Prompt gamma timing for proton range verification with TlBr and TlCl as pure Cherenkov emitters.

Objective. Prompt gamma timing (PGT) uses the detection time of prompt gammas emitted along the range of protons in proton radiotherapy to verify the position of the Bragg peak (BP). Cherenkov detectors offer the possibility of enhanced signal-to-noise ratio (SNR) due to the inherent physics of Cherenkov emission which enhances detection of high energy prompt gamma rays relative to other induced uncorrelated signals. In this work, the PGT technique was applied to 3 semiconductor material slabs that emit only Cherenkov light for use in a full scale system: a 3 × 3 × 20 mm3TlBr, a 12 × 12 × 12 mm3TlBr, and a 5 × 5 × 5 mm3TlCl.Approach. A polymethyl methacrylate (PMMA) target was exposed to a 67.5 MeV, 0.5 nA proton beam and shifted in 3 mm increments at the Crocker nuclear laboratory (CNL) in Davis, CA, USA. A fast plastic scintillator coupled to a photomultiplier tube (PMT) provided the start reference for the proton time of flight. Time of flight (TOF) distributions were generated using this reference and the gamma-ray timestamp in the Cherenkov detector.Main results. The SNR of the proton correlated peaks relative to the background was 20, 29, and 30 for each of the three samples, respectively. The upper limit of the position resolutions with the TlCl sample were 2 mm, 3 mm, and 5 mm for 30k, 10k, and 5k detected events, respectively. The time distribution of events with respect to the reference reproduced with clarity the periodicity of the beam, implying a very high SNR of the Cherenkov crystals to detect prompt gammas. Background presence from the neutron-induced continuum, prompt gammas from deuterium, or positron activation were not observed. Material choice and crystal dimensions did not seem to affect significantly the outcome of the results.Significance. These results show the high SNR of the pure Cherenkov emitters TlBr and TlCl for the detection of prompt gammas in a proton beam with current of clinical significance and their potential for verifying the proton range. The accuracy in determining shifts of the BP was highly dependent on the number of events acquired, therefore, the performance of these detectors are expected to vary with different beam conditions such as current, pulse repetition, and proton bunch width.

SPLIT: Statistical Positronium Lifetime Image Reconstruction via Time-Thresholding.

Positron emission tomography (PET) is a widely utilized medical imaging modality that uses positron-emitting radiotracers to visualize biochemical processes in a living body. The spatiotemporal distribution of a radiotracer is estimated by detecting the coincidence photon pairs generated through positron annihilations. In human tissue, about 40% of the positrons form positroniums prior to the annihilation. The lifetime of these positroniums is influenced by the microenvironment in the tissue and could provide valuable information for better understanding of disease progression and treatment response. Currently, there are few methods available for reconstructing high-resolution lifetime images in practical applications. This paper presents an efficient statistical image reconstruction method for positronium lifetime imaging (PLI). We also analyze the random triple-coincidence events in PLI and propose a correction method for random events, which is essential for real applications. Both simulation and experimental studies demonstrate that the proposed method can produce lifetime images with high numerical accuracy, low variance, and resolution comparable to that of the activity images generated by a PET scanner with currently available time-of-flight resolution.

Potential of Depth-of-Interaction-Based Detection Time Correction in Cherenkov Emitter Crystals for TOF-PET.

Cherenkov light can improve the timing resolution of Positron Emission Tomography (PET) radiation detectors, thanks to its prompt emission. Coincidence time resolutions (CTR) of ~30 ps were recently reported when using 3.2 mm-thick Cherenkov emitters. However, sufficient detection efficiency requires thicker crystals, causing the timing resolution to be degraded by the optical propagation inside the crystal. We report on depth-of-interaction (DOI) correction to mitigate the time-jitter due to the photon time spread in Cherenkov-based radiation detectors. We simulated the Cherenkov and scintillation light generation and propagation in 3 × 3 mm2 lead fluoride, lutetium oxyorthosilicate, bismuth germanate, thallium chloride, and thallium bromide. Crystal thicknesses varied from 9 to 18 mm with a 3-mm step. A DOI-based time correction showed a 2-to-2.5-fold reduction of the photon time spread across all materials and thicknesses. Results showed that highly refractive crystals, though producing more Cherenkov photons, were limited by an experimentally obtained high-cutoff wavelength and refractive index, restricting the propagation and extraction of Cherenkov photons mainly emitted at shorter wavelengths. Correcting the detection time using DOI information shows a high potential to mitigate the photon time spread. These simulations highlight the complexity of Cherenkov-based detectors and the competing factors in improving timing resolution.

