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Receptor occupancy (RO) studies using PET neuroimaging play a critical role in the development of drugs targeting the central nervous system (CNS). The conventional approach to estimate drug receptor occupancy consists in estimation of binding potential changes between two PET scans (baseline and post-drug injection). This estimation is typically performed separately for each scan by first reconstructing dynamic PET scan data before fitting a kinetic model to time activity curves. This approach fails to properly model the noise in PET measurements, resulting in poor RO estimates, especially in low receptor density regions., Objective: In this work, we evaluate a novel joint direct parametric reconstruction framework to directly estimate distributions of RO and other kinetic parameters in the brain from a pair of baseline and postdrug injection dynamic PET scans., Methods: The proposed method combines the use of regularization on RO maps with alternating optimization to enable estimation of occupancy even in low binding regions., Results: Simulation results demonstrate the quantitative improvement of this method over conventional approaches in terms of accuracy and precision of occupancy. The proposed method is also evaluated in preclinical in-vivo experiments using 11C-MK6884 and a muscarinic acetylcholine receptor 4 positive allosteric modulator drug, showing improved estimation of receptor occupancy as compared to traditional estimators., Conclusion: The proposed joint direct estimation framework improves RO estimation compared to conventional methods, especially in intermediate to low-binding regions., Significance: This work could potentially facilitate the evaluation of new drug candidates targeting the CNS.

Super-resolution (SR) is a methodology that seeks to improve image resolution by exploiting the increased spatial sampling information obtained from multiple acquisitions of the same target with accurately known sub-resolution shifts. This work aims to develop and evaluate an SR estimation framework for brain positron emission tomography (PET), taking advantage of a high-resolution infra-red tracking camera to measure shifts precisely and continuously. Moving phantoms and non-human primate (NHP) experiments were performed on a GE Discovery MI PET/CT scanner (GE Healthcare) using an NDI Polaris Vega (Northern Digital Inc), an external optical motion tracking device. To enable SR, a robust temporal and spatial calibration of the two devices was developed as well as a list-mode Ordered Subset Expectation Maximization PET reconstruction algorithm, incorporating the high-resolution tracking data from the Polaris Vega to correct motion for measured line of responses on an event-by-event basis. For both phantoms and NHP studies, the SR reconstruction method yielded PET images with visibly increased spatial resolution compared to standard static acquisitions, allowing improved visualization of small structures. Quantitative analysis in terms of SSIM, CNR and line profiles were conducted and validated our observations. The results demonstrate that SR can be achieved in brain PET by measuring target motion in real-time using a high-resolution infrared tracking camera., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier Inc.)

Objective . Positron emission tomography (PET) imaging of tau deposition using [ 18 F]-MK6240 often involves long acquisitions in older subjects, many of whom exhibit dementia symptoms. The resulting unavoidable head motion can greatly degrade image quality. Motion increases the variability of PET quantitation for longitudinal studies across subjects, resulting in larger sample sizes in clinical trials of Alzheimer's disease (AD) treatment. Approach . After using an ultra-short frame-by-frame motion detection method based on the list-mode data, we applied an event-by-event list-mode reconstruction to generate the motion-corrected images from 139 scans acquired in 65 subjects. This approach was initially validated in two phantoms experiments against optical tracking data. We developed a motion metric based on the average voxel displacement in the brain to quantify the level of motion in each scan and consequently evaluate the effect of motion correction on images from studies with substantial motion. We estimated the rate of tau accumulation in longitudinal studies (51 subjects) by calculating the difference in the ratio of standard uptake values in key brain regions for AD. We compared the regions' standard deviations across subjects from motion and non-motion-corrected images. Main results . Individually, 14% of the scans exhibited notable motion quantified by the proposed motion metric, affecting 48% of the longitudinal datasets with three time points and 25% of all subjects. Motion correction decreased the blurring in images from scans with notable motion and improved the accuracy in quantitative measures. Motion correction reduced the standard deviation of the rate of tau accumulation by -49%, -24%, -18%, and -16% in the entorhinal, inferior temporal, precuneus, and amygdala regions, respectively. Significance . The list-mode-based motion correction method is capable of correcting both fast and slow motion during brain PET scans. It leads to improved brain PET quantitation, which is crucial for imaging AD., (© 2023 Institute of Physics and Engineering in Medicine.)

