Publications
346 results found
Kohl P, Crampin EJ, Quinn TA, et al., 2010, Systems Biology: An Approach, Vol: 88, Pages: 25-33, ISSN: 0009-9236
In just over a decade, systems Biology has moved from being an idea, or rather a disparate set of ideas, to a mainstream feature of research and funding priorities. institutes, departments, and centers of various flavors of systems Biology have sprung up all over the world. an Internet search now produces more than 2 million hits. of the 2,800 entries in PubMed with "Systems Biology" in either the title or the abstract, only two papers were published before 2000, and >90% were published in the past five years. in this article, we interpret systems Biology as an approach rather than as a field or a destination of research. We illustrate that this approach is productive for the exploration of systems behavior, or "phenotypes," at all levels of structural and functional complexity, explicitly including the supracellular domain, and suggest how this may be related conceptually to genomes and biochemical networks. We discuss the role of models in systems Biology and conclude with a consideration of their utility in biomedical research and development.
Kohl P, Pellis T, 2010, International Liaison Committee on Resuscitation (ILCOR) 2010 worksheet # BLS-017C, In adult cardiac arrest (prehospital OHCA,in-hospital IHCA) (P), does the use of alternative methods of manual CPR (eg. cough CPR, precordial thump, fist-pacing) (I) compared with standard CPR (C), improve any outcomes (eg. ROSC, survival) (O)?, ILCOR 2010 BLS-017C
Kohl P, Sachs F, Franz MR, 2010, Cardiac mechano-electric feedback and arrhythmias: from pipette to patient, Publisher: W B Saunders Co
Bishop MJ, Plank G, Burton RAB, et al., 2010, Development of an anatomically detailed MRI-derived rabbit ventricular model and assessment of its impact on simulations of electrophysiological function, American Journal of Physiology-Heart and Circulatory Physiology, Vol: 298, Pages: H699-H718, ISSN: 0363-6135
Bishop MJ, Plank G, Burton RA, Schneider JE, Gavaghan DJ, Grau V, Kohl P. Development of an anatomically detailed MRI-derived rabbit ventricular model and assessment of its impact on simulations of electrophysiological function. Am J Physiol Heart Circ Physiol 298: H699-H718, 2010. First published November 20, 2009; doi:10.1152/ajpheart.00606.2009.-Recent advances in magnetic resonance (MR) imaging technology have unveiled a wealth of information regarding cardiac histoanatomical complexity. However, methods to faithfully translate this level of fine-scale structural detail into computational whole ventricular models are still in their infancy, and, thus, the relevance of this additional complexity for simulations of cardiac function has yet to be elucidated. Here, we describe the development of a highly detailed finite-element computational model (resolution: similar to 125 mu m) of rabbit ventricles constructed from high-resolution MR data (raw data resolution: 43 x 43 x 36 mu m), including the processes of segmentation (using a combination of level-set approaches), identification of relevant anatomical features, mesh generation, and myocyte orientation representation (using a rule-based approach). Full access is provided to the completed model and MR data. Simulation results were compared with those from a simplified model built from the same images but excluding finer anatomical features (vessels/endocardial structures). Initial simulations showed that the presence of trabeculations can provide shortcut paths for excitation, causing regional differences in activation after pacing between models. Endocardial structures gave rise to small-scale virtual electrodes upon the application of external field stimulation, which appeared to protect parts of the endocardium in the complex model from strong polarizations, whereas intramural virtual electrodes caused by blood vessels and extracellular cleft spaces appeared to reduce polarization of the epicardium. Postshock
Bordas R, Grau V, Burton RAB, et al., 2010, Integrated Approach for the Study of Anatomical Variability in the Cardiac Purkinje System: From High Resolution MRI to Electrophysiology Simulation, 2010 Annual International Conference of the Ieee Engineering in Medicine and Biology Society, Pages: 6793-6796, ISBN: 978-1-4244-4124-2
The ordered electrical stimulation of the ventricles is achieved by a specialized network of fibres known as the Purkinje system. The gross anatomy and basic functional role of the Purkinje system is well understood. However, very little is known about the detailed anatomy of the Purkinje system, its inter-individual variability and the implications of the variability in ventricular function, in part due to limitations in experimental techniques. In this study, we aim to provide new insight into the inter-individual variability of the free running Purkinje system anatomy and its impact on ventricular electrophysiological function. As a first step towards achieving this aim, high resolution magnetic resonance imaging ( MRI) datasets of rat and the rabbit ventricles are obtained and analysed using a novel semi- automatic image processing algorithm for segmentation of the free- running Purkinje system. Segmented geometry from the MRI datasets is used to construct a computational model of the Purkinje system, which is incorporated in to an anatomically- based ventricular geometry to simulate ventricular electrophysiological activity.
