Electrophysiological Simulations Research Articles

A Sketch-Based Interface for Modeling Myocardial Fiber Orientation that Considers the Layered Structure of the Ventricles

We propose a sketch-based interface for modeling the myocardial fiber orientation required in the electrophysiological simulation of the heart, especially the ventricles. The user can create a volumetric vector field that represents the myocardial fiber orientation in two steps. First, a depth field over the three-dimensional (3D) ventricular model is defined to create layers of myocardium. The user can then peel these layers and draw strokes on them to specify the myocardial fiber orientation in each layer. We represent the 3D ventricular model as a tetrahedral mesh and perform Laplacian smoothing over the mesh vertices to interpolate the vector field defined by the user-drawn strokes. Our method also allows the user to perform deformations on volumetric models of myocardial fiber orientation, which is very important for studying heart disease associated with morphological abnormalities. We created several examples of myocardial fiber orientation and applied them to a simplified simulator to demonstrate the effectiveness of our method.

Development of taste electrophysiological model and simulation

味质的结构和化学多样性决定了味觉有基于不同味觉物质的多种传导机制.近年来,随着分子生物学、细胞电生理研究方法的发展,有关味觉受体细胞电生理特性、味觉传导机制及味觉编码的研究取得了很大进展.综述了目前国际上味觉受体细胞电生理特性及其建模仿真方法的研究进展,同时评述目前味觉电生理建模仿真的几种主要方法的特点,最后论述了建模仿真方法对味觉机理以及味觉临床病理学研究的重要意义。

Successes and Rewards in Sharing Digital Reconstructions of Neuronal Morphology

The computer-assisted three-dimensional reconstruction of neuronal morphology is becoming an increasingly popular technique to quantify the arborization patterns of dendrites and axons. The resulting digital files are suitable for comprehensive morphometric analyses as well as for building anatomically realistic compartmental models of membrane biophysics and neuronal electrophysiology. The digital tracings acquired in a lab for a specific purpose can be often re-used by a different research group to address a completely unrelated scientific question, if the original investigators are willing to share the data. Since reconstructing neuronal morphology is a labor-intensive process, data sharing and re-analysis is particularly advantageous for the neuroscience and biomedical communities. Here we present numerous cases of "success stories" in which digital reconstructions of neuronal morphology were shared and re-used, leading to additional, independent discoveries and publications, and thus amplifying the impact of the "source" study for which the data set was first collected. In particular, we overview four main applications of this kind of data: comparative morphometric analyses, statistical estimation of potential synaptic connectivity, morphologically accurate electrophysiological simulations, and computational models of neuronal shape and development.

A Sketch-Based Interface for Modeling Myocardial Fiber Orientation

This article proposes a sketch-based interface for modeling muscle fiber orientation of a 3D virtual heart model. Our target was electrophysiological simulation of the heart and fiber orientation is one of the key elements to obtaining reliable simulation results. We designed the interface and algorithm based on the observation that fiber orientation is always parallel to the surface of the heart. The user specifies the fiber orientation by drawing a freeform stroke on the object surface. The system first builds a vector field on the surface by applying Laplacian smoothing to the mesh vertices and then builds a volumetric vector field by applying Laplacian smoothing to the voxels. We demonstrate the usefulness of the proposed method through a user study with a cardiologist.

Computational simulation of the input-output relationship in hippocampal pyramidal cells

The precise mapping of how complex patterns of synaptic inputs are integrated into specific patterns of spiking output is an essential step in the characterization of the cellular basis of network dynamics and function. Relative to other principal neurons of the hippocampus, the electrophysiology of CA1 pyramidal cells has been extensively investigated. Yet, the precise input-output relationship is to date unknown even for this neuronal class. CA1 pyramidal neurons receive laminated excitatory inputs from three distinct pathways: recurrent CA1 collaterals on basal dendrites, CA3 Schaffer collaterals, mostly on oblique and proximal apical dendrites, and entorhinal perforant pathway on distal apical dendrites. We implemented detailed computer simulations of pyramidal cell electrophysiology based on three-dimensional anatomical reconstructions and compartmental models of available biophysical properties from the experimental literature. To investigate the effect of synaptic input on axosomatic firing, we stochastically distributed a realistic number of excitatory synapses in each of the three dendritic layers. We then recorded the spiking response to different stimulation patterns. For all dendritic layers, synchronous stimuli resulted in trains of spiking output and a linear relationship between input and output firing frequencies. In contrast, asynchronous stimuli evoked non-bursting spike patterns and the corresponding firing frequency input-output function was logarithmic. The regular/irregular nature of the input synaptic intervals was only reflected in the regularity of output inter-burst intervals in response to synchronous stimulation, and never affected firing frequency. Synaptic stimulations in the basal and proximal apical trees across individual neuronal morphologies yielded remarkably similar input-output relationships. Results were also robust with respect to the detailed distributions of dendritic and synaptic conductances within a plausible range constrained by experimental evidence. In contrast, the input-output relationship in response to distal apical stimuli showed dramatic differences from the other dendritic locations as well as among neurons, and was more sensible to the exact channel densities.

