Novel voxelwise residual analysis of [11C]raclopride PET data improves detection of low-amplitude dopamine release.

Existing methods for voxelwise transient dopamine (DA) release detection rely on explicit kinetic modeling of the [11C]raclopride PET time activity curve, which at the voxel level is typically confounded by noise, leading to poor performance for detection of low-amplitude DA release-induced signals. Here we present a novel data-driven, task-informed method-referred to as Residual Space Detection (RSD)-that transforms PET time activity curves to a residual space where DA release-induced perturbations can be isolated and processed. Using simulations, we demonstrate that this method significantly increases detection performance compared to existing kinetic model-based methods for low-magnitude DA release (simulated +100% peak increase in basal DA concentration). In addition, results from nine healthy controls injected with a single bolus of [11C]raclopride performing a finger tapping motor task are shown as proof-of-concept. The ability to detect relatively low magnitudes of dopamine release in the human brain using a single bolus injection, while achieving higher statistical power than previous methods, may additionally enable more complex analyses of neurotransmitter systems. Moreover, RSD is readily generalizable to multiple tasks performed during a single PET scan, further extending the capabilities of task-based single-bolus protocols.

HYPR4D kernel method on TOF PET data with validations including image-derived input function.

BACKGROUND: Positron emission tomography (PET) images are typically noisy especially in dynamic imaging where the PET data are divided into a number of short temporal frames often with a low number of counts. As a result, image features such as contrast and time-activity curves are highly variable. Noise reduction in PET is thus essential. Typical noise reduction methods tend to not preserve image features/patterns (e.g. contrast and size dependent) accurately. In this work, we report the first application of our HYPR4D kernel method on time-of-flight (TOF) PET data (i.e. PSF-HYPR4D-K-TOFOSEM). The proposed HYPR4D kernel method makes use of the mean 4D high frequency features and inconsistent noise patterns over OSEM subsets as well as the low noise property of the early reconstruction updates to achieve prior-free de-noising. The method was implemented and tested on the GE SIGNA PET/MR and was compared to the TOF reconstructions with PSF resolution modeling available on the system, namely PSF-TOFOSEM with and without standard post filter and PSF-TOFBSREM (TOF Q.Clear) with various beta values (regularization strengths). RESULTS: Results from experimental contrast phantom and human subject data with various PET tracers showed that the proposed method provides more robust and accurate image features compared to other regularization methods. The preservation of contrast for the PSF-HYPR4D-K-TOFOSEM was observed to be better and less dependent on the contrast and size of the target structures as compared to TOF Q.Clear and PSF-TOFOSEM with filter. At the same contrast level, PSF-HYPR4D-K-TOFOSEM achieved better 4D noise suppression than other methods (e.g. >2 times lower noise than TOF Q.Clear at the highest contrast). We also present a novel voxel search method to obtain an image-derived input function (IDIF) and demonstrate that the obtained IDIF is the most quantitative w.r.t. the measured blood samples when the acquired data are reconstructed with PSF-HYPR4D-K-TOFOSEM. CONCLUSIONS: The overall results support superior performance of the PSF-HYPR4D-K-TOFOSEM for TOF PET data and demonstrate that the proposed method is likely suitable for all imaging tasks including the generation of IDIF without requiring any prior information as well as further improving the effective sensitivity of the imaging system.

Cross-validation study between the HRRT and the PET component of the SIGNA PET/MRI system with focus on neuroimaging.

