Diffusion tensor imaging (DTI), high angular resolution diffusion imaging (HARDI), and diffusion spectrum imaging (DSI) have been widely used in the neuroimaging field to examine the macro-scale fiber connection patterns in the cerebral cortex. However, the topographic and geometric relationships between diffusion imaging derived streamline fiber connection patterns and cortical folding patterns remain largely unknown. This paper specifically identifies and characterizes the U-shapes of diffusion imaging derived streamline fibers via a novel fiber clustering framework and examines their co-localization patterns with cortical sulci based on DTI, HARDI, and DSI datasets of human, chimpanzee and macaque brains. We verified the presence of these U-shaped streamline fibers that connect neighboring gyri by coursing around cortical sulci such as the central sulcus, pre-central sulcus, post-central sulcus, superior temporal sulcus, inferior frontal sulcus, and intra-parietal sulcus. This study also verified the existence of U-shape fibers across data modalities (DTI/HARDI/DSI) and primate species (macaque, chimpanzee and human), and suggests that the common pattern of U-shape fibers coursing around sulci is evolutionarily-preserved in cortical architectures.
Functional mitral regurgitation (FMR) is a significant complication of left ventricular dysfunction and strongly associated with a poor prognosis. In this study, we developed a patient-specific finite element (FE) model of the mitral apparatus in a FMR patient which included: both leaflets with thickness, annulus, chordae tendineae, and chordae insertions on the leaflets and origins on the papillary muscles. The FE model incorporated human age- and gender-matched anisotropic hyperelastic material properties, and MV closure at systole was simulated. The model was validated by comparing the FE results from valve closure simulation with the in vivo geometry of the MV at systole. It was found that the FE model could not replicate the in vivo MV geometry without the application of tethering pre-tension force in the chordae at diastole. Upon applying the pre-tension force and performing model optimization by adjusting the chordal length, position, and leaflet length, a good agreement between the FE model and the in vivo model was established. Not only were the chordal forces high at both diastole and systole, but the tethering force on the anterior papillary muscle was higher than that of the posterior papillary muscle, which resulted in an asymmetrical gap with a larger orifice area at the anterolateral commissure resulting in MR. The analyses further show that high peak stress and strain were found at the chordal insertions where large chordal tethering forces were found. This study shows that the pre-tension tethering force plays an important role in accurately simulating the MV dynamics in this FMR patient, particularly in quantifying the degree of leaflet coaptation and stress distribution. Due to the complexity of the disease, the patient-specific computational modeling procedure of FMR patients presented should be further evaluated using a large patient cohort. However, this study provides useful insights into the MV biomechanics of a FMR patient, and could serve as a tool to assist in pre-operative planning for MV repair or replacement surgical or interventional procedures.
The chordal structure is a part of mitral valve geometry that has been commonly neglected or simplified in computational modeling due to its complexity. However, these simplifications cannot be used when investigating the roles of individual chordae tendineae in mitral valve closure. For the first time, advancements in imaging, computational techniques, and hardware technology make it possible to create models of the mitral valve without simplifications to its complex geometry, and to quickly run validated computer simulations that more realistically capture its function. Such simulations can then be used for a detailed analysis of chordae-related diseases. In this work, a comprehensive model of a subject-specific mitral valve with detailed chordal structure is used to analyze the distinct role played by individual chordae in closure of the mitral valve leaflets. Mitral closure was simulated for 51 possible chordal rupture points. Resultant regurgitant orifice area and strain change in the chordae at the papillary muscle tips were then calculated to examine the role of each ruptured chorda in the mitral valve closure. For certain subclassifications of chordae, regurgitant orifice area was found to trend positively with ruptured chordal diameter, and strain changes correlated negatively with regurgitant orifice area. Further advancements in clinical imaging modalities, coupled with the next generation of computational techniques will enable more physiologically realistic simulations.
Computational models of the heart's mitral valve (MV) exhibit potential for preoperative surgical planning in ischemic mitral regurgitation (IMR). However challenges exist in defining boundary conditions to accurately model the function and response of the chordae tendineae to both IMR and surgical annuloplasty repair. Towards this goal, a ground-truth data set was generated by quantifying the isolated effects of IMR and mitral annuloplasty on leaflet coaptation, regurgitation, and tethering forces of the anterior strut and posterior intermediary chordae tendineae. MVs were excised from ovine hearts (N = 15) and mounted in a pulsatile heart simulator which has been demonstrated to mimic the systolic MV geometry and coaptation of healthy and chronic IMR sheep. Strut and intermediary chordae from both MV leaflets (N = 4) were instrumented with force transducers. Tested conditions included a healthy control, IMR, oversized annuloplasty, true-sized annuloplasty, and undersized mitral annuloplasty. A2-P2 leaflet coaptation length, regurgitation, and chordal tethering were quantified and statistically compared across experimental conditions. MR was successfully simulated with significant increases in MR, tethering forces for each of the chordae, and decrease in leaflet coaptation (p < .05). Compared to the IMR condition, increasing levels of downsized annuloplasty significantly reduced regurgitation, increased coaptation, reduced posteromedial papillary muscle strut chordal forces, and reduced intermediary chordal forces from the anterolateral papillary muscle (p < .05). These results provide for the first time a novel comprehensive data set for refining the ability of computational MV models to simulate IMR and varying sizes of complete rigid ring annuloplasty.
