Background: Effective thermal ablation of liver tumors requires precise monitoring of the ablation zone. Computed tomography (CT) thermometry can non-invasively monitor lethal temperatures but suffers from metal artifacts caused by ablation equipment. Purpose: This study assesses spectral CT thermometry's applicability during microwave ablation, comparing the reproducibility, precision, and accuracy of attenuation-based versus physical density-based thermometry. Furthermore, it identifies optimal metal artifact reduction (MAR) methods: O-MAR, deep learning-MAR, spectral CT, and combinations thereof. Methods: Four gel phantoms embedded with temperature sensors underwent a 10- minute, 60 W microwave ablation imaged by dual-layer spectral CT scanner in 23 scans over time. For each scan attenuation-based and physical density-based temperature maps were reconstructed. Attenuation-based and physical density-based thermometry models were tested for reproducibility over three repetitions; a fourth repetition focused on accuracy. MAR techniques were applied to one repetition to evaluate temperature precision in artifact-corrupted slices. Results: The correlation between CT value and temperature was highly linear with an R-squared value exceeding 96 %. Model parameters for attenuation-based and physical density-based thermometry were −0.38 HU/°C and 0.00039 °C⁻¹, with coefficients of variation of 2.3 % and 6.7 %, respectively. Physical density maps improved temperature precision in presence of needle artifacts by 73 % compared to attenuation images. O-MAR improved temperature precision with 49 % compared to no MAR. Attenuation-based thermometry yielded narrower Bland-Altman limits-of-agreement (−7.7 °C to 5.3 °C) than physical density-based thermometry. Conclusions: Spectral physical density-based CT thermometry at 150 keV, utilized alongside O-MAR, enhances temperature precision in presence of metal artifacts and achieves reproducible temperature measurements with high accuracy.

Objective.Clustered pinhole (CP) collimation currently supports sub-millimeter resolution imaging up to ∼1 MeV, enabling SPECT of alpha and beta emitters with gamma emissions, simultaneous multi-isotope PET and PET/SPECT, and positron range-free PET. Nonetheless, increasing sensitivity in the original CP designs by enlarging pinhole diameters is limited, as the resulting pinhole opening cones would overlap.Approach. To address this limitation, the use of Super-Cluster (SC) collimation was evaluated in a simulation study. Two SC designs were assessed: a standard configuration (SC-ST) offering a resolution-sensitivity trade-off similar to CP, and a high-sensitivity variant (SC-HS) with larger pinhole diameters to enhance sensitivity. Their performance was compared to CP collimation for18F at concentrations of 1.0, 0.1, 0.05 MBq ml-1and ⁸⁹Zr at 2.0, 0.2, 0.1 MBq ml-1, evaluating sensitivity, image resolution, recovery coefficients, and uniformity.Main results.CP and SC-ST showed comparable sensitivity and image resolution. Both resolved18F rods of 0.9, 1.4, and 1.8 mm at 1.0, 0.1, and 0.05 MBq ml-1, respectively. For ⁸⁹Zr, rods down to 1.0 mm and 1.6 mm were resolved at 2.0 and 0.2 MBq ml-1, but none at 0.1 MBq ml-1. Compared to CP and SC-ST, SC-HS increased sensitivity threefold for18F and twofold for ⁸⁹Zr. At the highest activity, SC-HS showed slightly reduced resolution for18F (1.0 mm) and similar for ⁸⁹Zr (1.0 mm). However, it clearly outperformed both other collimators at lower activities, resolving18F rods of 1.2 and 1.4 mm at 0.1 and 0.05 MBq ml-1, respectively, and ⁸⁹Zr rods of 1.4 and 1.6 mm at 0.2 and 0.1 MBq ml-1. Additionally, SC-HS showed superior contrast recovery. Image uniformity remained consistent across all collimators, confirming effective angular sampling.Significance.The new SC geometry enables high-sensitivity collimation for high gamma energies, improving image quality at low activities. These results demonstrate SC collimation's strong potential for sensitivity-critical applications.

Background
Photon counting detectors (PCDs) for x-ray computed tomography (CT) are the future of CT imaging. At present, semiconductor-based PCDs such as cadmium telluride (CdTe), cadmium zinc telluride, and silicon have been either used or investigated for clinical PCD CT. Unfortunately, all of them have the same major challenges, namely high cost and limited spectral signal-to-noise ratio (SNR). Recent studies showed that some high-quality scintillators, such as lanthanum bromide doped with cerium (LaBr3:Ce), are less expensive and almost as fast as CdTe.