Option generation is a critical process in decision making, but previous studies have largely focused on choices between options given by a researcher. Consequently, how we self-generate options for behaviour remain poorly understood. Here, we investigated option generation in major depressive disorder and how dopamine might modulate this process, as well as the effects of modafinil (a putative cognitive enhancer) on option generation in healthy individuals. We first compared differences in self-generated options between healthy non-depressed adults [n = 44, age = 26.3 years (SD 5.9)] and patients with major depressive disorder [n = 54, age = 24.8 years (SD 7.4)]. In the second study, a subset of depressed individuals [n = 22, age = 25.6 years (SD 7.8)] underwent PET scans with 11C-raclopride to examine the relationships between dopamine D2/D3 receptor availability and individual differences in option generation. Finally, a randomized, double-blind, placebo-controlled, three-way crossover study of modafinil (100 mg and 200 mg), was conducted in an independent sample of healthy people [n = 19, age = 23.2 years (SD 4.8)] to compare option generation under different doses of this drug. The first study revealed that patients with major depressive disorder produced significantly fewer options [t(96) = 2.68, P = 0.009, Cohen's d = 0.54], albeit with greater uniqueness [t(96) = -2.54, P = 0.01, Cohen's d = 0.52], on the option generation task compared to healthy controls. In the second study, we found that 11C-raclopride binding potential in the putamen was negatively correlated with fluency (r = -0.69, P = 0.001) but positively associated with uniqueness (r = 0.59, P = 0.007). Hence, depressed individuals with higher densities of unoccupied putamen D2/D3 receptors in the putamen generated fewer but more unique options, whereas patients with lower D2/D3 receptor availability were likely to produce a larger number of similar options. Finally, healthy participants were less unique [F(2,36) = 3.32, P = 0.048, partial η2 = 0.16] and diverse [F(2,36) = 4.31, P = 0.021, partial η2 = 0.19] after taking 200 mg versus 100 mg and 0 mg of modafinil, while fluency increased linearly with dosage at a trend level [F(1,18) = 4.11, P = 0.058, partial η2 = 0.19]. Our results show, for the first time, that option generation is affected in clinical depression and that dopaminergic activity in the putamen of patients with major depressive disorder may play a key role in the self-generation of options. Modafinil was also found to influence option generation in healthy people by reducing the creativity of options produced., (© The Author(s) (2022). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Mitochondrial dysfunction plays a key role in doxorubicin-induced cardiotoxicity (DIC). In this proof-of-principle study, we investigated whether PET mapping of cardiac membrane potential, an indicator of mitochondrial function, could detect an acute cardiotoxic effect of doxorubicin (DOX) in a large animal model. Eight Yucatan pigs were imaged dynamically with [ 18 F](4-Fluorophenyl)triphenylphosphonium ([ 18 F]FTPP + ) PET/CT. Our experimental protocol included a control saline infusion into the left anterior descending coronary artery (LAD) followed by a DOX test infusion of either 1 mg/kg or 2 mg/kg during PET. We measured the change in total cardiac membrane potential (ΔΨ T ), a proxy for the mitochondrial membrane potential, ΔΨ m , after the saline and DOX infusions. We observed a partial depolarization of the mitochondria following the DOX infusions, which occurred only in myocardial areas distal to the intracoronary catheter, thereby demonstrating a direct association between the exposure of the mitochondria to DOX and a change in ΔΨ T . Furthermore, doubling the DOX dose caused a more severe depolarization of myocardium in the LAD territory distal to the infusion catheter. In conclusion, [ 18 F]FTPP + PET-based ΔΨ T mapping can measure partial depolarization of myocardial mitochondria following intracoronary DOX infusion in a large animal model., (© 2022. The Author(s).)

Fragile X Syndrome (FXS) is a neurodevelopmental disorder caused by silencing of the Fragile X Mental Retardation (FMR1) gene. The resulting loss of Fragile X Mental Retardation Protein (FMRP) leads to excessive glutamate signaling via metabotropic glutamate subtype 5 receptors (mGluR5) which has been implicated in the pathogenesis of the disorder. In the present study we used the radioligand 3-[18F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([ 18 F]FPEB) in simultaneous PET-MR imaging of males with FXS and age- and gender-matched controls to assess the availability of mGlu5 receptors in relevant brain areas. Patients with FXS showed lower [ 18 F]FPEB binding potential (p <  0.01), reflecting reduced mGluR5 availability, than the healthy controls throughout the brain, with significant group differences in insula, anterior cingulate, parahippocampal, inferior temporal and olfactory cortices, regions associated with deficits in inhibition, memory, and visuospatial processes characteristic of the disorder. The results are among the first to provide in vivo evidence of decreased availability of mGluR5 in the brain in individuals with FXS than in healthy controls. The consistent results across the subjects, despite the tremendous challenges with neuroimaging this population, highlight the robustness of the protocol and support for its use in drug occupancy studies; extending our radiotracer development and application efforts from mice to humans., (© 2021. The Author(s).)

Purpose: 99m Tc-MDP single-photon emission computed tomography (SPECT) is an established tool for diagnosing lumbar stress, a common cause of low back pain (LBP) in pediatric patients. However, detection of small stress lesions is complicated by the low quality of SPECT, leading to significant interreader variability. The study objectives were to develop an approach based on a deep convolutional neural network (CNN) for detecting lumbar lesions in 99m Tc-MDP scans and to compare its performance to that of physicians in a localization receiver operating characteristic (LROC) study., Methods: Sixty-five lesion-absent (LA) 99m Tc-MDP studies performed in pediatric patients for evaluating LBP were retrospectively identified. Projections for an artificial focal lesion were acquired separately by imaging a 99m Tc capillary tube at multiple distances from the collimator. An approach was developed to automatically insert lesions into LA scans to obtain realistic lesion-present (LP) 99m Tc-MDP images while ensuring knowledge of the ground truth. A deep CNN was trained using 2.5D views extracted in LP and LA 99m Tc-MDP image sets. During testing, the CNN was applied in a sliding-window fashion to compute a 3D "heatmap" reporting the probability of a lesion being present at each lumbar location. The algorithm was evaluated using cross-validation on a 99m Tc-MDP test dataset which was also studied by five physicians in a LROC study. LP images in the test set were obtained by incorporating lesions at sites selected by a physician based on clinical likelihood of injury in this population., Results: The deep learning (DL) system slightly outperformed human observers, achieving an area under the LROC curve (AUC LROC ) of 0.830 (95% confidence interval [CI]: [0.758, 0.924]) compared with 0.785 (95% CI: [0.738, 0.830]) for physicians. The AUC LROC for the DL system was higher than that of two readers (difference in AUC LROC [ΔAUC LROC ] = 0.049 and 0.053) who participated to the study and slightly lower than that of two other readers (ΔAUC LROC  = -0.006 and -0.012). Another reader outperformed DL by a more substantial margin (ΔAUC LROC  = -0.053)., Conclusion: The DL system provides comparable or superior performance than physicians in localizing small 99m Tc-MDP positive lumbar lesions., (© 2021 American Association of Physicists in Medicine.)

