Speckle variance optical coherence tomography of blood flow in the beating mouse embryonic heart

Efficient separation of blood and cardiac wall in the beating embryonic heart is essential and critical for experiment‐based computational modelling and analysis of early‐stage cardiac biomechanics. Although speckle variance optical coherence tomography (SV‐OCT) relying on calculation of intensity variance over consecutively acquired frames is a powerful approach for segmentation of fluid flow from static tissue, application of this method in the beating embryonic heart remains challenging because moving structures generate SV signal indistinguishable from the blood. Here, we demonstrate a modified four‐dimensional SV‐OCT approach that effectively separates the blood flow from the dynamic heart wall in the beating mouse embryonic heart. The method takes advantage of the periodic motion of the cardiac wall and is based on calculation of the SV signal over the frames corresponding to the same phase of the heartbeat cycle. Through comparison with Doppler OCT imaging, we validate this speckle‐based approach and show advantages in its insensitiveness to the flow direction and velocity as well as reduced influence from the heart wall movement. This approach has a potential in variety of applications relying on visualization and segmentation of blood flow in periodically moving structures, such as mechanical simulation studies and finite element modelling. Picture : Four‐dimensional speckle variance OCT imaging shows the blood flow inside the beating heart of an E8.5 mouse embryo.     

Evidence for the existence of a functional helical myocardial band

Characterization of local and global contractile activities in the myocardium is essential for a better understanding of cardiac form and function. The spatial distribution of regions that contribute the most to cardiac function plays an important role in defining the pumping parameters of the myocardium like ejection fraction and dynamic aspects such as twisting and untwisting. In general, myocardium shortening, tangent to the wall, and ventricular wall thickening are important parameters that characterize the regional contribution within the myocardium to the global function of the heart. We have calculated these parameters using myocardium displacement fields, which were captured through the displacement-encoding with stimulated echoes (DENSE) MRI technique in three volunteers. High spatial resolution of the acquired data revealed transmural changes of thickening and tangential shortening with high fidelity in beating hearts. By filtering myocardium regions that showed a tangential shortening index of <0.23, we were able to identify the complete or a portion of a macrostructure composed of connected regions in the form of a helical bundle within the left ventricle mass. In this study, we present a representative case that shows the complete morphology of a helical myocardial band as well as two other cases that present ascending and descending portions of the helical myocardial band. Our observation of a helical functional band based on dynamics is in agreement with diffusion tensor MRI observations and gross dissection studies in the arrested heart.     

Whole Heart Coronary Imaging with Flexible Acquisition Window and Trigger Delay

Coronary magnetic resonance imaging (MRI) requires a correctly timed trigger delay derived from a scout cine scan to synchronize k-space acquisition with the quiescent period of the cardiac cycle. However, heart rate changes between breath-held cine and free-breathing coronary imaging may result in inaccurate timing errors. Additionally, the determined trigger delay may not reflect the period of minimal motion for both left and right coronary arteries or different segments. In this work, we present a whole-heart coronary imaging approach that allows flexible selection of the trigger delay timings by performing k-space sampling over an enlarged acquisition window. Our approach addresses coronary motion in an interactive manner by allowing the operator to determine the temporal window with minimal cardiac motion for each artery region. An electrocardiogram-gated, k-space segmented 3D radial stack-of-stars sequence that employs a custom rotation angle is developed. An interactive reconstruction and visualization platform is then employed to determine the subset of the enlarged acquisition window for minimal coronary motion. Coronary MRI was acquired on eight healthy subjects (5 male, mean age = 37 ± 18 years), where an enlarged acquisition window of 166–220 ms was set 50 ms prior to the scout-derived trigger delay. Coronary visualization and sharpness scores were compared between the standard 120 ms window set at the trigger delay, and those reconstructed using a manually adjusted window. The proposed method using manual adjustment was able to recover delineation of five mid and distal right coronary artery regions that were otherwise not visible from the standard window, and the sharpness scores improved in all coronary regions using the proposed method. This paper demonstrates the feasibility of a whole-heart coronary imaging approach that allows interactive selection of any subset of the enlarged acquisition window for a tailored reconstruction for each branch region.     