Engineering the gain and bandwidth in avalanche photodetectors.

Avalanche and Single-Photon Avalanche photodetectors (APDs and SPADs) rely on the probability of photogenerated carriers to trigger a multiplication process. Photon penetration depth plays a vital role in this process. In silicon APDs, a significant fraction of the short visible wavelengths is absorbed close to the device surface that is typically highly doped to serve as a contact. Most of the photogenerated carriers in this region can be lost by recombination, get slowly transported by diffusion, or multiplied with high excess noise. On the other hand, the extended penetration depth of near-infrared wavelengths requires thick semiconductors for efficient absorption. This diminishes the speed of the devices due to the long transit time in the thick absorption layer that is required for detecting most of these photons. Here, we demonstrate that it is possible to drive photons to a critical depth in a semiconductor film to maximize their gain-bandwidth performance and increase the absorption efficiency. This approach to engineering the penetration depth for different wavelengths in silicon is enabled by integrating photon-trapping nanoholes on the device surface. The penetration depth of short wavelengths such as 450 nm is increased from 0.25 µm to more than 0.62 µm. On the other hand, for a long-wavelength like 850 nm, the penetration depth is reduced from 18.3 µm to only 2.3 µm, decreasing the device transit time considerably. Such capabilities allow increasing the gain in APDs by almost 400× at 450 nm and by almost 9× at 850 nm. This engineering of the penetration depth in APDs would enable device designs requiring higher gain-bandwidth in emerging technologies such as Fluorescence Lifetime Microscopy (FLIM), Time-of-Flight Positron Emission Tomography (TOF-PET), quantum communications systems, and 3D imaging systems.

The Accuracy of Cerenkov Photons Simulation in Geant4/Gate Depends on the Parameterization of Primary Electron Propagation.

Energetic electrons traveling in a dispersive medium can produce Cerenkov radiation. Cerenkov photons' prompt emission, combined with their predominantly forward emission direction with respect to the parent electron, makes them extremely promising to improve radiation detector timing resolution. Triggering gamma detections based on Cerenkov photons to achieve superior timing resolution is challenging due to the low number of photons produced per interaction. Monte Carlo simulations are fundamental to understanding their behavior and optimizing their pathway to detection. Therefore, accurately modeling the electron propagation and Cerenkov photons emission is crucial for reliable simulation results. In this work, we investigated the physics characteristics of the primary electrons (velocity, energy) and those of all emitted Cerenkov photons (spatial and timing distributions) generated by 511 keV photoelectric interactions in a bismuth germanate crystal using simulations with Geant4/GATE. Geant4 uses a stepwise particle tracking approach, and users can limit the electron velocity change per step. Without limiting it (default Geant4 settings), an electron mean step length of ~250 µm was obtained, providing only macroscopic modeling of electron transport, with all Cerenkov photons emitted in the forward direction with respect to the incident gamma direction. Limiting the electron velocity change per step reduced the electron mean step length (~0.200 µm), leading to a microscopic approach to its transport which more accurately modeled the electron physical properties in BGO at 511 keV. The electron and Cerenkov photons rapidly lost directionality, affecting Cerenkov photons' transport and, ultimately, their detection. Results suggested that a deep understanding of low energy physics is crucial to perform accurate optical Monte Carlo simulations and ultimately use them in TOF PET detectors.

Study of Cerenkov Light Emission in the Semiconductors TlBr and TlCl for TOF-PET.

Thallium bromide (TlBr) and thallium chloride (TlCl) are semiconductor materials with high transparency to visible light, high index of refraction, and high detection efficiency for gamma rays and annihilation photons. This manuscript reports on measurements of the light intensity and timing response of Cerenkov light emitted in one 3 mm × 3 mm × 5 mm slab of each of these materials operated in coincidence with a lutetium fine silicate (LFS) crystal with dimensions of 3 mm × 3 mm × 20 mm. A 22Na radioactive source was used. The measured average number of detected photons per event was 1.5 photons for TlBr and 2.8 photons for TlCl when these materials were coupled to a silicon photomultiplier. Simulation predicts these results with an overestimation of 12%. The best coincidence time resolution (CTR) for events in TlBr and TlCl were 329 ± 9 ps and 316 ± 9 ps, respectively, when events with 4 photons and >7 photons were selected. Simulation showed the CTR degraded from 120 ps to 405 ps in TlCl, and from 160 ps to 700 ps in TlBr when the first or second Cerenkov photon were selected. Results of this work show TlCl has a stronger Cerenkov light emission compared to TlBr and a greater potential to obtain the best timing measurements. Results also stress the importance of improving detection efficiency and transport of light to capture the first Cerenkov photon in timing measurements.

