Lumbar trans-spinal direct current stimulation: A modeling-experimental approach to dorsal root ganglia stimulation.

Introduction: The excitability of spinal motor neurons (MN) can be altered through subthreshold currents, such as transcutaneous spinal direct-current stimulation (tsDCS). Current evidence shows that tsDCS can interfere with ascending somatosensory pathways and lower motor neurons' (LMN) excitability, which points to its therapeutic potential for repairing altered spinal responses. We aim to define the best tsDCS montage for maximizing the electric field (E-field) in the lumbar spinal cord (L-SC) by computer modeling; and to apply this montage to measure the effect on LMN excitability and somatosensory evoked potentials (SSEP). Methods: A human volume conductor model was obtained from an available database. The E-field distribution was calculated considering three different electrode settings aiming at maximizing the field at L-SC and right dorsal root ganglia (DRG). The best electrode setting was then selected and applied in a blind crossover pseudo-randomized study including 14 subjects. tsDCS was delivered for 15 min (cathodal vs. sham) over L2 vertebra level (4 mA, 144 mC/cm2), and its effect on F-waves, H-reflex (including homosynaptic depression, HD) and SSEPs was investigated in the lower limbs. Results: All simulated montages showed higher current density and E-field magnitudes between the electrodes (>0.15 V/m), with a major longitudinal component and with rostral-caudal direction. The induced E-field involved the sensory ganglia and was maximum in the right T8-left L2 montage, which was the one selected for the experimental protocol. We disclosed a statistically significant increase of the H-reflex amplitude at 0.1 Hz, after cathodal tsDCS (c-tsDCS) on both sides. No other significant change was observed. Discussion: Our results can suggest the c-tsDCS applied to the L-SC and DRG can modulate synaptic efficiency increasing lower motor neurons response to Ia fibers excitation. The possible implications of our findings for treating clinical conditions will be addressed in future studies.

Temperature and Impedance Variations During Tumor Treating Fields (TTFields) Treatment.

Tumor Treating Fields (TTFields) is an FDA-approved cancer treatment technique used for glioblastoma multiforme (GBM). It consists in the application of alternating (100-500 kHz) and low-intensity (1-3 V/cm) electric fields (EFs) to interfere with the mitotic process of tumoral cells. In patients, these fields are applied via transducer arrays strategically positioned on the scalp using the NovoTAL™ system. It is recommended that the patient stays under the application of these fields for as long as possible. Inevitably, the temperature of the scalp increases because of the Joule effect, and it will remain above basal values for most part of the day. Furthermore, it is also known that the impedance of the head changes throughout treatment and that it might also play a role in the temperature variations. The goals of this work were to investigate how to realistically account for these increases and to quantify their impact in the choice of optimal arrays positions using a realistic head model with arrays positions obtained through NovoTAL™. We also studied the impedance variations based on the log files of patients who participated in the EF-14 clinical trial. Our computational results indicated that the layouts in which the arrays were very close to each other led to the appearance of a temperature hotspot that limited how much current could be injected which could consequently reduce treatment efficacy. Based on these data, we suggest that the arrays should be placed at least 1 cm apart from each other. The analysis of the impedance showed that the variations seen during treatment could be explained by three main factors: slow and long-term variations, array placement, and circadian rhythm. Our work indicates that both the temperature and impedance variations should be accounted for to improve the accuracy of computational results when investigating TTFields.

How to correctly estimate the electric field in capacitively coupled systems for tissue engineering: a comparative study.

Capacitively Coupled (CCoupled) electric fields are used to stimulate cell cultures in Tissue Engineering. Knowing the electric field (E-Field) magnitude in the culture medium is fundamental to establish a relationship between stimulus strength and cellular effects. We analysed eight CCoupled studies and sought to corroborate the reported estimates of the E-Field in the culture medium. First, we reviewed the basic physics underlying CCoupled stimulation and delineated three approaches to estimate the E-field. Using these approaches, we found that the reported values were overestimated in five studies, four of which were based on incorrect assumptions. In all studies, insufficient information was provided to reproduce the setup exactly. Creating electrical models of the experimental setup should improve the accuracy of the E-field estimates and enhance reproducibility. For this purpose, we developed a free open-source tool, the E-field Calculator for CCoupled systems, which is available for download from an internet hosting platform.

Effects of Scaffold Electrical Properties on Electric Field Delivery in Bioreactors.

In tissue engineering, cell culture scaffolds have been widely used in combination with electrical stimulation to promote multiple cellular outcomes, like differentiation and proliferation. Nevertheless, the influence of scaffolds on the electric field delivered inside a bioreactor is often ignored and requires a deeper study. By performing numerical analysis in a capacitively coupled setup, this work aimed to predict the effects of the scaffold presence on the electric field, considering multiple combinations of scaffold and culture medium electrical properties. We concluded that the effect of the scaffold on the electric field in the surrounding culture medium was determined by the difference in electrical conductivity of these two materials. The numerical simulations pointed to significant variations in local electric field patterns, which could lead to different cellular outcomes and confound the interpretation of the experimental results.

