The direct incorporation of perfusion defect information to define ischemia and infarction in a finite element model of the left ventricle.

This paper describes the process in which complex lesion geometries (specified by computer generated perfusion defects) are incorporated in the description of nonlinear finite element (FE) mechanical models used for specifying the motion of the left ventricle (LV) in the 4D extended cardiac torso (XCAT) phantom to simulate gated cardiac image data. An image interrogation process was developed to define the elements in the LV mesh as ischemic or infarcted based upon the values of sampled intensity levels of the perfusion maps. The intensity values were determined for each of the interior integration points of every element of the FE mesh. The average element intensity levels were then determined. The elements with average intensity values below a user-controlled threshold were defined as ischemic or infarcted depending upon the model being defined. For the infarction model cases, the thresholding and interrogation process were repeated in order to define a border zone (BZ) surrounding the infarction. This methodology was evaluated using perfusion maps created by the perfusion cardiac-torso (PCAT) phantom an extension of the 4D XCAT phantom. The PCAT was used to create 3D perfusion maps representing 90% occlusions at four locations (left anterior descending (LAD) segments 6 and 9, left circumflex (LCX) segment 11, right coronary artery (RCA) segment 1) in the coronary tree. The volumes and shapes of the defects defined in the FE mechanical models were compared with perfusion maps produced by the PCAT. The models were incorporated into the XCAT phantom. The ischemia models had reduced stroke volume (SV) by 18-59 ml. and ejection fraction (EF) values by 14-50% points compared to the normal models. The infarction models, had less reductions in SV and EF, 17-54 ml. and 14-45% points, respectively. The volumes of the ischemic/infarcted regions of the models were nearly identical to those volumes obtained from the perfusion images and were highly correlated (R² = 0.99).

Targeted Deletion of Interleukin-6 in a Mouse Model of Chronic Inflammation Demonstrates Opposing Roles in Aging: Benefit and Harm.

Chronic inflammation (CI) in older adults is associated with reduced health span and life span. Interleukin-6 (IL-6) is one CI marker that is strongly associated with adverse health outcomes and mortality in aging. We have previously characterized a mouse model of frailty and chronic inflammatory pathway activation (IL-10tm/tm, IL-10 KO) that demonstrates the upregulation of numerous proinflammatory cytokines, including IL-6. We sought to identify a more specific role for IL-6 within the context of CI and aging and developed a mouse with targeted deletion of both IL-10 and IL-6 (IL-10tm/tm/IL-6tm/tm, DKO). Phenotypic characteristics, cytokine measurements, cardiac myocardial oxygen consumption, physical function, and survival were measured in DKO mice and compared to age- and gender-matched IL-10 KO and wild-type mice. Our findings demonstrate that selective knockdown of IL-6 in a frail mouse with CI resulted in the reversal of some of the CI-associated changes. We observed increased protective mitochondrial-associated lipid metabolites, decreased cardiac oxaloacetic acid, improved myocardial oxidative metabolism, and better short-term functional performance in DKO mice. However, the DKO mice also demonstrated higher mortality. This work shows the pleiotropic effects of IL-6 on aging and frailty.

Comparison of 3D OS-EM and 4D MAP-RBI-EM reconstruction algorithms for cardiac motion abnormality classification using a motion observer.