Purpose of Review: To present a method enabling in vivo quantification of tissue membrane potential (ΔΨ T ), a proxy of mitochondrial membrane potential (ΔΨ m ), to review the origin and role of ΔΨ m , and to highlight potential applications of myocardial ΔΨ T imaging., Recent Findings: Radiolabelled lipophilic cations have been used for decades to measure ΔΨ m in vitro. Using similar compounds labeled with positron emitters and appropriate compartment modeling, this technique now allows in vivo quantification of ΔΨ T with positron emission tomography. Studies have confirmed the feasibility of measuring myocardial ΔΨ T in both animals and humans. In addition, ΔΨ T showed very low variability among healthy subjects, suggesting that this method could allow detection of relatively small pathological changes. In vivo assessment of myocardial ΔΨ T provides a new tool to study the pathophysiology of cardiovascular diseases and has the potential to serve as a new biomarker to assess disease stage, prognosis, and response to therapy.

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 to quantify 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 ten years that will enable PET to realise its full quantitative potential, initially in research laboratories and, ultimately, in clinical practice.

Purpose: Alteration in mitochondrial membrane potential (ΔΨ m ) is an important feature of many pathologic processes, including heart failure, cardiotoxicity, ventricular arrhythmia, and myocardial hypertrophy. We present the first in vivo, non-invasive, assessment of regional ΔΨ m in the myocardium of normal human subjects., Methods: Thirteen healthy subjects were imaged using [ 18 F]-triphenylphosphonium ([ 18 F]TPP+) on a PET/MR scanner. The imaging protocol consisted of a bolus injection of 300 MBq followed by a 120-min infusion of 0.6 MBq/min. A 60 min, dynamic PET acquisition was started 1 h after bolus injection. The extracellular space fraction (f ECS ) was simultaneously measured using MR T1-mapping images acquired at baseline and 15 min after gadolinium injection with correction for the subject's hematocrit level. Serial venous blood samples were obtained to calculate the plasma tracer concentration. The tissue membrane potential (ΔΨ T ), a proxy of ΔΨ m , was calculated from the myocardial tracer concentration at secular equilibrium, blood concentration, and fECS measurements using a model based on the Nernst equation., Results: In 13 healthy subjects, average tissue membrane potential (ΔΨ T ), representing the sum of cellular membrane potential (ΔΨ c ) and ΔΨ m , was - 160.7 ± 3.7 mV, in excellent agreement with previous in vitro assessment., Conclusion: In vivo quantification of the mitochondrial function has the potential to provide new diagnostic and prognostic information for several cardiac diseases as well as allowing therapy monitoring. This feasibility study lays the foundation for further investigations to assess these potential roles. Clinical trial identifier: NCT03265431.

Image quality of positron emission tomography (PET) reconstructions is degraded by subject motion occurring during the acquisition. Magnetic resonance (MR)-based motion correction approaches have been studied for PET/MR scanners and have been successful at capturing regular motion patterns, when used in conjunction with surrogate signals (e.g. navigators) to detect motion. However, handling irregular respiratory motion and bulk motion remains challenging. In this work, we propose an MR-based motion correction method relying on subspace-based real-time MR imaging to estimate motion fields used to correct PET reconstructions. We take advantage of the low-rank characteristics of dynamic MR images to reconstruct high-resolution MR images at high frame rates from highly undersampled k-space data. Reconstructed dynamic MR images are used to determine motion phases for PET reconstruction and estimate phase-to-phase nonrigid motion fields able to capture complex motion patterns such as irregular respiratory and bulk motion. MR-derived binning and motion fields are used for PET reconstruction to generate motion-corrected PET images. The proposed method was evaluated on in vivo data with irregular motion patterns. MR reconstructions accurately captured motion, outperforming state-of-the-art dynamic MR reconstruction techniques. Evaluation of PET reconstructions demonstrated the benefits of the proposed method in terms of motion artifacts reduction, improving the contrast-to-noise ratio by up to a factor 3 and achieveing a target-to-background ratio up to 90% superior compared to standard/uncorrected methods. The proposed method can improve the image quality of motion-corrected PET reconstructions in clinical applications.

