetics than Taxol.
CONCLUSION: Overall, the results indicate that nanomicelle-formulated paclitaxel is a potentially superior formulation compared with Taxol in terms of water solubility, pharmacokinetics, and tumor accumulation, and may be clinically useful for both tumor imaging and improved chemotherapy applications.
In vivo Cerenkov luminescence imaging: a new tool for molecular imaging.
Philos Trans A Math Phys Eng Sci. 2011 Nov 28;369(1955):4605-19
Authors: Mitchell GS, Gill RK, Boucher DL, Li C, Cherry SR
Cerenkov radiation is a phenomenon where optical photons are emitted when a charged particle moves faster than the speed of light for the medium in which it travels. Recently, we and others have discovered that measurable visible light due to the Cerenkov effect is produced in vivo following the administration of β-emitting radionuclides to small animals. Furthermore, the amounts of injected activity required to produce a detectable signal are consistent with small-animal molecular imaging applications. This surprising observation has led to the development of a new hybrid molecular imaging modality known as Cerenkov luminescence imaging (CLI), which allows the spatial distribution of biomolecules labelled with β-emitting radionuclides to be imaged in vivo using sensitive charge-coupled device cameras. We review the physics of Cerenkov radiation as it relates to molecular imaging, present simulation results for light intensity and spatial distribution, and show an example of CLI in a mouse cancer model. CLI allows many common radiotracers to be imaged in widely available in vivo optical imaging systems, and, more importantly, provides a pathway for directly imaging β(-)-emitting radionuclides that are being developed for therapeutic applications in cancer and that are not readily imaged by existing methods.
Signal and noise properties of position-sensitive avalanche photodiodes.
Phys Med Biol. 2011 Oct 7;56(19):6327-36
Authors: Yang Y, Wu Y, Farrell R, Dokhale PA, Shah KS, Cherry SR
After many years of development, position-sensitive avalanche photodiodes (PSAPDs) are now being incorporated into a range of scintillation detector systems, including those used in high-resolution small-animal PET and PET/MR scanners. In this work, the signal, noise, signal-to-noise ratio (SNR), flood histogram and timing resolution were measured for lutetium oxyorthosilicate (LSO) scintillator arrays coupled to PSAPDs ranging in size from 10 to 20 mm, and the optimum bias voltage and working temperature were determined. Variations in the SNR performance of PSAPDs with the same dimensions were small, but the SNR decreased significantly with increasing PSAPD size and increasing temperature. Smaller PSAPDs (10 mm and 15 mm in width) produced acceptable flood histograms at 24 °C, and cooling lower than 16 °C produced little improvement. The optimum bias voltage was about 25 V below the break down voltage. The larger 20 mm PSAPDs have lower SNR and require cooling to 0-7 °C for acceptable performance. The optimum bias voltage is also lower (35 V or more below the break down voltage depending on the temperature). Significant changes in the timing resolution were observed as the bias voltage and temperature varied. Higher bias voltages provided better timing resolution. The best timing resolution obtained for individual crystals was 2.8 ns and 3.3 ns for the 10 mm and 15 mm PSAPDs, respectively. The results of this work provide useful guidance for selecting the bias voltage and working temperature for scintillation detectors that incorporate PSAPDs as the photodetector.
Experimental assessment of resolution improvement of a zoom-in PET.
Phys Med Biol. 2011 Sep 7;56(17):N165-74
Authors: Qi J, Yang Y, Zhou J, Wu Y, Cherry SR
We have proposed a zoom-in positron emission tomography (PET) system that incorporates a high-resolution detector into an existing PET scanner to obtain high-resolution images of a region of interest. Previously we have shown by computer simulations that the high-resolution detector can improve the overall system performance in terms of spatial resolution and lesion detectability. In this study, we assessed the resolution improvement in a real system by incorporating a high-resolution detector into our existing microPET II scanner. The high-resolution detector consists of a 14 × 28 array of 0.5 × 0.5 × 10 mm³ lutetium oxyorthosilicate scintillator elements and is placed near the center of the microPET II scanner. It is coupled to two 64-channel photomultiplier tubes (PMTs) via tapered optical fiber bundles. The PMT signals were read out by the electronics in the microPET II scanner. A 15 µCi Na-22 point source was positioned at various locations above the high-resolution detector. Images were reconstructed using the data measured by the microPET II scanner alone and the microPET II data combined with the high-resolution detector data. Profiles taken through the reconstructed point sources show substantial reduction in full-width-at-half-maximum along the direction parallel to the face of the high-resolution detector.
Simultaneous PET and multispectral 3-dimensional fluorescence optical tomography imaging system.
J Nucl Med. 2011 Aug;52(8):1268-75
Authors: Li C, Yang Y, Mitchell GS, Cherry SR
UNLABELLED: Integrated PET and 3-dimensional (3D) fluorescence optical tomography (FOT) imaging has unique and attractive features for in vivo molecular imaging applications. We have designed, built, and evaluated a simultaneous PET and 3D FOT system. The design of the FOT system is compatible with many existing small-animal PET scanners.
