The vestibular system is responsible for our sense of balance and spatial orientation. Recent studies have shown the possibility of partially restoring the function of this system using vestibular implants. Electrical modeling is a valuable tool in assisting the development of these implants by analyzing stimulation effects. However, previous modeling approaches of the vestibular system assumed quasi-static conditions. In this work, an extended modeling approach is presented that considers the reactive component of impedance and the electrode-tissue interface and their effects are investigated in a 3D human vestibular computer model. The Fourier finite element method was employed considering the frequency-dependent electrical properties of the different tissues. The electrode-tissue interface was integrated by an instrumental electrode model. A neuron model of myelinated fibers was employed to predict the nerve responses to the electrical stimulus. Morphological changes of the predicted voltage waveforms considering the dielectric tissue properties were found compared to quasi-static simulations, particularly during monopolar electrode configuration. Introducing the polarization capacitance and the scar tissue around the electrode in combination with a power limitation leads to a considerable current reduction applied through the active electrode and, consequently, to reduced voltage amplitudes of the stimulus waveforms. The reactive component of impedance resulted in better selectivity for the excitation of target nerves compared to the quasi-static simulation at the expense of slightly increased stimulus current amplitudes. We conclude that tissue permittivity and effects of the electrode-tissue interface should be considered to improve the accuracy of the simulations.

Objective. Several lumped and distributed parameter models of the inner ear have been proposed to improve vestibular implant stimulation. The models should account for all significant physical phenomena that influence the current propagation, such as the electrical double layer (EDL) and medium polarization. The electrical properties of the medium are reflected in the electrical impedance; therefore, the study aimed to measure the impedance in the guinea pig inner ear and construct its equivalent circuit.Approach. The electrical impedance was measured from 100 Hz to 50 kHz between a pair of platinum electrodes immersed in 0.9% NaCl saline solution using sinusoidal voltage signals. The Randles circuit was fitted to the measured impedance in the saline solution in order to estimate the EDL parameters (C,W,andRct) of the electrode interface in saline. Then, the electrical impedance was measured between all combinations of the electrodes located in the semicircular canal ampullae and the vestibular nerve in the guinea pigin vitro. The extended Randles circuit considering the medium polarization (Ri,Re,Cm) together with EDL parameters (C,Rct) obtained from the saline solution was fitted to the measured impedance of the guinea pig inner ear. The Warburg element was assumed negligible and was not considered in the guinea pig model.Main results. For the set-up used, the obtained EDL parameters were:C=27.09*10-8F,Rct=18.75kΩ.The average values of intra-, extracellular resistances, and membrane capacitance wereRi=4.74kΩ,Re=45.05kΩ,Cm=9.69*10-8F,respectively.Significance. The obtained values of the model parameters can serve as a good estimation of the EDL for modelling work. The EDL, together with medium polarization, plays a significant role in the electrical impedance of the guinea pig inner ear, therefore, they should be considered in electrical conductivity models to increase the credibility of the simulations.

⎯ A human inner ear model was extended to include a synthetic cochlea model for analyzing unintended stimulation of the auditory nerve by a vestibular implant. Stimulation amplitudes for activation of the auditory nerve during monopolar vestibular stimulation were simulated as well as alterations in neural activation of other nerve branches due to the insertion of the synthetic cochlea. Only small deviations were found for stimulus amplitudes and neural activation in neighboring nerve branches, indicating a negligible effect on the overall stimulation result when including the synthetic cochlea model. A more complete picture of the stimulation outcome can be obtained by considering the synthetic cochlea instead of incomplete segmentations of the auditory nerve. Keywords⎯ Vestibular implant, virtual model, synthetic cochlea, human anatomy, nerve stimulation