Using a heart motion observer, we compared the performance of two image reconstruction techniques, a 3D OS-EM algorithm with post Butterworth spatial filtering and a 4D MAP-RBI-EM algorithm. The task was to classify gated myocardial perfusion (GMP) SPECT images of beating hearts with or without regional motion abnormalities. Noise-free simulated GMP SPECT projection data was generated from two 4D NCAT beating heart phantom models, one with normal motion and the other with a 50% motion defect in a pie-shaped wedge region-of-interest (ROI) in the anterior-lateral left ventricular wall. The projection data were scaled to clinical GMP SPECT count level before Poisson noise was simulated to generate 40 noise realizations. The noise-free and noisy projection data were reconstructed using the two reconstruction algorithms, parameters chosen to optimize the tradeoff between image bias and noise. As a motion observer, a 3D motion estimation method previously developed was applied to estimate the radial motion on the ROI from two adjacent gates. The receiver operating characteristic (ROC) curves were computed for radial motion magnitudes corresponding to each reconstruction technique. The area under the ROC curve (AUC) was calculated as an index for classification of regional motion. The reconstructed images with better bias and noise tradeoff were found to offer better classification for hearts with or without regional motion defects. The 3D cardiac motion estimation algorithm, serving as a heart motion observer, was better able to distinguish the abnormal from the normal regional motion in GMP SPECT images obtained from the 4D MAP-RBI-EM algorithm than from the 3D OS-EM algorithm with post Butterworth spatial filtering.

The development and initial evaluation of a realistic simulated SPECT dataset with simultaneous respiratory and cardiac motion for gated myocardial perfusion SPECT.

We developed a realistic simulation dataset for simultaneous respiratory and cardiac (R&C) gated SPECT/CT using the 4D NURBS-based Cardiac-Torso (NCAT) Phantom and Monte Carlo simulation methods, and evaluated it for a sample application study. The 4D NCAT phantom included realistic respiratory motion and beating heart motion based on respiratory gated CT and cardiac tagged MRI data of normal human subjects. To model the respiratory motion, a set of 24 separate 3D NCAT phantoms excluding the heart was generated over a respiratory cycle. The beating heart motion was modeled separately with 48 frames per cardiac cycle for each of the 24 respiratory phases. The resultant set of 24  ×  48 3D NCAT phantoms provides a realistic model of a normal human subject at different phases of combined R&C motions. An almost noise-free SPECT projection dataset for each of the 1152 3D NCAT phantoms was generated using Monte Carlo simulation techniques and the radioactivity uptake distribution of (99m)Tc sestamibi in different organs. By grouping and summing the separate projection datasets, separate or simultaneous R&C gated acquired data with different gating schemes could be simulated. In the initial evaluation, we combined the projection datasets into ungated, 6 respiratory-gates only, 8 cardiac-gates only, and combined 6 respiratory-gates & 8 cardiac-gates projection datasets. Each dataset was reconstructed using 3D OS-EM without and with attenuation correction using the averaged and respiratory-gated attenuation maps, and the resulting reconstructed images were compared. These results were used to demonstrate the effects of R&C motions and the reduction of image artifact due to R&C motions by gating and attenuation corrections. We concluded that the realistic 4D NCAT phantom and Monte Carlo simulated SPECT projection datasets with R&C motions are powerful tools in the study of the effects of R&C motions, as well as in the development of R&C gating schemes and motion correction methods for improved SPECT/CT imaging.

Development of 4D mathematical observer models for the task-based evaluation of gated myocardial perfusion SPECT.

This paper presents two 4D mathematical observer models for the detection of motion defects in 4D gated medical images. Their performance was compared with results from human observers in detecting a regional motion abnormality in simulated 4D gated myocardial perfusion (MP) SPECT images. The first 4D mathematical observer model extends the conventional channelized Hotelling observer (CHO) based on a set of 2D spatial channels and the second is a proposed model that uses a set of 4D space-time channels. Simulated projection data were generated using the 4D NURBS-based cardiac-torso (NCAT) phantom with 16 gates/cardiac cycle. The activity distribution modelled uptake of (99m)Tc MIBI with normal perfusion and a regional wall motion defect. An analytical projector was used in the simulation and the filtered backprojection (FBP) algorithm was used in image reconstruction followed by spatial and temporal low-pass filtering with various cut-off frequencies. Then, we extracted 2D image slices from each time frame and reorganized them into a set of cine images. For the first model, we applied 2D spatial channels to the cine images and generated a set of feature vectors that were stacked for the images from different slices of the heart. The process was repeated for each of the 1,024 noise realizations, and CHO and receiver operating characteristics (ROC) analysis methodologies were applied to the ensemble of the feature vectors to compute areas under the ROC curves (AUCs). For the second model, a set of 4D space-time channels was developed and applied to the sets of cine images to produce space-time feature vectors to which the CHO methodology was applied. The AUC values of the second model showed better agreement (Spearman's rank correlation (SRC) coefficient = 0.8) to human observer results than those from the first model (SRC coefficient = 0.4). The agreement with human observers indicates the proposed 4D mathematical observer model provides a good predictor of the performance of human observers in detecting regional motion defects in 4D gated MP SPECT images. The result supports the use of the observer model in the optimization and evaluation of 4D image reconstruction and compensation methods for improving the detection of motion abnormalities in 4D gated MP SPECT images.