A computational study of the relation between the power density in the tumor and the maximum temperature in the scalp during Tumor Treating Fields (TTFields) therapy.

In this work we investigated the relation between the power density in the tumor and the maximum temperature reached in the scalp during TTFields treatment for glioblastoma. We used a realistic head model to perform the simulations in COMSOL Multiphysics and we solved Pennes' equation to obtain the temperature distribution. Our results indicate that there might be a linear relation between these two quantities and that TTFields are safe from a thermal point of view.

The impact of the uncertainty of biological tissue thermal parameters on the estimated maximum temperature during TTFields treatment.

In this work we evaluated the maximum temperature reached by the head tissues and transducers during TTFields treatment when the thermal parameters were changed. We used Pennes' equation to obtain the temperature distribution and we ran our studies using COMSOL Multiphysics. We observed that, among the parameters we tested, changes in the scalp thermal conductivity and grey matter blood perfusion were the ones that led to the highest temperature variations.Clinical Relevance- This work shows that the uncertainty regarding the thermal parameters of biological tissues might lead to significant changes in the temperature distribution when modeling heat transfer during TTFields therapy.

Heat transfer during TTFields treatment: Influence of the uncertainty of the electric and thermal parameters on the predicted temperature distribution.

BACKGROUND AND OBJECTIVES: Tumor Treating Fields (TTFields) is a technique currently used in the treatment of glioblastoma. It consists in applying an electric field (EF) with a frequency of 200 kHz using two pairs of transducer arrays placed on the head. Current should be injected at least 18 h/day and induce a minimum EF intensity of 1 V/cm at the tumor bed for the treatment to be effective. To avoid scalp burns, Optune, the device used to apply this technique in patients, monitors the temperature of the transducers and keeps them below 41 °C by reducing the injected current. The goal of this study was to quantify the impact of the uncertainty associated with the electric and thermal parameters on the predicted temperature of the transducers and of each tissue when TTFields were applied. METHODS: We used a realistic head model, added the two pairs of transducers arrays on the scalp and a virtual lesion, mimicking a glioblastoma tumor in the right hemisphere. Minimum, standard and maximum values for the electric and thermal properties of each tissue were taken from the literature after an extensive review. We used finite element methods (COMSOL Multiphysics) to solve Laplace's equation for the electric potential and Pennes' equation for the temperature distribution. RESULTS: We observed that the electric conductivity of the scalp and skull, as well as scalp's blood perfusion and thermal conductivity were the parameters to which tissue and transducers temperature were most sensitive to. Considering all simulations, scalp's maximum temperature was around 43.5 °C, skull's 42 °C, CSF's 41.2 °C and brain's 39.3 °C. According to the literature, for this temperature range, some physiological changes are predicted only for the brain. The average temperature of the transducers varied between 38.1 °C and 41.6 °C which suggests that modelling TTFields current injection is very sensitive to the parameters chosen. CONCLUSIONS: Better knowledge of the physical properties of tissues and materials and how they change with the temperature is needed to improve the accuracy of these predictions. This information would likely decrease the predicted temperature maxima in the brain and thus help ascertaining TTFields safety from a thermal point of view.

Temperature control in TTFields therapy of GBM: impact on the duty cycle and tissue temperature.

In TTFields therapy, Optune® is used to deliver the electric field to the tumor via 4 transducer arrays. This device monitors the temperature of the transducers and reduces the current whenever a transducer reaches 41 °C. Our aim is to quantify Optune's duty cycle and to predict the steady-state temperature distribution in the head during GBM treatment. We used a realistic head model and the finite element method to solve Pennes equation and to simulate how Optune operates considering that current reduces to zero when the thermal limit is reached. The thermal impact was evaluated considering the maximum temperature reached by each tissue and using the CEM 43 °C metric. We observed that Optune switches the current on and off intermittently. In our model, one transducer reached the temperature limit quicker than the others and consequently it was the one that controlled current injection. This led to different duty cycles for the anterior-posterior and left-right array pairs. The thermal analysis indicated that the highest temperature in the model, 41.7 °C, was reached on the scalp under a transducer. However, TTFields may lead to significant changes only at the brain level such as BBB permeability increase, cerebral blood flow variation and changes in the concentration of some neurotransmitters. The duty cycle may be increased, e.g. by controlling the current at the transducer level. These predictions should be validated by comparison with experimental data and reconciled with the lack of evidence of thermal impact in clinical trials.

Cervical trans-spinal direct current stimulation: a modelling-experimental approach.