METHODS: The 3D FOT system comprises a novel conical mirror that is used to view the whole-body surface of a mouse with an electron-multiplying charge-coupled device camera when a collimated laser beam is projected on the mouse to stimulate fluorescence. The diffusion equation was used to model the propagation of optical photons inside the mouse body, and 3D fluorescence images were reconstructed iteratively from the fluorescence intensity measurements measured from the surface of the mouse. Insertion of the conical mirror into the gantry of a small-animal PET scanner allowed simultaneous PET and 3D FOT imaging.
RESULTS: The mutual interactions between PET and 3D FOT were evaluated experimentally. PET has negligible effects on 3D FOT performance. The inserted conical mirror introduces a reduction in the sensitivity and noise-equivalent count rate of the PET system and increases the scatter fraction. PET-FOT phantom experiments were performed. An in vivo experiment using both PET and FOT was also performed.
CONCLUSION: Phantom and in vivo experiments demonstrate the feasibility of simultaneous PET and 3D FOT imaging. The first in vivo simultaneous PET-FOT results are reported.
New covalent capture probes for imaging and therapy, based on a combination of binding affinity and disulfide bond formation.
Bioconjug Chem. 2011 Aug 17;22(8):1479-83
Authors: Aweda TA, Eskandari V, Kukis DL, Boucher DL, Marquez BV, Beck HE, Mitchell GS, Cherry SR, Meares CF
We describe the synthesis and development of new reactive DOTA-metal complexes for covalently targeting engineered receptors in vivo, which have superior tumor uptake and clearance properties for biomedical applications. These probes are found to clear efficiently through the kidneys and minimally through other routes, but bind persistently in the tumor target. We also explore the new technique of Cerenkov luminescence imaging to optically monitor radiolabeled probe distribution and kinetics in vivo. Cerenkov luminescence imaging uniquely enables sensitive noninvasive in vivo imaging of a β(-) emitter such as (90)Y with an optical imager.
Application of silicon photomultipliers to positron emission tomography.
Ann Biomed Eng. 2011 Apr;39(4):1358-77
Historically, positron emission tomography (PET) systems have been based on scintillation crystals coupled to photomultipliers tubes (PMTs). However, the limited quantum efficiency, bulkiness, and relatively high cost per unit surface area of PMTs, along with the growth of new applications for PET, offers opportunities for other photodetectors. Among these, small-animal scanners, hybrid PET/MRI systems, and incorporation of time-of-flight information are of particular interest and require low-cost, compact, fast, and magnetic field compatible photodetectors. With high quantum efficiency and compact structure, avalanche photodiodes (APDs) overcome several of the drawbacks of PMTs, but this is offset by degraded signal-to-noise and timing properties. Silicon photomultipliers (SiPMs) offer an alternative solution, combining many of the advantages of PMTs and APDs. They have high gain, excellent timing properties and are insensitive to magnetic fields. At the present time, SiPM technology is rapidly developing and therefore an investigation into optimal design and operating conditions is underway together with detailed characterization of SiPM-based PET detectors. Published data are extremely promising and show good energy and timing resolution, as well as the ability to decode small scintillator arrays. SiPMs clearly have the potential to be the photodetector of choice for some, or even perhaps most, PET systems.
Functional whole-brain imaging in behaving rodents.
Nat Methods. 2011 Apr;8(4):301-3
Tapered LSO arrays for small animal PET.
Authors: Yang Y, James SS, Wu Y, Du H, Qi J, Farrell R, Dokhale PA, Shah KS, Vaigneur K, Cherry SR
By using detectors with good depth encoding accuracy (∼2 mm), an animal PET scanner can be built with a small ring diameter and thick crystals to simultaneously obtain high spatial resolution and high sensitivity. However, there will be large wedge-shaped gaps between detector modules in such a scanner if traditional cuboid crystal arrays are used in a polygonal arrangement. The gaps can be minimized by using tapered scintillator arrays enabling the sensitivity of the scanner to be further improved. In this work, tapered lutetium oxyorthosilicate (LSO) arrays with different crystal dimensions and different combinations of inter-crystal reflector and crystal surface treatments were manufactured and their performance was evaluated. Arrays were read out from both ends by position-sensitive avalanche photodiodes (PSAPDs). In the optimal configuration, arrays consisting of 0.5 mm LSO elements could be clearly resolved and a depth of interaction resolution of 2.6 mm was obtained for a 20 mm thick array. For this tapered array, the intrinsic spatial is degraded from 0.67 to 0.75 mm compared to a standard cuboidal array with similar dimensions, while the increase in efficiency is 41%. Tapered scintillator arrays offer the prospect of improvements in sensitivity and sampling for small-bore scanners, without large increases in manufacturing complexity.
DigiWarp: a method for deformable mouse atlas warping to surface topographic data.
