Activity-dependent spinal cord neuromodulation rapidly restores trunk and leg motor functions after complete paralysis.

Epidural electrical stimulation (EES) targeting the dorsal roots of lumbosacral segments restores walking in people with spinal cord injury (SCI). However, EES is delivered with multielectrode paddle leads that were originally designed to target the dorsal column of the spinal cord. Here, we hypothesized that an arrangement of electrodes targeting the ensemble of dorsal roots involved in leg and trunk movements would result in superior efficacy, restoring more diverse motor activities after the most severe SCI. To test this hypothesis, we established a computational framework that informed the optimal arrangement of electrodes on a new paddle lead and guided its neurosurgical positioning. We also developed software supporting the rapid configuration of activity-specific stimulation programs that reproduced the natural activation of motor neurons underlying each activity. We tested these neurotechnologies in three individuals with complete sensorimotor paralysis as part of an ongoing clinical trial ( www.clinicaltrials.gov identifier NCT02936453). Within a single day, activity-specific stimulation programs enabled these three individuals to stand, walk, cycle, swim and control trunk movements. Neurorehabilitation mediated sufficient improvement to restore these activities in community settings, opening a realistic path to support everyday mobility with EES in people with SCI.

Anatomical Model Uncertainty for RF Safety Evaluation of Metallic Implants Under MRI Exposure.

The Virtual Population (ViP) phantoms have been used in many dosimetry studies, yet, to date, anatomical phantom uncertainty in radiofrequency (RF) research has largely been neglected. The objective of this study is to gain insight, for the first time, regarding the uncertainty in RF-induced fields during magnetic resonance imaging associated with tissue assignment and segmentation quality and consistency in anatomical phantoms by evaluating the differences between two generations of ViP phantoms, ViP1.x and ViP3.0. The RF-induced 10g-average electric (E-) fields, tangential E-fields distribution along active implantable medical devices (AIMD) routings, and estimated AIMD heating were compared for five phantoms that are part of both ViP1.x and ViP3.0. The results demonstrated that differences exceeded 3 dB (-29%, +41%) for local quantities and 1 dB (±12% for field, ±25% for power) for integrated and volume-averaged quantities (e.g., estimated AIMD-heating and 10 g-average E-fields), while the variation across different ViP phantoms of the same generation can exceed 10 dB (-68% and +217% for field, -90% and +900% for power). In conclusion, the anatomical phantom uncertainty associated with tissue assignment and segmentation quality/consistency is larger than previously assumed, i.e., 0.6 dB or ±15% (k = 1) for AIMD heating. Further, multiple phantoms based on different volunteers covering the target population are required for quantitative analysis of dosimetric endpoints, e.g., AIMD heating, which depend on patient anatomy. Phantoms with the highest fidelity in tissue assignment and segmentation should be used, as these ensure the lowest uncertainty and possible underestimation of exposure. To verify that the uncertainty decreases monotonically with improved phantom quality, the evaluation of differences between phantom generations should be repeated for any improvement in segmentation. Bioelectromagnetics. 2019;40:458-471. © 2019 Bioelectromagnetics Society.

Advances in Computational Human Phantoms and Their Applications in Biomedical Engineering - A Topical Review.

Over the past decades, significant improvements have been made in the field of computational human phantoms (CHPs) and their applications in biomedical engineering. Their sophistication has dramatically increased. The very first CHPs were composed of simple geometric volumes, e.g., cylinders and spheres, while current CHPs have a high resolution, cover a substantial range of the patient population, have high anatomical accuracy, are poseable, morphable, and are augmented with various details to perform functionalized computations. Advances in imaging techniques and semi-automated segmentation tools allow fast and personalized development of CHPs. These advances open the door to quickly develop personalized CHPs, inherently including the disease of the patient. Because many of these CHPs are increasingly providing data for regulatory submissions of various medical devices, the validity, anatomical accuracy, and availability to cover the entire patient population is of utmost importance. The article is organized into two main sections: the first section reviews the different modeling techniques used to create CHPs, whereas the second section discusses various applications of CHPs in biomedical engineering. Each topic gives an overview, a brief history, recent developments, and an outlook into the future.

