In Vivo

International audienceSkeletal muscle system has nonlinear dynamics and subject-specific characteristics. Thus, it is essential to identify unknown parameters from noisy biomedical signals to improve the modeling accuracy in neuroprosthetic control. The objective of this work is to develop an experimental identification method for subject-specific biomechanical parameters of a physiological muscle model which can be employed to predict the nonlinear force properties of stimulated muscle. Our previously proposed muscle model, which can describe multi-scale physiological system based on the Hill and Huxley models, was used for the identification. The identification protocols were performed on two rabbit experiments, where the medial gastrocnemius was attached to a motorized lever system to record the force by the nerve stimulation. The muscle model was identified using nonlinear Kalman filters: Sigma-Point and Extended Kalman Filter. The identified model was evaluated by comparison with experimental measurements in cross-validation manner. The feasibility could be demonstrated by comparison between the estimated parameter and the measured value. The estimates with SPKF showed 5.7% and 2.9% error in each experiment with 7 different initial conditions. It reveals that SPKF has great advantage especially for the identification of multi-scale muscle model which accounts for the high nonlinearity and discontinuous states between muscle contraction and relaxation process

Multiscale modelling methods in biomechanics

More and more frequently, computational biomechanics deals with problems where the portion of physical reality to be modelled spans over such a large range of spatial and temporal dimensions, that it is impossible to represent it as a single space-time continuum. We are forced to consider multiple space-time continua, each representing the phenomenon of interest at a characteristic space-time scale. Multiscale models describe a complex process across multiple scales, and account for how quantities transform as we move from one scale to another. This review offers a set of definitions for this emerging field, and provides a brief summary of the most recent developments on multiscale modelling in biomechanics. Of all possible perspectives, we chose that of the modelling intent, which vastly affect the nature and the structure of each research activity. To the purpose we organised all papers reviewed in three categories: さcausal confirmationざ, where multiscale models are used as materialisations of the causation theories; さpredictive accuracyざ, where multiscale modelling is aimed to improve the predictive accuracy; and さdetermination of effectざ, where multiscale modelling is used to model how a change at one scale manifest in an effect at another, radically different space-time scale. Consistently with the how the volume of computational biomechanics research is distributed across application targets, we extensively reviewed papers targeting the musculoskeletal and the cardiovascular system, and covered only a few exemplary papers targeting other organ systems. The review shows a research sub-domain still in its infancy, where causal confirmation papers remain the most common

Investigating the Correlation between Force Output, Strains, and Pressure for Active Skeletal Muscle Contractions

Experimental observations suggest that the force output of the skeletal muscle tissue can be correlated to the intra-muscular pressure generated by the muscle belly. However, pressure often proves difficult to measure through in-vivo tests. Simulations on the other hand, offer a tool to model muscle contractions and analyze the relationship between muscle force generation and deformations as well as pressure outputs, enabling us to gain insight into correlations among experimentally measurable quantities such as principal and volumetric strains, and the force output. In this work, a correlation study is performed using Pearson's and Spearman's correlation coefficients on the force output of the skeletal muscle, the principal and volumetric strains experienced by the muscle and the pressure developed within the muscle belly as the muscle tissue undergoes isometric contractions due to varying activation profiles. The study reveals strong correlations between force output and the strains at all locations of the belly, irrespective of the type of activation profile used. This observation enables estimation on the contribution of various muscle groups to the total force by the experimentally measurable principal and volumetric strains in the muscle belly. It is also observed that pressure does not correlate well with force output due to stress relaxation near the boundary of muscle belly

Synthesis of optimal electrical stimulation patterns for functional motion restoration: applied to spinal cord-injured patients