CFD simulation of flow through heart: a perspective review

The heart is an organ which pumps blood around the body by contraction of muscular wall. There is a coupled system in the heart containing the motion of wall and the motion of blood fluid; both motions must be computed simultaneously, which make biological computational fluid dynamics (CFD) difficult. The wall of the heart is not rigid and hence proper boundary conditions are essential for CFD modelling. Fluid-wall interaction is very important for real CFD modelling. There are many assumptions for CFD simulation of the heart that make it far from a real model. A realistic fluid-structure interaction modelling the structure by the finite element method and the fluid flow by CFD use more realistic coupling algorithms. This type of method is very powerful to solve the complex properties of the cardiac structure and the sensitive interaction of fluid and structure. The final goal of heart modelling is to simulate the total heart function by integrating cardiac anatomy, electrical activation, mechanics, metabolism and fluid mechanics together, as in the computational framework.     

A real-time predictive simulation of abdominal viscera positions during quiet free breathing

Prediction of abdominal viscera and tumour positions during free breathing is a major challenge from which several medical applications could benefit. For instance, in radiotherapy it would reduce the healthy tissue irradiation. In this paper, we present a new approach to predict real-time abdominal viscera positions during free breathing. Our method needs an abdo-thoracic 3D preoperative CT or MR image, a second one limited to the diaphragmatic area, and a tracking of the patient's skin position. First, a physical analysis of the breathing motion shows it is possible to predict accurately abdominal viscera positions from the skin position and a modelling of the diaphragm motion. Secondly, a quantitative analysis of the skin and organ motion allows us to define the demands our real-time simulation has to fulfill. Then, we present in detail all the necessary steps of our original method to compute a deformation field from data extracted in both 3D preoperative image and skin surface tracking. Finally, experiments carried out with two human data show that our simulation model predicts abdominal viscera positions, such as liver, kidneys or spleen, at 50 Hz with an accuracy within 2-3 mm.     

Electrical Wave Propagation in an Anisotropic Model of the Left Ventricle Based on Analytical Description of Cardiac Architecture

We develop a numerical approach based on our recent analytical model of fiber structure in the left ventricle of the human heart. A special curvilinear coordinate system is proposed to analytically include realistic ventricular shape and myofiber directions. With this anatomical model, electrophysiological simulations can be performed on a rectangular coordinate grid. We apply our method to study the effect of fiber rotation and electrical anisotropy of cardiac tissue (i.e., the ratio of the conductivity coefficients along and across the myocardial fibers) on wave propagation using the ten Tusscher–Panfilov (2006) ionic model for human ventricular cells. We show that fiber rotation increases the speed of cardiac activation and attenuates the effects of anisotropy. Our results show that the fiber rotation in the heart is an important factor underlying cardiac excitation. We also study scroll wave dynamics in our model and show the drift of a scroll wave filament whose velocity depends non-monotonically on the fiber rotation angle; the period of scroll wave rotation decreases with an increase of the fiber rotation angle; an increase in anisotropy may cause the breakup of a scroll wave, similar to the mother rotor mechanism of ventricular fibrillation.     

Incremental window-based protein sequence alignment algorithms

MOTIVATION: Protein sequence alignment plays a critical role in computational biology as it is an integral part in many analysis tasks designed to solve problems in comparative genomics, structure and function prediction, and homology modeling. METHODS: We have developed novel sequence alignment algorithms that compute the alignment between a pair of sequences based on short fixed- or variable-length high-scoring subsequences. Our algorithms build the alignments by repeatedly selecting the highest scoring pairs of subsequences and using them to construct small portions of the final alignment. We utilize PSI-BLAST generated sequence profiles and employ a profile-to-profile scoring scheme derived from PICASSO. RESULTS: We evaluated the performance of the computed alignments on two recently published benchmark datasets and compared them against the alignments computed by existing state-of-the-art dynamic programming-based profile-to-profile local and global sequence alignment algorithms. Our results show that the new algorithms achieve alignments that are comparable with or better than those achieved by existing algorithms. Moreover, our results also showed that these algorithms can be used to provide better information as to which of the aligned positions are more reliable--a critical piece of information for comparative modeling applications.     