Bub G, Tecza M, Helmes M, et al., 2010, Temporal pixel multiplexing for simultaneous high-speed, high-resolution imaging, Nature Methods, Vol: 7, Pages: 209-U66, ISSN: 1548-7091
We introduce an imaging modality that, by offsetting pixel-exposure times during capture of a single image frame, embeds temporal information in each frame. This allows simultaneous acquisition of full-resolution images at native detector frame rates and high-speed image sequences at reduced resolution, without increasing bandwidth requirements. We demonstrate this method using macroscopic and microscopic examples, including imaging calcium transients in heart cells at 250 Hz using a 10-Hz megapixel camera.
Casero R, Burton RAB, Quinn TA, et al., 2010, Towards High-Resolution Cardiac Atlases: Ventricular Anatomy Descriptors for a Standardized Reference Frame, Statistical Atlases and Computational Models of the Heart, Editors: Camara, Pop, Rhode, Sermesant, Smith, Young, Pages: 75-84, ISBN: 978-3-642-15834-6
Increased resolution in cardiac Magnetic Resonance Imaging (MRI) and growing interest in the effect of small structures in electrophysiology of the heart pose new challenges for cardiac atlases. In this paper we discuss the limitations of current atlas-building models when trying to incorporate cardiac small structure and argue for the need of developing a standard coordinate system for the heart that separates this from the macro-structure common to all individual hearts, in a way analogous to the stereotactic coordinate system from brain atlases. With this goal, we propose a set of methods to obtain two descriptors of the ventricular macro-structure that can be used to build a standardized reference frame: the central curve on the Left Ventricle cavity and the smoothed internal envelope of the Right Ventricle crest (i.e. the curve in the endocardial surface marking the junction between the right ventricular free wall and the septum).
Hunter P, Coveney PV, de Bono B, et al., 2010, A vision and strategy for the virtual physiological human in 2010 and beyond, Vol: 368, Pages: 2595-2614, ISSN: 1364-503X
European funding under framework 7 (FP7) for the virtual physiological human (VPH) project has been in place now for nearly 2 years. The VPH network of excellence (NoE) is helping in the development of common standards, open-source software, freely accessible data and model repositories, and various training and dissemination activities for the project. It is also helping to coordinate the many clinically targeted projects that have been funded under the FP7 calls. An initial vision for the VPH was defined by framework 6 strategy for a European physiome (STEP) project in 2006. It is now time to assess the accomplishments of the last 2 years and update the STEP vision for the VPH. We consider the biomedical science, healthcare and information and communications technology challenges facing the project and we propose the VPH Institute as a means of sustaining the vision of VPH beyond the time frame of the NoE.
Kohl P, Viceconti M, 2010, The virtual physiological human: computer simulation for integrative biomedicine II INTRODUCTION, Philos Transact A Math Phys Eng Sci, Vol: 368, Pages: 2837-2839, ISSN: 1364-503X
Lawford PV, Narracott AV, McCormack K, et al., 2010, Virtual physiological human: training challenges, Philos Transact A Math Phys Eng Sci, Vol: 368, Pages: 2841-2851, ISSN: 1364-503X
The virtual physiological human (VPH) initiative encompasses a wide range of activities, including structural and functional imaging, data mining, knowledge discovery tool and database development, biomedical modelling, simulation and visualization. The VPH community is developing from a multitude of relatively focused, but disparate, research endeavours into an integrated effort to bring together, develop and translate emerging technologies for application, from academia to industry and medicine. This process initially builds on the evolution of multi-disciplinary interactions and abilities, but addressing the challenges associated with the implementation of the VPH will require, in the very near future, a translation of quantitative changes into a new quality of highly trained multi-disciplinary personnel. Current strategies for undergraduate and on-the-job training may soon prove insufficient for this. The European Commission seventh framework VPH network of excellence is exploring this emerging need, and is developing a framework of novel training initiatives to address the predicted shortfall in suitably skilled VPH-aware professionals. This paper reports first steps in the implementation of a coherent VPH training portfolio.