We investigated the synthesis of electrical stimulation patterns for functional movement restoration in human paralyzed limbs. We considered the knee joint system, co-activated by the stimulated quadriceps and hamstring muscles. This synthesis is based on optimized functional electrical stimulation (FES) patterns to minimize muscular energy consumption and movement efficiency criteria. This two-part work includes a multi-scale physiological muscle model, based on Huxley’s formulation. In the simulation, three synthesis strategies were investigated and compared in terms of muscular energy consumption and co-contraction levels. In the experimental validation, the synthesized FES patterns were carried out on the quadriceps-knee joint system of four complete spinal cord injured subjects. Surface stimulation was applied to all subjects, except for one FES-implanted subject who received neural stimulation. In each experimental validation, the model was adapted to the subject through a parameter identification procedure. Simulation results were successful and showed high co-contraction levels when reference trajectories were tracked. Experimental validation results were encouraging, as the desired and measured trajectories showed good agreement, with an 8.4 % rms error in a subject without substantial time-varying behavior. We updated the maximal isometric force in the model to account for time-varying behavior, which improved the average rms errors from 31.4 to 13.9 % for all subjects

Voluntary EMG-to-force estimation with a multi-scale physiological muscle model

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.International audienceBackgroundEMG-to-force estimation based on muscle models, for voluntary contraction has many applications in human motion analysis. The so-called Hill model is recognized as a standard model for this practical use. However, it is a phenomenological model whereby muscle activation, force-length and force-velocity properties are considered independently. Perreault reported Hill modeling errors were large for different firing frequencies, level of activation and speed of contraction. It may be due to the lack of coupling between activation and force-velocity properties. In this paper, we discuss EMG-force estimation with a multi-scale physiology based model, which has a link to underlying crossbridge dynamics. Differently from the Hill model, the proposed method provides dual dynamics of recruitment and calcium activation.MethodsThe ankle torque was measured for the plantar flexion along with EMG measurements of the medial gastrocnemius (GAS) and soleus (SOL). In addition to Hill representation of the passive elements, three models of the contractile parts have been compared. Using common EMG signals during isometric contraction in four able-bodied subjects, torque was estimated by the linear Hill model, the nonlinear Hill model and the multi-scale physiological model that refers to Huxley theory. The comparison was made in normalized scale versus the case in maximum voluntary contraction.ResultsThe estimation results obtained with the multi-scale model showed the best performances both in fast-short and slow-long term contraction in randomized tests for all the four subjects. The RMS errors were improved with the nonlinear Hill model compared to linear Hill, however it showed limitations to account for the different speed of contractions. Average error was 16.9% with the linear Hill model, 9.3% with the modified Hill model. In contrast, the error in the multi-scale model was 6.1% while maintaining a uniform estimation performance in both fast and slow contractions schemes.ConclusionsWe introduced a novel approach that allows EMG-force estimation based on a multi-scale physiology model integrating Hill approach for the passive elements and microscopic cross-bridge representations for the contractile element. The experimental evaluation highlights estimation improvements especially a larger range of contraction conditions with integration of the neural activation frequency property and force-velocity relationship through cross-bridge dynamics consideration

The Virtual Physiological Human: Ten Years After

Biomedical research and clinical practice are struggling to cope with the growing complexity that the progress of health care involves. The most challenging diseases, those with the largest socioeconomic impact (cardiovascular conditions; musculoskeletal conditions; cancer; metabolic, immunity, and neurodegenerative conditions), are all characterized by a complex genotype–phenotype interaction and by a “systemic” nature that poses a challenge to the traditional reductionist approach. In 2005 a small group of researchers discussed how the vision of computational physiology promoted by the Physiome Project could be translated into clinical practice and formally proposed the term Virtual Physiological Human. Our knowledge about these diseases is fragmentary, as it is associated with molecular and cellular processes on the one hand and with tissue and organ phenotype changes (related to clinical symptoms of disease conditions) on the other. The problem could be solved if we could capture all these fragments of knowledge into predictive models and then compose them into hypermodels that help us tame the complexity that such systemic behavior involves. In 2005 this was simply not possible—the necessary methods and technologies were not available. Now, 10 years later, it seems the right time to reflect on the original vision, the results achieved so far, and what remains to be done

Distributed multi-scale muscle simulation in a hybrid MPI–CUDA computational environment

