SCIENTIFIC COMPUTING AND IMAGING INSTITUTE
at the University of Utah

Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in adult cardiology.1,2 Several studies have demonstrated that AF is associated with electrical, contractile, and structural remodeling (SRM) in the left atrium (LA) that contributes to the persistence and sustainability of the arrhythmia.3-7 It has also been shown that the end result of this remodeling process is loss of atrial myocytes and increased collagen content and hence fibrosis of the LA wall.5 Delayed enhancement MRI (DE-MRI) using gadolinium contrast has been demonstrated to localize and quantify the degree of SRM or fibrosis associated with AF in the LA.8

DE-MRI has also been shown to be useful in localizing and quantifying scar formation in the LA following radiofrequency ablation (RFA).9,10 The pulmonary vein (PV) antral region can be visualized to assess circumferential PV scarring that results from RFA lesions/ablation. In addition, the amount of scarring to the LA after catheter ablation can be quantified as a proportion of the total left atrial volume.

Rhythm control of AF using catheter ablation has yielded varying results in different patient populations.11 Identifying the ideal candidate for catheter ablation remains a significant challenge. In addition, a number of different approaches to catheter ablation have been reported and most experts agree that 1 ablation strategy does not fit allAF patients.11-15 Therefore, selecting the proper strategy for a particular patient is also an important determinant of procedure success.

We used DE-MRI to quantify both the degree of SRM/fibrosis pre-ablation and scar formation post ablation. Our aim was to identify predictors of successful ablation in a group of patients stratified according to pre-ablation fibrosis. This would help select the most appropriate ablation strategy for the individual AF ablation candidate.

We present a sensitivity analysis of the optimization of the probe placement in radiofrequency (RF) ablation which takes the uncertainty associated with bio-physical tissue properties (electrical and thermal conductivity) into account. Our forward simulation of RF ablation is based upon a system of partial differential equations (PDEs) that describe the electric potential of the probe and the steady state of the induced heat. The probe placement is optimized by minimizing a temperature-based objective function such that the volume of destroyed tumor tissue is maximized. The resulting optimality system is solved with a multi-level gradient descent approach. By evaluating the corresponding optimality system for certain realizations of tissue parameters (i.e. at certain, well-chosen points in the stochastic space) the sensitivity of the system can be analyzed with respect to variations in the tissue parameters. For the interpolation in the stochastic space we use a stochastic finite element approach with piecewise multilinear ansatz functions on adaptively refined, hierarchical grids. We underscore the significance of the approach by applying the optimization to CT data obtained from a real RF ablation case.

Keywords: netl, stochastic sensitivity analysis, stochastic partial dierential equations, stochastic nite element method, adaptive sparse grid, heat transfer, multiscale modeling, representation of uncertainty

Purpose: A connectome is a comprehensive description of synaptic connectivity for a neural domain. Our goal was to produce a connectome data set for the inner plexiform layer of the mammalian retina. This paper describes our first retinal connectome, validates the method, and provides key initial findings.

Methods: We acquired and assembled a 16.5 terabyte connectome data set RC1 for the rabbit retina at .2 nm resolution using automated transmission electron microscope imaging, automated mosaicking, and automated volume registration. RC1 represents a column of tissue 0.25 mm in diameter, spanning the inner nuclear, inner plexiform, and ganglion cell layers. To enhance ultrastructural tracing, we included molecular markers for 4-aminobutyrate (GABA), glutamate, glycine, taurine, glutamine, and the in vivo activity marker, 1-amino-4-guanidobutane. This enabled us to distinguish GABAergic and glycinergic amacrine cells; to identify ON bipolar cells coupled to glycinergic cells; and to discriminate different kinds of bipolar, amacrine, and ganglion cells based on their molecular signatures and activity. The data set was explored and annotated with Viking, our multiuser navigation tool. Annotations were exported to additional applications to render cells, visualize network graphs, and query the database.