Purpose
The objective of this study is to assess the performance of a LaBr3:Ce PCD for clinical x-ray CT.

Methods
We performed Monte Carlo simulations and compared the performance of 3 mm thick LaBr3:Ce and 2 mm thick CdTe for PCD CT with x-rays at 120 kVp and 20–1000 mA. The two PCDs were operated with either a threshold–subtract (TS) counting scheme or a direct energy binning (DB) counting scheme. The performance was assessed in terms of the accuracy of registered spectra, counting capability, and count-rate-dependent spectral imaging-task performance, for conventional CT imaging, water–bone material decomposition, and K-edge imaging with tungsten as the K-edge material. The performance for these imaging-tasks was quantified by nCRLB, that is, the Cramér–Rao lower bound on the variance of basis line-integral estimation, normalized by the corresponding value of CdTe at 20 mA.

Results
The spectrum recorded by CdTe was distorted significantly due to charge sharing, whereas the spectra recorded by LaBr3:Ce better matched the incident spectrum. The dead time, estimated by fitting a paralyzable detector model to the count-rate curves, was 20.7, 15.0, 37.2, and 13.0 ns for CdTe with TS, CdTe with DB, LaBr3:Ce with TS, and LaBr3:Ce with DB, respectively. Conventional CT imaging showed an adverse effect of reduced geometrical efficiency due to optical reflectors in LaBr3:Ce PCD. The nCRLBs (a lower value indicates a better SNR) for CdTe with TS, CdTe with DB, LaBr3:Ce with TS, LaBr3:Ce with DB, and the ideal PCD, were 1.00 ± 0.01, 1.00 ± 0.01, 1.18 ± 0.02, 1.18 ± 0.02, and 0.79 ± 0.01, respectively, at 20 mA. The nCRLBs for water–bone material decomposition, in the same order, were 1.00 ± 0.02, 1.00 ± 0.02, 0.85 ± 0.02, 0.85 ± 0.02, and 0.24 ± 0.02, respectively, at 20 mA; and 0.98 ± 0.02, 0.98 ± 0.02, 1.09 ± 0.02, 0.83 ± 0.02, and 0.24 ± 0.02, respectively, at 1000 mA. Finally, the nCRLBs for K-edge imaging, the most demanding task among the five, were 1.00 ± 0.02, 1.00 ± 0.02, 0.55 ± 0.02, 0.55 ± 0.02, and 0.13 ± 0.02, respectively, at 20 mA; and 2.45 ± 0.02, 2.29 ± 0.02, 3.12 ± 0.02, 2.11 ± 0.02, and 0.13 ± 0.02, respectively, at 1,000 mA.

Conclusion
The Monte Carlo simulations showed that, compared to CdTe with either TS or DB, LaBr3:Ce with DB provided more accurate spectra, comparable or better counting capability, and superior spectral imaging-task performances, that is, water–bone material decomposition and K-edge imaging. CdTe had a better performance than LaBr3:Ce for the conventional CT imaging task due to its higher geometrical efficiency. LaBr3:Ce PCD with DB scheme may be an excellent alternative option for CdTe PCD.

Direct conversion photon counting detectors (PCDs) using CdTe, CZT, or Si for the sensor material are being investigated and manufactured. Indirect conversion, scintillator-based PCDs have historically thought to be too slow for the high flux requirements of diagnostic CT. Recent scintillators investigated for e.g. PET applications are very fast and inspire us to rethink this paradigm. We evaluate the potential of a LaBr3:Ce PCD using Monte Carlo simulations. We compared a CdTe PCD and a LaBr3:Ce PCD, assuming a pixel density of 9 pixels/mm2 in each case and a surrounding 2D anti-scatter grid. A 1x1 mm2 area was illuminated by flat field X-rays and the lower bound on the noise for varying contrast types and material decomposition scenarios was calculated. For conventional imaging without material decomposition, the LaBr3:Ce PCD performed worse than CdTe because of the need to wrap pixels in reflector, which reduces geometric efficiency. For water-bone material decomposition, the two PCDs performed similarly with our assumptions on pulse shape and PCD geometry. For three-material decomposition with a K-edge imaging agent, LaBr3:Ce reduced variance by about 35% because of the elimination of charge sharing that is present in CdTe. These results motivate further exploration of scintillator-based PCDs as an alternative to direct conversion PCDs, especially with future K-edge imaging agents.