Pellis T, Kohl P, 2010, Extracorporeal cardiac mechanical stimulation: precordial thump and precordial percussion, British Medical Bulletin, Vol: 93, Pages: 161-177, ISSN: 0007-1420
External cardiac mechanical stimulation is one of the fastest resuscitative manoeuvres possible in the emergency setting. Precordial thump (PT), initially reported for treatment of atrio-ventricular block, has been subsequently described to cardiovert also ventricular tachycardia (VT) and fibrillation (VF). PT efficacy, mechanics and mechanisms remain poorly characterized. Appropriate MESH and free terms were searched on PubMed, Embase and the Cochrane Library. Cross-referencing from articles and reviews, and forward search using SCOPUS and Google scholar have also been performed. Pre-set inclusion and exclusion criteria were applied to retrieved references on PT, which were then reviewed, summarized and interpreted. PT is not effective in treating VF, and of limited use for VT, although it has a very good safety profile (97% no changed/improved rhythm). If delivered, PT should be applied as early as possible after cardiac arrest, and cardio-pulmonary resuscitation (CPR) should begin with no delay if not effective. A relatively large fraction of reported positive outcomes (both for PT and the less forceful but serially applied precordial percussion) in witnessed asystole should be considered when critically reviewing present CPR recommendations. In addition, mechanisms, energy requirements and timing are analysed and discussed. The 2005 ALS guidelines recommend PT delivery only by healthcare professionals trained in the technique. The use of training aids should therefore be explored, regardless of whether they are based on stand-alone devices or integrated within resuscitation mannequins.
Rodriguez B, Burrage K, Gavaghan D, et al., 2010, The Systems Biology Approach to Drug Development: Application to Toxicity Assessment of Cardiac Drugs, Clin Pharmacol Ther, Vol: 88, Pages: 130-134, ISSN: 0009-9236
Side effects account for most of the instances of failure of candidate drugs at late stages of development. These development failures contribute to the exorbitant cost of bringing new compounds to market: a single withdrawal can represent a loss of more than $1 billion. Many unwanted actions of drugs affect the heart, resulting in potentially proarrhythmic alteration of ion channel function. Because these can be fatal, potential electrophysiological cardiotoxicity is among the most stringent exclusion criteria in the licensing process.
Vadakkumpadan F, Arevalo H, Prassl AJ, et al., 2010, Image-based models of cardiac structure in health and disease, Wiley Interdisciplinary Reviews-Systems Biology and Medicine, Vol: 2, Pages: 489-506, ISSN: 1939-5094
Computational approaches to investigating the electromechanics of healthy and diseased hearts are becoming essential for the comprehensive understanding of cardiac function. In this article, we first present a brief review of existing image-based computational models of cardiac structure. We then provide a detailed explanation of a processing pipeline which we have recently developed for constructing realistic computational models of the heart from high resolution structural and diffusion tensor (DT) magnetic resonance (MR) images acquired ex vivo. The presentation of the pipeline incorporates a review of the methodologies that can be used to reconstruct models of cardiac structure. In this pipeline, the structural image is segmented to reconstruct the ventricles, normal myocardium, and infarct. A finite element mesh is generated from the segmented structural image, and fiber orientations are assigned to the elements based on DTMR data. The methods were applied to construct seven different models of healthy and diseased hearts. These models contain millions of elements, with spatial resolutions in the order of hundreds of microns, providing unprecedented detail in the representation of cardiac structure for simulation studies. (C) 2010 John Wiley & Sons, Inc. WIREs Syst Biol Med 2010 2 489-506
Viceconti M, Kohl P, 2010, The virtual physiological human: computer simulation for integrative biomedicine I INTRODUCTION, Philos Transact A Math Phys Eng Sci, Vol: 368, Pages: 2591-2594, ISSN: 1364-503X
Bub G, Camelliti P, Bollensdorff C, et al., 2010, Measurement and analysis of sarcomere length in rat cardiomyocytes in situ and in vitro, Vol: 298, Pages: H1616-H1625, ISSN: 0363-6135