Receptor ligand-based dynamic Positron Emission Tomography (PET) permits the measurement of neurotransmitter release in the human brain. For single-scan paradigms, the conventional method of estimating changes in neurotransmitter levels relies on fitting a pharmacokinetic model to activity concentration histories extracted after PET image reconstruction. However, due to the statistical fluctuations of activity concentration data at the voxel scale, parametric images computed using this approach often exhibit low signal-to-noise ratio, impeding characterization of neurotransmitter release. Numerous studies have shown that direct parametric reconstruction (DPR) approaches, which combine image reconstruction and kinetic analysis in a unified framework, can improve the signal-to-noise ratio of parametric mapping. However, there is little experience with DPR in imaging of neurotransmission and the performance of the approach in this application has not been evaluated before in humans. In this report, we present and evaluate a DPR methodology that computes 3-D distributions of ligand transport, binding potential (BP ND ) and neurotransmitter release magnitude (γ) from a dynamic sequence of PET sinograms. The technique employs the linear simplified reference region model (LSRRM) of Alpert et al. (2003), which represents an extension of the simplified reference region model that incorporates time-varying binding parameters due to radioligand displacement by release of neurotransmitter. Estimation of parametric images is performed by gradient-based optimization of a Poisson log-likelihood function incorporating LSRRM kinetics and accounting for the effects of head movement, attenuation, detector sensitivity, random and scattered coincidences. A 11 C-raclopride simulation study showed that the proposed approach substantially reduces the bias and variance of voxel-wise γ estimates as compared to standard methods. Moreover, simulations showed that detection of release could be made more reliable and/or conducted using a smaller sample size using the proposed DPR estimator. Likewise, images of BP ND computed using DPR had substantially improved bias and variance properties. Application of the method in human subjects was demonstrated using 11 C-raclopride dynamic scans and a reward task, confirming the improved quality of the estimated parametric images using the proposed approach., Competing Interests: Declaration of competing interest Over the past three years, D.A.P has received consulting fees from Akili Interactive Labs, BlackThorn Therapeutics, Boehringer Ingelheim, and Takeda and an honorarium from Alkernes, for activities unrelated to the current paper. No funding from these entities was used to support the current work, and all views expressed are solely those of the authors. All other authors report no biomedical financial interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To develop a magnetic resonance (MR)-based method for estimation of continuous linear attenuation coefficients (LACs) in positron emission tomography (PET) using a physical compartmental model and ultrashort echo time (UTE)/multi-echo Dixon (mUTE) acquisitions., Methods: We propose a three-dimensional (3D) mUTE sequence to acquire signals from water, fat, and short T 2 components (e.g., bones) simultaneously in a single acquisition. The proposed mUTE sequence integrates 3D UTE with multi-echo Dixon acquisitions and uses sparse radial trajectories to accelerate imaging speed. Errors in the radial k-space trajectories are measured using a special k-space trajectory mapping sequence and corrected for image reconstruction. A physical compartmental model is used to fit the measured multi-echo MR signals to obtain fractions of water, fat, and bone components for each voxel, which are then used to estimate the continuous LAC map for PET attenuation correction., Results: The performance of the proposed method was evaluated via phantom and in vivo human studies, using LACs from computed tomography (CT) as reference. Compared to Dixon- and atlas-based MRAC methods, the proposed method yielded PET images with higher correlation and similarity in relation to the reference. The relative absolute errors of PET activity values reconstructed by the proposed method were below 5% in all of the four lobes (frontal, temporal, parietal, and occipital), cerebellum, whole white matter, and gray matter regions across all subjects (n = 6)., Conclusions: The proposed mUTE method can generate subject-specific, continuous LAC map for PET attenuation correction in PET/MR., (© 2020 American Association of Physicists in Medicine.)

Background: We recently reported a method using positron emission tomography (PET) and the tracer 18 F-labeled tetraphenylphosphonium ( 18 F-TPP + ) for mapping the tissue (i.e., cellular plus mitochondrial) membrane potential (ΔΨ T ) in the myocardium. The purpose of this work is to provide additional experimental evidence that our methods can be used to observe transient changes in the volume of distribution for 18 F-TPP + and mitochondrial membrane potential (ΔΨ m )., Methods: We tested these hypotheses by measuring decreases of 18 F-TPP + concentration elicited when a proton gradient uncoupler, BAM15, is administered by intracoronary infusion during PET scanning. BAM15 is the first proton gradient uncoupler shown to affect the mitochondrial membrane without affecting the cellular membrane potential. Preliminary dose response experiments were conducted in two pigs to determine the concentration of BAM15 infusate necessary to perturb the 18 F-TPP + concentration. More definitive experiments were performed in two additional pigs, in which we administered an intravenous bolus plus infusion of 18 F-TPP + to reach secular equilibrium followed by an intracoronary infusion of BAM15., Results: Intracoronary BAM15 infusion led to a clear decrease in 18 F-TPP + concentration, falling to a lower level, and then recovering. A second BAM15 infusion reduced the 18 F-TPP + level in a similar fashion. We observed a maximum depolarization of 10 mV as a result of the BAM15 infusion., Summary: This work provides evidence that the total membrane potential measured with 18 F-TPP + PET is sensitive to temporal changes in mitochondrial membrane potential., (Copyright © 2020 Alpert, Pelletier-Galarneau, Kim, Petibon, Sun, Ramos-Torres, Normandin and El Fakhri.)

Purpose: Patient body motion during a cardiac positron emission tomography (PET) scan can severely degrade image quality. We propose and evaluate a novel method to detect, estimate, and correct body motion in cardiac PET., Methods: Our method consists of three key components: motion detection, motion estimation, and motion-compensated image reconstruction. For motion detection, we first divide PET list-mode data into 1-s bins and compute the center of mass (COM) of the coincidences' distribution in each bin. We then compute the covariance matrix within a 25-s sliding window over the COM signals inside the window. The sum of the eigenvalues of the covariance matrix is used to separate the list-mode data into "static" (i.e., body motion free) and "moving" (i.e. contaminated by body motion) frames. Each moving frame is further divided into a number of evenly spaced sub-frames (referred to as "sub-moving" frames), in which motion is assumed to be negligible. For motion estimation, we first reconstruct the data in each static and sub-moving frame using a rapid back-projection technique. We then select the longest static frame as the reference frame and estimate elastic motion transformations to the reference frame from all other static and sub-moving frames using nonrigid registration. For motion-compensated image reconstruction, we reconstruct all the list-mode data into a single image volume in the reference frame by incorporating the estimated motion transformations in the PET system matrix. We evaluated the performance of our approach in both phantom and human studies., Results: Visually, the motion-corrected (MC) PET images obtained using the proposed method have better quality and fewer motion artifacts than the images reconstructed without motion correction (NMC). Quantitative analysis indicates that MC yields higher myocardium to blood pool concentration ratios. MC also yields sharper myocardium than NMC., Conclusions: The proposed body motion correction method improves image quality of cardiac PET., (© 2019 American Association of Physicists in Medicine.)

