Advanced photon counting CT imaging pipeline for cardiac phenotyping of apolipoprotein E mouse models.

BACKGROUND: Cardiovascular disease (CVD) is associated with the apolipoprotein E (APOE) gene and lipid metabolism. This study aimed to develop an imaging-based pipeline to comprehensively assess cardiac structure and function in mouse models expressing different APOE genotypes using photon-counting computed tomography (PCCT). METHODS: 123 mice grouped based on APOE genotype (APOE2, APOE3, APOE4, APOE knockout (KO)), gender, human NOS2 factor, and diet (control or high fat) were used in this study. The pipeline included PCCT imaging on a custom-built system with contrast-enhanced in vivo imaging and intrinsic cardiac gating, spectral and temporal iterative reconstruction, spectral decomposition, and deep learning cardiac segmentation. Statistical analysis evaluated genotype, diet, sex, and body weight effects on cardiac measurements. RESULTS: Our results showed that PCCT offered high quality imaging with reduced noise. Material decomposition enabled separation of calcified plaques from iodine enhanced blood in APOE KO mice. Deep learning-based segmentation showed good performance with Dice scores of 0.91 for CT-based segmentation and 0.89 for iodine map-based segmentation. Genotype-specific differences were observed in left ventricular volumes, heart rate, stroke volume, ejection fraction, and cardiac index. Statistically significant differences were found between control and high fat diets for APOE2 and APOE4 genotypes in heart rate and stroke volume. Sex and weight were also significant predictors of cardiac measurements. The inclusion of the human NOS2 gene modulated these effects. CONCLUSIONS: This study demonstrates the potential of PCCT in assessing cardiac structure and function in mouse models of CVD which can help in understanding the interplay between genetic factors, diet, and cardiovascular health.

A Deep Learning Approach for Rapid and Generalizable Denoising of Photon-Counting Micro-CT Images.

Photon-counting CT (PCCT) is powerful for spectral imaging and material decomposition but produces noisy weighted filtered backprojection (wFBP) reconstructions. Although iterative reconstruction effectively denoises these images, it requires extensive computation time. To overcome this limitation, we propose a deep learning (DL) model, UnetU, which quickly estimates iterative reconstruction from wFBP. Utilizing a 2D U-net convolutional neural network (CNN) with a custom loss function and transformation of wFBP, UnetU promotes accurate material decomposition across various photon-counting detector (PCD) energy threshold settings. UnetU outperformed multi-energy non-local means (ME NLM) and a conventional denoising CNN called UnetwFBP in terms of root mean square error (RMSE) in test set reconstructions and their respective matrix inversion material decompositions. Qualitative results in reconstruction and material decomposition domains revealed that UnetU is the best approximation of iterative reconstruction. In reconstructions with varying undersampling factors from a high dose ex vivo scan, UnetU consistently gave higher structural similarity (SSIM) and peak signal-to-noise ratio (PSNR) to the fully sampled iterative reconstruction than ME NLM and UnetwFBP. This research demonstrates UnetU's potential as a fast (i.e., 15 times faster than iterative reconstruction) and generalizable approach for PCCT denoising, holding promise for advancing preclinical PCCT research.

MCR toolkit: A GPU-based toolkit for multi-channel reconstruction of preclinical and clinical x-ray CT data.