Results: Exploration of RC1 showed that the 2 nm resolution readily recapitulated well known connections and revealed several new features of retinal organization: (1) The well known AII amacrine cell pathway displayed more complexity than previously reported, with no less than 17 distinct signaling modes, including ribbon synapse inputs from OFF bipolar cells, wide-field ON cone bipolar cells and rod bipolar cells, and extensive input from cone-pathway amacrine cells. (2) The axons of most cone bipolar cells formed a distinct signal integration compartment, with ON cone bipolar cell axonal synapses targeting diverse cell types. Both ON and OFF bipolar cells receive axonal veto synapses. (3) Chains of conventional synapses were very common, with intercalated glycinergic-GABAergic chains and very long chains associated with starburst amacrine cells. Glycinergic amacrine cells clearly play a major role in ON-OFF crossover inhibition. (4) Molecular and excitation mapping clearly segregates ultrastructurally defined bipolar cell groups into different response clusters. (5) Finally, low-resolution electron or optical imaging cannot reliably map synaptic connections by process geometry, as adjacency without synaptic contact is abundant in the retina. Only direct visualization of synapses and gap junctions suffices.

Conclusions: Connectome assembly and analysis using conventional transmission electron microscopy is now practical for network discovery. Our surveys of volume RC1 demonstrate that previously studied systems such as the AII amacrine cell network involve more network motifs than previously known. The AII network, primarily considered a scotopic pathway, clearly derives ribbon synapse input from photopic ON and OFF cone bipolar cell networks and extensive photopic GABAergic amacrine cell inputs. Further, bipolar cells show extensive inputs and outputs along their axons, similar to multistratified nonmammalian bipolar cells. Physiologic evidence of significant ON-OFF channel crossover is strongly supported by our anatomic data, showing alternating glycine-to-GABA paths. Long chains of amacrine cell networks likely arise from homocellular GABAergic synapses between starburst amacrine cells. Deeper analysis of RC1 offers the opportunity for more complete descriptions of specific networks.

Keywords: neuroscience, retina, vision, blindness, visus, crcns

Effectively evaluating visualization techniques is a difficult task often assessed through feedback from user studies and expert evaluations. This work presents an alternative approach to visualization evaluation in which brain activity is passively recorded using electroencephalography (EEG). These measurements are used to compare different visualization techniques in terms of the burden they place on a viewer's cognitive resources. In this paper, EEG signals and response times are recorded while users interpret different representations of data distributions. This information is processed to provide insight into the cognitive load imposed on the viewer. This paper describes the design of the user study performed, the extraction of cognitive load measures from EEG data, and how those measures are used to quantitatively evaluate the effectiveness of visualizations.

Most visualizations produced in academia or industry have a specific niche audience that is well versed in either the often complicated visualization methods or the scientific domain of the data. Sometimes it is useful to produce visualizations that can communicate results to a broad audience that will not have the domain specific knowledge often needed to understand the results. In this work, we present our experiences in disseminating the results of two studies to national audience. The resulting visualizations and press releases allowed the studies’ researchers to educate a national, if not global, audience.

Group differences in resting state functional magnetic resonance imaging connectivity between individuals with autism and typically developing controls have been widely replicated for a small number of discrete brain regions, yet the whole-brain distribution of connectivity abnormalities in autism is not well characterized. It is also unclear whether functional connectivity is sufficiently robust to be used as a diagnostic or prognostic metric in individual patients with autism. We obtained pairwise functional connectivity measurements from a lattice of 7266 regions of interest covering the entire grey matter (26.4 million connections) in a well-characterized set of 40 male adolescents and young adults with autism and 40 age-, sex- and IQ-matched typically developing subjects. A single resting state blood oxygen level-dependent scan of 8 min was used for the classification in each subject. A leave-one-out classifier successfully distinguished autism from control subjects with 83% sensitivity and 75\% specificity for a total accuracy of 79\% (P = 1.1 x 10^-7). In subjects less than 20 years of age, the classifier performed at 89\% accuracy (P = 5.4 x 10^-7). In a replication dataset consisting of 21 individuals from six families with both affected and unaffected siblings, the classifier performed at 71\% accuracy (91\% accuracy for subjects less than 20 years of age). Classification scores in subjects with autism were significantly correlated with the Social Responsiveness Scale (P = 0.05), verbal IQ (P = 0.02) and the Autism Diagnostic Observation Schedule-Generic's combined social and communication subscores (P = 0.05). An analysis of informative connections demonstrated that region of interest pairs with strongest correlation values were most abnormal in autism. Negatively correlated region of interest pairs showed higher correlation in autism (less anticorrelation), possibly representing weaker inhibitory connections, particularly for long connections (Euclidean distance greater than 10 cm). Brain regions showing greatest differences included regions of the default mode network, superior parietal lobule, fusiform gyrus and anterior insula. Overall, classification accuracy was better for younger subjects, with differences between autism and control subjects diminishing after 19 years of age. Classification scores of unaffected siblings of individuals with autism were more similar to those of the control subjects than to those of the subjects with autism. These findings indicate feasibility of a functional connectivity magnetic resonance imaging diagnostic assay for autism.