Bub G, Camelliti P, Bollensdorff C, Stuckey DJ, Picton G, Burton RA, Clarke K, Kohl P. Measurement and analysis of sarcomere length in rat cardiomyocytes in situ and in vitro. Am J Physiol Heart Circ Physiol 298: H1616-H1625, 2010. First published March 12, 2010; doi: 10.1152/ajpheart.00481.2009.-Sarcomere length (SL) is an important determinant and indicator of cardiac mechanical function; however, techniques for measuring SL in living, intact tissue are limited. Here, we present a technique that uses two-photon microscopy to directly image striations of living cells in cardioplegic conditions, both in situ (Langendorff-perfused rat hearts and ventricular tissue slices, stained with the fluorescent marker di-4-ANEPPS) and in vitro (acutely isolated rat ventricular myocytes). Software was developed to extract SL from two-photon fluorescence image sets while accounting for measurement errors associated with motion artifact in raster-scanned images and uncertainty of the cell angle relative to the imaging plane. Monte-Carlo simulations were used to guide analysis of SL measurements by determining error bounds as a function of measurement path length. The mode of the distribution of SL measurements in resting Langendorff-perfused heart is 1.95 mu m (n = 167 measurements from N = 11 hearts) after correction for tissue orientation, which was significantly greater than that in isolated cells (1.71 mu m, n = 346, N = 9 isolations) or ventricular slice preparations (1.79 mu m, n = 79, N = 3 hearts) under our experimental conditions. Furthermore, we find that edema in arrested Langendorff-perfused heart is associated with a mean SL increase; this occurs as a function of time ex vivo and correlates with tissue volume changes determined by magnetic resonance imaging. Our results highlight that the proposed method can be used to monitor SL in living cells and that different experimental models from the same species may display significantly different SL values under otherwise c
Swietach P, Camelliti P, Hulikova A, et al., 2010, Spatial regulation of intracellular pH in multicellular strands of neonatal rat cardiomyocytes, Vol: 85, Pages: 729-738, ISSN: 0008-6363
Intracellular pH (pH(i)), an important modulator of cardiac function, is normally regulated to within narrow limits (7.1-7.2). In adult ventricular cell pairs, localized cellular pH(i) disturbances are removed by sarcolemmal acid/base transporters, but can also be dissipated (diluted) across gap junctions, aboard mobile buffers such as CO(2)/HCO(3)(-) and histidine-containing dipeptides (HCDPs). In the present work, we test this model of spatial pH(i) regulation in multicellular strands of neonatal rat ventricular myocytes. We confocally image pH(i) (intracellular fluorescence emitted from the pH dye carboxy-SNARF-1) in multicellular (> 500 mu m long, similar to 30 mu m wide) cultured strands of electrically coupled, neonatal rat ventricular myocytes. Activity of sarcolemmal Na(+)/H(+) exchange and Na(+)-HCO(3)(-) co-transport resembles that in adult cells. Localized photolytic H(+) uncaging from intracellular 2-nitrobenzaldehyde, in the presence of CO(2)/HCO(3)(-) buffer, triggers considerable passive H(+) spread along a strand, thus helping to dissipate the acid load. Inhibition of gap junctions (with alpha-glycyrrhetinic acid) truncates the spread, indicating they are conduits for local intracellular H(+) flux. Without CO(2)/HCO(3)(-) buffer, longitudinal H(+) mobility is reduced by similar to 90%, indicating that intracellular and cell-to-cell H(+) flux relies far less on intrinsic mobile buffers (e.g. HCDPs) in neonates than in adults. This is consistent with five-fold lower HCDP levels in neonatal, compared to adult, ventricular tissue, and also with measurements of a lower intrinsic (non-CO(2)/HCO(3)(-)) H(+) buffering capacity in neonatal strands compared with freshly isolated adult cells. We conclude that mobile buffers and gap junctions are key spatial controllers of pH(i) in cardiac tissue, helping to maintain a myocardial pH(i) syncitium. In neonatal tissue, intracellular H(+) movement is CO(2)/HCO(3)(-) dependent, while adult tissue relies increasing
de Boer TP, Camelliti P, Ravens U, et al., 2009, Myocardial tissue slices: organotypic pseudo-2D models for cardiac research & development., Future Cardiol, Vol: 5, Pages: 425-430
Kohl P, Noble D, 2009, Systems biology and the virtual physiological human, Molecular Systems Biology, Vol: 10, ISSN: 1744-4292
The virtual physiological human (VPH) initiative is intended to support the development of patient‐specific computer models and their application in personalised and predictive healthcare. The VPH, a core target of the European Commission's 7th Framework Programme, will serve as a ‘methodological and technological framework that, once established, will enable collaborative investigation of the human body as a single complex system’ (http://www.europhysiome.org/roadmap/). As such, the VPH initiative constitutes an integral part of the international Physiome Project (http://www.physiome.org.nz/), a worldwide public domain effort to develop a computational framework for the quantitative description of biological processes in living systems across all relevant levels of structural and functional integration, from molecule to organism, including the human (Kohl et al, 2000; Bassingthwaighte et al, 2009).So, what is the connection between this grand challenge and systems biology? To explore this, we must first agree on what we take systems biology to mean.