Somatosensory evoked potentials are a well-established tool for assessing volley conduction in afferent neural pathways. However, from a clinical perspective, recording of spinal signals is still a demanding task due to the low amplitudes compared to relevant noise sources. Computer modeling is a powerful tool for gaining insight into signal genesis and, thus, for promoting future innovations in signal extraction. However, due to the complex structure of neural pathways, modeling is computationally demanding. We present a theoretical framework which allows computing the electric potential generated by a single axon in a body surface lead by the convolution of the neural lead field function with a propagating action potential term. The signal generated by a large cohort of axons was obtained by convoluting a single axonal signal with the statistical distribution of temporal dispersion of individual axonal signals. For establishing the framework, analysis was based on an analytical model. Our approach was further adopted for a numerical computation of body surface neuropotentials employing the lead field theory. Double convolution allowed straightforward analysis in the frequency domain. The highest frequency components occurred at the cellular membrane. A bandpass type spectral shape and a peak frequency of 1800 Hz was observed. The volume conductor transmitting the signal to the recording lead acted as an additional bandpass reducing the axonal peak frequency from 200 Hz to 500 Hz. The superposition of temporally dispersed axonal signals acted as an additional low-pass filter further reducing the compound action potential peak frequency from 90 Hz to 170 Hz. Our results suggest that the bandwidth of spinal evoked potentials might be narrower than the bandwidth requested by current clinical guidelines. The present findings will allow the optimization of noise suppression. Furthermore, our theoretical framework allows the adaptation in numerical methods and application in anatomically realistic geometries in future studies.

Spatial quantitative information about magnetic nanoparticle (MNP) distributions is a prerequisite for biomedical applications like magnetic hyperthermia and magnetic drug targeting. This information can be gathered by means of magnetorelaxometry (MRX) imaging, where the relaxation of previously aligned MNP’s magnetic moments is measured by sensitive magnetometers and an inverse problem is solved. To remove or minimize the magnetic shielding in which MRX imaging is carried out today, the knowledge of the influence of background magnetic fields on the MNP’s relaxation is a prerequisite. We show MRX measurements using an intensity-modulated optically pumped magnetometer (OPM) in background magnetic fields of up to $100~\upmu \mbox{T}$. We show that the relaxation parameters alter or may be intentionally altered significantly by applying static fields parallel or antiparallel to the MNP’s alignment direction. Further, not only the relaxation process of the MNP’s magnetic moments could be measured with OPM, but also their alignment due to the MRX excitation field.

Magnetorelaxometry imaging is a highly sensitive technique enabling noninvasive, quantitative detection of magnetic nanoparticles. Electromagnetic coils are sequentially energized, aligning the nanoparticles’ magnetic moments. Relaxation signals are recorded after turning off the coils. The forward model describing this measurement process is reformulated into a severely ill-posed inverse problem that is solved for estimating the particle distribution. Typically, many activation sequences employing different magnetic fields are required to obtain reasonable imaging quality. We seek to improve the imaging quality and accelerate the imaging process using fewer activation sequences by optimizing the applied magnetic fields. Minimizing the Frobenius condition number of the system matrix, we stabilize the inverse problem solution toward model uncertainties and measurement noise. Furthermore, our sensitivity-weighted reconstruction algorithms improve imaging quality in lowly sensitive areas. The optimization approach is employed to real measurement data and yields improved reconstructions with fewer activation sequences compared to non-optimized measurements.

Cryoimpedance is a potential new marker for monitoring catheter-wall contact, ice dimensions and temperature distributions within the frozen volume during cardiac cryoablation (CCA).Temperature and frequency dependent electrical impedances are measured in the domain surrounding the catheter by applying alternating currents through electrodes positioned on or close to the cryoapplicator.Computer models have previously been used to obtain insight into temperature distributions during CCA scenarios.The aim of this work is to assess characteristic effects of applicator positioning on simulated cryoimpedances using a finite element computer model.We considered a simplified model of a cryoapplicator positioned on a myocardial and pulmonary tissue layer and surrounded by an intracardiac blood domain.Previously measured temperature dependent admittivities of myocardial tissue and admittivities obtained from literature for blood and lung tissue were applied.The temporal progress of impedance between an active electrode at the catheter surface and a reference electrode in the blood domain during freezing and rewarming was simulated considering varying catheter-wall distances and insertion depths into the myocardial tissue layer.Considerably higher absolute impedances and phase shifts were obtained for catheter positions with catheter-wall contact.Additionally, impedance decreased significantly slower during rewarming in simulations, in which the catheter was inserted deeper into the myocardial tissue.This effect is caused by the lower admittivity of myocardial tissue compared to the surrounding blood as well as by the slower rewarming of the larger frozen myocardial volume when inserting the catheter deeper into the tissue.The results indicate that cryoimpedance measurement during CCA can be used as an effective tool to evaluate the positioning of the catheter as well as the performance of the procedure.Future studies are planned to validate the model, consider more realistic simulation domains and analyze the influence of altering electrode dimensions, positions, and current frequencies on the resulting impedance.