BACKGROUND: Trans-spinal direct current stimulation (tsDCS) is a non-invasive technique with promising neuromodulatory effects on spinal cord (SC) circuitry. Computational studies are essential to guide effective tsDCS protocols for specific clinical applications. This study aims to combine modelling and experimental studies to determine the electrode montage that maximizes electric field (E-field) delivery during cervical tsDCS. METHODS: Current and E-field distributions in the cervical SC were predicted for four electrode montages in a human realistic model using computational methods. A double-blind crossover and randomized exploratory study was conducted using the montage that maximized E-field delivery. tsDCS was applied for 15 min in 10 healthy subjects (anodal, cathodal, sham, with polarity assigned to the cervical electrode), with a current intensity of 2.5 mA, resulting in a total current charge density delivery of 90 mC/cm2. Upper limb motor (transcranial magnetic stimulation) and sensory evoked potentials (MEP, SEP), M-waves, H-reflex and F-wave responses were analysed. Central and peripheral conduction times were determined using MEP. Repeated measures ANOVA and Friedman test were used for statistical analysis (significance level α = 0.05). RESULTS: All montages presented higher current density and E-field magnitudes in the cervical SC region between the electrodes. However, electrodes at C3 and T3 spinous processes (C3-T3) originated the highest E-field magnitude (0.50 V/m). Using C3-T3 montage we observed significant changes in N9 SEP latency (p = 0.006), but significance did not persist in pairwise comparisons (sham-anodal: p = 0.022; sham-cathodal: p = 0.619; anodal-cathodal: p = 0.018; α = 0.017, Bonferroni corrected). MEP latency and central motor conduction time (CMCT) modified significantly on stimulation (p = 0.007 and p = 0.015, respectively). In addition, pairwise comparisons confirmed significant differences between sham and cathodal conditions after Bonferroni correction for MEP latency (sham-anodal: p = 0.868; sham-cathodal: p = 0.011; anodal-cathodal: p = 0.023) and CMCT (sham-anodal: p = 0.929; sham-cathodal: p = 0.010; anodal-cathodal: p = 0.034). CONCLUSIONS: Computational models predicted higher E-field delivery in the cervical SC for the C3-T3 montage. Polarity-dependent effects in motor responses were reported using this montage consistent with spinal motor modulation. tsDCS experimental protocol designs should be guided by modelling studies to improve effectiveness.

Optimization of multifocal transcranial current stimulation for weighted cortical pattern targeting from realistic modeling of electric fields.

Recently, multifocal transcranial current stimulation (tCS) devices using several relatively small electrodes have been used to achieve more focal stimulation of specific cortical targets. However, it is becoming increasingly recognized that many behavioral manifestations of neurological and psychiatric disease are not solely the result of abnormality in one isolated brain region but represent alterations in brain networks. In this paper we describe a method for optimizing the configuration of multifocal tCS for stimulation of brain networks, represented by spatially extended cortical targets. We show how, based on fMRI, PET, EEG or other data specifying a target map on the cortical surface for excitatory, inhibitory or neutral stimulation and a constraint on the maximal number of electrodes, a solution can be produced with the optimal currents and locations of the electrodes. The method described here relies on a fast calculation of multifocal tCS electric fields (including components normal and tangential to the cortical boundaries) using a five layer finite element model of a realistic head. Based on the hypothesis that the effects of current stimulation are to first order due to the interaction of electric fields with populations of elongated cortical neurons, it is argued that the optimization problem for tCS stimulation can be defined in terms of the component of the electric field normal to the cortical surface. Solutions are found using constrained least squares to optimize current intensities, while electrode number and their locations are selected using a genetic algorithm. For direct current tCS (tDCS) applications, we provide some examples of this technique using an available tCS system providing 8 small Ag/AgCl stimulation electrodes. We demonstrate the approach both for localized and spatially extended targets defined using rs-fcMRI and PET data, with clinical applications in stroke and depression. Finally, we extend these ideas to more general stimulation protocols, such as alternating current tCS (tACS).

Physics of effects of transcranial brain stimulation.

The effects of transcranial stimulation are determined to a large extent by the spatial distribution and temporal variation of the electric field produced in the brain. In this chapter, we first describe some of the factors that affect the electric field in the brain generally, such as the effect of tissue heterogeneity and anisotropy, or focality. These are common to transcranial magnetic stimulation (TMS) and to several forms of transcranial current stimulation (tCS), such as transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), and transcranial random noise stimulation (tRNS). Then the main features of the electric field in the human brain during TMS and tCS are presented. This knowledge is important to predict the location and extent of the stimulated region as well as the stimulation intensity in the brain.

The electric field in the cortex during transcranial current stimulation.