Representation of planar motion of complex joints by means of rolling pairs. Application to neck motion

We propose to model planar movements between two human segments by means of rolling-without-slipping kinematic pairs. We compute the path traced by the instantaneous center of rotation (ICR) as seen from the proximal and distal segments, thus obtaining the fixed and moving centrodes, respectively. The joint motion is then represented by the rolling-without-slipping of one centrode on the other. The resulting joint kinematic model is based on the real movement and accounts for nonfixed axes of rotation; therefore it could improve current models based on revolute pairs in those cases where joint movement implies displacement of the ICR. Previous authors have used the ICR to characterize human joint motion, but they only considered the fixed centrode. Such an approach is not adequate for reproducing motion because the fixed centrode by itself does not convey information about body position. The combination of the fixed and moving centrodes gathers the kinematic information needed to reproduce the position and velocities of moving bodies. To illustrate our method, we applied it to the flexion-extension movement of the head relative to the thorax. The model provides a good estimation of motion both for position variables (mean R(pos)=0.995) and for velocities (mean R(vel)=0.958). This approach is more realistic than other models of neck motion based on revolute pairs, such as the dual-pivot model. The geometry of the centrodes can provide some information about the nature of the movement. For instance, the ascending and descending curves of the fixed centrode suggest a sequential movement of the cervical vertebrae.     

Unconscious Local Motion Alters Global Image Speed

Accurate motion perception of self and object speed is crucial for successful interaction in the world. The context in which we make such speed judgments has a profound effect on their accuracy. Misperceptions of motion speed caused by the context can have drastic consequences in real world situations, but they also reveal much about the underlying mechanisms of motion perception. Here we show that motion signals suppressed from awareness can warp simultaneous conscious speed perception. In Experiment 1, we measured global speed discrimination thresholds using an annulus of 8 local Gabor elements. We show that physically removing local elements from the array attenuated global speed discrimination. However, removing awareness of the local elements only had a small effect on speed discrimination. That is, unconscious local motion elements contributed to global conscious speed perception. In Experiment 2 we measured the global speed of the moving Gabor patterns, when half the elements moved at different speeds. We show that global speed averaging occurred regardless of whether local elements were removed from awareness, such that the speed of invisible elements continued to be averaged together with the visible elements to determine the global speed. These data suggest that contextual motion signals outside of awareness can both boost and affect our experience of motion speed, and suggest that such pooling of motion signals occurs before the conscious extraction of the surround motion speed.     

Protein flexibility and rigidity predicted from sequence

Structural flexibility has been associated with various biological processes such as molecular recognition and catalytic activity. In silico studies of protein flexibility have attempted to characterize and predict flexible regions based on simple principles. B-values derived from experimental data are widely used to measure residue flexibility. Here, we present the most comprehensive large-scale analysis of B-values. We used this analysis to develop a neural network-based method that predicts flexible-rigid residues from amino acid sequence. The system uses both global and local information (i.e., features from the entire protein such as secondary structure composition, protein length, and fraction of surface residues, and features from a local window of sequence-consecutive residues). The most important local feature was the evolutionary exchange profile reflecting sequence conservation in a family of related proteins. To illustrate its potential, we applied our method to 4 different case studies, each of which related our predictions to aspects of function. The first 2 were the prediction of regions that undergo conformational switches upon environmental changes (switch II region in Ras) and the prediction of surface regions, the rigidity of which is crucial for their function (tunnel in propeller folds). Both were correctly captured by our method. The third study established that residues in active sites of enzymes are predicted by our method to have unexpectedly low B-values. The final study demonstrated how well our predictions correlated with NMR order parameters to reflect motion. Our method had not been set up to address any of the tasks in those 4 case studies. Therefore, we expect that this method will assist in many attempts at inferring aspects of function.     