Phys Med Biol. 2010 Oct 21;55(20):6197-214
Authors: Joshi AA, Chaudhari AJ, Li C, Dutta J, Cherry SR, Shattuck DW, Toga AW, Leahy RM
For pre-clinical bioluminescence or fluorescence optical tomography, the animal's surface topography and internal anatomy need to be estimated for improving the quantitative accuracy of reconstructed images. The animal's surface profile can be measured by all-optical systems, but estimation of the internal anatomy using optical techniques is non-trivial. A 3D anatomical mouse atlas may be warped to the estimated surface. However, fitting an atlas to surface topography data is challenging because of variations in the posture and morphology of imaged mice. In addition, acquisition of partial data (for example, from limited views or with limited sampling) can make the warping problem ill-conditioned. Here, we present a method for fitting a deformable mouse atlas to surface topographic range data acquired by an optical system. As an initialization procedure, we match the posture of the atlas to the posture of the mouse being imaged using landmark constraints. The asymmetric L(2) pseudo-distance between the atlas surface and the mouse surface is then minimized in order to register two data sets. A Laplacian prior is used to ensure smoothness of the surface warping field. Once the atlas surface is normalized to match the range data, the internal anatomy is transformed using elastic energy minimization. We present results from performance evaluation studies of our method where we have measured the volumetric overlap between the internal organs delineated directly from MRI or CT and those estimated by our proposed warping scheme. Computed Dice coefficients indicate excellent overlap in the brain and the heart, with fair agreement in the kidneys and the bladder.
Cerenkov luminescence tomography for small-animal imaging.
Opt Lett. 2010 Apr 1;35(7):1109-11
Authors: Li C, Mitchell GS, Cherry SR
Cerenkov radiation is a well-known phenomenon in which optical photons are emitted by charged particles moving faster than the speed of light in a medium. We have observed Cerenkov photons emitted from beta-emitting radiotracers such as (18)F-fluorodeoxyglucose using a sensitive CCD camera. Phantom and in vivo mouse imaging experiments have demonstrated that surface measurements of the emitted Cerenkov optical photons could be used to reconstruct the radiotracer activity distribution inside an object by modeling the optical photon propagation with the diffusion equation and reconstructing the optical emission source distribution iteratively with a preconditioned conjugate gradient method.
Simulation study of spatial resolution and sensitivity for the tapered depth of interaction PET detectors for small animal imaging.
Phys Med Biol. 2010 Jan 21;55(2):N63-74
Authors: St James S, Yang Y, Bowen SL, Qi J, Cherry SR
Improvements to current small animal PET scanners can be made by improving the sensitivity and the spatial resolution of the scanner. In the past, efforts have been made to minimize the crystal dimensions in the axial and transaxial directions to improve the spatial resolution and to increase the crystal length to improve the sensitivity of the scanner. We have designed tapered PET detectors with the purpose of reducing the gaps between detector modules and optimizing the sensitivity of a future-generation small animal PET scanner. In this work, we investigate spatial resolution and sensitivity of a scanner based on tapered detector elements using Monte Carlo simulations. For tapered detector elements more scintillation material is used per detector resulting in a higher sensitivity of the scanner. However, since the detector elements are not uniform in size, degradation in spatial resolution is also expected. To investigate characteristics of tapered PET detectors, the spatial resolution and sensitivity of a one-ring scanner were simulated for a system based on traditional cuboid detectors and a scanner based on tapered detectors. Additionally, the effect of depth of interaction (DOI) resolution on the spatial resolution for the traditional and tapered detectors was evaluated. All simulations were performed using the Monte Carlo simulation package GATE. Using the tapered arrays, a 64% improvement in the sensitivity across the field of view was found compared with traditional detectors for the same ring diameter. The level of DOI encoding was found to be the dominating factor in determining the radial spatial resolution and not the detector shape. For all levels of DOI encoding, no significant difference was found for the spatial resolution when comparing the tapered and the cuboid detectors. Detectors employing the tapered crystal design along with excellent DOI resolution will lead to PET scanners with higher sensitivity and uniform spatial resolution across the field of view.
Studies of the interactions of an MRI system with the shielding in a combined PET/MRI scanner.
Authors: Peng BJ, Walton JH, Cherry SR, Willig-Onwuachi J
A positron emission tomography (PET) system or 'insert' has been constructed for placement and operation in the bore of a small animal magnetic resonance imaging (MRI) scanner to allow simultaneous MR and PET imaging. The insert contains electronics, components with a variety of magnetic properties and large continuous sheets of metal--all characteristics of an object that should, by conventional wisdom, never be placed in the bore of an MR scanner, especially near the imaging volume. There are a variety of ways the two systems might be expected to interact that could negatively impact the performance of either or both. In this article, the interaction mechanisms, particularly the impact of the PET insert and shielding on MR imaging, are defined and explored. Additionally, some of the difficulties in quantifying errors introduced into the MR images as a result of the presence of the PET components are demonstrated. Several different approaches are used to characterize image artifacts and determine optimal placement of the shielding. Data are also presented that suggest ways the shielding could be modified to reduce errors and enable placement closer to the isocenter of the magnet.
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