BACKGROUND: The advancement of x-ray CT into the domains of photon counting spectral imaging and dynamic cardiac and perfusion imaging has created many new challenges and opportunities for clinicians and researchers. To address challenges such as dose constraints and scanning times while capitalizing on opportunities such as multi-contrast imaging and low-dose coronary angiography, these multi-channel imaging applications require a new generation of CT reconstruction tools. These new tools should exploit the relationships between imaging channels during reconstruction to set new image quality standards while serving as a platform for direct translation between the preclinical and clinical domains. PURPOSE: We outline and demonstrate a new Multi-Channel Reconstruction (MCR) Toolkit for GPU-based analytical and iterative reconstruction of preclinical and clinical multi-energy and dynamic x-ray CT data. To promote open science, open-source distribution of the Toolkit will coincide with the release of this publication (GPL v3; gitlab.oit.duke.edu/dpc18/mcr-toolkit-public). METHODS: The MCR Toolkit source code is implemented in C/C++ and NVIDIA's CUDA GPU programming interface, with scripting support from MATLAB and Python. The Toolkit implements matched, separable footprint CT reconstruction operators for projection and backprojection in two geometries: planar, cone-beam CT (CBCT) and 3rd generation, cylindrical multi-detector row CT (MDCT). Analytical reconstruction is performed using filtered backprojection (FBP) for circular CBCT, weighted FBP (WFBP) for helical CBCT, and cone-parallel projection rebinning followed by WFBP for MDCT. Arbitrary combinations of energy and temporal channels are iteratively reconstructed under a generalized multi-channel signal model for joint reconstruction. We solve this generalized model algebraically using the split Bregman optimization method and the BiCGSTAB(l) linear solver interchangeably for both CBCT and MDCT data. Rank-sparse kernel regression (RSKR) and patch-based singular value thresholding (pSVT) are used to regularize the energy and time dimensions, respectively. Under a Gaussian noise model, regularization parameters are estimated automatically from the input data, dramatically reducing algorithm complexity for end users. Multi-GPU parallelization of the reconstruction operators is supported to manage reconstruction times. RESULTS: Denoising with RSKR and pSVT and post-reconstruction material decomposition are illustrated with preclinical and clinical cardiac photon-counting (PC)CT data. A digital MOBY mouse phantom with cardiac motion is used to illustrate single energy (SE), multi-energy (ME), time resolved (TR), and combined multi-energy and time-resolved (METR) helical, CBCT reconstruction. A fixed set of projection data is used across all reconstruction cases to demonstrate the Toolkit's robustness to increasing data dimensionality. Identical reconstruction code is applied to in vivo cardiac PCCT data acquired in a mouse model of atherosclerosis (METR). Clinical cardiac CT reconstruction is illustrated using the XCAT phantom and the DukeSim CT simulator, while dual-source, dual-energy CT reconstruction is illustrated for data acquired with a Siemens Flash scanner. Benchmarking results with NVIDIA RTX 8000 GPU hardware demonstrate 61%-99% efficiency in scaling computation from one to four GPUs for these reconstruction problems. CONCLUSIONS: The MCR Toolkit provides a robust solution for temporal and spectral x-ray CT reconstruction problems and was built from the ground up to facilitate translation of CT research and development between preclinical and clinical applications.

Evaluation of the impact of a novel denoising algorithm on image quality in dual-energy abdominal CT of obese patients.

OBJECTIVES: Evaluate a novel algorithm for noise reduction in obese patients using dual-source dual-energy (DE) CT imaging. METHODS: Seventy-nine patients with contrast-enhanced abdominal imaging (54 women; age: 58 ± 14 years; BMI: 39 ± 5 kg/m2, range: 35-62 kg/m2) from seven DECT (SOMATOM Flash or Force) were retrospectively included (01/2019-12/2020). Image domain data were reconstructed with the standard clinical algorithm (ADMIRE/SAFIRE 2), and denoised with a comparison (ME-NLM) and a test algorithm (rank-sparse kernel regression). Contrast-to-noise ratio (CNR) was calculated. Four blinded readers evaluated the same original and denoised images (0 (worst)-100 (best)) in randomized order for perceived image noise, quality, and their comfort making a diagnosis from a table of 80 options. Comparisons between algorithms were performed using paired t-tests and mixed-effects linear modeling. RESULTS: Average CNR was 5.0 ± 1.9 (original), 31.1 ± 10.3 (comparison; p < 0.001), and 8.9 ± 2.9 (test; p < 0.001). Readers were in good to moderate agreement over perceived image noise (ICC: 0.83), image quality (ICC: 0.71), and diagnostic comfort (ICC: 0.6). Diagnostic accuracy was low across algorithms (accuracy: 66, 63, and 67% (original, comparison, test)). The noise received a mean score of 54, 84, and 66 (p < 0.05); image quality 59, 61, and 65; and the diagnostic comfort 63, 68, and 68, respectively. Quality and comfort scores were not statistically significantly different between algorithms. CONCLUSIONS: The test algorithm produces quantitatively higher image quality than current standard and existing denoising algorithms in obese patients imaged with DECT and readers show a preference for it. CLINICAL RELEVANCE STATEMENT: Accurate diagnosis on CT imaging of obese patients is challenging and denoising algorithms can increase the diagnostic comfort and quantitative image quality. This could lead to better clinical reads. KEY POINTS: • Improving image quality in DECT imaging of obese patients is important for accurate and confident clinical reads, which may be aided by novel denoising algorithms using image domain data. • Accurate diagnosis on CT imaging of obese patients is especially challenging and denoising algorithms can increase quantitative and qualitative image quality. • Image domain algorithms can generalize well and can be implemented at other institutions.

Material decomposition from photon-counting CT using a convolutional neural network and energy-integrating CT training labels.

