CutFEM forward modeling for EEG source analysis.

Introduction: Source analysis of Electroencephalography (EEG) data requires the computation of the scalp potential induced by current sources in the brain. This so-called EEG forward problem is based on an accurate estimation of the volume conduction effects in the human head, represented by a partial differential equation which can be solved using the finite element method (FEM). FEM offers flexibility when modeling anisotropic tissue conductivities but requires a volumetric discretization, a mesh, of the head domain. Structured hexahedral meshes are easy to create in an automatic fashion, while tetrahedral meshes are better suited to model curved geometries. Tetrahedral meshes, thus, offer better accuracy but are more difficult to create. Methods: We introduce CutFEM for EEG forward simulations to integrate the strengths of hexahedra and tetrahedra. It belongs to the family of unfitted finite element methods, decoupling mesh and geometry representation. Following a description of the method, we will employ CutFEM in both controlled spherical scenarios and the reconstruction of somatosensory-evoked potentials. Results: CutFEM outperforms competing FEM approaches with regard to numerical accuracy, memory consumption, and computational speed while being able to mesh arbitrarily touching compartments. Discussion: CutFEM balances numerical accuracy, computational efficiency, and a smooth approximation of complex geometries that has previously not been available in FEM-based EEG forward modeling.

Brainstorm-DUNEuro: An integrated and user-friendly Finite Element Method for modeling electromagnetic brain activity.

Human brain activity generates scalp potentials (electroencephalography - EEG), intracranial potentials (iEEG), and external magnetic fields (magnetoencephalography - MEG). These electrophysiology (e-phys) signals can often be measured simultaneously for research and clinical applications. The forward problem involves modeling these signals at their sensors for a given equivalent current dipole configuration within the brain. While earlier researchers modeled the head as a simple set of isotropic spheres, today's magnetic resonance imaging (MRI) data allow for a detailed anatomic description of brain structures and anisotropic characterization of tissue conductivities. We present a complete pipeline, integrated into the Brainstorm software, that allows users to automatically generate an individual and accurate head model based on the subject's MRI and calculate the electromagnetic forward solution using the finite element method (FEM). The head model generation is performed by integrating the latest tools for MRI segmentation and FEM mesh generation. The final head model comprises the five main compartments: white-matter, gray-matter, CSF, skull, and scalp. The anisotropic brain conductivity model is based on the effective medium approach (EMA), which estimates anisotropic conductivity tensors from diffusion-weighted imaging (DWI) data. The FEM electromagnetic forward solution is obtained through the DUNEuro library, integrated into Brainstorm, and accessible with either a user-friendly graphical interface or scripting. With tutorials and example data sets available in an open-source format on the Brainstorm website, this integrated pipeline provides access to advanced FEM tools for electromagnetic modeling to a broader neuroscience community.

Feasibility and clinical usefulness of modelling glioblastoma migration in adjuvant radiotherapy.

Glioblastoma (GBM) is one of the most common primary brain tumours in adults, with a dismal prognosis despite aggressive multimodality treatment by a combination of surgery and adjuvant radiochemotherapy. A detailed knowledge of the spreading of glioma cells in the brain might allow for more targeted escalated radiotherapy, aiming to reduce locoregional relapse. Recent years have seen the development of a large variety of mathematical modelling approaches to predict glioma migration. The aim of this study is hence to evaluate the clinical applicability of a detailed micro- and meso-scale mathematical model in radiotherapy. First and foremost, a clinical workflow is established, in which the tumour is automatically segmented as input data and then followed in time mathematically based on the diffusion tensor imaging data. The influence of several free model parameters is individually evaluated, then the full model is retrospectively validated for a collective of 3 GBM patients treated at our institution by varying the most important model parameters to achieve optimum agreement with the tumour development during follow-up. Agreement of the model predictions with the real tumour growth as defined by manual contouring based on the follow-up MRI images is analyzed using the dice coefficient. The tumour evolution over 103-212 days follow-up could be predicted by the model with a dice coefficient better than 60% for all three patients. In all cases, the final tumour volume was overestimated by the model by a factor between 1.05 and 1.47. To evaluate the quality of the agreement between the model predictions and the ground truth, we must keep in mind that our gold standard relies on a single observer's (CB) manually-delineated tumour contours. We therefore decided to add a short validation of the stability and reliability of these contours by an inter-observer analysis including three other experienced radiation oncologists from our department. In total, a dice coefficient between 63% and 89% is achieved between the four different observers. Compared with this value, the model predictions (62-66%) perform reasonably well, given the fact that these tumour volumes were created based on the pre-operative segmentation and DTI.

