Auditory nerve fiber excitability for alternative electrode placement in the obstructed human cochlea: electrode insertion in scala vestibuli versus scala tympani.

OBJECTIVE: The cochlear implant (CI) belongs to the most successful neuro-prostheses. Traditionally, the stimulating electrode arrays are inserted into the scala tympani (ST), the lower cochlear cavity, which enables simple surgical access. However, often deep insertion is blocked, e.g., by ossification, and the auditory nerve fibers (ANFs) of lower frequency regions cannot be stimulated causing severe restrictions in speech understanding. As an alternative, the CI can be inserted into the scala vestibuli (SV), the other upper cochlear cavity. APPROACH: In this computational study, the excitability of 25 ANFs are compared for stimulation with ST and SV implants. We employed a 3-dimensional realistic human cochlear model with lateral wall electrodes based on a µ-CT dataset and manually traced fibers. A finite element approach in combination with a compartment model of a spiral ganglion cell was used to simulate monophasic stimulation with anodic (ANO) and cathodic (CAT) pulses of 50 µs. MAIN RESULTS: ANO thresholds are lower in ST (mean/std = µ/σ =189/55 µA) stimulation compared to SV (µ/σ = 323/119 µA) stimulation. Contrary, CAT thresholds are higher for the ST array (µ/σ = 165/42 µA) compared to the SV array (µ/σ = 122/46 µA). The threshold amplitude depends on the specific fiber-electrode spatial relationship, such as lateral distance from the cochlear axis, the angle between electrode and target ANF, and the curvature of the peripheral process. For CAT stimulation the SV electrodes show a higher selectivity leading to less cross-stimulation of additional fibers from different cochlear areas. SIGNIFICANCE: We present a first simulation study with a human cochlear model that investigates an additional CI placement into the SV and its impact on the excitation behavior. Results predict comparable outcomes to ST electrodes which confirms that SV implantation might be an alternative for patients with a highly obstructed ST.

Finite element analysis and three-dimensional reconstruction of tonotopically aligned human auditory fiber pathways: A computational environment for modeling electrical stimulation by a cochlear implant based on micro-CT.

The application of cochlear implants can be studied with computational models. The electrical potential distribution induced by an implanted device is evaluated with a volume conductor model, which is used as input for neuron models to simulate the reaction of cochlear neurons to micro-stimulation. In order to reliably predict the complex excitation profiles it is vital to consider an accurate representation of the human cochlea geometry including detailed three-dimensional pathways of auditory neurons reaching from the organ of Corti through the cochlea-volume. In this study, high-resolution micro-CT imaging (Δx = Δy = Δz = 3 µm) was used to reconstruct the pathways of 30 tonotopically organized nerve fiber bundles, distributed over eight octaves (11500-40 Hz). Results of the computational framework predict: (i) the peripheral process is most sensitive to cathodic stimulation (CAT), (ii) in many cases CAT elicits spikes in the peripheral terminal at threshold but with larger stimuli there is a second spike initiation site within the peripheral process, (iii) anodic stimuli (ANO) can excite the central process even at threshold, (iv) the recruitment of fibers by electrodes located in the narrowing middle- and apical turn is complex and impedes focal excitation of low frequency fibers, (v) degenerated cells which lost the peripheral process are more sensitive to CAT when their somata are totally covered with 2 membranes of a glial cell but they become ANO sensitive when the myelin covering is reduced.

A Review on Tumor-Treating Fields (TTFields): Clinical Implications Inferred From Computational Modeling.

Tumor-treating fields (TTFields) are a cancer treatment modality that uses alternating electric fields of intermediate frequency (∼100-500 kHz) and low intensity (1-3 V/cm) to disrupt cell division. TTFields are delivered by transducer arrays placed on the skin close to the tumor and act regionally and noninvasively to inhibit tumor growth. TTFields therapy is U.S. Food and Drug Administration approved for the treatment of glioblastoma multiforme, the most common and aggressive primary human brain cancer. Clinical trials testing the safety and efficacy of TTFields for other solid tumor types are underway. The objective of this paper is to review computational approaches used to characterize TTFields. The review covers studies of the macroscopic spatial distribution of TTFields generated in the human head, and of the microscopic field distribution in tumor cells. In addition, preclinical and clinical findings related to TTFields and principles of its operation are summarized. Particular emphasis is put on outlining the potential clinical value inferred from computational modeling.