Increasing impedance during freezing might be a valuable marker for guiding cardiac cryo-ablation. We provide model based insights on how decreasing temperature below the freezing point of tissue relates to the percentage of frozen water. Furthermore, we provide experimental data for comparing this percentage with the increase in impedance. Measurements were performed on a bovine tissue sample at frequencies between 5 and 80 kHz. Slow cooling and heating rates were applied to minimize temperature gradients in the myocardial sample and to allow accurate assessment of the freezing point. Computer simulation was applied to link impedance with temperature dependent conductivities. The osmotic virial equation was used to estimate the percentage of frozen water. Measurements identified the freezing point at -0.6 degrees C. At -5 degrees C, impedance rose by more than a factor of ten compared to that at the freezing point and the percentage of frozen water was estimated as being 89%. At -49 degrees C impedance had increased by up to three orders of magnitude and ice formation was most pronounced in the extracellular space. Progressive ice formation in tissue is reflected by a large increase in impedance, and impedance increases monotonically with the percentage of frozen water. Its analysis allows for experimental assessment of factors relevant to cell death. Solid ice contributes to the rupture of the micro-vasculature, while phase shifts reflect concentration differences between extra- and intracellular space driving osmotic water transfer across cell membranes. (C) 2019 IPEM. Published by Elsevier Ltd. All rights reserved.

Somatosensory evoked potentials (SEPs) are produced by stimulation of a peripheral nerve and the related conduction of the volley to the somatosensory cortex.Lumbosacral SEPs may contain mixed signal components originating from synaptic potentials and volley conduction along the white mater of the spinal cord.In this study, we present an analytical model to study the frequency components in longitudinal spinal volley conduction.For simulating the body surface potential generated by pulse conduction along a single axon the model contains a source term related to the action potential and a volume conductor term related to pulse propagation along the axon.The body surface potential and its frequency spectrum are obtained by convolution of the source and volume conductor terms.The compound action potential (CAP) propagating along a neural pathway is obtained by the superposition of multiple axonal signals with individual temporal dispersion.Assuming a normal distribution of temporal dispersion, the CAP and its frequency spectrum are obtained.For mimicking the anatomy of a neural tract within the lumbosacral spinal cord we investigated three values of depth (35, 50 and 65 mm).Furthermore, we assigned three different conduction velocities (45, 60 and 75 m/s) to each depth.We assumed that temporal dispersion is reduced for higher conduction velocity and assigned three values for its standard deviation (1.0, 1.25 and 1.5 ms).For all simulation we obtained a welldefined frequency spectrum with a single peak in the frequency range of 115 to 215 Hz.The 50% amplitude bandwidth was always between 42 Hz and 396 Hz.Our simulation suggests, that signal components generated by longitudinal spinal volley conduction are mainly contained in a well-defined frequency band of approximately 40 to 400 Hz, whereas a relatively large bandwidth of 20 Hz to 3000 Hz is an accepted standard to measure signals over the spinal cord.

A dysfunctional vestibular system can be a severe detriment to the quality of life of a patient. Recent studies have shown the feasibility for a vestibular implant to restore rotational sensation via electrical stimulation of vestibular ampullary nerves. However, the optimal stimulation site for selective elicitation of the desired nerve is still unknown. We realized a finite element model on the basis of μCT scans of a human inner ear and incorporated naturally distributed, artificial neural trajectories. A well validated neuron model of myelinated fibers was incorporated to predict nerve responses to electrical stimulation. Several virtual electrodes were placed in locations of interest inside the bony labyrinth (intra-labyrinthine) and inside the temporal bone, near the target nerves (extra-labyrinthine), to determine preferred stimulation sites and electrode insertion depths. We investigated various monopolar and bipolar electrode configurations as well as different pulse waveform shapes for their ability to selectively stimulate the target nerve and for their energy consumption. The selectivity was evaluated with an objective measure of the fiber recruitment. Considerable differences of required energy and achievable selectivity between the configurations were observed. Bipolar, intra-labyrinthine electrodes provided the best selectivities but also consumed the highest amount of energy. Bipolar, extra-labyrinthine configurations did not offer any advantages compared to the monopolar approach. No selective stimulation could be performed with the monopolar, intra-labyrinthine approach. The monopolar, extra-labyrinthine electrodes required the least energy for satisfactory selectivities, making it the most promising approach for functional vestibular implants. Different pulse waveform shapes did not affect the achieved selectivity considerably but shorter pulse durations showed consistently a more selective activation of the target nerves. A cathodic, centered triangular waveform shape was identified as the most energy-efficient of the tested shapes. Based on these simulations we are able to recommend the monopolar, extra-labyrinthine stimulation approach with cathodic, centered triangular pulses as good trade-off between selectivity and energy consumption. Future implant designs could benefit from the findings presented here.