Objective. Utilizing prompt gammas in preclinical pinhole-collimated positron emission tomography (PET) avoids image degradation due to positron range blurring and photon down scatter, enables multi-isotope PET and can improve counting statistics for low-abundance positron emitters. This was earlier reported for 124I, 89Zr and simultaneous 124I −18F PET using the VECTor scanner (MILabs, The Netherlands), demonstrating sub-mm resolution despite long positron ranges. The aim of the present study is to investigate if such sub-mm PET imaging is also feasible for a large variety of other isotopes including those with extremely high energy prompt gammas (>1 MeV) or with complex emission spectra of prompt gammas. Approach. We use Monte Carlo simulations to assess achievable image resolutions and uniformity across a broad range of spectrum types and emitted prompt gamma energies (603 keV–2.2 MeV), using 52Mn, 94Tc, 89Zr, 44Sc, 86Y, 72As, 124I, 38K, and 66Ga. Main results. Our results indicate that sub-millimeter resolution imaging may be feasible for almost all isotopes investigated, with the currently used cluster pinhole collimators. At prompt gamma energies of 603 keV of 124I, an image resolution of ∼0.65 mm was achieved, while for emissions at 703, 744, 834, and 909 keV of 94Tc, 52Mn, 72As, and 89Zr, respectively, ∼0.7 mm resolution was obtained. Finally, at ultra-high energies of 1.2 (44Sc) and 1.4 MeV (52Mn) resolutions of ∼0.75 mm and ∼0.8 mm could still be achieved although ring artifacts were observed at the highest energies (1.4 MeV). For 38K (2.2 MeV), an image resolution of 1.2 mm was achieved utilizing its 2.2 MeV prompt emission. Significance. This work shows that current cluster pinhole collimators are suitable for sub-mm resolution prompt PET up till at least 1.4 MeV. This may open up new avenues to developing new tracer applications and therapies utilizing these PET isotopes.

Objective.Many SPECT and PET radionuclides, along with radionuclides used in targeted alpha or beta therapy and their imaging surrogates have multiple gamma and/or positron emissions. Images of these radionuclides are usually obtained from the photopeak with the most convenient energy and/or highest intensity or by adding counts from different photopeaks. Smart utilization of multiple energy peaks may improve reconstructed images, especially in low-count scans.Approach.We investigate and compare various dual-photopeak joint reconstruction (JR) approaches, namely (i) Single-Band (SB-JR)-projections from two energy windows are summed and reconstructed with a system matrix at a single average energy, (ii) mixed Multi-Band (mMB-JR)-like SB-JR but the system matrix incorporates the element-wise contributions from the photopeak energies, (iii) Multi-Band (MB-JR)-separate projections for each window and separate system matrices at relevant gamma energies are utilized. We evaluate these methods for a multi-pinhole PET-SPECT system (VECTor, MILabs, the Netherlands) using Monte Carlo generated Derenzo phantom projections of225Ac (218 keV and 440 keV gammas),226Ac (158 keV and 230 keV gammas) and89Zr (511 keV annihilation gammas and 909 keV prompt gammas) at three different activity concentrations. A contrast-to-noise ratio (CNR) based quantitative performance analysis was done.Main results.The MB-JR scheme of JR showed superior visual image quality and highest CNRs in almost all cases, across all radionuclides and activity concentrations. The CNR improvement over images acquired from the single best-performing photopeak ranged from 30%-65% for225Ac, 20%-54% for226Ac, and 25%-47% for89Zr, respectively, for the smallest visible rods in the Derenzo phantom. CNR improvements/degradations for the other two methods, mMB-JR and SB-JR, were: for225Ac, -16%-51% and -21%-51%; for226Ac, 9%-61% and 0.2%-38%; and for89Zr, 19%-52% and -3%-16%, respectively.Significance.We believe the proposed image reconstruction methods can enhance SPECT, PET, and PET-SPECT imaging of a wide range of radionuclides that emit gamma's with multiple energies.