Transcutaneous spinal direct current stimulation of the lumbar and sacral spinal cord: a modelling study.

OBJECTIVE: Our aim was to perform a computational study of the electric field (E-field) generated by transcutaneous spinal direct current stimulation (tsDCS) applied over the thoracic, lumbar and sacral spinal cord, in order to assess possible neuromodulatory effects on spinal cord circuitry related with lower limb functions. APPROACH: A realistic volume conductor model of the human body consisting of 14 tissues was obtained from available databases. Rubber pad electrodes with a metallic connector and a conductive gel layer were modelled. The finite element (FE) method was used to calculate the E-field when a current of 2.5 mA was passed between two electrodes. The main characteristics of the E-field distributions in the spinal grey matter (spinal-GM) and spinal white matter (spinal-WM) were compared for seven montages, with the anode placed either over T10, T8 or L2 spinous processes (s.p.), and the cathode placed over right deltoid (rD), umbilicus (U) and right iliac crest (rIC) areas or T8 s.p. Anisotropic conductivity of spinal-WM and of a group of dorsal muscles near the vertebral column was considered. MAIN RESULTS: The average E-field magnitude was predicted to be above 0.15 V m-1 in spinal cord regions located between the electrodes. L2-T8 and T8-rIC montages resulted in the highest E-field magnitudes in lumbar and sacral spinal segments (>0.30 V m-1). E-field longitudinal component is 3 to 6 times higher than the ventral-dorsal and right-left components in both the spinal-GM and WM. Anatomical features such as CSF narrowing due to vertebrae bony edges or disks intrusions in the spinal canal correlate with local maxima positions. SIGNIFICANCE: Computational modelling studies can provide detailed information regarding the electric field in the spinal cord during tsDCS. They are important to guide the design of clinical tsDCS protocols that optimize stimulation of application-specific spinal targets.

Of Fields and Phantoms : The Importance of Virtual Humans in Optimizing Cancer Treatment with Tumor Treating Fields.

Cancer represents a compilation of diseases characterized by rapidly dividing, invasive cells. Worldwide data indicate that over 14 million new cancers were diagnosed in 2012, with a projected increase of more than 19 million diagnosed cases by 2025 [1]. Survival rates for some cancers have increased dramatically, but there are still cancer types for which the prognosis is poor and few treatments exist. Thus, there is a growing need for new therapies targeting these difficult-to-treat cancers.

Optimizing Electric-Field Delivery for tDCS: Virtual Humans Help to Design Efficient, Noninvasive Brain and Spinal Cord Electrical Stimulation.

Noninvasive electrical stimulation of the central nervous system is attracting increasing interest from the clinical and academic communities as well as from high-tech companies. This interest was sparked by two landmark studies conducted in 2000 and 2001 at the University of G?ttingen, Germany. Michael Nitsche and Walter Paulus showed that by passing a weak, almost imperceptible electric current between two electrodes on the scalp, they could alter the way the human brain responds to stimuli and that the effect persisted for some time after the current was stopped. These findings opened the prospect of therapeutic applications of transcranial direct-current stimulation (tDCS).

An Overview of Sub-Cellular Mechanisms Involved in the Action of TTFields.

Long-standing research on electric and electromagnetic field interactions with biological cells and their subcellular structures has mainly focused on the low- and high-frequency regimes. Biological effects at intermediate frequencies between 100 and 300 kHz have been recently discovered and applied to cancer cells as a therapeutic modality called Tumor Treating Fields (TTFields). TTFields are clinically applied to disrupt cell division, primarily for the treatment of glioblastoma multiforme (GBM). In this review, we provide an assessment of possible physical interactions between 100 kHz range alternating electric fields and biological cells in general and their nano-scale subcellular structures in particular. This is intended to mechanistically elucidate the observed strong disruptive effects in cancer cells. Computational models of isolated cells subject to TTFields predict that for intermediate frequencies the intracellular electric field strength significantly increases and that peak dielectrophoretic forces develop in dividing cells. These findings are in agreement with in vitro observations of TTFields' disruptive effects on cellular function. We conclude that the most likely candidates to provide a quantitative explanation of these effects are ionic condensation waves around microtubules as well as dielectrophoretic effects on the dipole moments of microtubules. A less likely possibility is the involvement of actin filaments or ion channels.