We present Mexie, an extensible and scalable software solution for distributed multi-scale muscle simulations in a hybrid MPI–CUDA environment. Since muscle contraction relies on the integration of physical and biochemical properties across multiple length and time scales, these models are highly processor and memory intensive. Existing parallelization efforts for accelerating multi-scale muscle simulations imply the usage of expensive large-scale computational resources, which produces overwhelming costs for the everyday practical application of such models. In order to improve the computational speed within a reasonable budget, we introduce the concept of distributed calculations of multi-scale muscle models in a mixed CPU–GPU environment. The concept is applied to a two-scale muscle model, in which a finite element macro model is coupled with the microscopic Huxley kinetics model. Finite element calculations of a continuum macroscopic model take place strictly on the CPU, while numerical solutions of the partial differential equations of Huxley’s cross-bridge kinetics are calculated on both CPUs and GPUs. We present a modular architecture of the solution, along with an internal organization and a specific load balancer that is aware of memory boundaries in such a heterogeneous environment. Solution was verified on both benchmark and real-world examples, showing high utilization of involved processing units, ensuring high scalability. Speed-up results show a boost of two orders of magnitude over any previously reported distributed multi-scale muscle models. This major improvement in computational feasibility of multi-scale muscle models paves the way for new discoveries in the field of muscle modeling and future clinical applications.Author's versio

In silico assessment of biomedical products: the conundrum of rare but not so rare events in two case studies

In silico clinical trials, defined as “The use of individualized computer simulation in the development or regulatory evaluation of a medicinal product, medical device, or medical intervention,” have been proposed as a possible strategy to reduce the regulatory costs of innovation and the time to market for biomedical products. We review some of the the literature on this topic, focusing in particular on those applications where the current practice is recognized as inadequate, as for example, the detection of unexpected severe adverse events too rare to be detected in a clinical trial, but still likely enough to be of concern. We then describe with more details two case studies, two successful applications of in silico clinical trial approaches, one relative to the University of Virginia/Padova simulator that the Food and Drug Administration has accepted as possible replacement for animal testing in the preclinical assessment of artificial pancreas technologies, and the second, an investigation of the probability of cardiac lead fracture, where a Bayesian network was used to combine in vivo and in silico observations, suggesting a whole new strategy of in silico-augmented clinical trials, to be used to increase the numerosity where recruitment is impossible, or to explore patients’ phenotypes that are unlikely to appear in the trial cohort, but are still frequent enough to be of concern

Multi-scale computer models of lymphatic pumping

The lymphatic system maintains fluid homeostasis by returning interstitial fluid to the veins. Lymphatics pump fluid locally with contracting segments of the vessel (lymphangions) bounded by valves. Contractions are generated by specialized muscle exhibiting phasic and tonic contractions. Deficient pumping can result in accumulation of interstitial fluid, called lymphoedema. Lymphoedema treatments have limited effectiveness, partially attributable to a lack of understanding of contractions. A lumped parameter computational model of lymphangion pumping has previously been developed in the group. In this thesis I detail development of two multiscale models of lymphatic pumping to facilitate improved treatments for lymphoedema. The first model captures subcellular mechanisms of lymphatic muscle contraction. This model is based on the sliding filament model and its smooth muscle adaptation. Contractile elements are combined with passive viscoelastic elements to model a cell. Many arrangements were trialled but only one behaved physiologically. The muscle model was then combined with the lymphangion model for comparison with experiments. This model captures mechanical and energetic aspects of both contraction types. I show that the model provides results similar to published experiments from rat mesenteric lymphatics. The model predicted a peak efficiency of 35%, in the upper range from other muscle types. In the range of frequencies and amplitudes simulated, the direct effect of calcium oscillations can increase lymphangion outflow by up to 40% of the flow in their absence. The second model aims to improve our understanding of lymphangion interaction in large networks through computational homogenisation. In this model we do not directly simulate all lymphangions but sample lymphangions at evenly spaced intervals to reduce the computational intensity. We show through this model that increased external pressure at the network inlet collapses lymphangions and that this disruption of pumping for a few lymphangions reduces the outflow from the entire network.Open Acces