Objective.Photon-counting CT (PCCT) has better dose efficiency and spectral resolution than energy-integrating CT, which is advantageous for material decomposition. Unfortunately, the accuracy of PCCT-based material decomposition is limited due to spectral distortions in the photon-counting detector (PCD).Approach.In this work, we demonstrate a deep learning (DL) approach that compensates for spectral distortions in the PCD and improves accuracy in material decomposition by using decomposition maps provided by high-dose multi-energy-integrating detector (EID) data as training labels. We use a 3D U-net architecture and compare networks with PCD filtered back projection (FBP) reconstruction (FBP2Decomp), PCD iterative reconstruction (Iter2Decomp), and PCD decomposition (Decomp2Decomp) as the input.Main results.We found that our Iter2Decomp approach performs best, but DL outperforms matrix inversion decomposition regardless of the input. Compared to PCD matrix inversion decomposition, Iter2Decomp gives 27.50% lower root mean squared error (RMSE) in the iodine (I) map and 59.87% lower RMSE in the photoelectric effect (PE) map. In addition, it increases the structural similarity (SSIM) by 1.92%, 6.05%, and 9.33% in the I, Compton scattering (CS), and PE maps, respectively. When taking measurements from iodine and calcium vials, Iter2Decomp provides excellent agreement with multi-EID decomposition. One limitation is some blurring caused by our DL approach, with a decrease from 1.98 line pairs/mm at 50% modulation transfer function (MTF) with PCD matrix inversion decomposition to 1.75 line pairs/mm at 50% MTF when using Iter2Decomp.Significance.Overall, this work demonstrates that our DL approach with high-dose multi-EID derived decomposition labels is effective at generating more accurate material maps from PCD data. More accurate preclinical spectral PCCT imaging such as this could serve for developing nanoparticles that show promise in the field of theranostics (therapy and diagnostics).

Photon Counting CT and Radiomic Analysis Enables Differentiation of Tumors Based on Lymphocyte Burden.

The purpose of this study was to investigate if radiomic analysis based on spectral micro-CT with nanoparticle contrast-enhancement can differentiate tumors based on lymphocyte burden. High mutational load transplant soft tissue sarcomas were initiated in Rag2+/- and Rag2-/- mice to model varying lymphocyte burden. Mice received radiation therapy (20 Gy) to the tumor-bearing hind limb and were injected with a liposomal iodinated contrast agent. Five days later, animals underwent conventional micro-CT imaging using an energy integrating detector (EID) and spectral micro-CT imaging using a photon-counting detector (PCD). Tumor volumes and iodine uptakes were measured. The radiomic features (RF) were grouped into feature-spaces corresponding to EID, PCD, and spectral decomposition images. The RFs were ranked to reduce redundancy and increase relevance based on TL burden. A stratified repeated cross validation strategy was used to assess separation using a logistic regression classifier. Tumor iodine concentration was the only significantly different conventional tumor metric between Rag2+/- (TLs present) and Rag2-/- (TL-deficient) tumors. The RFs further enabled differentiation between Rag2+/- and Rag2-/- tumors. The PCD-derived RFs provided the highest accuracy (0.68) followed by decomposition-derived RFs (0.60) and the EID-derived RFs (0.58). Such non-invasive approaches could aid in tumor stratification for cancer therapy studies.

Detection of Lung Nodules in Micro-CT Imaging Using Deep Learning.

We are developing imaging methods for a co-clinical trial investigating synergy between immunotherapy and radiotherapy. We perform longitudinal micro-computed tomography (micro-CT) of mice to detect lung metastasis after treatment. This work explores deep learning (DL) as a fast approach for automated lung nodule detection. We used data from control mice both with and without primary lung tumors. To augment the number of training sets, we have simulated data using real augmented tumors inserted into micro-CT scans. We employed a convolutional neural network (CNN), trained with four competing types of training data: (1) simulated only, (2) real only, (3) simulated and real, and (4) pretraining on simulated followed with real data. We evaluated our model performance using precision and recall curves, as well as receiver operating curves (ROC) and their area under the curve (AUC). The AUC appears to be almost identical (0.76-0.77) for all four cases. However, the combination of real and synthetic data was shown to improve precision by 8%. Smaller tumors have lower rates of detection than larger ones, with networks trained on real data showing better performance. Our work suggests that DL is a promising approach for fast and relatively accurate detection of lung tumors in mice.

Evaluating renal lesions using deep-learning based extension of dual-energy FoV in dual-source CT-A retrospective pilot study.