Electrophysiological simulation study of ECG T-wave alternation caused by ultrahigh static magnetic fields

目的 初步仿真研究超高强度静磁场中的心电图T波幅度的改变机制.方法基于磁流体动力学模型,应用有限差分方法进行数值求解,通过改变磁场强度得到对应主动脉血流率;基于离子通道心室肌细胞模型,通过改变与ATP浓度相关的L型钙通道渗透率来仿真不同程度的心肌缺血情况.结果在超高静磁场中,人体主动脉的血流率减少可超过10%,可能会导致一定程度上的急性心肌缺血症;在不同心肌缺血情况下,心肌动作电位平台期受抑制,动作电位持续时间缩短,而透壁特异性增强,动态电生理力学心脏模型仿真得到心电图T波有较大改变.结论超高静磁场下主动脉血流率减少导致的心肌缺血会引起心电图T波幅度的明显增长,可能是超高静磁场对心电图T波影响的重要因素之一。

On the Computational Complexity of the Bidomain and the Monodomain Models of Electrophysiology

The bidomain model, coupled with accurate models of cell membrane kinetics, is generally believed to provide a reasonable basis for numerical simulations of cardiac electrophysiology. Because of changes occurring in very short time intervals and over small spatial domains, discretized versions of these models must be solved on fine computational grids, and small time-steps must be applied. This leads to huge computational challenges that have been addressed by several authors. One popular way of reducing the CPU demands is to approximate the bidomain model by the monodomain model, and thus reducing a two by two set of partial differential equations to one scalar partial differential equation; both of which are coupled to a set of ordinary differential equations modeling the cell membrane kinetics. A reduction in CPU time of two orders of magnitude has been reported. It is the purpose of the present paper to provide arguments that such a reduction is not present when order-optimal numerical methods are applied. Theoretical considerations and numerical experiments indicate that the reduction factor of the CPU requirements from bidomain to monodomain computations, using order-optimal methods, typically is about 10 for simple cell models and less than two for more complex cell models.

Heterogeneous three-dimensional anatomical and electrophysiological model of human atria

Investigating the mechanisms underlying the genesis and conduction of electrical excitation in the atria at physiological and pathological states is of great importance. To provide knowledge concerning the mechanisms of excitation, we constructed a biophysical detailed and anatomically accurate computer model of human atria that incorporates both structural and electrophysiological heterogeneities. The three-dimensional geometry was extracted from the visible female dataset. The sinoatrial node (SAN) and atrium, including crista terminalis (CT), pectinate muscles (PM), appendages (APG) and Bachmann's bundle (BB) were segmented in this work. Fibre orientation in CT, PM and BB was set to local longitudinal direction. Descriptions for all used cell types were based on modifications of the Courtemanche et al. model of a human atrial cell. Maximum conductances of Ito, IKr and ICa,L were modified for PM, CT, APG and atrioventricular ring to reproduce measured action potentials (AP). Pacemaker activity in the human SAN was reproduced by removing IK1, but including If, ICa,T, and gradients of channel conductances as described in previous studies for heterogeneous rabbit SAN. Anisotropic conduction was computed with a monodomain model using the finite element method. The transversal to longitudinal ratio of conductivity for PM, CT and BB was 1:9. Atrial working myocardium (AWM) was set to be isotropic. Simulation of atrial electrophysiology showed initiation of APs in the SAN centre. The excitation spread afterwards to the periphery near to the region of the CT and preferentially towards the atrioventricular region. The excitation extends over the right atrium along PM. Both CT and PM activated the right AWM. Earliest activation of the left atrium was through BB and excitation spread over to the APG. The conduction velocities were 0.6ms-1 for AWM, 1.2ms-1 for CT, 1.6ms-1 for PM and 1.1ms-1 for BB at a rate of 63bpm. The simulations revealed that bundles form dominant pathways for atrial conduction. The preferential conduction towards CT and along PM is comparable with clinical mapping. Repolarization is more homogeneous than excitation due to the heterogeneous distribution of electrophysiological properties and hence the action potential duration.