Task-based evaluation of a 4D MAP-RBI-EM image reconstruction method for gated myocardial perfusion SPECT using a human observer study.

We evaluated the performance of a new 4D image reconstruction method for improved 4D gated myocardial perfusion (MP) SPECT using a task-based human observer study. We used a realistic 4D NURBS-based Cardiac-Torso (NCAT) phantom that models cardiac beating motion. Half of the population was normal; the other half had a regional hypokinetic wall motion abnormality. Noise-free and noisy projection data with 16 gates/cardiac cycle were generated using an analytical projector that included the effects of attenuation, collimator-detector response, and scatter (ADS), and were reconstructed using the 3D FBP without and 3D OS-EM with ADS corrections followed by different cut-off frequencies of a 4D linear post-filter. A 4D iterative maximum a posteriori rescaled-block (MAP-RBI)-EM image reconstruction method with ADS corrections was also used to reconstruct the projection data using various values of the weighting factor for its prior. The trade-offs between bias and noise were represented by the normalized mean squared error (NMSE) and averaged normalized standard deviation (NSDav), respectively. They were used to select reasonable ranges of the reconstructed images for use in a human observer study. The observers were trained with the simulated cine images and were instructed to rate their confidence on the absence or presence of a motion defect on a continuous scale. We then applied receiver operating characteristic (ROC) analysis and used the area under the ROC curve (AUC) index. The results showed that significant differences in detection performance among the different NMSE-NSDav combinations were found and the optimal trade-off from optimized reconstruction parameters corresponded to a maximum AUC value. The 4D MAP-RBI-EM with ADS correction, which had the best trade-off among the tested reconstruction methods, also had the highest AUC value, resulting in significantly better human observer detection performance when detecting regional myocardial wall motion abnormality. We concluded that the NMSE-NSDav trade-off was shown to agree with observer performance for the detection task of the regional motion abnormality, and the optimized 4D MAP-RBI-EM method with ADS corrections provides significant improvement compared to 3D FBP and 3D OS-EM with ADS corrections in detecting regional myocardial wall motion abnormali in 4D gated MP SPECT.

A Simulation Study of the Effect of Phase-Shift on Dual Gated Myocardial Perfusion ECT.

We evaluated the effect of relative phase-shift of cardiac and respiratory (C&R) motions in myocardial perfusion (MP) ECT. Previously, we generated a set of realistic 3D XCAT (eXtended CArdiac Torso) phantoms that model simultaneous C&R motions for use in the study of new data acquisition methods and corrective image reconstruction techniques for improved gated MP ECT, including PET and SPECT. The respiratory motion (RM) over a respiration cycle was modeled using 24 equally-spaced time frames while the cardiac beating motion (CBM) over a cardiac cycle was divided into 48 equally-spaced time frames for each of the 24 RM phases. Almost noise-free projection datasets were generated separately from the heart, blood pool, lungs, liver, kidneys, stomach, gall bladder and remaining body at each of the 24 × 48 time points using Monte Carlo simulation techniques that include the effect of collimator detector response, photon attenuation and scatter. To demonstrate the effect of relative phase-shift, a typical 99mTc Sestamibi MP SPECT projection dataset were generated. They were then scaled and combined to model different degrees of relative C&R phase shifting and grouped into 6 respiratory-gates with 8 cardiac-gates. Each projection was reconstructed using a 3D OS-EM without and with attenuation correction using an averaged and phase-mismatched gated attenuation maps. The image artifacts of the reconstructed images were compared by visual inspection of the MP polar maps. The results showed significant changes of artifactual non-uniformity in the polar maps for off-phase of RM compared to those of CBM. The changes in the polar maps also demonstrated the effect of phase shifting accordingly. We conclude that the 4D XCAT phantom dataset with simultaneous C&R motions provides a powerful tool in the study of the effects of C&R motions with relative phase shifts, and development of C&R gating schemes and motion correction methods for improved ECT/CT imaging.