PURPOSE: Dual-source (DS) CT, dual-energy (DE) field of view (FoV) is limited to the size of the smaller detector array. The purpose was to establish a deep learning-based approach to DE extrapolation by estimating missing image data using data from both tubes to evaluate renal lesions. METHOD: A DE extrapolation deep-learning (DEEDL) algorithm had been trained on DECT data of 50 patients using a DSCT with DE-FoV = 33 cm (Somatom Flash). Data from 128 patients with known renal lesions falling within DE-FoV was retrospectively collected (100/140 kVp; reference dataset 1). A smaller DE-FoV = 20 cm was simulated excluding the renal lesion of interest (dataset 2) and the DEEDL was applied to this dataset. Output from the DEEDL algorithm was evaluated using ReconCT v14.1 and Syngo.via. Mean attenuation values in lesions on mixed images (HU) were compared calculating the root-mean-squared-error (RMSE) between the datasets using MATLAB R2019a. RESULTS: The DEEDL algorithm performed well reproducing the image data of the kidney lesions (Bosniak 1 and 2: 125, Bosniak 2F: 6, Bosniak 3: 1 and Bosniak 4/(partially) solid: 32) with RSME values of 10.59 HU, 15.7 HU for attenuation, virtual non-contrast, respectively. The measurements performed in dataset 1 and 2 showed strong correlation with linear regression (r2: attenuation = 0.89, VNC = 0.63, iodine = 0.75), lesions were classified as enhancing with an accuracy of 0.91. CONCLUSION: This DEEDL algorithm can be used to reconstruct a full dual-energy FoV from restricted data, enabling reliable HU value measurements in areas not covered by the smaller FoV and evaluation of renal lesions.

Deep learning based spectral extrapolation for dual-source, dual-energy x-ray computed tomography.

PURPOSE: Data completion is commonly employed in dual-source, dual-energy computed tomography (CT) when physical or hardware constraints limit the field of view (FoV) covered by one of two imaging chains. Practically, dual-energy data completion is accomplished by estimating missing projection data based on the imaging chain with the full FoV and then by appropriately truncating the analytical reconstruction of the data with the smaller FoV. While this approach works well in many clinical applications, there are applications which would benefit from spectral contrast estimates over the larger FoV (spectral extrapolation)-e.g. model-based iterative reconstruction, contrast-enhanced abdominal imaging of large patients, interior tomography, and combined temporal and spectral imaging. METHODS: To document the fidelity of spectral extrapolation and to prototype a deep learning algorithm to perform it, we assembled a data set of 50 dual-source, dual-energy abdominal x-ray CT scans (acquired at Duke University Medical Center with 5 Siemens Flash scanners; chain A: 50 cm FoV, 100 kV; chain B: 33 cm FoV, 140 kV + Sn; helical pitch: 0.8). Data sets were reconstructed using ReconCT (v14.1, Siemens Healthineers): 768 × 768 pixels per slice, 50 cm FoV, 0.75 mm slice thickness, "Dual-Energy - WFBP" reconstruction mode with dual-source data completion. A hybrid architecture consisting of a learned piecewise linear transfer function (PLTF) and a convolutional neural network (CNN) was trained using 40 scans (five scans reserved for validation, five for testing). The PLTF learned to map chain A spectral contrast to chain B spectral contrast voxel-wise, performing an image domain analog of dual-source data completion with approximate spectral reweighting. The CNN with its U-net structure then learned to improve the accuracy of chain B contrast estimates by copying chain A structural information, by encoding prior chain A, chain B contrast relationships, and by generalizing feature-contrast associations. Training was supervised, using data from within the 33-cm chain B FoV to optimize and assess network performance. RESULTS: Extrapolation performance on the testing data confirmed our network's robustness and ability to generalize to unseen data from different patients, yielding maximum extrapolation errors of 26 HU following the PLTF and 7.5 HU following the CNN (averaged per target organ). Degradation of network performance when applied to a geometrically simple phantom confirmed our method's reliance on feature-contrast relationships in correctly inferring spectral contrast. Integrating our image domain spectral extrapolation network into a standard dual-source, dual-energy processing pipeline for Siemens Flash scanner data yielded spectral CT data with adequate fidelity for the generation of both 50 keV monochromatic images and material decomposition images over a 30-cm FoV for chain B when only 20 cm of chain B data were available for spectral extrapolation. CONCLUSIONS: Even with a moderate amount of training data, deep learning methods are capable of robustly inferring spectral contrast from feature-contrast relationships in spectral CT data, leading to spectral extrapolation performance well beyond what may be expected at face value. Future work reconciling spectral extrapolation results with original projection data is expected to further improve results in outlying and pathological cases.

Photon-counting cine-cardiac CT in the mouse.