DUNEuro-A software toolbox for forward modeling in bioelectromagnetism.

Accurate and efficient source analysis in electro- and magnetoencephalography using sophisticated realistic head geometries requires advanced numerical approaches. This paper presents DUNEuro, a free and open-source C++ software toolbox for the numerical computation of forward solutions in bioelectromagnetism. Building upon the DUNE framework, it provides implementations of modern fitted and unfitted finite element methods to efficiently solve the forward problems of electro- and magnetoencephalography. The user can choose between a variety of different source models that are implemented. The software's aim is to provide interfaces that are extendable and easy-to-use. In order to enable a closer integration into existing analysis pipelines, interfaces to Python and MATLAB are provided. The practical use is demonstrated by a source analysis example of somatosensory evoked potentials using a realistic six-compartment head model. Detailed installation instructions and example scripts using spherical and realistic head models are appended.

Estimating the extent of glioblastoma invasion : Approximate stationalization of anisotropic advection-diffusion-reaction equations in the context of glioblastoma invasion.

Glioblastoma Multiforme is a malignant brain tumor with poor prognosis. There have been numerous attempts to model the invasion of tumorous glioma cells via partial differential equations in the form of advection-diffusion-reaction equations. The patient-wise parametrization of these models, and their validation via experimental data has been found to be difficult, as time sequence measurements are mostly missing. Also the clinical interest lies in the actual (invisible) tumor extent for a particular MRI/DTI scan and not in a predictive estimate. Therefore we propose a stationalized approach to estimate the extent of glioblastoma (GBM) invasion at the time of a given MRI/DTI scan. The underlying dynamics can be derived from an instationary GBM model, falling into the wide class of advection-diffusion-reaction equations. The stationalization is introduced via an analytic solution of the Fisher-KPP equation, the simplest model in the considered model class. We investigate the applicability in 1D and 2D, in the presence of inhomogeneous diffusion coefficients and on a real 3D DTI-dataset.

A comprehensive study on electroencephalography and magnetoencephalography sensitivity to cortical and subcortical sources.

Signal-to-noise ratio (SNR) maps are a good way to visualize electroencephalography (EEG) and magnetoencephalography (MEG) sensitivity. SNR maps extend the knowledge about the modulation of EEG and MEG signals by source locations and orientations and can therefore help to better understand and interpret measured signals as well as source reconstruction results thereof. Our work has two main objectives. First, we investigated the accuracy and reliability of EEG and MEG finite element method (FEM)-based sensitivity maps for three different head models, namely an isotropic three and four-compartment and an anisotropic six-compartment head model. As a result, we found that ignoring the cerebrospinal fluid leads to an overestimation of EEG SNR values. Second, we examined and compared EEG and MEG SNR mappings for both cortical and subcortical sources and their modulation by source location and orientation. Our results for cortical sources show that EEG sensitivity is higher for radial and deep sources and MEG for tangential ones, which are the majority of sources. As to the subcortical sources, we found that deep sources with sufficient tangential source orientation are recordable by the MEG. Our work, which represents the first comprehensive study where cortical and subcortical sources are considered in highly detailed FEM-based EEG and MEG SNR mappings, sheds a new light on the sensitivity of EEG and MEG and might influence the decision of brain researchers or clinicians in their choice of the best modality for their experiment or diagnostics, respectively.

A realistic, accurate and fast source modeling approach for the EEG forward problem.