CESE

Cell electrophysiology simulation environment (CESE) is an integrated environment for performing simulations with a variety of electrophysiological models that have Hodgkin-Huxley and Markovian formulations of ionic currents. CESE is written in Java 2 and is readily portable to a number of operating systems. CESE allows execution of single-cell models and modification and clamping of model parameters, as well as data visualisation and analysis using a consistent interface. Model creation for CESE is facilitated by an object-oriented approach and use of an extensive modelling framework. The Web-based model repository is available. CESE and the Web-based model repository are available at http://cese.sourceforge.net/.

Planning of surgical antiarrhythmic interventions based on simulations of cardiac electrophysiology

Objectives: Surgical ablation procedures in atrial fibrillation originate from experiences made with the Cox-/Maze-procedure. Aiming at a better adaptation of the extent of surgery in individuals, a computer model based planning environment for this rhythm disorder was developed and validated using a Langendorff preparation of domestic pig hearts (n=8).

P1567 Simulation of cardiac electrophysiology using mathematical models and computer based processing of digital image data

P1567 Simulation of cardiac electrophysiology using mathematical models and computer based processing of digital image data

Effects of dendritic morphology on CA3 pyramidal cell electrophysiology: a simulation study

We investigated the effect of morphological differences on neuronal firing behavior within the hippocampal CA3 pyramidal cell family by using three-dimensional reconstructions of dendritic morphology in computational simulations of electrophysiology. In this paper, we report for the first time that differences in dendritic structure within the same morphological class can have a dramatic influence on the firing rate and firing mode (spiking versus bursting and type of bursting). Our method consisted of converting morphological measurements from three-dimensional neuroanatomical data of CA3 pyramidal cells into a computational simulator format. In the simulation, active channels were distributed evenly across the cells so that the electrophysiological differences observed in the neurons would only be due to morphological differences. We found that differences in the size of the dendritic tree of CA3 pyramidal cells had a significant qualitative and quantitative effect on the electrophysiological response. Cells with larger dendritic trees: (1) had a lower burst rate, but a higher spike rate within a burst, (2) had higher thresholds for transitions from quiescent to bursting and from bursting to regular spiking and (3) tended to burst with a plateau. Dendritic tree size alone did not account for all the differences in electrophysiological responses. Differences in apical branching, such as the distribution of branch points and terminations per branch order, appear to effect the duration of a burst. These results highlight the importance of considering the contribution of morphology in electrophysiological and simulation studies.

Prolonged Decay of Evoked Inhibitory Postsynaptic Currents in Hippocampal Neurons Is Not Shaped by Asynchronous Release

During evoked release, several quanta of neurotransmitter are synchronously released in several GABA-ergic synapses. Assuming that not more than one vesicle is released at each release site, the decay of miniature and evoked IPSC (mIPSC and eIPSC, respectively) should coincide. In this study, we found that in a considerable part of the cultured hippocampal neurons eIPSC decayed more slowly than mIPSC did. We investigated the mechanisms underlying this difference using conventional electrophysiological approaches, deconvolution, simulations, and nonstationary noise analysis. Our results indicate that asynchronous release of synaptic vesicles cannot explain the prolonged decay of the GABA-ergic IPSC. We suggest that some interaction between the quanta at the pre- and/or post-synaptic level should result in a slower decay of the eIPSC in comparison with that of mIPSC.

Role of Potassium Channels in Facilitation of Transmitter Release from Frog Motor Nerve Ending (Electrophysiology and Mathematical Simulation)