Objective. Cone-beam computed tomography (CBCT) is used for patient positioning in proton therapy, but not directly for treatment planning due to its inferior image quality compared to fan-beam CT. One way to improve its value for proton radiotherapy might be to use CBCT setups capable of extracting spectral information, which can be realised through several hardware configurations. Here, we compare different setups w.r.t. to their capability of predicting proton stopping power ratios (SPRs). Approach. We investigate six different spectral CBCT realisations in a simulation study, namely a single-source setup with either a dual-layer detector or a photon-counting detector (PCD), a kVp-switching setup with either an energy-integrating detector (EID) or a PCD, and a dual-source setup with either EIDs or PCDs. Our figure of merit is the normalised Cramér–Rao Lower Bound (nCRLB) on SPR variance based on projection data. We take (cross)scatter into account, and compare ideal and realistic detector models to help guide future detector developments. Each setup is optimised w.r.t. source spectra, mAs ratios and energy bin settings (where applicable). Main results. Assuming a realistic detector response, setups with a kVp-switching source perform best, with the setup paired with an EID slightly outperforming the PCD-based setup (nCRLBs of 2.74 and 2.81, respectively). However, if the mAs ratio of the kVp-switching source is fixed, the performance of the kVp-switching setup with an EID is significantly degraded (nCRLB = 9.46) and outperformed by PCD-based setups, with nCRLBs of 3.27, 3.45 and 3.60 for the dual-source setup with two PCDs, the single-source setup and the kVp-switching setup with one PCD, respectively. Spectra with higher source voltage or wider spectral separation generally yield lower CRLB values, and avoiding the spectral distortion caused by charge sharing in direct-conversion PCDs promises to lower CRLB values by about a third. Significance. We present an extensive comparison of spectral CBCT setups for their application in proton radiotherapy, using a methodology that allows to compare their theoretical limit of performance without being influenced by the choice of reconstruction algorithm or the conversion scheme from Hounsfield units to SPR values.

Purpose
While X-ray photon-counting detectors (PCDs) promise to revolutionize medical imaging, theoretical frameworks to evaluate them are commonly limited to incident fluence rates sufficiently low that the detector response can be considered linear. However, typical clinical operating conditions lead to a significant level of pile-up, invalidating this assumption of a linear response. Here, we present a framework that aims to evaluate PCDs, taking into account their non-linear behavior.

Approach
We employ small-signal analysis to study the behavior of PCDs under pile-up conditions. The response is approximated as linear around a given operating point, determined by the incident spectrum and fluence rate. The detector response is subsequently described by the proposed perturbation point spread function (pPSF). We demonstrate this approach using Monte-Carlo simulations of idealized direct- and indirect-conversion PCDs.

Results
The pPSFs of two PCDs are calculated. It is then shown how the pPSF allows to determine the sensitivity of the detector signal to an arbitrary lesion. This example illustrates the detrimental influence of pile-up, which may cause non-intuitive effects such as contrast/contrast-to-noise ratio inversion or cancellation between/within energy bins.

Conclusions
The proposed framework permits quantifying the spectral and spatial performance of PCDs under clinically realistic conditions at a given operating point. The presented example illustrates why PCDs should not be analyzed assuming that they are linear systems. The framework can, for example, be used to guide the development of PCDs and PCD-based systems. Furthermore, it can be applied to adapt commonly used measures, such as the modulation transfer function, to non-linear PCDs.

Cone-beam computed tomography (CBCT) and X-ray projection radiography are commonly used in the proton therapy workflow for the verification of patient positioning. The prospect of using the CBCT images for dose calculation purposes is attractive but currently hampered by the poorer image quality compared to the planning (fan-beam) CT. Ideally, the CBCT scan with the patient's anatomy of the day would provide sufficiently accurate proton stopping power ratios (SPR) to directly replan the treatment if needed. Dual-energy fan-beam CT has been proven to increase the accuracy of calculated SPR values compared to single-energy CT. A similar outcome may therefore be expected for dual-energy/spectral CBCT. This work aims to compare two possible realizations of dual-energy CBCT, namely a rapid kVp-switching source CBCT and a photon-counting detector (PCD) CBCT with two energy bins, with respect to their suitability for extracting SPR values. To perform this comparison, we determine the Cramér-Rao Lower Bound on the variance of the estimated electron density and effective atomic number. In our simulation study, we find that for the rapid kVp-switching setup the optimum voltage pair is 80/140 kVp, and the optimum ratio of the source current at 80 kVp to the source current at 140 kVp is 2:1 (4:1) for extracting the electron density (effective atomic number). In case of the PCD-based setup, a 140 kVp (100 kVp) spectrum and energy bins of [20; 50), [50; 150) keV appear best suited for extracting electron density (effective atomic number), outperforming the kVp-switching setup by a factor of 3.8 (4.9).