Motion of the myocardium deteriorates the quality and quantitative accuracy of cardiac PET images. We present a method for MR-based cardiac and respiratory motion correction of cardiac PET data and evaluate its impact on estimation of activity and kinetic parameters in human subjects. Three healthy subjects underwent simultaneous dynamic 18 F-FDG PET and MRI on a hybrid PET/MR scanner. A cardiorespiratory motion field was determined for each subject using navigator, tagging and golden-angle radial MR acquisitions. Acquired coincidence events were binned into cardiac and respiratory phases using electrocardiogram and list mode-driven signals, respectively. Dynamic PET images were reconstructed with MR-based motion correction (MC) and without motion correction (NMC). Parametric images of 18 F-FDG consumption rates (K i ) were estimated using Patlak's method for both MC and NMC images. MC alleviated motion artifacts in PET images, resulting in improved spatial resolution, improved recovery of activity in the myocardium wall and reduced spillover from the myocardium to the left ventricle cavity. Significantly higher myocardium contrast-to-noise ratio and lower apparent wall thickness were obtained in MC versus NMC images. Likewise, parametric images of K i calculated with MC data had improved spatial resolution as compared to those obtained with NMC. Consistent with an increase in reconstructed activity concentration in the frames used during kinetic analyses, MC led to the estimation of higher K i values almost everywhere in the myocardium, with up to 18% increase (mean across subjects) in the septum as compared to NMC. This study shows that MR-based motion correction of cardiac PET results in improved image quality that can benefit both static and dynamic studies.

Mapping the longitudinal relaxation time constant (T1) of the myocardium using Magnetic Resonance Imaging (MRI) is an emerging technique for quantitative assessment of the morphology and viability of the myocardium. However, three-dimensional (3D) T1 mapping of the heart is challenging due to the high dimensionality of the signal and the presence of cardiac and respiratory motions. We propose a subspace-based method for free-breathing 3D T1 mapping of the heart without respiratory gating. The image function is represented as a high-order partially separable (PS) function to explore the inherent spatiotemporal correlations of the underlying signal. A special data acquisition scheme enabled by the high-order PS model is used for sparse sampling of the (k,t)-space, where complementary sparse datasets are acquired, each covering only a small portion of the (k,t)-space to characterize a single subspace (spatial or temporal). High-resolution dynamic MR images are reconstructed from the highly undersampled (k,t)-space using low-rank tensor and sparsity constraints. We demonstrate the feasibility of our proposed method using in vivo data obtained from healthy subjects on a 3T MR scanner. The proposed method can enable new clinical applications of T1 mapping in cardiac MR.

Background: Both cardiac and respiratory motions bias the kinetic parameters measured by dynamic PET. The aim of this study was to perform a realistic positron emission tomography-magnetic resonance (PET-MR) simulation study using 4D XCAT to evaluate the impact of MR-based motion correction on the estimation of PET myocardial kinetic parameters using PET-MR. Dynamic activity distributions were obtained based on a one-tissue compartment model with realistic kinetic parameters and an arterial input function. Realistic proton density/T1/T2 values were also defined for the MRI simulation. Two types of motion patterns, cardiac motion only (CM) and both cardiac and respiratory motions (CRM), were generated. PET sinograms were obtained by the projection of the activity distributions. PET image for each time frame was obtained using static (ST), gated (GA), non-motion-corrected (NMC), and motion-corrected (MC) methods. Voxel-wise unweighted least squares fitting of the dynamic PET data was then performed to obtain K 1 values for each study. For each study, the mean and standard deviation of K 1 values were computed for four regions of interest in the myocardium across 25 noise realizations., Results: Both cardiac and respiratory motions introduce blurring in the PET parametric images if the motion is not corrected. Conventional cardiac gating is limited by high noise level on parametric images. Dual cardiac and respiratory gating further increases the noise level. In contrast to GA, the MR-based MC method reduces motion blurring in parametric images without increasing noise level. It also improves the myocardial defect delineation as compared to NMC method. Finally, the MR-based MC method yields lower bias and variance in K 1 values than NMC and GA, respectively. The reductions of K 1 bias by MR-based MC are 7.7, 5.1, 15.7, and 29.9% in four selected 0.18-mL myocardial regions of interest, respectively, as compared to NMC for CRM. MR-based MC yields 85.9, 75.3, 71.8, and 95.2% less K 1 standard deviation in the four regions, respectively, as compared to GA for CRM., Conclusions: This simulation study suggests that the MR-based motion-correction method using PET-MR greatly reduces motion blurring on parametric images and yields less K 1 bias without increasing noise level.