Kohl P, Coveney PV, Gavaghan D, 2009, The virtual physiological human: tools and applications II., Philos Trans A Math Phys Eng Sci, Vol: 367, Pages: 2121-2123, ISSN: 1364-503X
Bollensdorff C, Lookin O, Helmes M, et al., 2009, Length-Dependent Active Tension Development In Single Intact Cardiomyocytes, Isolated From Different Regions Of Guinea Pig Heart, Publisher: CELL PRESS, Pages: 223A-223A, ISSN: 0006-3495
Gibb M, Bishop M, Burton R, et al., 2009, The Role of Blood Vessels in Rabbit Propagation Dynamics and Cardiac Arrhythmias, Functional Imaging and Modeling of the Heart, Proceedings, Editors: Ayache, Delingette, Sermesant, Pages: 268-276, ISBN: 978-3-642-01931-9
Recent experimental findings have suggested the important role played by blood vessels within the heart in stabilising arrhythmias. However, this link has yet to be explored computationally. In this paper, we develop a computational framework to model fibre orientation around structural inhomogeneities in myocardial tissue based on information obtained from high-resolution histological and MRI images. This framework allows the simulation of cardiac wavefront propagation for a generalised vessel orientation and position within the ventricular wall and transmural fibre architecture around it. We simulate propagation following different stimulation protocols around a transmural and a subepicardial vessel, using both bidomain and monodomain representations. We demonstrate the importance of accurately modelling the fibre structure around blood vessels relative to a simplistic transmurally varying fibre orientation model and suggest how this may impact pro-arrhythmic electrical dynamics.
Goodyer C, Hodrien J, Wood J, et al., 2009, Using high-resolution displays for high-resolution cardiac data, Philos Transact A Math Phys Eng Sci, Vol: 367, Pages: 2667-2677, ISSN: 1364-503X
The ability to perform fast, accurate, high-resolution visualization is fundamental to improving our understanding of anatomical data. As the volumes of data increase from improvements in scanning technology, the methods applied to visualization must evolve. In this paper, we address the interactive display of data from high-resolution magnetic resonance imaging scanning of a rabbit heart and subsequent histological imaging. We describe a visualization environment involving a tiled liquid crystal display panel display wall and associated software, which provides an interactive and intuitive user interface. The OVIEW software is an OpenGL application that is written for the VR JUGGLER environment. This environment abstracts displays and devices away from the application itself, aiding portability between different systems, from desktop PCs to multi-tiled display walls. Portability between display walls has been demonstrated through its use on walls at the universities of both Leeds and Oxford. We discuss important factors to be considered for interactive two-dimensional display of large three-dimensional datasets, including the use of intuitive input devices and level of detail aspects.