Background: Gamma camera imaging, including single photon emission computed tomography (SPECT), is crucial for research, diagnostics, and radionuclide therapy. Gamma cameras are predominantly based on arrays of photon multipliers tubes (PMTs) that read out NaI(Tl) scintillation crystals. In this way, standard gamma cameras can localize ɣ-rays with energies typically ranging from 30 to 360 keV. In the last decade, there has been an increasing interest towards gamma imaging outside this conventional clinical energy range, for example, for theragnostic applications and preclinical multi-isotope positron emission tomography (PET) and PET-SPECT. However, standard gamma cameras are typically equipped with 9.5 mm thick NaI(Tl) crystals which can result in limited sensitivity for these higher energies. Purpose: Here we investigate to what extent thicker scintillators can improve the photopeak sensitivity for higher energy isotopes while attempting to maintain spatial resolution. Methods: Using Monte Carlo simulations, we analyzed multiple PMT-based configurations of gamma detectors with monolithic NaI (Tl) crystals of 20 and 40 mm thickness. Optimized light guide thickness together with 2-inch round, 3-inch round, 60 × 60 mm² square, and 76 × 76 mm² square PMTs were tested. For each setup, we assessed photopeak sensitivity, energy resolution, spatial, and depth-of-interaction (DoI) resolution for conventional (140 keV) and high (511 keV) energy ɣ using a maximum-likelihood algorithm. These metrics were compared to those of a “standard” 9.5 mm-thick crystal detector with 3-inch round PMTs. Results: Estimated photopeak sensitivities for 511 keV were 27% and 53% for 20 and 40 mm thick scintillators, which is respectively, 2.2 and 4.4 times higher than for 9.5 mm thickness. In most cases, energy resolution benefits from using square PMTs instead of round ones, regardless of their size. Lateral and DoI spatial resolution are best for smaller PMTs (2-inch round and 60 × 60 mm² square) which outperform the more cost-effective larger PMT setups (3-inch round and 76 × 76 mm² square), while PMT layout and shape have negligible (< 10%) effect on resolution. Best spatial resolution was obtained with 60 × 60 mm² PMTs; for 140 keV, lateral resolution was 3.5 mm irrespective of scintillator thickness, improving to 2.8 and 2.9 mm for 511 keV with 20 and 40 mm thick crystals, respectively. Using the 3-inch round PMTs, lateral resolutions of 4.5 and 3.9 mm for 140 keV and of 3.5 and 3.7 mm for 511 keV were obtained with 20 and 40 mm thick crystals respectively, indicating a moderate performance degradation compared to the 3.5 and 2.9 mm resolution obtained by the standard detector for 140 and 511 keV. Additionally, DoI resolution for 511 keV was 7.0 and 5.6 mm with 20 and 40 mm crystals using 60 × 60 mm² square PMTs, while with 3-inch round PMTs 12.1 and 5.9 mm were obtained. Conclusion: Depending on PMT size and shape, the use of thicker scintillator crystals can substantially improve detector sensitivity at high gamma energies, while spatial resolution is slightly improved or mildly degraded compared to standard crystals.

Microscopic nuclear imaging down to spatial resolutions of a few hundred microns can already be achieved using low-energy gamma emitters (e.g. ¹²⁵I, ∼30 keV) and a basic single micro-pinhole gamma camera. This has been applied to in vivo mouse thyroid imaging, for example. For clinically used radionuclides such as ^99mTc, this approach fails due to penetration of the higher-energy gamma photons through the pinhole edges. To overcome these resolution degradation effects, we propose a new imaging approach: scanning focus nuclear microscopy (SFNM). We assess SFNM using Monte Carlo simulations for clinically used isotopes. SFNM is based on the use of a 2D scanning stage with a focused multi-pinhole collimator containing 42 pinholes with narrow pinhole aperture opening angles to reduce photon penetration. All projections of different positions are used to iteratively reconstruct a three-dimensional image from which synthetic planar images are generated. SFNM imaging was tested using a digital Derenzo resolution phantom and a mouse ankle joint phantom containing ^99mTc (140 keV). The planar images were compared with those obtained using a single-pinhole collimator, either with matched pinhole diameter or with matched sensitivity. The simulation results showed an achievable ^99mTc image resolution of 0.04 mm and detailed ^99mTc bone images of a mouse ankle with SFNM. SFNM has strong advantages over single-pinhole imaging in terms of spatial resolution.