OpenSim Moco: Musculoskeletal optimal control

Musculoskeletal simulations are used in many different applications, ranging from the design of wearable robots that interact with humans to the analysis of patients with impaired movement. Here, we introduce OpenSim Moco, a software toolkit for optimizing the motion and control of musculoskeletal models built in the OpenSim modeling and simulation package. OpenSim Moco uses the direct collocation method, which is often faster and can handle more diverse problems than other methods for musculoskeletal simulation. Moco frees researchers from implementing direct collocation themselves—which typically requires extensive technical expertise—and allows them to focus on their scientific questions. The software can handle a wide range of problems that interest biomechanists, including motion tracking, motion prediction, parameter optimization, model fitting, electromyography-driven simulation, and device design. Moco is the first musculoskeletal direct collocation tool to handle kinematic constraints, which enable modeling of kinematic loops (e.g., cycling models) and complex anatomy (e.g., patellar motion). To show the abilities of Moco, we first solved for muscle activity that produced an observed walking motion while minimizing squared muscle excitations and knee joint loading. Next, we predicted how muscle weakness may cause deviations from a normal walking motion. Lastly, we predicted a squat-to-stand motion and optimized the stiffness of an assistive device placed at the knee. We designed Moco to be easy to use, customizable, and extensible, thereby accelerating the use of simulations to understand the movement of humans and other animals.     

Statistical Detection of EEG Synchrony Using Empirical Bayesian Inference

There is growing interest in understanding how the brain utilizes synchronized oscillatory activity to integrate information across functionally connected regions. Computing phase-locking values (PLV) between EEG signals is a popular method for quantifying such synchronizations and elucidating their role in cognitive tasks. However, high-dimensionality in PLV data incurs a serious multiple testing problem. Standard multiple testing methods in neuroimaging research (e.g., false discovery rate, FDR) suffer severe loss of power, because they fail to exploit complex dependence structure between hypotheses that vary in spectral, temporal and spatial dimension. Previously, we showed that a hierarchical FDR and optimal discovery procedures could be effectively applied for PLV analysis to provide better power than FDR. In this article, we revisit the multiple comparison problem from a new Empirical Bayes perspective and propose the application of the local FDR method (locFDR; Efron, 2001) for PLV synchrony analysis to compute FDR as a posterior probability that an observed statistic belongs to a null hypothesis. We demonstrate the application of Efron''s Empirical Bayes approach for PLV synchrony analysis for the first time. We use simulations to validate the specificity and sensitivity of locFDR and a real EEG dataset from a visual search study for experimental validation. We also compare locFDR with hierarchical FDR and optimal discovery procedures in both simulation and experimental analyses. Our simulation results showed that the locFDR can effectively control false positives without compromising on the power of PLV synchrony inference. Our results from the application locFDR on experiment data detected more significant discoveries than our previously proposed methods whereas the standard FDR method failed to detect any significant discoveries.     

Three-dimensional heart motion estimation using endoscopic monocular vision system: From artificial landmarks to texture analysis

In robot-assisted beating heart surgery, motion of the heart surface might be virtually stabilized to let the surgeon work as in on-pump cardiac surgery. Virtual stabilization means to compensate physically the relative motion between the instrument tool tip and the region of interest on the heart surface, and to offer surgeon a stable visual display of the scene. To this end, motion of the heart must be estimated. This article focusses on motion estimation of the heart surface. Two approaches are considered in the paper. The first one is based on landmark tracking allowing 3D pose estimation. The second is based on texture tracking. Classical computer vision methods, as well as a new texture-based tracking scheme has been applied to track the heart motion, and, when possible, reconstruct 3D distance to the heart surface. Experimental results obtained on in vivo images show the estimated motion of heart surface points.     

Consistent dissection of the protein interaction network by combining global and local metrics

We propose a new network decomposition method to systematically identify protein interaction modules in the protein interaction network. Our method incorporates both a global metric and a local metric for balance and consistency. We have compared the performance of our method with several earlier approaches on both simulated and real datasets using different criteria, and show that our method is more robust to network alterations and more effective at discovering functional protein modules.     