Accurate anatomical head segmentations: a data set for biomedical simulations.

Detailed computational anatomical models of the entire head are needed for accurate in silico modeling in a variety of transcranial stimulation applications. Models from different subjects help to understand and account for population variability. To this end, we have developed a new library of head models of 20 individuals, segmented from co-aligned multi-modal medical image data. The acquired image modalities allow to accurately model tissues with different material properties, such as electrical conductivity or spatially varying acoustic properties. The usefulness of the models is illustrated for two example applications.

Functionalized Anatomical Models for Computational Life Sciences.

The advent of detailed computational anatomical models has opened new avenues for computational life sciences (CLS). To date, static models representing the anatomical environment have been used in many applications but are insufficient when the dynamics of the body prevents separation of anatomical geometrical variability from physics and physiology. Obvious examples include the assessment of thermal risks in magnetic resonance imaging and planning for radiofrequency and acoustic cancer treatment, where posture and physiology-related changes in shape (e.g., breathing) or tissue behavior (e.g., thermoregulation) affect the impact. Advanced functionalized anatomical models can overcome these limitations and dramatically broaden the applicability of CLS in basic research, the development of novel devices/therapies, and the assessment of their safety and efficacy. Various forms of functionalization are discussed in this paper: (i) shape parametrization (e.g., heartbeat, population variability), (ii) physical property distributions (e.g., image-based inhomogeneity), (iii) physiological dynamics (e.g., tissue and organ behavior), and (iv) integration of simulation/measurement data (e.g., exposure conditions, "validation evidence" supporting model tuning and validation). Although current model functionalization may only represent a small part of the physiology, it already facilitates the next level of realism by (i) driving consistency among anatomy and different functionalization layers and highlighting dependencies, (ii) enabling third-party use of validated functionalization layers as established simulation tools, and (iii) therefore facilitating their application as building blocks in network or multi-scale computational models. Integration in functionalized anatomical models thus leverages and potentiates the value of sub-models and simulation/measurement data toward ever-increasing simulation realism. In our o2S2PARC platform, we propose to expand the concept of functionalized anatomical models to establish an integration and sharing service for heterogeneous computational models, ranging from the molecular to the organ level. The objective of o2S2PARC is to integrate all models developed within the National Institutes of Health SPARC initiative in a unified anatomical and computational environment, to study the role of the peripheral nervous system in controlling organ physiology. The functionalization concept, as outlined for the o2S2PARC platform, could form the basis for many other application areas of CLS. The relationship to other ongoing initiatives, such as the Physiome Project, is also presented.

MIDA: A Multimodal Imaging-Based Detailed Anatomical Model of the Human Head and Neck.

Computational modeling and simulations are increasingly being used to complement experimental testing for analysis of safety and efficacy of medical devices. Multiple voxel- and surface-based whole- and partial-body models have been proposed in the literature, typically with spatial resolution in the range of 1-2 mm and with 10-50 different tissue types resolved. We have developed a multimodal imaging-based detailed anatomical model of the human head and neck, named "MIDA". The model was obtained by integrating three different magnetic resonance imaging (MRI) modalities, the parameters of which were tailored to enhance the signals of specific tissues: i) structural T1- and T2-weighted MRIs; a specific heavily T2-weighted MRI slab with high nerve contrast optimized to enhance the structures of the ear and eye; ii) magnetic resonance angiography (MRA) data to image the vasculature, and iii) diffusion tensor imaging (DTI) to obtain information on anisotropy and fiber orientation. The unique multimodal high-resolution approach allowed resolving 153 structures, including several distinct muscles, bones and skull layers, arteries and veins, nerves, as well as salivary glands. The model offers also a detailed characterization of eyes, ears, and deep brain structures. A special automatic atlas-based segmentation procedure was adopted to include a detailed map of the nuclei of the thalamus and midbrain into the head model. The suitability of the model to simulations involving different numerical methods, discretization approaches, as well as DTI-based tensorial electrical conductivity, was examined in a case-study, in which the electric field was generated by transcranial alternating current stimulation. The voxel- and the surface-based versions of the models are freely available to the scientific community.