Generation and Evaluation of a Simultaneous Cardiac and Respiratory Gated Rb-82 PET Simulation.

The goal is to generate and evaluate a simulated 4D Rb-82 PET dataset that realistically models simultaneous respiratory and cardiac motions for use to study the effects of the motions and their compensation using various gating schemes. Normal cardiac and respiratory (C&R) motions were simulated separately using the realistic 4D XCAT phantoms. The C&R motion cycles were divided into 24 and 48 equally-spaced time points, respectively. The simultaneous dual motions were modeled by 24 × 48 phantoms with different combinations of C&R motion phases. Almost noise-free projections of the heart, blood pool, lungs, liver, stomach, spleen, and the remaining body were simulated separately using the combined SimSET and GATE Monte Carlo simulation program which is 12 times faster than GATE alone. The projections were scaled and combined to simulate a typical Rb-82 myocardial perfusion (MP) PET patient study. The no gating, 6-frame respiratory gating only, 8-frame cardiac gating only, and simultaneous 6-frame respiratory and 8-frame cardiac gating schemes were applied. Each gated projection dataset was reconstructed using a 2D OS-EM without and with attenuation correction (AC) using an averaged and gated attenuation maps. The reconstructed images were evaluated in terms of artifactual non-uniformity in the MP polar map. Significant artifactual non-uniformity was found in the MP polar map over all gating scheme without AC. With AC, the artifactual decreases in both the anterior and inferior regions were reduced with respiratory gating. Cardiac motion alone did not cause significant artifactual non-uniformity. In addition, the combination of dual gating and AC using the gated attenuation map provided the most uniform MP polar map. We demonstrated the flexibility and utility of the 4D XCAT phantom set with simultaneous C&R motions. It is a powerful tool to study motion effects on MP PET studies and to evaluate C&R gating schemes, AC and quantitative 4D PET image reconstruction methods.

Quantitative study of cardiac motion estimation and abnormality classification in emission computed tomography.

Quantitative description of cardiac motion is desirable to assist in detecting myocardial abnormalities from gated myocardial perfusion (GMP) emission computed tomography (ECT) images. While "optical flow" type of cardiac motion estimation (ME) techniques have been developed in the past, there has been no quantitative evaluation of their performance. Moreover, no investigation has been performed in terms of applying an ME technique to quantify cardiac motion abnormalities. Using the four-dimensional NCAT beating heart phantom with known built-in motion, the current work aimed at addressing the aforementioned two issues. A three-dimensional cardiac ME technique was developed to search for a motion vector field (MVF) that establishes voxel-by-voxel correspondence between two GMP ECT images. The weighted myocardial strain energy served as the constraint in the process to minimize the difference between one intensity image and the MVF warped other. We studied the convergence of the ME technique using different initial estimates and cost functions. The dependence of estimated MVF on the initialization was attributed to the tangential motion that is undetectable while not suppressed by the strain energy constraint. We optimized the strain energy constraint weighting using noise-free phantom images and noisy reconstructed images, the former against the known MVF and the later in the task of regional motion classification. While the results from the above two studies well coincide with each other, we also demonstrated that upon appropriate optimization the ME method has the capability of serving as a computer motion observer in separating simulated noisy reconstructed GMP SPECT images corresponding to hearts with and without regional motion abnormalities.