Improving Tumor Treating Fields Treatment Efficacy in Patients With Glioblastoma Using Personalized Array Layouts.

PURPOSE: To investigate tumors of different size, shape, and location and the effect of varying transducer layouts on Tumor Treating Fields (TTFields) distribution in an anisotropic model. METHODS AND MATERIALS: A realistic human head model was generated from MR images of 1 healthy subject. Four different virtual tumors were placed at separate locations. The transducer arrays were modeled to mimic the TTFields-delivering commercial device. For each tumor location, varying array layouts were tested. The finite element method was used to calculate the electric field distribution, taking into account tissue heterogeneity and anisotropy. RESULTS: In all tumors, the average electric field induced by either of the 2 perpendicular array layouts exceeded the 1-V/cm therapeutic threshold value for TTFields effectiveness. Field strength within a tumor did not correlate with its size and shape but was higher in more superficial tumors. Additionally, it always increased when the array was adapted to the tumor's location. Compared with a default layout, the largest increase in field strength was 184%, and the highest average field strength induced in a tumor was 2.21 V/cm. CONCLUSIONS: These results suggest that adapting array layouts to specific tumor locations can significantly increase field strength within the tumor. Our findings support the idea of personalized treatment planning to increase TTFields efficacy for patients with GBM.

Computational Trials: Unraveling Motility Phenotypes, Progression Patterns, and Treatment Options for Glioblastoma Multiforme.

Glioblastoma multiforme is a malignant brain tumor with poor prognosis and high morbidity due to its invasiveness. Hypoxia-driven motility and concentration-driven motility are two mechanisms of glioblastoma multiforme invasion in the brain. The use of anti-angiogenic drugs has uncovered new progression patterns of glioblastoma multiforme associated with significant differences in overall survival. Here, we apply a mathematical model of glioblastoma multiforme growth and invasion in humans and design computational trials using agents that target angiogenesis, tumor replication rates, or motility. The findings link highly-dispersive, moderately-dispersive, and hypoxia-driven tumors to the patterns observed in glioblastoma multiforme treated by anti-angiogenesis, consisting of progression by Expanding FLAIR, Expanding FLAIR + Necrosis, and Expanding Necrosis, respectively. Furthermore, replication rate-reducing strategies (e.g. Tumor Treating Fields) appear to be effective in highly-dispersive and moderately-dispersive tumors but not in hypoxia-driven tumors. The latter may respond to motility-reducing agents. In a population computational trial, with all three phenotypes, a correlation was observed between the efficacy of the rate-reducing agent and the prolongation of overall survival times. This research highlights the potential applications of computational trials and supports new hypotheses on glioblastoma multiforme phenotypes and treatment options.

The effect of inter-electrode distance on the electric field distribution during transcutaneous lumbar spinal cord direct current stimulation.

Previous studies have indicated potential neuromodulation of the spinal circuitry by transcutaneous spinal direct current stimulation (tsDCS), such as changes in motor unit recruitment, shortening of the peripheral silent period and interference with supraspinal input to lower motor neurons. All of these effects were dependent on the polarity of the electrodes. The present study investigates how the distance between the electrodes during tsDCS influences the electric field's (E-field) spatial distribution in the lumbar and sacral spinal cord (SC). The electrodes were placed longitudinally along the SC, with the target electrode over the lumbar spine, and the return electrode above the former, considering four different distances (4, 8, 12 and 16 cm from the target). A fifth configuration was also tested with the return electrode over the right deltoid muscle. Peak values of the E-field's magnitude are found in the lumbo-sacral region of the SC for all tested configurations. Increasing the distance between the electrodes results in a wider spread of the E-field magnitude distribution along the SC, with larger maximum peak values and a smoother variation. The fifth configuration does not present the highest maximum values when compared to the other configurations. The results indicate that the choice of the return electrode position relative to the target can influence the distribution and the range of values of the E-field magnitude in the SC. Possible clinical significance of the observed effects will be discussed.

Evaluation of the electric field in the brain during transcranial direct current stimulation: A sensitivity analysis.