Avalanche photodetectors with photon trapping structures for biomedical imaging applications.

Enhancing photon detection efficiency and time resolution in photodetectors in the entire visible range is critical to improve the image quality of time-of-flight (TOF)-based imaging systems and fluorescence lifetime imaging (FLIM). In this work, we evaluate the gain, detection efficiency, and timing performance of avalanche photodiodes (APD) with photon trapping nanostructures for photons with 450 nm and 850 nm wavelengths. At 850 nm wavelength, our photon trapping avalanche photodiodes showed 30 times higher gain, an increase from 16% to >60% enhanced absorption efficiency, and a 50% reduction in the full width at half maximum (FWHM) pulse response time close to the breakdown voltage. At 450 nm wavelength, the external quantum efficiency increased from 54% to 82%, while the gain was enhanced more than 20-fold. Therefore, silicon APDs with photon trapping structures exhibited a dramatic increase in absorption compared to control devices. Results suggest very thin devices with fast timing properties and high absorption between the near-ultraviolet and the near infrared region can be manufactured for high-speed applications in biomedical imaging. This study paves the way towards obtaining single photon detectors with photon trapping structures with gains above 106 for the entire visible range.

Energy and electron drift time measurements in a pixel CCI TlBr detector with 1.3 MeV prompt-gammas.

Assessing the position of the Bragg peak (BP) in hadron radiotherapy utilizing prompt-gamma imaging (PGI) presents many challenges in terms of detector physics. Gamma detectors with the capability of extracting the best energy, timing, and spatial information from each gamma interaction, as well as with high detection efficiency and count rate performance, are needed for this application. In this work we present the characterization of a pixel Cerenkov charge induction (CCI) thallium bromide (TlBr) detector in terms of energy and and electron drift time for its potential use in PGI. The CCI TlBr detector had dimensions of 4 × 4 × 5 mm3 and one of its electrodes was segmented in pixels with 1.7 mm pitch. A silicon photomultiplier (SiPM) was optically coupled to one of the faces of the TlBr slab to read out the Cerenkov light promptly emitted after the interaction of a gamma ray. The detector was operated stand-alone and the 1.275 prompt gammas from a 22Na radioactive source were used for the study. The electron drift time was obtained by combining the Cerenkov and charge induction signals and then used as a measure of the depth of interaction. The electron mobility in TlBr was estimated as ∼27 cm2 V-1 s-1. Energy resolutions between 3.4% and 4.0% at 1.275 MeV were obtained after depth-correction. These values improved to 3.0%-3.3% when events with drift times of 3-6 µs were selected. These results show the potential of pixel CCI TlBr detectors to resolve gamma interactions in the detector with mm-like accuracy in 3D and with excellent energy resolution. Previous studies with CCI TlBr devices have shown a timing resolution of <400 ps full width at half maximum when detecting 511 keV gamma rays, therefore, the timing accuracy is expected to improve with the increased energy of the gamma rays in PGI. While other important detector characteristics such as count rate capability remain to be studied, results from this work combined with other preliminary data show pixel CCI detectors can simultaneously provide excellent energy, timing, and spatial resolution performance and are a very promising option for PGI in hadron therapy.

Chondrosesamoidean ligament enthesopathy: Prevalence and findings in a population of lame horses imaged with positron emission tomography.