The aim of this paper is to advance electroencephalography (EEG) source analysis using finite element method (FEM) head volume conductor models that go beyond the standard three compartment (skin, skull, brain) approach and take brain tissue inhomogeneity (gray and white matter and cerebrospinal fluid) into account. The new approach should enable accurate EEG forward modeling in the thin human cortical structures and, more specifically, in the especially thin cortices in children brain research or in pathological applications. The source model should thus be focal enough to be usable in the thin cortices, but should on the other side be more realistic than the current standard mathematical point dipole. Furthermore, it should be numerically accurate and computationally fast. We propose to achieve the best balance between these demands with a current preserving (divergence conforming) dipolar source model. We develop and investigate a varying number of current preserving source basis elements n (n=1,…,n=5). For validation, we conducted numerical experiments within a multi-layered spherical domain, where an analytical solution exists. We show that the accuracy increases along with the number of basis elements, while focality decreases. The results suggest that the best balance between accuracy and focality in thin cortices is achieved with n=4 (or in extreme cases even n=3) basis functions, while in thicker cortices n=5 is recommended to obtain the highest accuracy. We also compare the current preserving approach to two further FEM source modeling techniques, namely partial integration and St. Venant, and show that the best current preserving source model outperforms the competing methods with regard to overall balance. For all tested approaches, FEM transfer matrices enable high computational speed. We implemented the new EEG forward modeling approaches into the open source duneuro library for forward modeling in bioelectromagnetism to enable its broader use by the brain research community. This library is build upon the DUNE framework for parallel finite elements simulations and integrates with high-level toolboxes like FieldTrip. Additionally, an inversion test has been implemented using the realistic head model to demonstrate and compare the differences between the aforementioned source models.

The Discontinuous Galerkin Finite Element Method for Solving the MEG and the Combined MEG/EEG Forward Problem.

In Electro- (EEG) and Magnetoencephalography (MEG), one important requirement of source reconstruction is the forward model. The continuous Galerkin finite element method (CG-FEM) has become one of the dominant approaches for solving the forward problem over the last decades. Recently, a discontinuous Galerkin FEM (DG-FEM) EEG forward approach has been proposed as an alternative to CG-FEM (Engwer et al., 2017). It was shown that DG-FEM preserves the property of conservation of charge and that it can, in certain situations such as the so-called skull leakages, be superior to the standard CG-FEM approach. In this paper, we developed, implemented, and evaluated two DG-FEM approaches for the MEG forward problem, namely a conservative and a non-conservative one. The subtraction approach was used as source model. The validation and evaluation work was done in statistical investigations in multi-layer homogeneous sphere models, where an analytic solution exists, and in a six-compartment realistically shaped head volume conductor model. In agreement with the theory, the conservative DG-FEM approach was found to be superior to the non-conservative DG-FEM implementation. This approach also showed convergence with increasing resolution of the hexahedral meshes. While in the EEG case, in presence of skull leakages, DG-FEM outperformed CG-FEM, in MEG, DG-FEM achieved similar numerical errors as the CG-FEM approach, i.e., skull leakages do not play a role for the MEG modality. In particular, for the finest mesh resolution of 1 mm sources with a distance of 1.59 mm from the brain-CSF surface, DG-FEM yielded mean topographical errors (relative difference measure, RDM%) of 1.5% and mean magnitude errors (MAG%) of 0.1% for the magnetic field. However, if the goal is a combined source analysis of EEG and MEG data, then it is highly desirable to employ the same forward model for both EEG and MEG data. Based on these results, we conclude that the newly presented conservative DG-FEM can at least complement and in some scenarios even outperform the established CG-FEM approaches in EEG or combined MEG/EEG source analysis scenarios, which motivates a further evaluation of DG-FEM for applications in bioelectromagnetism.

Simple and fast spectral domain algorithm for quantitative phase imaging of living cells with digital holographic microscopy.

We present a simple and fast phase aberration compensation method in digital holographic microscopy (DHM) for quantitative phase imaging of living cells. By analyzing the frequency spectrum of an off-axis hologram, phase aberrations can be compensated for automatically without fitting or pre-knowledge of the setup and/or the object. Simple and effective computation makes the method suitable for quantitative online monitoring with highly variable DHM systems. Results from automated quantitative phase imaging of living NIH-3T3 mouse fibroblasts demonstrate the effectiveness and the feasibility of the method.