The maturation of photon-counting detector (PCD) technology promises to enhance routine CT imaging applications with high-fidelity spectral information. In this paper, we demonstrate the power of this synergy and our complementary reconstruction techniques, performing 4D, cardiac PCD-CT data acquisition and reconstruction in a mouse model of atherosclerosis, including calcified plaque. Specifically, in vivo cardiac micro-CT scans were performed in four ApoE knockout mice, following their development of calcified plaques. The scans were performed with a prototype PCD (DECTRIS, Ltd.) with 4 energy thresholds. Projections were sampled every 10 ms with a 10 ms exposure, allowing the reconstruction of 10 cardiac phases at each of 4 energies (40 total 3D volumes per mouse scan). Reconstruction was performed iteratively using the split Bregman method with constraints on spectral rank and spatio-temporal gradient sparsity. The reconstructed images represent the first in vivo, 4D PCD-CT data in a mouse model of atherosclerosis. Robust regularization during iterative reconstruction yields high-fidelity results: an 8-fold reduction in noise standard deviation for the highest energy threshold (relative to unregularized algebraic reconstruction), while absolute spectral bias measurements remain below 13 Hounsfield units across all energy thresholds and scans. Qualitatively, image domain material decomposition results show clear separation of iodinated contrast and soft tissue from calcified plaque in the in vivo data. Quantitatively, spatial, spectral, and temporal fidelity are verified through a water phantom scan and a realistic MOBY phantom simulation experiment: spatial resolution is robustly preserved by iterative reconstruction (10% MTF: 2.8-3.0 lp/mm), left-ventricle, cardiac functional metrics can be measured from iodine map segmentations with ~1% error, and small calcifications (615 µm) can be detected during slow moving phases of the cardiac cycle. Given these preliminary results, we believe that PCD technology will enhance dynamic CT imaging applications with high-fidelity spectral and material information.

Computational 3D histological phenotyping of whole zebrafish by X-ray histotomography.

Organismal phenotypes frequently involve multiple organ systems. Histology is a powerful way to detect cellular and tissue phenotypes, but is largely descriptive and subjective. To determine how synchrotron-based X-ray micro-tomography (micro-CT) can yield 3-dimensional whole-organism images suitable for quantitative histological phenotyping, we scanned whole zebrafish, a small vertebrate model with diverse tissues, at ~1 micron voxel resolutions. Micro-CT optimized for cellular characterization (histotomography) allows brain nuclei to be computationally segmented and assigned to brain regions, and cell shapes and volumes to be computed for motor neurons and red blood cells. Striking individual phenotypic variation was apparent from color maps of computed densities of brain nuclei. Unlike histology, the histotomography also allows the study of 3-dimensional structures of millimeter scale that cross multiple tissue planes. We expect the computational and visual insights into 3D cell and tissue architecture provided by histotomography to be useful for reference atlases, hypothesis generation, comprehensive organismal screens, and diagnostics.

Overcoming detector limitations of x-ray photon counting for preclinical microcomputed tomography.

Spectral computed tomography (CT) using photon counting detectors (PCDs) can provide accurate tissue composition measurements by utilizing the energy dependence of x-ray attenuation in different materials. PCDs are especially suited for K-edge imaging, revealing the spatial distribution of select imaging probes through quantitative material decomposition. We report on a prototype spectral micro-CT system with a CZT-based PCD (DxRay, Inc.) that has 16 × 16 pixels of 0.5 × 0.5 mm 2 , a thickness of 3 mm, and four energy thresholds. Due to the PCD's limited size ( 8 × 8 mm 2 ), our system uses a translate-rotate projection acquisition strategy to cover a field of view relevant for preclinical imaging ( ∼ 4.5 cm ). Projection corrections were implemented to minimize artifacts associated with dead pixels and projection stitching. A sophisticated iterative algorithm was used to reconstruct both phantom and ex vivo mouse data. To achieve preclinically relevant spatial resolution, we trained a convolutional neural network to perform pan-sharpening between low-resolution PCD data ( 247 - µ m voxels) and high-resolution energy-integrating detector data ( 82 - µ m voxels), recovering a high-resolution estimate of the spectral contrast suitable for material decomposition. Long-term, preclinical spectral CT systems such as ours could serve in the developing field of theranostics (therapy and diagnostics) for cancer research.

Rigid Embedding of Fixed and Stained, Whole, Millimeter-Scale Specimens for Section-free 3D Histology by Micro-Computed Tomography.

For over a hundred years, the histological study of tissues has been the gold standard for medical diagnosis because histology allows all cell types in every tissue to be identified and characterized. Our laboratory is actively working to make technological advances in X-ray micro-computed tomography (micro-CT) that will bring the diagnostic power of histology to the study of full tissue volumes at cellular resolution (i.e., an X-ray Histo-tomography modality). Toward this end, we have made targeted improvements to the sample preparation pipeline. One key optimization, and the focus of the present work, is a straightforward method for rigid embedding of fixed and stained millimeter-scale samples. Many of the published methods for sample immobilization and correlative micro-CT imaging rely on placing the samples in paraffin wax, agarose, or liquids such as alcohol. Our approach extends this work with custom procedures and the design of a 3-dimensional printable apparatus to embed the samples in an acrylic resin directly into polyimide tubing, which is relatively transparent to X-rays. Herein, sample preparation procedures are described for the samples from 0.5 to 10 mm in diameter, which would be suitable for whole zebrafish larvae and juveniles, or other animals and tissue samples of similar dimensions. As proof of concept, we have embedded the specimens from Danio, Drosophila, Daphnia, and a mouse embryo; representative images from 3-dimensional scans for three of these samples are shown. Importantly, our methodology leads to multiple benefits including rigid immobilization, long-term preservation of laboriously-created resources, and the ability to re-interrogate samples.