Modern microscope automation permits the collection of vast amounts of continuous anatomical imagery in both two and three dimensions. These large data sets present significant challenges for data storage, access, viewing, annotation and analysis. The cost and overhead of collecting and storing the data can be extremely high. Large data sets quickly exceed an individual's capability for timely analysis and present challenges in efficiently applying transforms, if needed. Finally annotated anatomical data sets can represent a significant investment of resources and should be easily accessible to the scientific community. The Viking application was our solution created to view and annotate a 16.5 TB ultrastructural retinal connectome volume and we demonstrate its utility in reconstructing neural networks for a distinctive retinal amacrine cell class. Viking has several key features. (1) It works over the internet using HTTP and supports many concurrent users limited only by hardware. (2) It supports a multi-user, collaborative annotation strategy. (3) It cleanly demarcates viewing and analysis from data collection and hosting. (4) It is capable of applying transformations in real-time. (5) It has an easily extensible user interface, allowing addition of specialized modules without rewriting the viewer.

Keywords: Annotation, automated electron microscopy, citizen science, computational methods, connectome, networks, visualization

Biological soft tissues and cells may be subjected to mechanical as well as chemical (osmotic) loading under their natural physiological environment or various experimental conditions. The interaction of mechanical and chemical effects may be very significant under some of these conditions, yet the highly nonlinear nature of the set of governing equations describing these mechanisms poses a challenge for the modeling of such phenomena. This study formulated and implemented a finite element algorithm for analyzing mechanochemical events in neutral deformable porous media under finite deformation. The algorithm employed the framework of mixture theory to model the porous permeable solid matrix and interstitial fluid, where the fluid consists of a mixture of solvent and solute. A special emphasis was placed on solute-solid matrix interactions, such as solute exclusion from a fraction of the matrix pore space (solubility) and frictional momentum exchange that produces solute hindrance and pumping under certain dynamic loading conditions. The finite element formulation implemented full coupling of mechanical and chemical effects, providing a framework where material properties and response functions may depend on solid matrix strain as well as solute concentration. The implementation was validated using selected canonical problems for which analytical or alternative numerical solutions exist. This finite element code includes a number of unique features that enhance the modeling of mechanochemical phenomena in biological tissues. The code is available in the public domain, open source finite element program FEBio (http://mrl.sci.utah.edu/software). [DOI: 10.1115/1.4004810]

Understanding fluid flow is a difficult problem and of increasing importance as computational fluid dynamics (CFD) produces an abundance of simulation data. Experimental flow analysis has employed techniques such as shadowgraph, interferometry, and schlieren imaging for centuries, which allow empirical observation of inhomogeneous flows. Shadowgraphs provide an intuitive way of looking at small changes in flow dynamics through caustic effects while schlieren cutoffs introduce an intensity gradation for observing large scale directional changes in the flow. Interferometry tracks changes in phase-shift resulting in bands appearing. The combination of these shading effects provides an informative global analysis of overall fluid flow. Computational solutions for these methods have proven too complex until recently due to the fundamental physical interaction of light refracting through the flow field. In this paper, we introduce a novel method to simulate the refraction of light to generate synthetic shadowgraph, schlieren and interferometry images of time-varying scalar fields derived from computational fluid dynamics data. Our method computes physically accurate schlieren and shadowgraph images at interactive rates by utilizing a combination of GPGPU programming, acceleration methods, and data-dependent probabilistic schlieren cutoffs. Applications of our method to multifield data and custom application-dependent color filter creation are explored. Results comparing this method to previous schlieren approximations are finally presented.