Dynamic PET myocardial perfusion imaging (MPI) used in conjunction with tracer kinetic modeling enables the quantification of absolute myocardial blood flow (MBF). However, MBF maps computed using the traditional indirect method (i.e. post-reconstruction voxel-wise fitting of kinetic model to PET time-activity-curves-TACs) suffer from poor signal-to-noise ratio (SNR). Direct reconstruction of kinetic parameters from raw PET projection data has been shown to offer parametric images with higher SNR compared to the indirect method. The aim of this study was to extend and evaluate the performance of a direct parametric reconstruction method using in vivo dynamic PET MPI data for the purpose of quantifying MBF. Dynamic PET MPI studies were performed on two healthy pigs using a Siemens Biograph mMR scanner. List-mode PET data for each animal were acquired following a bolus injection of ~7-8 mCi of 18 F-flurpiridaz, a myocardial perfusion agent. Fully-3D dynamic PET sinograms were obtained by sorting the coincidence events into 16 temporal frames covering ~5 min after radiotracer administration. Additionally, eight independent noise realizations of both scans-each containing 1/8th of the total number of events-were generated from the original list-mode data. Dynamic sinograms were then used to compute parametric maps using the conventional indirect method and the proposed direct method. For both methods, a one-tissue compartment model accounting for spillover from the left and right ventricle blood-pools was used to describe the kinetics of 18 F-flurpiridaz. An image-derived arterial input function obtained from a TAC taken in the left ventricle cavity was used for tracer kinetic analysis. For the indirect method, frame-by-frame images were estimated using two fully-3D reconstruction techniques: the standard ordered subset expectation maximization (OSEM) reconstruction algorithm on one side, and the one-step late maximum a posteriori (OSL-MAP) algorithm on the other side, which incorporates a quadratic penalty function. The parametric images were then calculated using voxel-wise weighted least-square fitting of the reconstructed myocardial PET TACs. For the direct method, parametric images were estimated directly from the dynamic PET sinograms using a maximum a posteriori (MAP) parametric reconstruction algorithm which optimizes an objective function comprised of the Poisson log-likelihood term, the kinetic model and a quadratic penalty function. Maximization of the objective function with respect to each set of parameters was achieved using a preconditioned conjugate gradient algorithm with a specifically developed pre-conditioner. The performance of the direct method was evaluated by comparing voxel- and segment-wise estimates of [Formula: see text], the tracer transport rate (ml · min -1 · ml -1 ), to those obtained using the indirect method applied to both OSEM and OSL-MAP dynamic reconstructions. The proposed direct reconstruction method produced [Formula: see text] maps with visibly lower noise than the indirect method based on OSEM and OSL-MAP reconstructions. At normal count levels, the direct method was shown to outperform the indirect method based on OSL-MAP in the sense that at matched level of bias, reduced regional noise levels were obtained. At lower count levels, the direct method produced [Formula: see text] estimates with significantly lower standard deviation across noise realizations than the indirect method based on OSL-MAP at matched bias level. In all cases, the direct method yielded lower noise and standard deviation than the indirect method based on OSEM. Overall, the proposed direct reconstruction offered a better bias-variance tradeoff than the indirect method applied to either OSEM and OSL-MAP. Direct parametric reconstruction as applied to in vivo dynamic PET MPI data is therefore a promising method for producing MBF maps with lower variance.

PET is an established modality for myocardial perfusion imaging (MPI) which enables quantification of absolute myocardial blood flow (MBF) using dynamic imaging and kinetic modeling. However, heart motion and partial volume effects (PVE) significantly limit the spatial resolution and quantitative accuracy of PET MPI. Simultaneous PET-MR offers a solution to the motion problem in PET by enabling MR-based motion correction of PET data. The aim of this study was to develop a motion and PVE correction methodology for PET MPI using simultaneous PET-MR, and to assess its impact on both static and dynamic PET MPI using 18 F-Flurpiridaz, a novel 18 F-labeled perfusion tracer. Two dynamic 18 F-Flurpiridaz MPI scans were performed on healthy pigs using a PET-MR scanner. Cardiac motion was tracked using a dedicated tagged-MRI (tMR) sequence. Motion fields were estimated using non-rigid registration of tMR images and used to calculate motion-dependent attenuation maps. Motion correction of PET data was achieved by incorporating tMR-based motion fields and motion-dependent attenuation coefficients into image reconstruction. Dynamic and static PET datasets were created for each scan. Each dataset was reconstructed as (i) Ungated, (ii) Gated (end-diastolic phase), and (iii) Motion-Corrected (MoCo), each without and with point spread function (PSF) modeling for PVE correction. Myocardium-to-blood concentration ratios (MBR) and apparent wall thickness were calculated to assess image quality for static MPI. For dynamic MPI, segment- and voxel-wise MBF values were estimated by non-linear fitting of a 2-tissue compartment model to tissue time-activity-curves. MoCo and Gating respectively decreased mean apparent wall thickness by 15.1% and 14.4% and increased MBR by 20.3% and 13.6% compared to Ungated images (P  <  0.01). Combined motion and PSF correction (MoCo-PSF) yielded 30.9% (15.7%) lower wall thickness and 82.2% (20.5%) higher MBR compared to Ungated data reconstructed without (with) PSF modeling (P  <  0.01). For dynamic PET, mean MBF across all segments were comparable for MoCo (0.72  ±  0.21 ml/min/ml) and Gating (0.69  ±  0.18 ml/min/ml). Ungated data yielded significantly lower mean MBF (0.59  ±  0.16 ml/min/ml). Mean MBF for MoCo-PSF was 0.80  ±  0.22 ml/min/ml, which was 37.9% (25.0%) higher than that obtained from Ungated data without (with) PSF correction (P  <  0.01). The developed methodology holds promise to improve the image quality and sensitivity of PET MPI studies performed using PET-MR.

Purpose: Degradation of image quality caused by cardiac and respiratory motions hampers the diagnostic quality of cardiac PET. It has been shown that improved diagnostic accuracy of myocardial defect can be achieved by tagged MR (tMR) based PET motion correction using simultaneous PET-MR. However, one major hurdle for the adoption of tMR-based PET motion correction in the PET-MR routine is the long acquisition time needed for the collection of fully sampled tMR data. In this work, the authors propose an accelerated tMR acquisition strategy using parallel imaging and/or compressed sensing and assess the impact on the tMR-based motion corrected PET using phantom and patient data., Methods: Fully sampled tMR data were acquired simultaneously with PET list-mode data on two simultaneous PET-MR scanners for a cardiac phantom and a patient. Parallel imaging and compressed sensing were retrospectively performed by GRAPPA and kt-FOCUSS algorithms with various acceleration factors. Motion fields were estimated using nonrigid B-spline image registration from both the accelerated and fully sampled tMR images. The motion fields were incorporated into a motion corrected ordered subset expectation maximization reconstruction algorithm with motion-dependent attenuation correction., Results: Although tMR acceleration introduced image artifacts into the tMR images for both phantom and patient data, motion corrected PET images yielded similar image quality as those obtained using the fully sampled tMR images for low to moderate acceleration factors (<4). Quantitative analysis of myocardial defect contrast over ten independent noise realizations showed similar results. It was further observed that although the image quality of the motion corrected PET images deteriorates for high acceleration factors, the images were still superior to the images reconstructed without motion correction., Conclusions: Accelerated tMR images obtained with more than 4 times acceleration can still provide relatively accurate motion fields and yield tMR-based motion corrected PET images with similar image quality as those reconstructed using fully sampled tMR data. The reduction of tMR acquisition time makes it more compatible with routine clinical cardiac PET-MR studies.