Stable posture and body movement in humans is dictated by the precise functioning of the ampulla organs in the semi-circular canals. Statistical analysis of the interrelationship between bony and membranous compartments within the semi-circular canals is dependent on the visualization of soft tissue structures. Thirty-one human inner ears were prepared, post-fixed with osmium tetroxide and decalcified for soft tissue contrast enhancement. High resolution X-ray microtomography images at 15 μm voxel-size were manually segmented. This data served as templates for centerline generation and cross-sectional area extraction. Our estimates demonstrate the variability of individual specimens from averaged centerlines of both bony and membranous labyrinth. Centerline lengths and cross-sectional areas along these lines were identified from segmented data. Using centerlines weighted by the inverse squares of the cross-sectional areas, plane angles could be quantified. The fit planes indicate that the bony labyrinth resembles a Cartesian coordinate system more closely than the membranous labyrinth. A widening in the membranous labyrinth of the lateral semi-circular canal was observed in some of the specimens. Likewise, the cross-sectional areas in the perilymphatic spaces of the lateral canal differed from the other canals. For the first time we could precisely describe the geometry of the human membranous labyrinth based on a large sample size. Awareness of the variations in the canal geometry of the membranous and bony labyrinth would be a helpful reference in designing electrodes for future vestibular prosthesis and simulating fluid dynamics more precisely.

Our sense of balance and spatial orientation strongly depends on the correct functionality of our vestibular system. Vestibular dysfunction can lead to blurred vision and impaired balance and spatial orientation, causing a significant decrease in quality of life. Recent studies have shown that vestibular implants offer a possible treatment for patients with vestibular dysfunction. The close proximity of the vestibular nerve bundles, the facial nerve and the cochlear nerve poses a major challenge to targeted stimulation of the vestibular system. Modeling the electrical stimulation of the vestibular system allows for an efficient analysis of stimulation scenarios previous to time and cost intensive in vivo experiments. Current models are based on animal data or CAD models of human anatomy. In this work, a (semi-)automatic modular workflow is presented for the stepwise transformation of segmented vestibular anatomy data of human vestibular specimens to an electrical model and subsequently analyzed. The steps of this workflow include (i) the transformation of labeled datasets to a tetrahedra mesh, (ii) nerve fiber anisotropy and fiber computation as a basis for neuron models, (iii) inclusion of arbitrary electrode designs, (iv) simulation of quasistationary potential distributions, and (v) analysis of stimulus waveforms on the stimulation outcome. Results obtained by the workflow based on human datasets and the average shape of a statistical model revealed a high qualitative agreement and a quantitatively comparable range compared to data from literature, respectively. Based on our workflow, a detailed analysis of intra- and extra-labyrinthine electrode configurations with various stimulation waveforms and electrode designs can be performed on patient specific anatomy, making this framework a valuable tool for current optimization questions concerning vestibular implants in humans.

Hypothermia has a profound impact on the electrophysiological mechanisms of the heart. Experimental investigations provide a better understanding of electrophysiological alterations associated with cooling. However, there is a lack of computer models suitable for simulating the effects of hypothermia in cardio-electrophysiology. In this work, we propose a model that describes the cooling-induced electrophysiological alterations in ventricular tissue in a temperature range from 27°C to 37°C. To model the electrophysiological conditions in a 3D left ventricular tissue block it was essential to consider the following anatomical and physiological parameters in the model: the different cell types (endocardial, M, epicardial), the heterogeneous conductivities in longitudinal, transversal and transmural direction depending on the prevailing temperature, the distinct fiber orientations and the transmural repolarization sequences. Cooling-induced alterations on the morphology of the action potential (AP) of single myocardial cells thereby are described by an extension of the selected Bueno-Orovio model for human ventricular tissue using Q10 temperature coefficients. To evaluate alterations on tissue level, the corresponding pseudo electrocardiogram (pECG) was calculated. Simulations show that cooling-induced AP and pECG-related parameters, i.e. AP duration, morphology of the notch of epicardial AP, maximum AP upstroke velocity, AP rise time, QT interval, QRS duration and J wave formation are in good accordance with literature and our experimental data. The proposed model enables us to further enhance our knowledge of cooling-induced electrophysiological alterations from cellular to tissue level in the heart and may help to better understand electrophysiological mechanisms, e.g. in arrhythmias, during hypothermia.