In experiments on neuromuscular junctions in the frog m. thoraco-cutaneous, we studied changes in the transmitter release and shape of the nerve ending (NE) response related to high-frequency (10 or 50 sec-1) rhythmic stimulation of the motor nerve; an extracellular recording technique was used. At a low extracellular Ca2+ concentration, rhythmic stimulation resulted in a gradual increase in the quantum content of end-plate currents, i.e., in facilitation. Simultaneously, the third (positive) phase of the NE response became smaller, the amplitude of the second (negative) phase of this response also decreased, while the duration of this phase increased. Modifications of the NE response upon stimulation with a 10 sec-1 frequency were more clearly expressed than those at 50 sec-1 stimulation. In Ca2+-free solutions, rhythmic stimulation was accompanied by analogous modifications of the shape of NE responses, and the dynamics of these changes were the same at both the above-mentioned stimulation frequencies. When 0.5-1.0 mM tetraethylammonium was applied, 10 sec-1 stimulation was accompanied by no facilitation of transmitter release; at 50 sec-1 stimulation, this phenomenon was observed but was weaker than in the control, and the shape of NE responses underwent only mild changes. Simulation of electrogenesis in the studied structure showed that modifications of the NE response shape related to rhythmic 10 sec-1 stimulation can develop in the case of a gradual decrease in the voltage-dependent potassium membrane conductivity, which results in prolongation of the de- and repolarization phases of action potentials and increases in the amplitude and duration of the inward calcium current. At higher stimulation frequencies (50 sec-1), this mechanism is accompanied by a gradual increase in the Ca2+-dependent potassium conductivity, due to an increase in the intracellular Ca2+ concentration. These data allow us to conclude that the intensity of facilitation of transmitter release from the frog motor NE is related not only to accumulation of “residual” calcium, but also to changes of presynaptic calcium current due to modification of the kinetics of functioning of the potassium channels.

L-neuron: A modeling tool for the efficient generation and parsimonious description of dendritic morphology

We introduce L-Neuron (www.krasnow.gmu.edu/L-Neuron), a software package for the generation and study of anatomically accurate neuronal analogs. L-Neuron is based on sets of recursive rules that parsimoniously describe dendritic geometry and topology by locally inter-correlating morphological parameters (e.g. branch diameter and length). The L-Neuron algorithm stochastically samples parameter values from experimental statistical distributions, to generate multiple, non-identical virtual neurons within various morphological classes. Such neuronal structures, described by an L-system/Turtle graphic formalism, can be converted in various 3D-graphic formats and/or in compartmental anatomical files to be used in electrophysiological simulation studies with modeling programs such as Genesis or Neuron.

Ion currents in a motor nerve terminal of the mouse (electrophysiology and computer simulation)

Electrical responses to stimulation of a motor nerve were extracellularly recorded from the nerve terminals (NT) in the experiments on neuromuscular preparations of the long ear levator of mice. Depending on the site of recording, NT membrane responses were considerably modified. In the preterminal NT region the response was negative, but it was inverted into positivity in more distal regions. The developed model of the murine NT allowed us to simulate membrane currents resembling the NT responses in corresponding recording sites. Fitting of model graphs to the experimental curves was achieved by an exponential decrease in the densities of sodium and potassium voltage-dependent channels, calcium-activated potassium channels, and leakage channels along the NT with the spatial decay constants of 1,6,6, and 6μm for each above channel type. The problems of spatial distribution of various ion channels within the NT, modifications of the shape of action potential (AP), and dynamics of the transmitter release along the NT, as well as the peculiarities of AP spreading in the NT, are discussed.

Computer software for development and simulation of compartmental models of neurons

A software package ‘Nodus’ for simulation and development of compartmental models of neurons is described. Passive or excitable membranes with voltage dependent ion conductances or synaptic conductances can be modeled. Detailed simulations of morphology and electrophysiology of neurons are possible. Neurophysiological experiments like voltage clamps and complex current injections can be simulated. Two integration methods are available: a fast hybrid method and an accurate fifth order Runge-Kutta method, with variable time steps. Nodus is implemented on Apple Macintosh microcomputers, with the standard user interface and interactive graphics. Simulations of simple test models demonstrate the accuracy and computation speed of the application.

Quantitative formulations of electrophysiological sources of potential fields in volume conductors.

The noninvasive measurement of electrical potentials at the surface of the body (e.g., the electrocardiogram) has long been considered an important tool in clinical diagnosis. Electrophysiological modeling and simulation is valuable as an aid in the interpretation of such potential recordings. In all cases, the potential field can be considered to arise from bioelectric sources operating in a volume conductor. This paper concentrates on the appropriate quantitative formulation for these sources. Such sources arise from excitable cells undergoing action potentials (primary sources) or at passive boundaries between regions of different conductivity (secondary sources). These sources are described and discussed for arbitrary cell shapes, circular cylindrical cells, conductive media with piecewise constant conductivity, and for syncytial tissue whose macroscopic properties are anisotropic.