The Evaluation of Corrective Reconstruction Method For Reduced Acquisition Time and Various Anatomies of Perfusion Defect Using Channelized Hotelling Observer for Myocardial Perfusion SPECT.

We evaluated the effect of conventional and corrective image reconstruction methods on reduced acquisition time for detecting a myocardial perfusion (MP) defect in MP SPECT using the Channelized Hotelling Observer (CHO). Using the 4D Extended Cardiac-Torso (XCAT) phantom, we simulated realistic transmural and endocardial MP defects in various location and size. Realistic Tc-99m Sestamibi MP projection data were generated using an analytical projector that included the effects of attenuation (A), collimator-detector response (D) and scatter (S) for various count levels simulating different acquisition times. They were reconstructed using the 3D FBP without correction and a 3D OS-EM method with ADS correction followed by a smoothing filter with various cut-off frequencies. The CHO followed by receiver operating characteristics (ROC) methodology was applied to the reconstructed images to evaluate the detectability of a MP defect in each method for different defect anatomies and count levels. Areas under the ROC curve (AUC) were computed to assess the changes in the MP defect detection. The results showed that the 3D OS-EM with ADS corrections showed significantly less changes in AUC value and gave overall higher AUC values than FBP at all cut-off frequencies of the post smoothing filter, count levels and MP defect sizes. The difference in AUC increased towards less smoothed images where the 3D OS-EM with correction was able to provide similar AUC values with 20 - 40% reduction in acquisition time compared to FBP. The AUC values for smaller MP defects were lower for both reconstruction methods with smaller differences. We concluded that the 3D OS-EM with ADS corrections provides higher performance in the MP defect detection task. It allows increased reduction of acquisition time without loss of MP defect detection in MP SPECT compared to the conventional FBP method especially towards less smoothed images.

Realistic Simulation of Regional Myocardial Perfusion Defects for Cardiac SPECT Studies.

The current 3D XCAT phantom allows users to manually define the regional myocardial perfusion defect (MPD) as a simple pie-shaped wedge region with reduced activity level in the myocardium of left ventricle. To more accurately and realistically model the MPD, we have developed a new regional MPD model for the 3D XCAT phantom for myocardial perfusion SPECT (MP-SPECT) studies based on the location and the severity of the stenosis in a computer generated coronary arterial tree. First, we generated a detailed coronary arterial tree by extending the large proximal branches segmented from patient CT images to cover the whole heart using an iterative rule-based algorithm. Second, we determined the affected downstream vascular segments of a given stenosis. Third, we computed the activity of each myocardial region as a function of the inverse-distance-weighted average of the flow of the neighboring vascular segments. Fourth, we generated a series of bull's-eye maps of MP-SPECT images of different coronary artery stenosis scenarios. Fifth, we had expert physician readers to qualitatively assess the bull's-eye maps based on their similarity to typical clinical cases in terms of the shape, the extent, and the severity of the MPDs. Their input was used to iteratively revise the coronary artery tree model so that the MPDs were closely matched to those found in bull's-eye maps from patient studies. Finally, from our simulated MP-SPECT images, we observed that (1) the locations of the MPDs caused by stenoses at different main arteries were different largely according to their vascular territories, (2) a stenosis at a proximal branch produced a larger MPD than the one at a distal branch, and (3) a more severe stenosis produced a larger MPD than the less severe one. These observations were consistent to those found in clinical cases. Therefore, this new regional MPD model has enhanced the generation of realistic pathological MP-SPECT images using the XCAT phantom. When combining with the mechanical model of the myocardium, the new model can be extended for the simulation of 4D gated MP-SPECT simulation of a pathological heart with both perfusion and motion defects.