Comparative analysis of fixation and embedding techniques for optimized histological preparation of zebrafish.

In recognition of the importance of zebrafish as a model organism for studying human disease, we have created zebrafish content for a web-based reference atlas of microanatomy for comparing histology and histopathology between model systems and with humans (http://bio-atlas.psu.edu). Fixation, decalcification, embedding, and sectioning of zebrafish were optimized to maximize section quality. A comparison of protocols involving six fixatives showed that 10% Neutral Buffered Formalin at 21°C for 24h yielded excellent results. Sectioning of juveniles and adults requires bone decalcification; EDTA at 0.35M produced effective decalcification in 21-day-old juveniles through adults (≥~3Months). To improve section plane consistency in sets of larvae, we have developed new array casting molds based on the outside contours of larvae derived from 3D microCT images. Tissue discontinuity in sections, a common barrier to creating quality sections of zebrafish, was minimized by processing and embedding the formalin-fixed zebrafish tissues in plasticized forms of paraffin wax, and by periodic hydration of the block surface in ice water between sets of sections. Optimal H&E (Hematoxylin and Eosin) staining was achieved through refinement of standard protocols. High quality slide scans produced from glass histology slides were digitally processed to maximize image quality, and experimental replicates posted as full slides as part of this publication. Modifications to tissue processing are still needed to eliminate the need for block surface hydration. The further addition of slide collections from other model systems and 3D tools for visualizing tissue architecture would greatly increase the utility of the digital atlas.

Hybrid spectral CT reconstruction.

Current photon counting x-ray detector (PCD) technology faces limitations associated with spectral fidelity and photon starvation. One strategy for addressing these limitations is to supplement PCD data with high-resolution, low-noise data acquired with an energy-integrating detector (EID). In this work, we propose an iterative, hybrid reconstruction technique which combines the spectral properties of PCD data with the resolution and signal-to-noise characteristics of EID data. Our hybrid reconstruction technique is based on an algebraic model of data fidelity which substitutes the EID data into the data fidelity term associated with the PCD reconstruction, resulting in a joint reconstruction problem. Within the split Bregman framework, these data fidelity constraints are minimized subject to additional constraints on spectral rank and on joint intensity-gradient sparsity measured between the reconstructions of the EID and PCD data. Following a derivation of the proposed technique, we apply it to the reconstruction of a digital phantom which contains realistic concentrations of iodine, barium, and calcium encountered in small-animal micro-CT. The results of this experiment suggest reliable separation and detection of iodine at concentrations ≥ 5 mg/ml and barium at concentrations ≥ 10 mg/ml in 2-mm features for EID and PCD data reconstructed with inherent spatial resolutions of 176 µm and 254 µm, respectively (point spread function, FWHM). Furthermore, hybrid reconstruction is demonstrated to enhance spatial resolution within material decomposition results and to improve low-contrast detectability by as much as 2.6 times relative to reconstruction with PCD data only. The parameters of the simulation experiment are based on an in vivo micro-CT experiment conducted in a mouse model of soft-tissue sarcoma. Material decomposition results produced from this in vivo data demonstrate the feasibility of distinguishing two K-edge contrast agents with a spectral separation on the order of the energy resolution of the PCD hardware.

A neural network-based method for spectral distortion correction in photon counting x-ray CT.