Simultaneous positron emission tomography and magnetic resonance imaging (PET-MR) is an innovative and promising imaging modality that is generating substantial interest in the medical imaging community, while offering many challenges and opportunities. In this study, we investigated whether MR surface coils need to be accounted for in PET attenuation correction. Furthermore, we integrated motion correction, attenuation correction, and point spread function modeling into a single PET reconstruction framework. We applied our reconstruction framework to in vivo animal and patient PET-MR studies. We have demonstrated that our approach greatly improved PET image quality.

Purpose: Respiratory-gated positron emission tomography (PET)/computed tomography protocols reduce lesion smearing and improve lesion detection through a synchronized acquisition of emission data. However, an objective assessment of image quality of the improvement gained from respiratory-gated PET is mainly limited to a three-dimensional (3D) approach. This work proposes a 4D numerical observer that incorporates both spatial and temporal informations for detection tasks in pulmonary oncology., Methods: The authors propose a 4D numerical observer constructed with a 3D channelized Hotelling observer for the spatial domain followed by a Hotelling observer for the temporal domain. Realistic (18)F-fluorodeoxyglucose activity distributions were simulated using a 4D extended cardiac torso anthropomorphic phantom including 12 spherical lesions at different anatomical locations (lower, upper, anterior, and posterior) within the lungs. Simulated data based on Monte Carlo simulation were obtained using geant4 application for tomographic emission (GATE). Fifty noise realizations of six respiratory-gated PET frames were simulated by GATE using a model of the Siemens Biograph mMR scanner geometry. PET sinograms of the thorax background and pulmonary lesions that were simulated separately were merged to generate different conditions of the lesions to the background (e.g., lesion contrast and motion). A conventional ordered subset expectation maximization (OSEM) reconstruction (5 iterations and 6 subsets) was used to obtain: (1) gated, (2) nongated, and (3) motion-corrected image volumes (a total of 3200 subimage volumes: 2400 gated, 400 nongated, and 400 motion-corrected). Lesion-detection signal-to-noise ratios (SNRs) were measured in different lesion-to-background contrast levels (3.5, 8.0, 9.0, and 20.0), lesion diameters (10.0, 13.0, and 16.0 mm), and respiratory motion displacements (17.6-31.3 mm). The proposed 4D numerical observer applied on multiple-gated images was compared to the conventional 3D approach applied on the nongated and motion-corrected images., Results: On average, the proposed 4D numerical observer improved the detection SNR by 48.6% (p < 0.005), whereas the 3D methods on motion-corrected images improved by 31.0% (p < 0.005) as compared to the nongated method. For all different conditions of the lesions, the relative SNR measurement (Gain = SNRObserved/SNRNongated) of the 4D method was significantly higher than one from the motion-corrected 3D method by 13.8% (p < 0.02), where Gain4D was 1.49 ± 0.21 and Gain3D was 1.31 ± 0.15. For the lesion with the highest amplitude of motion, the 4D numerical observer yielded the highest observer-performance improvement (176%). For the lesion undergoing the smallest motion amplitude, the 4D method provided superior lesion detectability compared with the 3D method, which provided a detection SNR close to the nongated method. The investigation on a structure of the 4D numerical observer showed that a Laguerre-Gaussian channel matrix with a volumetric 3D function yielded higher lesion-detection performance than one with a 2D-stack-channelized function, whereas a different kind of channels that have the ability to mimic the human visual system, i.e., difference-of-Gaussian, showed similar performance in detecting uniform and spherical lesions. The investigation of the detection performance when increasing noise levels yielded decreasing detection SNR by 27.6% and 41.5% for the nongated and gated methods, respectively. The investigation of lesion contrast and diameter showed that the proposed 4D observer preserved the linearity property of an optimal-linear observer while the motion was present. Furthermore, the investigation of the iteration and subset numbers of the OSEM algorithm demonstrated that these parameters had impact on the lesion detectability and the selection of the optimal parameters could provide the maximum lesion-detection performance. The proposed 4D numerical observer outperformed the other observers for the lesion-detection task in various lesion conditions and motions., Conclusions: The 4D numerical observer shows substantial improvement in lesion detectability over the 3D observer method. The proposed 4D approach could potentially provide a more reliable objective assessment of the impact of respiratory-gated PET improvement for lesion-detection tasks. On the other hand, the 4D approach may be used as an upper bound to investigate the performance of the motion correction method. In future work, the authors will validate the proposed 4D approach on clinical data for detection tasks in pulmonary oncology.