The use of computational modeling studies accounts currently for the best approach to predict the electric field (E-field) distribution in transcranial direct current stimulation. As with any model, the values attributed to the physical properties, namely the electrical conductivity of the tissues, affect the predicted E-field distribution. A wide range of values for the conductivity of most tissues is reported in the literature. In this work, we used the finite element method to compute the E-field induced in a realistic human head model for two electrode montages targeting the left dorso-lateral prefrontal cortex (DLPFC). A systematic analysis of the effect of different isotropic conductivity profiles on the E-field distribution was performed for the standard bipolar 7×5 cm2 electrodes configuration and also for an optimized multielectrode montage. Average values of the E-field's magnitude, normal and tangential components were calculated in the target region in the left DLPFC. Results show that the field decreases with increasing scalp, cerebrospinal fluid (CSF) and grey matter (GM) conductivities, while the opposite is observed for the skull and white matter conductivities. The tissues whose conductivity most affects the E-field in the cortex are the scalp and the CSF, followed by the GM and the skull. Uncertainties in the conductivity of individual tissues may affect electric field values by up to about 80%.

First steps to creating a platform for high throughput simulation of TTFields.

Tumor Treating Fields (TTFields) are low intensity alternating electric fields in the 100-500 KHz frequency range that are known to have an anti-mitotic effect on cancerous cells. In the USA, TTFields are approved by the Food and Drug Administration (FDA) for the treatment of glioblastoma (GBM) in both the newly diagnosed and recurrent settings. Optimizing treatment with TTFields requires a deep understanding of how TTFields distribute within the brain. To address this issue, simulations using realistic head models have been performed. However, the preparation of such models is time-consuming and requires a high level of expertise, limiting the usefulness of these models for systematic studies in which the testing of multiple cases is required. Here we present a platform for rapidly simulating TTFields distributions in multiple scenarios. This platform enables high throughput computational simulations to be performed, allowing comparison of field distributions within the head in multiple clinically relevant scenarios. The simulation setup is simple and intuitive, allowing non-expert users to run simulations and evaluate results, thereby providing a valuable tool for studying how to optimize TTFields delivery in the clinic.

Investigating an alternative ring design of transducer arrays for tumor treating fields (TTFields).

Tumor treating fields (TTFields) is a therapy that inhibits cell proliferation and has been approved by the U.S Food and Drug Administration (FDA) for the treatment of Glioblastoma Multiforme. This anti-mitotic technique works non-invasively and regionally, and is associated with less toxicity and a better quality of life. Currently a device called Optune™ is clinically used which works with two perpendicular and alternating array pairs each consisting of 3×3 transducers. The aim of this study is to investigate a theoretical alternative array design which consists of two rings of 16 transducers and thus permits various field directions. A realistic human head model with isotropic tissues was used to simulate the electric field distribution induced by the two types of array layouts. One virtual tumour was modelled as a sphere in the white matter close to one lateral ventricle. Four alternative ring design directions were evaluated by activating arrays of 2×2 transducers on opposite sides of the head. The same amount of current was passed through active transducer arrays of the Optune system and the ring design. The electric field distribution in the brain differs for the various array configurations, with higher fields between activated transducer pairs and lower values in distant areas. Nonetheless, the average electric field strength values in the tumour are comparable for the various configurations. Values between 1.00 and 1.91 V/cm were recorded, which are above the threshold for effective treatment. Increasing the amount of field directions could possibly also increase treatment efficacy, because TTFields' effect on cancer cells is highest when the randomly distributed cell division axis is aligned with the field. The results further predict that slightly changing transducer positions only has a minor effect on the electric field. Thus patients might have some freedom to adjust array positions without major concern for treatment efficacy.

Simplified realistic human head model for simulating Tumor Treating Fields (TTFields).