Kohl P, Coveney PV, Gavaghan D, 2009, The virtual physiological human: tools and applications II INTRODUCTION, Philos Transact A Math Phys Eng Sci, Vol: 367, Pages: 2121-2123, ISSN: 1364-503X
Kohl P, Noble D, 2009, Systems biology and the virtual physiological human, Molecular Systems Biology, Vol: 5, ISSN: 1744-4292
Pellis T, Kette F, Lovisa D, et al., 2009, Utility of pre-cordial thump for treatment of out of hospital cardiac arrest: A prospective study, Resuscitation, Vol: 80, Pages: 17-23, ISSN: 0300-9572
Background: Prospective data on pre-cordial thump (PT), one of the fastest possible resuscitative manoeuvres, are scant, particularly in out-of-hospital (OOH) cardiac arrest (CA). Methods: In this study, conducted in the Pordenone-province (north-east Italy), suspected OOH-CA victims were connected to a cardiac monitor and, upon confirmation of CA, subjected to a swift PT before any other resuscitatory intervention, without notable delay in other procedures. Investigation targets were: (i) effects on heart rhythm, (ii) return of spontaneous circulation (ROSC), (iii) hospital discharge, (iv) presence of adverse effects. Outcomes were additionally grouped by presenting rhythms into ventricular tachyarrhythmias (CA(VF/VT)), pulseless electrical activity (CA(PEA)), and asystole (CA(AS)). Results: Out of 144 OOH-CA cases, PT had no effect on heart rhythm in 138 patients (CA(VF/VT)-23/24; CA(PEA)-41/42; CA(AS)-74/78). In 112 of the 138 non-responders, ROSC was neither achieved by other interventions (CA(VF)/(VT)-13/23; CA(PEA)-38/41; CA(AS)-61/74); overall Survival was 5.6% (CA(VF/VT)-16.7%; CA(PEA)-0%; CA(As)-5.1%). PT caused ROSC in 3 patients with witnessed CAAS (time-to-intervention <3 min), representing one quarter of ROSC among witnessed CA victims. Survival of PT-induced ROSC patients (2/3) was certainly no worse than among PT-irresponsive ROSC patients (6 of 28). Overall, one quarter of patients, discharged from hospital, had been resuscitated by PT. No adverse effects of PT were observed. Conclusions: PT can be combined with standard resuscitatory interventions without significant time-delay or apparent side effects. PT efficacy in CA(VF/VT) and CA(PEA) is lacking. However, PT may offer potential for the increasing proportion of asystolic OOH-CA, in particular when witnessed. (C) 2008 Elsevier Ireland Ltd. All rights reserved.
Quinn TA, Rodriguez B, Kohl P, 2009, INTEGRATED EXPERIMENTAL AND COMPUTATIONAL RESEARCH TOOLS FOR THE STUDY OF ACUTE ISCHEMIC EFFECTS ON CARDIAC MECHANO-ELECTRICAL INTERACTIONS, Conf Proc IEEE Eng Med Biol Soc, Vol: 59, Pages: 125-125, ISSN: 1880-6546
Gavaghan D, Coveney PV, Kohl P, 2009, The virtual physiological human: tools and applications I, Philos Transact A Math Phys Eng Sci, Vol: 367, Pages: 1817-1821, ISSN: 1364-503X
Garny A, Noble D, Hunter PJ, et al., 2009, CELLULAR OPEN RESOURCE (COR): current status and future directions, Journal: Philosophical Transactions A: Mathematical, Physical and Engineering Sciences, Vol: 367, Pages: 1885-1905, ISSN: 1364-503X
The need for tools to aid the description and sharing of biological models was highlighted at the launch of the International Union of Physiological Sciences Physiome Project in 1997. This has resulted in the release, in 2001, of the CellML specifications (http://www.cellml.org/speci.cations/). CELLULAR OPEN RESOURCE (COR) was among the early adopters of this standard, eventually forming the first publicly available CellML-based modelling and collaboration environment. From the onset, COR was designed to provide an environment that could not only be used by experienced modellers, but also by experimentalists, teachers and students. It therefore tries to combine a user-friendly interface with a computationally efficient numerical engine. In this paper, we introduce the philosophy behind COR, explain its user interface and current functionality, including the editing and running of CellML files, highlight lessons learned from user feedback and problems experienced during the development of COR and conclude by exploring future development potential.
Plank G, Burton RAB, Hales P, et al., 2009, Generation of histo-anatomically representative models of the individual heart: tools and application, Vol: 367, Pages: 2257-2292, ISSN: 1364-503X
This paper presents methods to build histo-anatomically detailed individualized cardiac models. The models are based on high-resolution three-dimensional anatomical and/or diffusion tensor magnetic resonance images, combined with serial histological sectioning data, and are used to investigate individualized cardiac function. The current state of the art is reviewed, and its limitations are discussed. We assess the challenges associated with the generation of histo-anatomically representative individualized in silico models of the heart. The entire processing pipeline including image acquisition, image processing, mesh generation, model set-up and execution of computer simulations, and the underlying methods are described. The multifaceted challenges associated with these goals are highlighted, suitable solutions are proposed, and an important application of developed high-resolution structure-function models in elucidating the effect of individual structural heterogeneity upon wavefront dynamics is demonstrated.
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