The Unfitted Discontinuous Galerkin Method for Solving the EEG Forward Problem.

OBJECTIVE: The purpose of this study is to introduce and evaluate the unfitted discontinuous Galerkin finite element method (UDG-FEM) for solving the electroencephalography (EEG) forward problem. METHODS: This new approach for source analysis does not use a geometry conforming volume triangulation, but instead uses a structured mesh that does not resolve the geometry. The geometry is described using level set functions and is incorporated implicitly in its mathematical formulation. As no triangulation is necessary, the complexity of a simulation pipeline and the need for manual interaction for patient-specific simulations can be reduced and is comparable with that of the FEM for hexahedral meshes. In addition, it maintains conservation laws on a discrete level. Here, we present the theory for UDG-FEM forward modeling, its verification using quasi-analytical solutions in multilayer sphere models and an evaluation in a comparison with a discontinuous Galerkin (DG-FEM) method on hexahedral and on conforming tetrahedral meshes. We furthermore apply the UDG-FEM forward approach in a realistic head model simulation study. RESULTS: The results show convergence to the quasi-analytical solution and indicate a good accuracy of UDG-FEM. UDG-FEM performs comparable or even better than DG-FEM on a conforming tetrahedral mesh while providing a less complex simulation pipeline. When compared to DG-FEM on hexahedral meshes, an overall better accuracy is achieved. CONCLUSION: The UDG-FEM approach is an accurate, flexible, and promising method to solve the EEG forward problem. SIGNIFICANCE: This study shows the first application of the UDG-FEM approach to the EEG forward problem.

A multiscale model for glioma spread including cell-tissue interactions and proliferation.

Glioma is a broad class of brain and spinal cord tumors arising from glia cells, which are the main brain cells that can develop into neoplasms. They are highly invasive and lead to irregular tumor margins which are not precisely identifiable by medical imaging, thus rendering a precise enough resection very difficult. The understanding of glioma spread patterns is hence essential for both radiological therapy as well as surgical treatment. In this paper we propose a multiscale model for glioma growth including interactions of the cells with the underlying tissue network, along with proliferative effects. Our current accounting for two subpopulations of cells to accomodate proliferation according to the go-or-grow dichtomoty is an extension of the setting in [16]. As in that paper, we assume that cancer cells use neuronal fiber tracts as invasive pathways. Hence, the individual structure of brain tissue seems to be decisive for the tumor spread. Diffusion tensor imaging (DTI) is able to provide such information, thus opening the way for patient specific modeling of glioma invasion. Starting from a multiscale model involving subcellular (microscopic) and individual (mesoscale) cell dynamics, we perform a parabolic scaling to obtain an approximating reaction-diffusion-transport equation on the macroscale of the tumor cell population. Numerical simulations based on DTI data are carried out in order to assess the performance of our modeling approach.

Effective equations for anisotropic glioma spread with proliferation: a multiscale approach and comparisons with previous settings.

Glioma is a common type of primary brain tumour, with a strongly invasive potential, often exhibiting non-uniform, highly irregular growth. This makes it difficult to assess the degree of extent of the tumour, hence bringing about a supplementary challenge for the treatment. It is therefore necessary to understand the migratory behaviour of glioma in greater detail. In this paper, we propose a multiscale model for glioma growth and migration. Our model couples the microscale dynamics (reduced to the binding of surface receptors to the surrounding tissue) with a kinetic transport equation for the cell density on the mesoscopic level of individual cells. On the latter scale, we also include the proliferation of tumour cells via effects of interaction with the tissue. An adequate parabolic scaling yields a convection-diffusion-reaction equation, for which the coefficients can be explicitly determined from the information about the tissue obtained by diffusion tensor imaging (DTI). Numerical simulations relying on DTI measurements confirm the biological findings that glioma spread along white matter tracts.

Influence of cell shape, inhomogeneities and diffusion barriers in cell polarization models.