BACKGROUND: The Siemens high-resolution research tomograph (HRRT - a dedicated brain PET scanner) is to this day one of the highest resolution PET scanners; thus, it can serve as useful benchmark when evaluating performance of newer scanners. Here, we report results from a cross-validation study between the HRRT and the whole-body GE SIGNA PET/MR focusing on brain imaging. Phantom data were acquired to determine recovery coefficients (RCs), % background variability (%BG), and image voxel noise (%). Cross-validation studies were performed with six healthy volunteers using [11C]DTBZ, [11C]raclopride, and [18F]FDG. Line profiles, regional time-activity curves, regional non-displaceable binding potentials (BPND) for [11C]DTBZ and [11C]raclopride scans, and radioactivity ratios for [18F]FDG scans were calculated and compared between the HRRT and the SIGNA PET/MR. RESULTS: Phantom data showed that the PET/MR images reconstructed with an ordered subset expectation maximization (OSEM) algorithm with time-of-flight (TOF) and TOF + point spread function (PSF) + filter revealed similar RCs for the hot spheres compared to those obtained on the HRRT reconstructed with an ordinary Poisson-OSEM algorithm with PSF and PSF + filter. The PET/MR TOF + PSF reconstruction revealed the highest RCs for all hot spheres. Image voxel noise of the PET/MR system was significantly lower. Line profiles revealed excellent spatial agreement between the two systems. BPND values revealed variability of less than 10% for the [11C]DTBZ scans and 19% for [11C]raclopride (based on one subject only). Mean [18F]FDG ratios to pons showed less than 12% differences. CONCLUSIONS: These results demonstrated comparable performances of the two systems in terms of RCs with lower voxel-level noise (%) present in the PET/MR system. Comparison of in vivo human data confirmed the comparability of the two systems. The whole-body GE SIGNA PET/MR system is well suited for high-resolution brain imaging as no significant performance degradation was found compared to that of the reference standard HRRT.

Dynamic PET image reconstruction utilizing intrinsic data-driven HYPR4D denoising kernel.

PURPOSE: Reconstructed PET images are typically noisy, especially in dynamic imaging where the acquired data are divided into several short temporal frames. High noise in the reconstructed images translates to poor precision/reproducibility of image features. One important role of "denoising" is therefore to improve the precision of image features. However, typical denoising methods achieve noise reduction at the expense of accuracy. In this work, we present a novel four-dimensional (4D) denoised image reconstruction framework, which we validate using 4D simulations, experimental phantom, and clinical patient data, to achieve 4D noise reduction while preserving spatiotemporal patterns/minimizing error introduced by denoising. METHODS: Our proposed 4D denoising operator/kernel is based on HighlY constrained backPRojection (HYPR), which is applied either after each update of OSEM reconstruction of dynamic 4D PET data or within the recently proposed kernelized reconstruction framework inspired by kernel methods in machine learning. Our HYPR4D kernel makes use of the spatiotemporal high frequency features extracted from a 4D composite, generated within the reconstruction, to preserve the spatiotemporal patterns and constrain the 4D noise increment of the image estimate. RESULTS: Results from simulations, experimental phantom, and patient data showed that the HYPR4D kernel with our proposed 4D composite outperformed other denoising methods, such as the standard OSEM with spatial filter, OSEM with 4D filter, and HYPR kernel method with the conventional 3D composite in conjunction with recently proposed High Temporal Resolution kernel (HYPRC3D-HTR), in terms of 4D noise reduction while preserving the spatiotemporal patterns or 4D resolution within the 4D image estimate. Consequently, the error in outcome measures obtained from the HYPR4D method was less dependent on the region size, contrast, and uniformity/functional patterns within the target structures compared to the other methods. For outcome measures that depend on spatiotemporal tracer uptake patterns such as the nondisplaceable Binding Potential (BPND ), the root mean squared error in regional mean of voxel BPND values was reduced from ~8% (OSEM with spatial or 4D filter) to ~3% using HYPRC3D-HTR and was further reduced to ~2% using our proposed HYPR4D method for relatively small target structures (~10 mm in diameter). At the voxel level, HYPR4D produced two to four times lower mean absolute error in BPND relative to HYPRC3D-HTR. CONCLUSION: As compared to conventional methods, our proposed HYPR4D method can produce more robust and accurate image features without requiring any prior information.

A Monte Carlo approach for improving transient dopamine release detection sensitivity.

Current methods using a single PET scan to detect voxel-level transient dopamine release-using F-test (significance) and cluster size thresholding-have limited detection sensitivity for clusters of release small in size and/or having low release levels. Specifically, simulations show that voxels with release near the peripheries of such clusters are often rejected-becoming false negatives and ultimately distorting the F-distribution of rejected voxels. We suggest a Monte Carlo method that incorporates these two observations into a cost function, allowing erroneously rejected voxels to be accepted under specified criteria. In simulations, the proposed method improves detection sensitivity by up to 50% while preserving the cluster size threshold, or up to 180% when optimizing for sensitivity. A further parametric-based voxelwise thresholding is then suggested to better estimate the release dynamics in detected clusters. We apply the Monte Carlo method to a pilot scan from a human gambling study, where additional parametrically unique clusters are detected as compared to the current best methods-results consistent with our simulations.