Tumor Treating Fields (TTFields) are alternating electric fields in the intermediate frequency range (100-300 kHz) of low-intensity (1-3 V/cm). TTFields are an anti-mitotic treatment against solid tumors, which are approved for Glioblastoma Multiforme (GBM) patients. These electric fields are induced non-invasively by transducer arrays placed directly on the patient's scalp. Cell culture experiments showed that treatment efficacy is dependent on the induced field intensity. In clinical practice, a software called NovoTalTM uses head measurements to estimate the optimal array placement to maximize the electric field delivery to the tumor. Computational studies predict an increase in the tumor's electric field strength when adapting transducer arrays to its location. Ideally, a personalized head model could be created for each patient, to calculate the electric field distribution for the specific situation. Thus, the optimal transducer layout could be inferred from field calculation rather than distance measurements. Nonetheless, creating realistic head models of patients is time-consuming and often needs user interaction, because automated image segmentation is prone to failure. This study presents a first approach to creating simplified head models consisting of convex hulls of the tissue layers. The model is able to account for anisotropic conductivity in the cortical tissues by using a tensor representation estimated from Diffusion Tensor Imaging. The induced electric field distribution is compared in the simplified and realistic head models. The average field intensities in the brain and tumor are generally slightly higher in the realistic head model, with a maximal ratio of 114% for a simplified model with reasonable layer thicknesses. Thus, the present pipeline is a fast and efficient means towards personalized head models with less complexity involved in characterizing tissue interfaces, while enabling accurate predictions of electric field distribution.

Computational models of non-invasive brain and spinal cord stimulation.

Non-invasive brain and spinal cord stimulation techniques are increasingly used for diagnostic and therapeutic purposes. Knowledge of the spatial distribution of the induced electric field is necessary to interpret experimental results and to optimize field delivery. Since the induced electric field cannot be measured in vivo in humans, computational models play a fundamental role in determining the characteristics of the electric field. We produced computational models of the head and trunk to calculate the electric field induced in the brain and spinal cord by transcranial magnetic stimulation, transcranial direct current stimulation and transcutaneous spinal cord direct current stimulation. The field distribution is highly non-uniform and depends on the type of technique used, on the position of the stimulation sources, and on anatomy. In future these models may be improved by using more accurate and precise values for the physical parameters as they become available, by combining them with neuronal models to predict the outcome of stimulation, and by better segmentation and meshing techniques that make producing individual models practicable.

Using computational phantoms to improve delivery of Tumor Treating Fields (TTFields) to patients.

This paper reviews the state-of-the-art in simulation-based studies of Tumor Treating Fields (TTFields) and highlights major aspects of TTFields in which simulation-based studies could affect clinical outcomes. A major challenge is how to simulate multiple scenarios rapidly for TTFields delivery. Overcoming this challenge will enable a better understanding of how TTFields distribution is correlated with disease progression, leading to better transducer array designs and field optimization procedures, ultimately improving patient outcomes.

Influence of electrode configuration on the electric field distribution during transcutaneous spinal direct current stimulation of the cervical spine.

Transcutaneous spinal direct current stimulation (tsDCS) is a recent technique with promising neuromodulatory effects on spinal neuronal circuitry. The main objective of the present study was to perform a finite element analysis of the electric field distribution in tsDCS in the cervical spine region, with varying electrode configurations and geometry. A computational model of a human trunk was generated with nine tissue meshes. Three electrode configurations were tested: A) rectangular saline-soaked sponge target and return electrodes placed over C3 and T3 spinous processes, respectively; B1) circular saline-soaked sponge target and return electrodes placed over C7 spinous process and right deltoid muscle, respectively; B2) same configuration as B1, considering circular shaped electrodes with sponge and rubber layers and a small circular connector on the top surface. The electric field distribution for cervical tsDCS predicted higher magnitude in configurations B1 and B2, reaching a maximum of 0.71 V/m in the spinal white matter and 0.43 V/m in the spinal grey matter, with values above 0.15 V/m in the region of the spinal circuits related with upper limb innervation. In configuration A, the values were found to be <; 0.15 V/m through the entire spinal cord. Electric fields with magnitude above 0.15 V/m are thought to be effective in neuromodulation of the human cerebral cortex, so the configurations B1 and B2 could be an optimal choice for cervical tsDCS protocols. Computational studies using realistic models may be a powerful tool to predict physical effects of tsDCS on the cervical spinal cord and to optimize electrode placement focused on specific neurologic patient needs related with upper limb function.

Investigating the cortical regions involved in MEP modulation in tDCS.