Spectral CT using a photon counting x-ray detector (PCXD) shows great potential for measuring material composition based on energy dependent x-ray attenuation. Spectral CT is especially suited for imaging with K-edge contrast agents to address the otherwise limited contrast in soft tissues. We have developed a micro-CT system based on a PCXD. This system enables both 4 energy bins acquisition, as well as full-spectrum mode in which the energy thresholds of the PCXD are swept to sample the full energy spectrum for each detector element and projection angle. Measurements provided by the PCXD, however, are distorted due to undesirable physical effects in the detector and can be very noisy due to photon starvation in narrow energy bins. To address spectral distortions, we propose and demonstrate a novel artificial neural network (ANN)-based spectral distortion correction mechanism, which learns to undo the distortion in spectral CT, resulting in improved material decomposition accuracy. To address noise, post-reconstruction denoising based on bilateral filtration, which jointly enforces intensity gradient sparsity between spectral samples, is used to further improve the robustness of ANN training and material decomposition accuracy. Our ANN-based distortion correction method is calibrated using 3D-printed phantoms and a model of our spectral CT system. To enable realistic simulations and validation of our method, we first modeled the spectral distortions using experimental data acquired from (109)Cd and (133)Ba radioactive sources measured with our PCXD. Next, we trained an ANN to learn the relationship between the distorted spectral CT projections and the ideal, distortion-free projections in a calibration step. This required knowledge of the ground truth, distortion-free spectral CT projections, which were obtained by simulating a spectral CT scan of the digital version of a 3D-printed phantom. Once the training was completed, the trained ANN was used to perform distortion correction on any subsequent scans of the same system with the same parameters. We used joint bilateral filtration to perform noise reduction by jointly enforcing intensity gradient sparsity between the reconstructed images for each energy bin. Following reconstruction and denoising, the CT data was spectrally decomposed using the photoelectric effect, Compton scattering, and a K-edge material (i.e. iodine). The ANN-based distortion correction approach was tested using both simulations and experimental data acquired in phantoms and a mouse with our PCXD-based micro-CT system for 4 bins and full-spectrum acquisition modes. The iodine detectability and decomposition accuracy were assessed using the contrast-to-noise ratio and relative error in iodine concentration estimation metrics in images with and without distortion correction. In simulation, the material decomposition accuracy in the reconstructed data was vastly improved following distortion correction and denoising, with 50% and 20% reductions in material concentration measurement error in full-spectrum and 4 energy bins cases, respectively. Overall, experimental data confirms that full-spectrum mode provides superior results to 4-energy mode when the distortion corrections are applied. The material decomposition accuracy in the reconstructed data was vastly improved following distortion correction and denoising, with as much as a 41% reduction in material concentration measurement error for full-spectrum mode, while also bringing the iodine detectability to 4-6 mg ml(-1). Distortion correction also improved the 4 bins mode data, but to a lesser extent. The results demonstrate the experimental feasibility and potential advantages of ANN-based distortion correction and joint bilateral filtration-based denoising for accurate K-edge imaging with a PCXD. Given the computational efficiency with which the ANN can be applied to projection data, the proposed scheme can be readily integrated into existing CT reconstruction pipelines.

Spectrotemporal CT data acquisition and reconstruction at low dose.

PURPOSE: X-ray computed tomography (CT) is widely used, both clinically and preclinically, for fast, high-resolution anatomic imaging; however, compelling opportunities exist to expand its use in functional imaging applications. For instance, spectral information combined with nanoparticle contrast agents enables quantification of tissue perfusion levels, while temporal information details cardiac and respiratory dynamics. The authors propose and demonstrate a projection acquisition and reconstruction strategy for 5D CT (3D+dual energy+time) which recovers spectral and temporal information without substantially increasing radiation dose or sampling time relative to anatomic imaging protocols. METHODS: The authors approach the 5D reconstruction problem within the framework of low-rank and sparse matrix decomposition. Unlike previous work on rank-sparsity constrained CT reconstruction, the authors establish an explicit rank-sparse signal model to describe the spectral and temporal dimensions. The spectral dimension is represented as a well-sampled time and energy averaged image plus regularly undersampled principal components describing the spectral contrast. The temporal dimension is represented as the same time and energy averaged reconstruction plus contiguous, spatially sparse, and irregularly sampled temporal contrast images. Using a nonlinear, image domain filtration approach, the authors refer to as rank-sparse kernel regression, the authors transfer image structure from the well-sampled time and energy averaged reconstruction to the spectral and temporal contrast images. This regularization strategy strictly constrains the reconstruction problem while approximately separating the temporal and spectral dimensions. Separability results in a highly compressed representation for the 5D data in which projections are shared between the temporal and spectral reconstruction subproblems, enabling substantial undersampling. The authors solved the 5D reconstruction problem using the split Bregman method and GPU-based implementations of backprojection, reprojection, and kernel regression. Using a preclinical mouse model, the authors apply the proposed algorithm to study myocardial injury following radiation treatment of breast cancer. RESULTS: Quantitative 5D simulations are performed using the MOBY mouse phantom. Twenty data sets (ten cardiac phases, two energies) are reconstructed with 88 µm, isotropic voxels from 450 total projections acquired over a single 360° rotation. In vivo 5D myocardial injury data sets acquired in two mice injected with gold and iodine nanoparticles are also reconstructed with 20 data sets per mouse using the same acquisition parameters (dose: ∼60 mGy). For both the simulations and the in vivo data, the reconstruction quality is sufficient to perform material decomposition into gold and iodine maps to localize the extent of myocardial injury (gold accumulation) and to measure cardiac functional metrics (vascular iodine). Their 5D CT imaging protocol represents a 95% reduction in radiation dose per cardiac phase and energy and a 40-fold decrease in projection sampling time relative to their standard imaging protocol. CONCLUSIONS: Their 5D CT data acquisition and reconstruction protocol efficiently exploits the rank-sparse nature of spectral and temporal CT data to provide high-fidelity reconstruction results without increased radiation dose or sampling time.