Abstract Recent studies show that vestibular implants have the potential to compensate the loss of functionality of the organ of equilibrium. The objective of this study was the development of a simulation framework which estimates the capability of various electrode arrangements and stimulation waveforms to selectively excite the ampullary nerves in the vestibular system. The choice of electrode configuration and stimulation waveform shows a significant influence in resulting selectivity, energy expenditure and injected charge in our simulations. This simulation environment could be beneficial in the development of safe and selective stimulation electrode designs.

High-throughput technologies such as mass spectrometry produce large amounts of data that require sophisticated computational methods to preprocess and identify highly discriminatory features (biomarker candidates) from these data. In this chapter, a computational workflow for the search and identification of biomarker candidates using mass spectrometry data is presented. First, preprocessing steps necessary to transform raw spectra into comparable data sets are described, followed by a novel three-step feature selection approach that combines the advantages of efficient filter and effective wrapper techniques. The proposed workflow has been integrated into the Knowledge Discovery in Databases (KD 3 ) Designer tool, our self-designed and cost-free software package. One of the main advantages of this tool is its straightforward design, which visualizes processing steps that can be easily connected to workflows. Due to its modular software architecture, new algorithms can be readily implemented into the system. This analysis strategy was evaluated using an example mass spectrometry data set.

Background Cardiac cryoablation is a minimally invasive procedure to treat cardiac arrhythmias by cooling cardiac tissues responsible for the cardiac arrhythmia to freezing temperatures. Although cardiac cryoablation offers a gentler treatment than radiofrequency ablation, longer interventions and higher recurrence rates reduce the clinical acceptance of this technique. Computer models of ablation scenarios allow for a closer examination of temperature distributions in the myocardium and evaluation of specific effects of applied freeze-thaw protocols in a controlled environment. Methods In this work multiple intervention scenarios with two freeze-thaw cycles were simulated with varying durations and starting times of the interim thawing phase using a finite element model verified by in-vivo measurements and data from literature. To evaluate the effects of different protocols, transmural temperature distributions and iceball dimensions were compared over time. Cryoadhesion durations of the applicator were estimated in the interim thawing phase with varying thawing phase starting times. In addition, the increase of cooling rates was compared between the freezing phases, and the thawing rates of interim thawing phases were analyzed over transmural depth. Results It could be shown that the increase of cooling rate, the regions undergoing additional phase changes and depths of selected temperatures depend on the chosen ablation protocol. Only small differences of the estimated cryoadhesion duration were found for ablation scenarios with interim thawing phase start after 90 s freezing. Conclusions By the presented model a quantification of effects responsible for cell death is possible, allowing for the analysis and optimization of cryoablation scenarios which contribute to a higher clinical acceptance of cardiac cryoablation.

The use of autonomous contracting randomly grown cardiomyocyte monolayers cultivated on microelectrode arrays (MEAs) represents an accepted experimental setting for preclinical experimental research in the field of cardiac electrophysiology. A dominant pacemaker forces a monolayer to adhere to a regular and synchronized contraction. Randomly distributed multiple pacemakers interfere with this dominant center, resulting in more or less frequent changes of propagation direction. This study aims to characterize the impact of changing propagation directions at single electrodes of the MEA on the four intrinsic parameters of registered field potentials (FPs) FPrise, FPMIN, FPpre, and FPdur and conduction velocity (CV) under normal and hypothermal conditions. Primary cultures of chicken cardiomyocytes (n = 18) were plated directly onto MEAs and FPs were recorded in a temperature range between 37 and 29°C. The number and spatiotemporal distribution of biological and artificial pacemakers of each cell layer inside and outside of the MEA registration area were evaluated using an algorithm developed in-house. In almost every second myocardial cell layer, interfering autonomous pacemakers were detected at stable temperatures, showing random spatial distributions with similar beating rates. Additionally, a temperature-dependent change of the dominant pacemaker center was observed in n = 16 experiments. A significant spread-direction-dependent variation of CV, FPrise, FPMIN, and FPpre up to 14% could be measured between different endogenous pacemakers. In conclusion, based on our results, disregarding the spatial origin of excitation may lead to misinterpretations and erroneous conclusions of FP parameters in the verification of research hypotheses in cellular electrocardiology.