Keywords: uintah, c-safe

Computational modeling in electrocardiography often requires the examination of cardiac forward and inverse problems in order to non-invasively analyze physiological events that are otherwise inaccessible or unethical to explore. The study of these models can be performed in the open-source SCIRun problem solving environment developed at the Center for Integrative Biomedical Computing (CIBC). A new toolkit within SCIRun provides researchers with essential frameworks for constructing and manipulating electrocardiographic forward and inverse models in a highly efficient and interactive way. The toolkit contains sample networks, tutorials and documentation which direct users through SCIRun-specific approaches in the assembly and execution of these specific problems.

Deep brain stimulation (DBS) is an established therapy for the treatment of Parkinson's disease (PD) and shows great promise for the treatment of several other disorders. However, while the clinical analysis of DBS has received great attention, a relative paucity of quantitative techniques exists to define the optimal surgical target and most effective stimulation protocol for a given disorder. In this study we describe a methodology that represents an evolutionary addition to the concept of a probabilistic brain atlas, which we call a probabilistic stimulation atlas (PSA). We outline steps to combine quantitative clinical outcome measures with advanced computational models of DBS to identify regions where stimulation-induced activation could provide the best therapeutic improvement on a per-symptom basis. While this methodology is relevant to any form of DBS, we present example results from subthalamic nucleus (STN) DBS for PD. We constructed patient-specific computer models of the volume of tissue activated (VTA) for 163 different stimulation parameter settings which were tested in six patients. We then assigned clinical outcome scores to each VTA and compiled all of the VTAs into a PSA to identify stimulation-induced activation targets that maximized therapeutic response with minimal side effects. The results suggest that selection of both electrode placement and clinical stimulation parameter settings could be tailored to the patient's primary symptoms using patient-specific models and PSAs.

Functional electrical stimulation (FES) is a general term for therapeutic methods that use electrical stimulation to aid or replace lost ability. For FES systems that communicate with the nervous system, one critical component is the electrode interface through which the machine-body information transfer must occur. In this paper, we examine the influence of inhomogeneous tissue conductivities and positions of nodes of Ranvier on activation of myelinated axons for neuromuscular control as a function of electrode configuration. To evaluate these effects, we developed a high-resolution bioelectric model of a fascicle from a stained cross-section of cat sciatic nerve. The model was constructed by digitizing a fixed specimen of peripheral nerve, extruding the image along the axis of the nerve, and assigning each anatomical component to one of several different tissue types. Electrodes were represented by current sources in monopolar, transverse bipolar, and longitudinal bipolar configurations; neural activation was determined using coupled field-neuron simulations with myelinated axon cable models. We found that the use of an isotropic tissue medium overestimated neural activation thresholds compared with the use of physiologically based, inhomogeneous tissue medium, even after controlling for mean impedance levels. Additionally, the positions of the cathodic sources relative to the nodes of Ranvier had substantial effects on activation, and these effects were modulated by the electrode configuration. Our results indicate that physiologically based tissue properties cause considerable variability in the neural response, and the inclusion of these properties is an important component in accurately predicting activation. The results are used to suggest new electrode designs to enable selective stimulation of small diameter fibers.

The stochastic collocation method using sparse grids has become a popular choice for performing stochastic computations in high dimensional (random) parameter space. In addition to providing highly accurate stochastic solutions, the sparse grid collocation results naturally contain sensitivity information with respect to the input random parameters. In this paper, we use the sparse grid interpolation and cubature methods of Smolyak together with combinatorial analysis to give a computationally efficient method for computing the global sensitivity values of Sobol'. This method allows for approximation of all main effect and total effect values from evaluation of f on a single set of sparse grids. We discuss convergence of this method, apply it to several test cases and compare to existing methods. As a result which may be of independent interest, we recover an explicit formula for evaluating a Lagrange basis interpolating polynomial associated with the Chebyshev extrema. This allows one to manipulate the sparse grid collocation results in a highly efficient manner.

Keywords: Stochastic collocation, sparse grids, sensitivity analysis, Smolyak, Sobol