X-ray detectors with photon-counting capabilities promise to revolutionise medical imaging. For an efficient comparison of detectors of various materials and with different setup choices, reliable detector performance measures are needed. The detector point spread function (PSF) is a commonly used measure, which describes the spatial response of an X-ray detector to the irradiation of a single pixel, given the energy spectrum of the source. In the case of an energy-resolving PCD, the detector PSF is typically derived for each energy bin and characterises its resolution. Moreover, it is commonly determined under low count rate conditions, to avoid dead time and pile-up related distortions. Under these assumptions, the PSF can be determined in a straightforward manner, but does not fully characterise the detector under all conditions encountered in clinical practice. This is especially true since the number of registered counts per energy bin depends on both the incident spectrum and the fluence rate, due to pile-up and dead time. We therefore propose a new metric, the differential point spread function (dPSF), which describes the change in the output count rate due to a small change in the input spectrum, for a given combination of incident spectrum and fluence rate. The dPSF can be used to characterize the spectral and spatial performance of a PCD under high-fluence conditions, i.e. when its response becomes non-linear. We illustrate the use of the dPSF by performing a Monte-Carlo study in which we compare the response of direct-conversion and scintillationbased PCDs at different fluence rates.

SPECT imaging with 123I-FP-CIT is used for diagnosis of neurodegenerative disorders like Parkinson's disease. Attenuation correction (AC) can be useful for quantitative analysis of 123I-FP-CIT SPECT. Ideally, AC would be performed based on attenuation maps (μ-maps) derived from perfectly registered CT scans. Such μ-maps, however, are most times not available and possible errors in image registration can induce quantitative inaccuracies in AC corrected SPECT images. Earlier, we showed that a convolutional neural network (CNN) based approach allows to estimate SPECT-aligned μ-maps for full brain perfusion imaging using only emission data. Here we investigate the feasibility of similar CNN methods for axially focused 123I-FP-CIT scans. We tested our approach on a high-resolution multi-pinhole prototype clinical SPECT system in a Monte Carlo simulation study. Three CNNs that estimate μ-maps in a voxel-wise, patch-wise and image-wise manner were investigated. As the added value of AC on clinical 123I-FP-CIT scans is still debatable, the impact of AC was also reported to check in which cases CNN based AC could be beneficial. AC using the ground truth μ-maps (GT-AC) and CNN estimated μ-maps (CNN-AC) were compared with the case when no AC was done (No-AC). Results show that the effect of using GT-AC versus CNN-AC or No-AC on striatal shape and symmetry is minimal. Specific binding ratios (SBRs) from localized regions show a deviation from GT-AC ≤ 2.5% for all three CNN-ACs while No-AC systematically underestimates SBRs by 13.1%. A strong correlation (r ≥ 0.99) was obtained between GT-AC based SBRs and SBRs from CNN-ACs and No-AC. Absolute quantification (in kBq ml-1) shows a deviation from GT-AC within 2.2% for all three CNN-ACs and of 71.7% for No-AC. To conclude, all three CNNs show comparable performance in accurate μ-map estimation and 123I-FP-CIT quantification. CNN-estimated μ-map can be a promising substitute for CT-based μ-map.

In clinical brain SPECT, correction for photon attenuation in the patient is essential to obtain images which provide quantitative information on the regional activity concentration per unit volume (kBq). This correction generally requires an attenuation map (map) denoting the attenuation coefficient at each voxel which is often derived from a CT or MRI scan. However, such an additional scan is not always available and the method may suffer from registration errors. Therefore, we propose a SPECT-only-based strategy for map estimation that we apply to a stationary multi-pinhole clinical SPECT system (G-SPECT-I) for 99mTc-HMPAO brain perfusion imaging. The method is based on the use of a convolutional neural network (CNN) and was validated with Monte Carlo simulated scans. Data acquired in list mode was used to employ the energy information of both primary and scattered photons to obtain information about the tissue attenuation as much as possible. Multiple SPECT reconstructions were performed from different energy windows over a large energy range. Locally extracted 4D SPECT patches (three spatial plus one energy dimension) were used as input for the CNN which was trained to predict the attenuation coefficient of the corresponding central voxel of the patch. Results show that Attenuation Correction using the Ground Truth maps (GT-AC) or using the CNN estimated maps (CNN-AC) achieve comparable accuracy. This was confirmed by a visual assessment as well as a quantitative comparison; the mean deviation from the GT-AC when using the CNN-AC is within 1.8% for the standardized uptake values in all brain regions. Therefore, our results indicate that a CNN-based method can be an automatic and accurate tool for SPECT attenuation correction that is independent of attenuation data from other imaging modalities or human interpretations about head contours.