We investigated whether local hemodynamics were associated with sites of plaque erosion and hypothesized that patients with plaque erosion have locally elevated WSS magnitude in regions where erosion has occurred. We generated 3D, patient-specific models of coronary arteries from biplane angiographic images in 3 human patients with plaque erosion diagnosed by optical coherence tomography. Using computational fluid dynamics, we simulated pulsatile blood flow and calculated both wall shear stress (WSS) and oscillatory shear index (OSI). We also investigated anatomic features of plaque erosion sites by examining branching and local curvature in X-ray angiograms of barium-perfused autopsy hearts. Neither high nor low magnitudes of mean WSS were associated with sites of plaque erosion. OSI and local curvature were also not associated with erosion. Anatomically, 8 of 13 hearts had a nearby bifurcation upstream of the site of plaque erosion. This study provides preliminary evidence that neither hemodynamics nor anatomy are predictors of plaque erosion, based upon a very unique dataset. Our sample sizes are small, but this dataset suggests that high magnitudes of WSS, one potential mechanism for inducing plaque erosion, are not necessary for erosion to occur.
Over the years, three-dimensional models of the mitral valve have generally been organized around a simplified anatomy. Leaflets have been typically modeled as membranes, tethered to discrete chordae typically modeled as one-dimensional, non-linear cables. Yet, recent, high-resolution medical images have revealed that there is no clear boundary between the chordae and the leaflets. In fact, the mitral valve has been revealed to be more of a webbed structure whose architecture is continuous with the chordae and their extensions into the leaflets. Such detailed images can serve as the basis of anatomically accurate, subject-specific models, wherein the entire valve is modeled with solid elements that more faithfully represent the chordae, the leaflets, and the transition between the two. These models have the potential to enhance our understanding of mitral valve mechanics and to re-examine the role of the mitral valve chordae, which heretofore have been considered to be ‘invisible’ to the fluid and to be of secondary importance to the leaflets. However, these new models also require a rethinking of modeling assumptions. In this study, we examine the conventional practice of loading the leaflets only and not the chordae in order to study the structural response of the mitral valve apparatus. Specifically, we demonstrate that fully resolved 3D models of the mitral valve require a fluid–structure interaction analysis to correctly load the valve even in the case of quasi-static mechanics. While a fluid–structure interaction mode is still more computationally expensive than a structural-only model, we also show that advances in GPU computing have made such models tractable.
Numerical models of the mitral valve have been used to elucidate mitral valve function and mechanics. These models have evolved from simple two-dimensional approximations to complex three-dimensional fully coupled fluid structure interaction models. However, to date these models lack direct one-to-one experimental validation. As computational solvers vary considerably, experimental benchmark data are critically important to ensure model accuracy. In this study, a novel left heart simulator was designed specifically for the validation of numerical mitral valve models. Several distinct experimental techniques were collectively performed to resolve mitral valve geometry and hemodynamics. In particular, micro-computed tomography was used to obtain accurate and high-resolution (39 μm voxel) native valvular anatomy, which included the mitral leaflets, chordae tendinae, and papillary muscles. Three-dimensional echocardiography was used to obtain systolic leaflet geometry. Stereoscopic digital particle image velocimetry provided all three components of fluid velocity through the mitral valve, resolved every 25 ms in the cardiac cycle. A strong central filling jet (V ∼ 0.6 m/s) was observed during peak systole with minimal out-of-plane velocities. In addition, physiologic hemodynamic boundary conditions were defined and all data were synchronously acquired through a central trigger. Finally, the simulator is a precisely controlled environment, in which flow conditions and geometry can be systematically prescribed and resultant valvular function and hemodynamics assessed. Thus, this work represents the first comprehensive database of high fidelity experimental data, critical for extensive validation of mitral valve fluid structure interaction simulations.