BACKGROUND: Increased 18 F-Sodium Fluoride (18 F-NaF) uptake at the chondrosesamoidean ligament (ChSL) attachment on the distal phalanx was identified in an exploratory positron emission tomography (PET) study. The prevalence and significance of this lesion has not been previously investigated. OBJECTIVES: The goal of this study was to assess the prevalence of this lesion, its association with other imaging findings and with clinical signs. STUDY DESIGN: Retrospective cross-sectional analytical study. METHODS: All horses with 18 F-NaF PET and computed tomography (CT) imaging of the feet performed between October 2016 and December 2017 were included in the study. All PET scans were independently assessed by two radiologists for increased uptake at the ChSL attachment site and concurrent imaging was reviewed. Clinical findings, treatment and outcome were retrieved from the medical records. RESULTS: Fourteen of 30 horses (20/56 feet) had increased 18 F-NaF uptake in the region of interest. ChSL enthesopathy was the primary lesion in three horses. Other PET abnormalities included navicular bone uptake (13 feet) and ipsilateral palmar process uptake (9 feet). There was no significant association between ChSL enthesopathy and other lesions. ChSL enthesopathy was significantly associated with foot lameness. CT abnormalities at the ChSL attachment were initially identified in one foot, and retrospectively noted in another five following the results of PET imaging. MAIN LIMITATIONS: The study is retrospective and there was a limited sample size. CONCLUSIONS: PET led to identification of ChSL enthesopathy in a large proportion of horses with foot pain. This finding is most commonly associated with other lesions but may also represent the main abnormality. The axial border of the palmar processes of the distal phalanx should be carefully assessed on cross sectional imaging to identify this lesion. ChSL enthesopathy may be an important but previously not recognised component of foot pathology in horses.

Performance comparison of dual-ended readout depth-encoding PET detectors based on BGO and LYSO crystals.

The performance of dual-ended readout depth-encoding positron emission tomography (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.

Imaging Salt Uptake Dynamics in Plants Using PET.

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.

First Cerenkov charge-induction (CCI) TlBr detector for TOF-PET and proton range verification.

Thallium bromide (TlBr) is a semiconductor material and, simultaneously, a good Cerenkov radiator. The performance of a TlBr detector that integrates two different readouts, the charge induction readout and the detection of Cerenkov light, was evaluated. A TlBr detector with dimensions of 4 × 4 × 5 mm3, with a monolithic cathode and an anode segmented into strips, was manufactured. One of the bare and polished 4 × 4 mm2 faces of the detector was coupled to a silicon photomultiplier (SiPM) to read out the Cerenkov light. Simultaneous timing and energy resolutions of <400 ps full width at half maximum (FWHM) and ~8.5% at 511 keV were measured using the Cerenkov detection and charge induction readouts, respectively. A coincidence time resolution of 330 ps was obtained when selecting Cerenkov events with amplitudes above 70 mV. The combination of both readouts showed the potential to resolve the depth-of-interaction (DOI) positioning, based on the improvement of energy resolution when selecting events with similar electron drift times. This manuscript sets the stage for a new family of semiconductor detectors that combine charge induction readout with the Cerenkov light detection. Such detectors can provide, simultaneously, outstanding timing, energy, and spatial resolution, and will be an excellent fit for applications that require the detection of high-energy gamma photons with high timing accuracy, such as time-of-flight positron emission tomography (TOF-PET) and prompt gamma imaging (PGI) to assess the particle range in hadron therapy.

Development of TlBr detectors for PET imaging.

Thallium bromide (TlBr) is a promising semiconductor detector material for positron emission tomography (PET) because it can offer very good energy resolution and 3D 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 (6.4 ± 1.3)% at 511 keV was achieved at -400 V bias voltage and at room temperature. A timing resolution of (27.8 ± 4.1) 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.

Towards time-of-flight PET with a semiconductor detector.

The feasibility of using Cerenkov light, generated by energetic electrons following 511 keV photon interactions in the semiconductor TlBr, to obtain fast timing information for positron emission tomography (PET) was evaluated. Due to its high refractive index, TlBr is a relatively good Cerenkov radiator and with its wide bandgap, has good optical transparency across most of the visible spectrum. Coupling an SiPM photodetector to a slab of TlBr (TlBr-SiPM) yielded a coincidence timing resolution of 620 ps FWHM between the TlBr-SiPM detector and a LFS reference detector. This value improved to 430 ps FWHM by applying a high pulse amplitude cut based on the TlBr-SiPM and reference detector signal amplitudes. These results are the best ever achieved with a semiconductor PET detector and already approach the performance required for time-of-flight. As TlBr has higher stopping power and better energy resolution than the conventional scintillation detectors currently used in PET scanners, a hybrid TlBr-SiPM detector with fast timing capability becomes an interesting option for further development.