Despite improvements in small animal PET instruments, many tracers cannot be imaged at sufficiently high resolutions due to positron range, while multi-tracer PET is hampered by the fact that all annihilation photons have equal energies. Here we realize multi-isotope and sub-mm resolution PET of isotopes with several mm positron range by utilizing prompt gamma photons that are commonly neglected. A PET-SPECT-CT scanner (VECTor/CT, MILabs, The Netherlands) equipped with a high-energy cluster-pinhole collimator was used to image 124I and a mix of 124I and 18F in phantoms and mice. In addition to positrons (mean range 3.4 mm) 124I emits large amounts of 603 keV prompt gammas that - aided by excellent energy discrimination of NaI - were selected to reconstruct 124I images that are unaffected by positron range. Photons detected in the 511 keV window were used to reconstruct 18F images. Images were reconstructed iteratively using an energy dependent matrix for each isotope. Correction of 18F images for contamination with 124I annihilation photons was performed by Monte Carlo based range modelling and scaling of the 124I prompt gamma image before subtracting it from the 18F image. Additionally, prompt gamma imaging was tested for 89Zr that emits very high-energy prompts (909 keV). In Derenzo resolution phantoms 0.75 mm rods were clearly discernable for 124I, 89Zr and for simultaneously acquired 124I and 18F imaging. Image quantification in phantoms with reservoirs filled with both 124I and 18F showed excellent separation of isotopes and high quantitative accuracy. Mouse imaging showed uptake of 124I in tiny thyroid parts and simultaneously injected 18F-NaF in bone structures. The ability to obtain PET images at sub-mm resolution both for isotopes with several mm positron range and for multi-isotope PET adds to many other unique capabilities of VECTor's clustered pinhole imaging, including simultaneous sub-mm PET-SPECT and theranostic high energy SPECT.

The use of multi-pinhole collimation has enabled ultra-high-resolution imaging of SPECT and PET tracers in small animals. Key for obtaining high-quality images is the use of statistical iterative image reconstruction with accurate energy-dependent photon transport modelling through collimator and detector. This can be incorporated in a system matrix that contains the probabilities that a photon emitted from a certain voxel is detected at a specific detector pixel. Here we introduce a fast Monte-Carlo based (FMC-based) matrix generation method for pinhole imaging that is easy to apply to various radionuclides. The method is based on accelerated point source simulations combined with model-based interpolation to straightforwardly change or combine photon energies of the radionuclide of interest. The proposed method was evaluated for a VECTor PET-SPECT system with (i) a HE-UHR-M collimator and (ii) an EXIRAD-3D 3D autoradiography collimator. Both experimental scans with 99mTc, 111In, and 123I, and simulated scans with 67Ga and 90Y were performed for evaluation. FMC was compared with two currently used approaches, one based on a set of point source measurements with 99mTc (dubbed traditional method), and the other based on an energy-dependent ray-tracing simulation (ray-tracing method). The reconstruction results show better image quality when using FMC-based matrices than when applying the traditional or ray-tracing matrices in various cases. FMC-based matrices generalise better than the traditional matrices when imaging radionuclides with energies deviating too much from the energy used in the calibration and are computationally more efficient for very-high-resolution imaging than the ray-tracing matrices. In addition, FMC has the advantage of easily combining energies in a single matrix which is relevant when imaging radionuclides with multiple photopeak energies (e.g. 67Ga and 111In) or with a continuous energy spectrum (e.g. 90Y). To conclude, FMC is an efficient, accurate, and versatile tool for creating system matrices for ultra-high-resolution pinhole SPECT.

We recently developed a dedicated focusing multi-pinhole collimator for a stationary SPECT system that offers down to 120 m (or 1.7 nL) spatial resolution SPECT images of cryo-cooled tissue samples (EXIRAD-3D). This collimator is suitable for imaging isotopes that are often used in small animal and diagnostic SPECT such as 125I (27 keV), 201Tl (71 keV), 99mTc (140 keV), and 111In (171 and 245 keV). The goal of the present work is to develop high-resolution pinhole imaging of tissue samples containing isotopes with high-energy photon emissions, for example, therapeutic alpha and beta emitters that co-emit high energy gammas (e.g. 213Bi (440 keV) and 131I (364 keV)) or 511 keV annihilation photons from PET isotopes. To this end, we optimise and evaluate a new high energy small-bore multi-pinhole collimator through simulations. The collimator-geometry was first optimised by simulating a Derenzo phantom scan with a biologically realistic activity concentration of 18F at two system sensitivities (0.30% and 0.60%) by varying pinhole placements. Subsequently, the wall thickness was selected based on reconstructions of a Derenzo phantom and a uniform phantom. The obtained collimators were then evaluated for 131I (364 keV), 213Bi (440 keV), 64Cu (511 keV), and 124I (511 + 603 keV) with biologically realistic activity concentrations, and also for some high activity concentrations of 18F, using digital resolution, mouse knee joint, and xenograft phantoms. Our results show that placing pinhole centres at a distance of 8 mm from the collimator inner wall yields good image quality, while a wall thickness of 43 mm resulted in sufficient shielding. The collimators offer resolutions down to 0.35 mm, 0.6 mm, 0.5 mm, 0.6 mm, and 0.5 mm when imaging 131I, 213Bi, 18F, 64Cu, and 124I, respectively, contained in tissue samples at biologically achievable activity concentrations.