On the Mechanics of Cardiac Function of Drosophila Embryo

The heart is a vital organ that provides essential circulation throughout the body. Malfunction of cardiac pumping, thus, leads to serious and most of the times, to fatal diseases. Mechanics of cardiac pumping is a complex process, and many experimental and theoretical approaches have been undertaken to understand this process. We have taken advantage of the simplicity of the embryonic heart of an invertebrate, Drosophila melanogaster, to understand the fundamental mechanics of the beating heart. We applied a live imaging technique to the beating embryonic heart combined with analytical imaging tools to study the dynamic mechanics of the pumping. Furthermore, we have identified one mutant line that exhibits aberrant pumping mechanics. The Drosophila embryonic heart consists of only 104 cardiac cells forming a simple straight tube that can be easily accessed for real-time imaging. Therefore, combined with the wealth of available genetic tools, the embryonic Drosophila heart may serve as a powerful model system for studies of human heart diseases, such as arrhythmia and congenital heart diseases. We, furthermore, believe our mechanistic data provides important information that is useful for our further understanding of the design of biological structure and function and for engineering the pumps for medical uses.     

Using motion planning to study RNA folding kinetics.

We propose a novel, motion planning based approach to approximately map the energy landscape of an RNA molecule. A key feature of our method is that it provides a sparse map that captures the main features of the energy landscape which can be analyzed to compute folding kinetics. Our method is based on probabilistic roadmap motion planners that we have previously successfully applied to protein folding. In this paper, we provide evidence that this approach is also well suited to RNA. We compute population kinetics and transition rates on our roadmaps using the master equation for a few moderately sized RNA and show that our results compare favorably with results of other existing methods.     

Electromechanics of paced left ventricle simulated by straightforward mathematical model: comparison with experiments

Intraventricular synchrony of cardiac activation is important for efficient pump function. Ventricular pacing restores the beating frequency but induces more asynchronous depolarization and more inhomogeneous contraction than in the normal heart. We investigated whether the increased inhomogeneity in the left ventricle can be described by a relatively simple mathematical model of cardiac electromechanics, containing normal mechanical and impulse conduction properties. Simulations of a normal heartbeat and of pacing at the right ventricular apex (RVA) were performed. All properties in the two simulations were equal, except for the depolarization sequence. Simulation results of RVA pacing on local depolarization time and systolic midwall circumferential strain were compared with those measured in dogs, using an epicardial sock electrode and MRI tagging, respectively. We used the same methods for data processing for simulation and experiment. Model and experiment agreed in the following aspects. 1) Ventricular pacing decreased systolic pressure and ejection fraction relative to natural sinus rhythm. 2) Shortening during ejection and stroke work declined in early depolarized regions and increased in late depolarized regions. 3) The relation between epicardial depolarization time and systolic midwall circumferential strain was linear and similar for the simulation (slope = -3.80 +/- 0.28 s(-1), R2 = 0.87) and the experiments [slopes for 3 animals -2.62 +/- 0.43 s(-1) (R2 = 0.59), -2.97 +/- 0.38 s(-1) (R2 = 0.69), and -4.44 +/- 0.51 s(-1) (R2 = 0.76)]. We conclude that our model of electromechanics is suitable to simulate ventricular pacing and that the apparently complex events observed during pacing are caused by well-known basic physiological processes.     

Control of cardiac rhythm by ORK1, a Drosophila two-pore domain potassium channel

Unravelling the mechanisms controlling cardiac automatism is critical to our comprehension of heart development and cardiac physiopathology. Despite the extensive characterization of the ionic currents at work in cardiac pacemakers, the precise mechanisms initiating spontaneous rhythmic activity and, particularly, those responsible for the specific control of the pacemaker frequency are still matters of debate and have not been entirely elucidated. By using Drosophila as a model animal to analyze automatic cardiac activity, we have investigated the function of a K+ channel, ORK1 (outwardly rectifying K+ channel-1) in cardiac automatic activity. ORK1 is a two-pore domain K+ (K2P) channel, which belongs to a diverse and highly regulated superfamily of potassium-selective leak channels thought to provide baseline regulation of membrane excitability. Cardiac-specific inactivation of Ork1 led to an increase in heart rhythm. By contrast, when overexpressed, ORK1 completely prevented heart beating. In addition, by recording action potentials, we showed that the level of Ork1 activity sets the cardiac rhythm by controlling the duration of the slow diastolic depolarization phase. Our observations identify a new mechanism for cardiac rhythm control and provide the first demonstration that K2P channels regulate the automatic cardiac activity.