by
Tyrone D. Cannon;
Frank Sun;
Sarah Jacobson McEwen;
Xenophon Papademetris;
George He;
Theo G. M. van Erp;
Aron Jacobson;
Carrie E. Bearden;
Elaine Walker;
Xiaoping Hu;
Lei Zhou;
Larry J. Seidman;
Heidi W. Thermenos;
Barbara Cornblatt;
Doreen M. Olvet;
Diana Perkins;
Aysenil Belger;
Kristin Cadenhead;
Ming Tsuang;
Heline Mirzakhanian;
Jean Addington;
Richard Frayne;
Scott W. Woods;
Thomas H. McGlashan;
R. Todd Constable;
Maolin Qiu;
Daniel H. Mathalon;
Paul Thompson;
Arthur W. Toga
Multisite longitudinal neuroimaging designs are used to identify differential brain structural change associated with onset or progression of disease. The reliability of neuroanatomical measurements over time and across sites is a crucial aspect of power in such studies. Prior work has found that while within-site reliabilities of neuroanatomical measurements are excellent, between-site reliability is generally more modest. Factors that may increase between-site reliability include standardization of scanner platform and sequence parameters and correction for between-scanner variations in gradient nonlinearities. Factors that may improve both between- and within-site reliability include use of registration algorithms that account for individual differences in cortical patterning and shape. In this study 8 healthy volunteers were scanned twice on successive days at 8 sites participating in the North American Prodrome Longitudinal Study (NAPLS). All sites employed 3 Tesla scanners and standardized acquisition parameters. Site accounted for 2 to 30% of the total variance in neuroanatomical measurements. However, site-related variations were trivial (<1%) among sites using the same scanner model and 12-channel coil or when correcting for between-scanner differences in gradient nonlinearity and scaling. Adjusting for individual differences in sulcal-gyral geometries yielded measurements with greater reliabilities than those obtained using an automated approach. Neuroimaging can be performed across multiple sites at the same level of reliability as at a single site, achieving within- and between-site reliabilities of 0.95 or greater for gray matter density in the majority of voxels in the prefrontal and temporal cortical surfaces as well as for the volumes of most subcortical structures.
Computational fluid dynamics (CFD) tools have been extensively applied to study the hemodynamics in the total cavopulmonary connection (TCPC) in patients with only a single functioning ventricle. Without the contraction of a sub-pulmonary ventricle, pulsatility of flow through this connection is low and variable across patients, which is usually neglected in most numerical modeling studies. Recent studies suggest that such pulsatility can be non-negligible and can be important in hemodynamic predictions. The goal of this work is to compare the results of an in-house numerical methodology for simulating pulsatile TCPC flow with experimental results. Digital particle image velocimetry (DPIV) was acquired on TCPC in vitro models to evaluate the capability of the CFD tool in predicting pulsatile TCPC flow fields. In vitro hemodynamic measurements were used to compare the numerical prediction of power loss across the connection. The results demonstrated the complexity of the pulsatile TCPC flow fields and the validity of the numerical approach in simulating pulsatile TCPC flow dynamics in both idealized and complex patient specific models.
Pluripotent embryonic stem cells (ESCs) have the unique ability to differentiate into cells from all germ lineages, making them a potentially robust cell source for regenerative medicine therapies, but difficulties in predicting and controlling ESC differentiation currently limit the development of therapies and applications from such cells. A common approach to induce the differentiation of ESCs in vitro is via the formation of multicellular aggregates known as embryoid bodies (EBs), yet cell fate specification within EBs is generally considered an ill-defined and poorly controlled process. Thus, the objective of this study was to use rules-based cellular modeling to provide insight into which processes influence initial cell fate transitions in 3-dimensional microenvironments. Mouse embryonic stem cells (D3 cell line) were differentiated to examine the temporal and spatial patterns associated with loss of pluripotency as measured through Oct4 expression. Global properties of the multicellular aggregates were accurately recapitulated by a physics-based aggregation simulation when compared to experimentally measured physical parameters of EBs. Oct4 expression patterns were analyzed by confocal microscopy over time and compared to simulated trajectories of EB patterns. The simulations demonstrated that loss of Oct4 can be modeled as a binary process, and that associated patterns can be explained by a set of simple rules that combine baseline stochasticity with intercellular communication. Competing influences between Oct4+ and Oct4- neighbors result in the observed patterns of pluripotency loss within EBs, establishing the utility of rules-based modeling for hypothesis generation of underlying ESC differentiation processes. Importantly, the results indicate that the rules dominate the emergence of patterns independent of EB structure, size, or cell division. In combination with strategies to engineer cellular microenvironments, this type of modeling approach is a powerful tool to predict stem cell behavior under a number of culture conditions that emulate characteristics of 3D stem cell niches.