Photomultiplier tube (PMT)-based scintillation cameras are predominant in molecular imaging but have the drawback that position estimation is severely degraded near the edges (dead edge effect). This leads to sensitivity losses and can cause severe problems in applications like molecular breast imaging and in certain SPECT devices. Using smaller light sensors or semiconductor detectors can solve this issue but leads to increased costs. Here we present a gamma detector based on standard PMTs with a novel light-guide-PMT geometry that strongly reduces dead edges. In our design, a monolithic NaI(Tl) scintillator is read out by square PMTs placed in a staggered arrangement. At the edge of the scintillator we inserted additional light-guides to emulate half-size PMTs. Detector performance was assessed for 99m Tc imaging; an average spatial resolution of 3.6 mm was measured over the whole detector, degrading to 4.0 mm within 30 mm to the critical edge. The dead edge of the scintillator is <; 3 mm. Since a 12-mm seal was used, the overall dead edge is <; 15 mm, which is a significant improvement over conventional Anger cameras (~40-mm dead edge). Therefore, the presented geometry can be useful in creating economical gamma detectors with reduced dead edges.

Introduction: Autoradiography is an established technique for high-resolution imaging of radiolabelled molecules in biological tissue slices. Unfortunately, creating a 3D image from a set of these 2D images is extremely time-consuming and error-prone. MicroSPECT systems provide such 3D images but have a low resolution. Here we present EXIRAD-3D, a fast automated method as an alternative for 3D autoradiography from coupes based on ultra-high resolution microSPECT technology. Methods: EXIRAD-3D uses a very small bore focusing multi-pinhole collimator mounted in a SPECT system with stationary detectors (U-SPECT/CT, MILabs B.V. The Netherlands) using a sample holder with integrated tissue cooling to avoid activity leaking or tissue deformation during the scan. The system performance was experimentally evaluated using various phantoms and tissue samples of animals in vivo injected with technetium-99m and iodine-123. Results: The reconstructed spatial resolution obtained with a Derenzo hot rod phantom was 120 μm (or 1.7 nl). The voxel values of a syringe phantom image appear to be uniform and scale linearly with activity. Uptake in tiny details of the mouse knee joint, thyroid, and kidney could be clearly visualized. Conclusion: EXIRAD-3D opens up the possibility for fast and quantitative 3D imaging of radiolabelled molecules at a resolution far better than in vivo microSPECT and saves tremendous amounts of work compared to obtaining 3D data from a set of 2D autoradiographs. Advances in knowledge and implications for patient care: EXIRAD-3D offers superior image resolution over microSPECT, and it can be a very efficient alternative for autoradiography in pharmaceutical and biological studies.

In recent years, breast imaging using radiolabelled molecules has attracted significant interest. Our group has proposed a multi-pinhole molecular breast tomosynthesis (MP-MBT) scanner to obtain 3D functional molecular breast images at high resolutions. After conducting extensive optimisation studies using simulations, we here present a first prototype of MP-MBT and evaluate its performance using physical phantoms. The MP-MBT design is based on two opposing gamma cameras that can image a lightly compressed pendant breast. Each gamma camera consists of a 250 × 150 mm² detector equipped with a collimator with multiple pinholes focusing on a line. The NaI(Tl) gamma detector is a customised design with 3.5 mm intrinsic spatial resolution and high spatial linearity near the edges due to a novel light-guide geometry and the use of square PMTs. A volume-of-interest is scanned by translating the collimator and gamma detector together in a sequence that optimises count yield from the scan region. Derenzo phantom images showed that the system can reach 3.5 mm resolution for a clinically realistic ^99mTc activity concentration in an 11-minute scan, while in breast phantoms the smallest spheres visible were 6 mm in diameter for the same scan time. To conclude, the experimental results of the novel MP-MBT scanner showed that the setup had sub-centimetre breast tumour detection capability which might facilitate 3D molecular breast cancer imaging in the future.