Transcranial magnetic stimulation (TMS) is used in several studies to evaluate cortical excitability changes induced by transcranial direct current stimulation (tDCS) of the primary motor cortex. Interpretation of these results, however, is hindered by the very different spatial distribution of the electric field (E-field) induced by the two techniques and by the different target neurons that they might act upon. In this study we used the finite element method to calculate the E-field distribution induced by TMS and tDCS in a realistically shaped model of a human head. A model of a commercially available figure-8 coil was placed over a position above the identified hand knob (HK) region. We also modeled two configurations of bipolar tDCS montages with one of the electrodes placed over the HK and a return electrode over the contralateral orbital region. The electrodes over the HK were either rectangular in shape, with an area of 35 cm(2) or cylindrical with an area of π cm(2) (1 cm radius). To compare the E-field distribution in TMS and the two tDCS models, average values of the E-field's magnitude as well as the polar and azimuthal angle were investigated in the HK region and premotor areas. The results show that both techniques induce fields with different magnitudes and directions in the HK: the field in tDCS is predominantly perpendicular to the cortical surface, contrary to what happens in TMS where the field is mostly parallel to it. In the premotor areas, the magnitude of the E-field induced in TMS was well below the accepted threshold for MEP generation, 100 V/m. In tDCS, the magnitude of the field in these areas was comparable to that induced at the HK with a significant component perpendicular to the cortical surface. These results indicate that tDCS and TMS target preferentially different neuronal structures at the HK. Besides, they show that premotor areas may play a role in the tDCS-induced after effects on motor cortex excitability.

The electric field distribution in the brain during TTFields therapy and its dependence on tissue dielectric properties and anatomy: a computational study.

Tumor treating fields (TTFields) are a non-invasive, anti-mitotic and approved treatment for recurrent glioblastoma multiforme (GBM) patients. In vitro studies have shown that inhibition of cell division in glioma is achieved when the applied alternating electric field has a frequency in the range of 200 kHz and an amplitude of 1-3 V cm(-1). Our aim is to calculate the electric field distribution in the brain during TTFields therapy and to investigate the dependence of these predictions on the heterogeneous, anisotropic dielectric properties used in the computational model. A realistic head model was developed by segmenting MR images and by incorporating anisotropic conductivity values for the brain tissues. The finite element method (FEM) was used to solve for the electric potential within a volume mesh that consisted of the head tissues, a virtual lesion with an active tumour shell surrounding a necrotic core, and the transducer arrays. The induced electric field distribution is highly non-uniform. Average field strength values are slightly higher in the tumour when incorporating anisotropy, by about 10% or less. A sensitivity analysis with respect to the conductivity and permittivity of head tissues shows a variation in field strength of less than 42% in brain parenchyma and in the tumour, for values within the ranges reported in the literature. Comparing results to a previously developed head model suggests significant inter-subject variability. This modelling study predicts that during treatment with TTFields the electric field in the tumour exceeds 1 V cm(-1), independent of modelling assumptions. In the future, computational models may be useful to optimize delivery of TTFields.

Modeling Tumor Treating fields (TTFields) application within a realistic human head model.

Tumor Treating Fields (TTFields) are an antimitotic treatment against brain and other tumors. They are applied regionally and non-invasively by inducing intermediate frequency (100-300 kHz) alternating electric field of intensities between 1 to 3 V/cm through transducer arrays placed on the patient's skin close to the tumor. All TTFields studies predicted variability in treatment response among patients, whereas in vitro experiments indicate that the magnitude and direction of the electric field in the tumor might be crucial determinants of efficacy. Differences in the field might arise from varying tumor positions or array placement. By investigating different scenarios within a realistic human head model we hope to advance our understanding of TTFields therapy in clinical practice. We constructed a model from MRI data to calculate the electric field distribution in the brain using the Finite Element Method. An anisotropic electrical conductivity tensor was estimated using diffusion tensor imaging data. The head model contained different tissue types: scalp, skull, cerebrospinal fluid, gray and white matter. Additionally a virtual spherical tumor was included, two positions for the tumor were considered. Transducer arrays were placed on the scalp to model the commonly used device for TTFields delivery. One additional setup of the two transducer pairs was specifically adapted to the second tumor position. The results predict that the electric field strength exceeds the assumed therapeutic threshold value of 1 V/cm in both tumors for both active array pairs. For the second tumor the adapted transducer layout improved field delivery. The average field strength in the tumor further depends on tumor electrical properties. Yet a cystic and a solid tumor experience the same average field strength when treated with TTFields. As a next step towards personalized TTFields therapy, we will explore possible benefits of individualized treatment planning.