Spectral diffusion: an algorithm for robust material decomposition of spectral CT data.

Clinical successes with dual energy CT, aggressive development of energy discriminating x-ray detectors, and novel, target-specific, nanoparticle contrast agents promise to establish spectral CT as a powerful functional imaging modality. Common to all of these applications is the need for a material decomposition algorithm which is robust in the presence of noise. Here, we develop such an algorithm which uses spectrally joint, piecewise constant kernel regression and the split Bregman method to iteratively solve for a material decomposition which is gradient sparse, quantitatively accurate, and minimally biased. We call this algorithm spectral diffusion because it integrates structural information from multiple spectral channels and their corresponding material decompositions within the framework of diffusion-like denoising algorithms (e.g. anisotropic diffusion, total variation, bilateral filtration). Using a 3D, digital bar phantom and a material sensitivity matrix calibrated for use with a polychromatic x-ray source, we quantify the limits of detectability (CNR = 5) afforded by spectral diffusion in the triple-energy material decomposition of iodine (3.1 mg mL(-1)), gold (0.9 mg mL(-1)), and gadolinium (2.9 mg mL(-1)) concentrations. We then apply spectral diffusion to the in vivo separation of these three materials in the mouse kidneys, liver, and spleen.

Dual-energy micro-CT functional imaging of primary lung cancer in mice using gold and iodine nanoparticle contrast agents: a validation study.

PURPOSE: To provide additional functional information for tumor characterization, we investigated the use of dual-energy computed tomography for imaging murine lung tumors. Tumor blood volume and vascular permeability were quantified using gold and iodine nanoparticles. This approach was compared with a single contrast agent/single-energy CT method. Ex vivo validation studies were performed to demonstrate the accuracy of in vivo contrast agent quantification by CT. METHODS: Primary lung tumors were generated in LSL-Kras(G12D); p53(FL/FL) mice. Gold nanoparticles were injected, followed by iodine nanoparticles two days later. The gold accumulated in tumors, while the iodine provided intravascular contrast. Three dual-energy CT scans were performed-two for the single contrast agent method and one for the dual contrast agent method. Gold and iodine concentrations in each scan were calculated using a dual-energy decomposition. For each method, the tumor fractional blood volume was calculated based on iodine concentration, and tumor vascular permeability was estimated based on accumulated gold concentration. For validation, the CT-derived measurements were compared with histology and inductively-coupled plasma optical emission spectroscopy measurements of gold concentrations in tissues. RESULTS: Dual-energy CT enabled in vivo separation of gold and iodine contrast agents and showed uptake of gold nanoparticles in the spleen, liver, and tumors. The tumor fractional blood volume measurements determined from the two imaging methods were in agreement, and a high correlation (R(2) = 0.81) was found between measured fractional blood volume and histology-derived microvascular density. Vascular permeability measurements obtained from the two imaging methods agreed well with ex vivo measurements. CONCLUSIONS: Dual-energy CT using two types of nanoparticles is equivalent to the single nanoparticle method, but allows for measurement of fractional blood volume and permeability with a single scan. As confirmed by ex vivo methods, CT-derived nanoparticle concentrations are accurate. This method could play an important role in lung tumor characterization by CT.

In vivo characterization of tumor vasculature using iodine and gold nanoparticles and dual energy micro-CT.

Tumor blood volume and vascular permeability are well established indicators of tumor angiogenesis and important predictors in cancer diagnosis, planning and treatment. In this work, we establish a novel preclinical imaging protocol which allows quantitative measurement of both metrics simultaneously. First, gold nanoparticles are injected and allowed to extravasate into the tumor, and then liposomal iodine nanoparticles are injected. Combining a previously optimized dual energy micro-CT scan using high-flux polychromatic x-ray sources (energies: 40 kVp, 80 kVp) with a novel post-reconstruction spectral filtration scheme, we are able to decompose the results into 3D iodine and gold maps, allowing simultaneous measurement of extravasated gold and intravascular iodine concentrations. Using a digital resolution phantom, the mean limits of detectability (mean CNR = 5) for each element are determined to be 2.3 mg mL(-1) (18 mM) for iodine and 1.0 mg mL(-1) (5.1 mM) for gold, well within the observed in vivo concentrations of each element (I: 0-24 mg mL(-1), Au: 0-9 mg mL(-1)) and a factor of 10 improvement over the limits without post-reconstruction spectral filtration. Using a calibration phantom, these limits are validated and an optimal sensitivity matrix for performing decomposition using our micro-CT system is derived. Finally, using a primary mouse model of soft-tissue sarcoma, we demonstrate the in vivo application of the protocol to measure fractional blood volume and vascular permeability over the course of five days of active tumor growth.