In silico experiments bear the potential for further understanding of biological transport processes by allowing a systematic modification of any spatial property and providing immediate simulation results. Cell polarization and spatial reorganization of membrane proteins are fundamental for cell division, chemotaxis and morphogenesis. We chose the yeast Saccharomyces cerevisiae as an exemplary model system which entails the shuttling of small Rho GTPases such as Cdc42 and Rho, between an active membrane-bound form and an inactive cytosolic form. We used partial differential equations to describe the membrane-cytosol shuttling of proteins. In this study, a consistent extension of a class of 1D reaction-diffusion systems into higher space dimensions is suggested. The membrane is modeled as a thin layer to allow for lateral diffusion and the cytosol is modeled as an enclosed volume. Two well-known polarization mechanisms were considered. One shows the classical Turing-instability patterns, the other exhibits wave-pinning dynamics. For both models, we investigated how cell shape and diffusion barriers like septin structures or bud scars influence the formation of signaling molecule clusters and subsequent polarization. An extensive set of in silico experiments with different modeling hypotheses illustrated the dependence of cell polarization models on local membrane curvature, cell size and inhomogeneities on the membrane and in the cytosol. In particular, the results of our computer simulations suggested that for both mechanisms, local diffusion barriers on the membrane facilitate Rho GTPase aggregation, while diffusion barriers in the cytosol and cell protrusions limit spontaneous molecule aggregations of active Rho GTPase locally.

Glioma follow white matter tracts: a multiscale DTI-based model.

Gliomas are a class of rarely curable tumors arising from abnormal glia cells in the human brain. The understanding of glioma spreading patterns is essential for both radiological therapy as well as surgical treatment. Diffusion tensor imaging (DTI) allows to infer the white matter fibre structure of the brain in a noninvasive way. Painter and Hillen (J Theor Biol 323:25-39, 2013) used a kinetic partial differential equation to include DTI data into a class of anisotropic diffusion models for glioma spread. Here we extend this model to explicitly include adhesion mechanisms between glioma cells and the extracellular matrix components which are associated to white matter tracts. The mathematical modelling follows the multiscale approach proposed by Kelkel and Surulescu (Math Models Methods Appl Sci 23(3), 2012). We use scaling arguments to deduce a macroscopic advection-diffusion model for this process. The tumor diffusion tensor and the tumor drift velocity depend on both, the directions of the white matter tracts as well as the binding dynamics of the adhesion molecules. The advanced computational platform DUNE enables us to accurately solve our macroscopic model. It turns out that the inclusion of cell binding dynamics on the microlevel is an important factor to explain finger-like spread of glioma.

Modelling in vitro growth of dense root networks.

Hairy roots are plants genetically transformed by Agrobacterium rhizogenes, which do not produce shoots and are composed mainly by roots. Hairy roots of Ophiorrhiza mungos Linn. are currently gaining interest of pharmacologists, since a secondary product of their metabolism, camptothecin, is used in chemotherapy. To optimize the production of valuable secondary metabolites it is necessary to understand the metabolism and growth of these roots systems. In this work, a mathematical model for description of apical growth of a dense root network (e.g. hairy roots) is derived. A continuous approach is used to define densities of root tips and root volume. Equations are posed to describe the evolution of these and are coupled to the distribution of nutrient concentration in the medium and inside the network. Following the principles of irreversible thermodynamics, growth velocity is defined as the sum over three different driving forces: nutrient concentration gradients, space gradients and root tip diffusion. A finite volume scheme was used for the simulation and parameters were chosen to fit experimental data from O. mungos Linn. hairy roots. Internal nutrient concentration determines short-term growth. Long-term behavior is limited by the total nutrient amount in the medium. Therefore, mass yield could be increased by guaranteeing a constant supply of nutrients. Increasing the initial mass of inoculation did not result in higher mass yields, since nutrient consumption due to metabolism also rose. Four different growth strategies are compared and their properties discussed. This allowed to understand which strategy might be the best to increase mass production optimally. The model is able to describe very well the temporal evolution of mass increase and nutrient uptake. Our results provide further understanding of growth and density distribution of hairy root network and therefore it is a sound base for future applications to describe, e.g., secondary metabolite production.