Detection of transient neurotransmitter response using personalized neural networks.

Measurement of stimulus-induced dopamine release and other types of transient neurotransmitter response (TNR) from dynamic positron emission tomography (PET) images typically suffers from limited detection sensitivity and high false positive (FP) rates. Measurement of TNR of a voxel-level can be particularly problematic due to high image noise. In this work, we perform voxel-level TNR detection using artificial neural networks (ANN) and compare their performance to previously used standard statistical tests. Different ANN architectures were trained and tested using simulated and real human PET imaging data, obtained with the tracer [11C]raclopride (a D2 receptor antagonist). A distinguishing feature of our approach is the use of 'personalized' ANNs that are designed to operate on the image from a specific subject and scan. Training of personalized ANNs was performed using simulated images that have been matched with the acquired image in terms of the signal, resolution, and noise. In our tests of TNR detection performance, the F-test of the linear parametric neurotransmitter PET model fit residuals was used as the reference method. For a moderate TNR magnitude, the areas under the receiver operating characteristic curves in simulated tests were 0.64 for the F-test and 0.77-0.79 for the best ANNs. At a fixed FP rate of 0.01, the true positive rates were 0.6 for the F-test and 0.8-0.9 for the ANNs. The F-test detected on average 28% of a 8.4 mm cluster with a strong TNR, while the best ANN detected 47%. When applied to a real image, no significant abnormalities in the ANN outputs were observed. These results demonstrate that personalized ANNs may offer a greater detection sensitivity of dopamine release and other types of TNR compared to previously used method based on the F-test.

Incorporating HYPR de-noising within iterative PET reconstruction (HYPR-OSEM).

HighlY constrained back-PRojection (HYPR) is a post-processing de-noising technique originally developed for time-resolved magnetic resonance imaging. It has been recently applied to dynamic imaging for positron emission tomography and shown promising results. In this work, we have developed an iterative reconstruction algorithm (HYPR-OSEM) which improves the signal-to-noise ratio (SNR) in static imaging (i.e. single frame reconstruction) by incorporating HYPR de-noising directly within the ordered subsets expectation maximization (OSEM) algorithm. The proposed HYPR operator in this work operates on the target image(s) from each subset of OSEM and uses the sum of the preceding subset images as the composite which is updated every iteration. Three strategies were used to apply the HYPR operator in OSEM: (i) within the image space modeling component of the system matrix in forward-projection only, (ii) within the image space modeling component in both forward-projection and back-projection, and (iii) on the image estimate after the OSEM update for each subset thus generating three forms: (i) HYPR-F-OSEM, (ii) HYPR-FB-OSEM, and (iii) HYPR-AU-OSEM. Resolution and contrast phantom simulations with various sizes of hot and cold regions as well as experimental phantom and patient data were used to evaluate the performance of the three forms of HYPR-OSEM, and the results were compared to OSEM with and without a post reconstruction filter. It was observed that the convergence in contrast recovery coefficients (CRC) obtained from all forms of HYPR-OSEM was slower than that obtained from OSEM. Nevertheless, HYPR-OSEM improved SNR without degrading accuracy in terms of resolution and contrast. It achieved better accuracy in CRC at equivalent noise level and better precision than OSEM and better accuracy than filtered OSEM in general. In addition, HYPR-AU-OSEM has been determined to be the more effective form of HYPR-OSEM in terms of accuracy and precision based on the studies conducted in this work.

Investigation of practical initial attenuation image estimates in TOF-MLAA reconstruction for PET/MR.