The electric field in the cortex during transcranial current stimulation was calculated based on a realistic head model derived from structural MR images. The aim of this study was to investigate the effect of tissue heterogeneity and of the complex cortical geometry on the electric field distribution. To this end, the surfaces separating the different tissues were represented as accurately as possible, particularly the cortical surfaces. Our main finding was that the complex cortical geometry combined with the high conductivity of the CSF which covers the cortex and fills its sulci gives rise to a very distinctive electric field distribution in the cortex, with a strong normal component confined to the bottom of sulci under or near the electrodes and a weaker tangential component that covers large areas of the gyri that lie near each electrode in the direction of the other electrode. These general features are shaped by the details of the sulcal and gyral geometry under and between the electrodes. Smaller electrodes resulted in a significant improvement in the focality of the tangential component but not of the normal component, when focality is defined in terms of percentages of the maximum values in the cortex. Experimental validation of these predictions could provide a better understanding of the mechanisms underlying the acute effects of tCS.

A finite element analysis of the effect of electrode area and inter-electrode distance on the spatial distribution of the current density in tDCS.

We investigated the effect of electrode area and inter-electrode distance on the spatial distribution of the current density in transcranial direct current stimulation (tDCS). For this purpose, we used the finite element method to compute the distribution of the current density in a four-layered spherical head model using various electrode montages, corresponding to a range of electrode sizes and inter-electrode distances. We found that smaller electrodes required slightly less current to achieve a constant value of the current density at a reference point on the brain surface located directly under the electrode center. Under these conditions, smaller electrodes also produced a more focal current density distribution in the brain, i.e. the magnitude of the current density fell more rapidly with distance from the reference point. The combination of two electrodes with different areas produced an asymmetric current distribution that could lead to more effective and localized neural modulation under the smaller electrode than under the larger one. Focality improved rapidly with decreasing electrode size when the larger electrode sizes were considered but the improvement was less marked for the smaller electrode sizes. Also, focality was not affected significantly by inter-electrode distance unless two large electrodes were placed close together. Increasing the inter-electrode distance resulted in decreased shunting of the current through the scalp and the cerebrospinal fluid, and decreasing electrode area resulted in increased current density on the scalp under the edges of the electrode. Our calculations suggest that when working with conventional electrodes (25-35 cm(2)), one of the electrodes should be placed just 'behind' the target relative to the other electrode, for maximum current density on the target. Also electrodes with areas in the range 3.5-12 cm(2) may provide a better compromise between focality and current density in the scalp than the traditional electrodes. Finally, the use of multiple small return electrodes may be more efficient than the use of a single large return electrode.

What does the ratio of injected current to electrode area tell us about current density in the brain during tDCS?

OBJECTIVE: To examine the relationship between the ratio of injected current to electrode area (I/A) and the current density at a fixed target point in the brain under the electrode during transcranial direct current stimulation (tDCS). METHODS: Numerical methods were used to calculate the current density distribution in a standard spherical head model as well as in a homogeneous cylindrical conductor. RESULTS: The calculations using the cylindrical model showed that, for the same I/A ratio, the current density at a fixed depth under the electrode was lower for the smaller of the two electrodes. Using the spherical model, the current density at a fixed target point in the brain under the electrode was found to be a non-linear function of the I/A ratio. For smaller electrodes, more current than predicted by the I/A ratio was required to achieve a predetermined current density in the brain. CONCLUSIONS: A non-linear relationship exists between the injected current, the electrode area and the current density at a fixed target point in the brain, which can be described in terms of a montage-specific I-A curve. SIGNIFICANCE: I-A curves calculated using realistic head models or obtained experimentally should be used when adjusting the current for different electrode sizes or when comparing the effect of different current-electrode area combinations.

Modeling the current distribution during transcranial direct current stimulation.

OBJECTIVE: To investigate the spatial distribution of the magnitude and direction of the current density in the human head during transcranial direct current stimulation (tDCS). METHODS: The current density distribution was calculated using a numerical method to implement a standard spherical head model into which current was injected by means of large electrodes. The model was positioned in 'MNI space' to facilitate the interpretation of spatial coordinates. RESULTS: The magnitude and direction of the current density vector are illustrated in selected brain slices for four different electrode montages. Approximately half of the current injected during tDCS is shunted through the scalp, depending on electrode dimension and position. Using stimulating currents of 2.0 mA, the magnitude of the current density in relevant regions of the brain is of the order of 0.1 A/m2, corresponding to an electric field of 0.22 V/m. CONCLUSIONS: Calculations based on a spherical model of the head can provide useful information about the magnitude and direction of the current density vector in the brain during tDCS, taking into account the geometry and position of the electrodes. Despite the inherent limitations of the spherical head model, the calculated values are comparable to those used in the most recent in vitro studies on modulation of neuronal activity. SIGNIFICANCE: The methodology presented in this paper may be used to assess the current distribution during tDCS using new electrode montages, to help optimize montages that target a specific region of the brain or to preliminarily investigate compliance with safety guidelines.