Brain PET scanning plays an important role in the diagnosis, prognostication and monitoring of many brain diseases. Motion artifacts from head motion are one of the major hurdles in brain PET. In this work, we propose to use wireless MR active markers to track head motion in real time during a simultaneous PET-MR brain scan and incorporate the motion measured by the markers in the listmode PET reconstruction. Several wireless MR active markers and a dedicated fast MR tracking pulse sequence module were built. Data were acquired on an ACR Flangeless PET phantom with multiple spheres and a non-human primate with and without motion. Motions of the phantom and monkey's head were measured with the wireless markers using a dedicated MR tracking sequence module. The motion PET data were reconstructed using list-mode reconstruction with and without motion correction. Static reference was used as gold standard for quantitative analysis. The motion artifacts, which were prominent on the images without motion correction, were eliminated by the wireless marker based motion correction in both the phantom and monkey experiments. Quantitative analysis was performed on the phantom motion data from 24 independent noise realizations. The reduction of bias of sphere-to-background PET contrast by active marker based motion correction ranges from 26% to 64% and 17% to 25% for hot (i.e., radioactive) and cold (i.e., non-radioactive) spheres, respectively. The motion correction improved the channelized Hotelling observer signal-to-noise ratio of the spheres by 1.2 to 6.9 depending on their locations and sizes. The proposed wireless MR active marker based motion correction technique removes the motion artifacts in the reconstructed PET images and yields accurate quantitative values., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: Respiratory motion and partial-volume effects are the two main sources of image degradation in whole-body PET imaging. Simultaneous PET-MR allows measurement of respiratory motion using MRI while collecting PET events. Improved PET images may be obtained by modeling respiratory motion and point spread function (PSF) within the PET iterative reconstruction process. In this study, the authors assessed the relative impact of PSF modeling and MR-based respiratory motion correction in phantoms and patient studies using a whole-body PET-MR scanner., Methods: An asymmetric exponential PSF model accounting for radially varying and axial detector blurring effects was obtained from point source acquisitions performed in the PET-MR scanner. A dedicated MRI acquisition protocol using single-slice steady state free-precession MR acquisitions interleaved with pencil-beam navigator echoes was developed to track respiratory motion during PET-MR studies. An iterative ordinary Poisson fully 3D OSEM PET reconstruction algorithm modeling all the physical effects of the acquisition (attenuation, scatters, random events, detectors efficiencies, PSF), as well as MR-based nonrigid respiratory deformations of tissues (in both emission and attenuation maps) was developed. Phantom and(18)F-FDG PET-MR patient studies were performed to evaluate the proposed quantitative PET-MR methods., Results: The phantom experiment results showed that PSF modeling significantly improved contrast recovery while limiting noise propagation in the reconstruction process. In patients with soft-tissue static lesions, PSF modeling improved lesion contrast by 19.7%-109%, enhancing the detectability and assessment of small tumor foci. In a patient study with small moving hepatic lesions, the proposed reconstruction technique improved lesion contrast by 54.4%-98.1% and reduced apparent lesion size by 21.8%-34.2%. Improvements were particularly important for the smallest lesion undergoing large motion at the lung-liver interface. Heterogeneous tumor structures delineation was substantially improved. Enhancements offered by PSF modeling were more important when correcting for motion at the same time., Conclusions: The results suggest that the proposed quantitative PET-MR methods can significantly enhance the performance of tumor diagnosis and staging as compared to conventional methods. This approach may enable utilization of the full potential of the scanner in oncologic studies of both the lower abdomen, with moving lesions, as well as other parts of the body unaffected by motion., (© 2014 American Association of Physicists in Medicine.)

Purpose: Artifacts caused by head motion present a major challenge in brain positron emission tomography (PET) imaging. The authors investigated the feasibility of using wired active MR microcoils to track head motion and incorporate the measured rigid motion fields into iterative PET reconstruction., Methods: Several wired active MR microcoils and a dedicated MR coil-tracking sequence were developed. The microcoils were attached to the outer surface of an anthropomorphic(18)F-filled Hoffman phantom to mimic a brain PET scan. Complex rotation/translation motion of the phantom was induced by a balloon, which was connected to a ventilator. PET list-mode and MR tracking data were acquired simultaneously on a PET-MR scanner. The acquired dynamic PET data were reconstructed iteratively with and without motion correction. Additionally, static phantom data were acquired and used as the gold standard., Results: Motion artifacts in PET images were effectively removed by wired active MR microcoil based motion correction. Motion correction yielded an activity concentration bias ranging from -0.6% to 3.4% as compared to a bias ranging from -25.0% to 16.6% if no motion correction was applied. The contrast recovery values were improved by 37%-156% with motion correction as compared to no motion correction. The image correlation (mean ± standard deviation) between the motion corrected (uncorrected) images of 20 independent noise realizations and static reference was R(2) = 0.978 ± 0.007 (0.588 ± 0.010, respectively)., Conclusions: Wired active MR microcoil based motion correction significantly improves brain PET quantitative accuracy and image contrast., (© 2014 American Association of Physicists in Medicine.)

This study was to obtain voxel-wise PET accuracy and precision using tissue-segmentation for attenuation correction. We applied multiple thresholds to the CTs of 23 patients to classify tissues. For six of the 23 patients, MR images were also acquired. The MR fat/in-phase ratio images were used for fat segmentation. Segmented tissue classes were used to create attenuation maps, which were used for attenuation correction in PET reconstruction. PET bias images were then computed using the PET reconstructed with the original CT as the reference. We registered the CTs for all the patients and transformed the corresponding bias images accordingly. We then obtained the mean and standard deviation bias atlas using all the registered bias images. Our CT-based study shows that four-class segmentation (air, lungs, fat, other tissues), which is available on most PET-MR scanners, yields 15.1%, 4.1%, 6.6%, and 12.9% RMSE bias in lungs, fat, non-fat soft-tissues, and bones, respectively. An accurate fat identification is achievable using fat/in-phase MR images. Furthermore, we have found that three-class segmentation (air, lungs, other tissues) yields less than 5% standard deviation of bias within the heart, liver, and kidneys. This implies that three-class segmentation can be sufficient to achieve small variation of bias for imaging these three organs. Finally, we have found that inter- and intra-patient lung density variations contribute almost equally to the overall standard deviation of bias within the lungs.