Development of a new generation of high-resolution anatomical models for medical device evaluation: the Virtual Population 3.0.

The Virtual Family computational whole-body anatomical human models were originally developed for electromagnetic (EM) exposure evaluations, in particular to study how absorption of radiofrequency radiation from external sources depends on anatomy. However, the models immediately garnered much broader interest and are now applied by over 300 research groups, many from medical applications research fields. In a first step, the Virtual Family was expanded to the Virtual Population to provide considerably broader population coverage with the inclusion of models of both sexes ranging in age from 5 to 84 years old. Although these models have proven to be invaluable for EM dosimetry, it became evident that significantly enhanced models are needed for reliable effectiveness and safety evaluations of diagnostic and therapeutic applications, including medical implants safety. This paper describes the research and development performed to obtain anatomical models that meet the requirements necessary for medical implant safety assessment applications. These include implementation of quality control procedures, re-segmentation at higher resolution, more-consistent tissue assignments, enhanced surface processing and numerous anatomical refinements. Several tools were developed to enhance the functionality of the models, including discretization tools, posing tools to expand the posture space covered, and multiple morphing tools, e.g., to develop pathological models or variations of existing ones. A comprehensive tissue properties database was compiled to complement the library of models. The results are a set of anatomically independent, accurate, and detailed models with smooth, yet feature-rich and topologically conforming surfaces. The models are therefore suited for the creation of unstructured meshes, and the possible applications of the models are extended to a wider range of solvers and physics. The impact of these improvements is shown for the MRI exposure of an adult woman with an orthopedic spinal implant. Future developments include the functionalization of the models for specific physical and physiological modeling tasks.

A computational framework for modelling solid tumour growth.

The biology of cancer is a complex interplay of many underlying processes, taking place at different scales both in space and time. A variety of theoretical models have been developed, which enable one to study certain components of the cancerous growth process. However, most previous approaches only focus on specific aspects of tumour development, largely ignoring the influence of the evolving tumour environment. In this paper, we present an integrative framework to simulate tumour growth, including those model components that are considered to be of major importance. We start by addressing issues at the tissue level, where the phenomena are modelled as continuum partial differential equations. We extend this model with relevant components at the cellular or even sub-cellular level in a vertical fashion. We present an implementation of this framework, covering the major processes and treat the mechanical deformation due to growth, the biochemical response to hypoxia, blood flow, oxygenation and the explicit development of a vascular system in a coupled way. The results demonstrate the feasibility of the approach and its applicability to in silico studies of the influence of different treatment strategies (like the usage of novel anti-cancer drugs) for more effective therapy design.

A coupled finite element model of tumor growth and vascularization.

We present a model of solid tumor growth which can account for several stages of tumorigenesis, from the early avascular phase to the angiogenesis driven proliferation. The model combines several previously identified components in a consistent framework, including neoplastic tissue growth, blood and oxygen transport, and angiogenic sprouting. First experiments with the framework and comparisons with observations made on solid tumors in vivo illustrate the plausibility of the approach. Explanations of several experimental observations are naturally provided by the model. To the best of our knowledge this is the first report of a model coupling tumor growth and angiogenesis.

Identification of spring parameters for deformable object simulation.

Mass spring models are frequently used to simulate deformable objects because of their conceptual simplicity and computational speed. Unfortunately, the model parameters are not related to elastic material constitutive laws in an obvious way. Several methods to set optimal parameters have been proposed, but so far only with limited success. We analyze the parameter identification problem and show the difficulties, which have prevented previous work from reaching wide usage. Our main contribution is a new method to derive analytical expressions for the spring parameters from an isotropic linear elastic reference model. The method is described and expressions for several mesh topologies are derived. These include triangle, rectangle and tetrahedron meshes. The formulae are validated by comparing the static deformation of the MSM with reference deformations simulated with the finite element method.