PURPOSE: Time-of-flight joint attenuation and activity positron emission tomography reconstruction requires additional calibration (scale factors) or constraints during or post-reconstruction to produce a quantitative µ-map. In this work, the impact of various initializations of the joint reconstruction was investigated, and the initial average mu-value (IAM) method was introduced such that the forward-projection of the initial µ-map is already very close to that of the reference µ-map, thus reducing/minimizing the offset (scale factor) during the early iterations of the joint reconstruction. Consequently, the accuracy and efficiency of unconstrained joint reconstruction such as time-of-flight maximum likelihood estimation of attenuation and activity (TOF-MLAA) can be improved by the proposed IAM method. METHODS: 2D simulations of brain and chest were used to evaluate TOF-MLAA with various initial estimates which include the object filled with water uniformly (conventional initial estimate), bone uniformly, the average µ-value uniformly (IAM magnitude initialization method), and the perfect spatial µ-distribution but with a wrong magnitude (initialization in terms of distribution). 3D gate simulation was also performed for the chest phantom under a typical clinical scanning condition, and the simulated data were reconstructed with a fully corrected list-mode TOF-MLAA algorithm with various initial estimates. The accuracy of the average µ-values within the brain, chest, and abdomen regions obtained from the MR derived µ-maps was also evaluated using computed tomography µ-maps as the gold-standard. RESULTS: The estimated µ-map with the initialization in terms of magnitude (i.e., average µ-value) was observed to reach the reference more quickly and naturally as compared to all other cases. Both 2D and 3D gate simulations produced similar results, and it was observed that the proposed IAM approach can produce quantitative µ-map/emission when the corrections for physical effects such as scatter and randoms were included. The average µ-value obtained from MR derived µ-map was accurate within 5% with corrections for bone, fat, and uniform lungs. CONCLUSIONS: The proposed IAM-TOF-MLAA can produce quantitative µ-map without any calibration provided that there are sufficient counts in the measured data. For low count data, noise reduction and additional regularization/rescaling techniques need to be applied and investigated. The average µ-value within the object is prior information which can be extracted from MR and patient database, and it is feasible to obtain accurate average µ-value using MR derived µ-map with corrections as demonstrated in this work.

Quantitative accuracy of MAP reconstruction for dynamic PET imaging in small animals.

PURPOSE: Iterative reconstruction algorithms are becoming more commonly employed in positron emission tomography (PET) imaging; however, the quantitative accuracy of the reconstructed images still requires validation for various levels of contrast and counting statistics. METHODS: The authors present an evaluation of the quantitative accuracy of the 3D maximum a posteriori (3D-MAP) image reconstruction algorithm for dynamic PET imaging with comparisons to two of the most widely used reconstruction algorithms: the 2D filtered-backprojection (2D-FBP) and 2D-ordered subsets expectation maximization (2D-OSEM) on the Siemens microPET scanners. The study was performed for various levels of count density encountered in typical dynamic scanning as well as the imaging of cardiac activity concentration in small animal studies on the Focus 120. Specially designed phantoms were used for evaluation of the spatial resolution, image quality, and quantitative accuracy. A normal mouse was employed to evaluate the accuracy of the blood time activity concentration extracted from left ventricle regions of interest (ROIs) within the images as compared to the actual blood activity concentration measured from arterial blood sampling. RESULTS: For MAP reconstructions, the spatial resolution and contrast have been found to reach a stable value after 20 iterations independent of the ß values (i.e., hyper parameter which controls the weight of the penalty term) and count density within the frame. The spatial resolution obtained with 3D-MAP reaches values of ∼1.0 mm with a ß of 0.01 while the 2D-FBP has value of 1.8 mm and 2D-OSEM has a value of 1.6 mm. It has been observed that the lower the hyper parameter ß used in MAP, more iterations are needed to reach the stable noise level (i.e., image roughness). The spatial resolution is improved by using a lower ß value at the expense of higher image noise. However, with similar noise level the spatial resolution achieved by 3D-MAP was observed to be better than that by 2D-FBP or 2D-OSEM. Using an image quality phantom containing hot spheres, the estimated activity concentration in the largest sphere has the expected concentration relative to the background area for all the MAP images. The obtained recovery coefficients have been also shown to be almost independent of the count density. 2D-FBP and 2D-OSEM do not perform as well, yielding recovery coefficients lower than those observed with 3D-MAP (approximately 33% lower for the smallest sphere). However, a small positive bias was observed in MAP reconstructed images for frames of very low count density. This bias is present in the uniform area for count density of less than 0.05 × 10(6) counts/ml. For the dynamic mouse study, it was observed that 3D-MAP (even gated at diastole) cannot predict accurately the blood activity concentration due to residual spill-over activity from the myocardium into the left ventricle (approximately 15%). However, 3D-MAP predicts blood activity concentration closer to blood sampling than 2D-FBP. CONCLUSIONS: The authors observed that 3D-MAP produces more accurate activity concentration estimates than 2D-FBP or 2D-OSEM at all practical levels of statistics and contrasts due to improved spatial resolution leading to lesser partial volume effect.