Research Article  Open Access
Edward T. Dougherty, James C. Turner, Frank Vogel, "Multiscale Coupling of Transcranial Direct Current Stimulation to Neuron Electrodynamics: Modeling the Influence of the Transcranial Electric Field on Neuronal Depolarization", Computational and Mathematical Methods in Medicine, vol. 2014, Article ID 360179, 14 pages, 2014. https://doi.org/10.1155/2014/360179
Multiscale Coupling of Transcranial Direct Current Stimulation to Neuron Electrodynamics: Modeling the Influence of the Transcranial Electric Field on Neuronal Depolarization
Abstract
Transcranial direct current stimulation (tDCS) continues to demonstrate success as a medical intervention for neurodegenerative diseases, psychological conditions, and traumatic brain injury recovery. One aspect of tDCS still not fully comprehended is the influence of the tDCS electric field on neural functionality. To address this issue, we present a mathematical, multiscale model that couples tDCS administration to neuron electrodynamics. We demonstrate the model’s validity and medical applicability with computational simulations using an idealized twodimensional domain and then an MRIderived, threedimensional human head geometry possessing inhomogeneous and anisotropic tissue conductivities. We exemplify the capabilities of these simulations with realworld tDCS electrode configurations and treatment parameters and compare the model’s predictions to those attained from medical research studies. The model is implemented using efficient numerical strategies and solution techniques to allow the use of fine computational grids needed by the medical community.
1. Introduction
Transcranial direct current stimulation (tDCS) is a medical procedure that delivers electrical stimulation to the brain through electrodes positioned on the scalp. The electrodes deliver an electrical current on the order of 12 mA and produce an electric field in the patient’s cerebral cavity that alters neuron excitability. A common use of this treatment is to assist neurons in firing action potentials (APs) by increasing their resting membrane potential. Current biomedical research continues to demonstrate the benefits of tDCS as a medical treatment. Recognition memory in Alzheimer disease patients has improved [1, 2]. Individuals who suffer from Parkinson’s disease have demonstrated enhanced physical and mental skills [3, 4]. Patients diagnosed with neuropsychiatric disorders, including great depression, have shown improved cognitive capabilities [5, 6]. Further, poststroke recovery can be expedited with strategic administrations of tDCS [7, 8].
Current components of tDCS include the Laplace equation [9–13], which is given by where is the electric potential, represents the tissue conductivity tensor field, and is the entire head cavity, including the brain. In isotropic tissues, can be represented as a scalar which will vary among different tissue types.
Computational simulations of tDCS that utilize (1) have the capability to compute the strength of the tDCS electric potential and electric current at specific points in the brain and head cavity [11, 14]. What these models do not have, however, is the capability to provide a description of cellularlevel functionality. The fundamental objective of tDCS is to alter neuron excitability by increasing or decreasing neural transmembrane voltage [15, 16]; without this level of biological abstraction included in a tDCS model, it is not possible to examine tDCS effects on brain cells within a computational simulation.
Beyond the tDCS modeling and simulation field, the computational neuroscience community possesses a large collection of biologically inspired, mathematical models of neurallevel dynamics. The HodgkinHuxley model, for example, emulates voltagegated ion channel functionality [17]. The HindmarshRose model incorporates neuron bursting, which is the diverse and chaotic behavior of rapid action potential spiking, believed to be very important in information encoding and propagation [18]. More recently, models have included individual neurotransmitter species, receptors, and binding kinetics to emulate neuronneuron influences and communication [19].
A multiscale model that couples tDCS and cellular level functionality would enable researchers to simulate the impact that tDCS has on neurons. For instance, correlations between tDCS and ion channel functionality, action potential behavior, and neurotransmitter dynamics could be studied. In addition, patientspecific electrode configurations and treatment parameters could be optimized based on neuron behavior. Furthermore, a multiscale model would provide a bridge between the tDCS numerical simulation field and the computational neuroscience field, thereby enabling tDCS simulations access to the sophisticated, physiologically based cellular and subcellular models of the neuroscience community.
Several researchers have investigated the influence of extracellular electrical fields on the transmembrane voltage of individual and small groups of cells [15, 16, 20, 21]. At the organ level, Szmurło et al. [22, 23] demonstrated the applicability of the bidomain model [24] (see Section 2.1) to electroencephalograph (EEG) applications. They showed that this model, which has historically been used in cardiac applications, can reproduce scalp surface electric potential measurements originating from neuron action potentials.
In this paper, we combine these modeling strategies to produce a multiscale model of tDCS. We begin by coupling the bidomain model partial differential equations (PDEs) with boundary conditions that model tDCS treatments. We validate the model against several test cases on two different geometries. First, we simulate the model on an idealized twodimensional domain, which provides a basic environment for visualizing and investigating electric potential and electric field characteristics. Then, we utilize an MRIderived, threedimensional human head geometry that possesses inhomogeneous and anisotropic tissue conductivities. In this setting, we examine the electric potential, electric current, electric field, and transmembrane voltage results produced from realworld tDCS electrode configurations. In both geometries, five distinct tissue types are used: skin, skull, cerebrospinal fluid (CSF), and the grey matter (GM) and white matter (WM) portions of the brain. Further, we detail the numerical methods and solution techniques that we implemented to enable reasonable simulation execution times.
To our knowledge, this paper presents the first multiscale tDCS model and simulations. We hope that the modeling and computational approaches presented in this paper help to expand tDCS simulation capabilities and further our understanding of tDCS impacts at the cellular level.
2. Materials and Methods
This section presents details of the model, numerics, and computational simulations used in this paper. First, an overview of the bidomain model is provided, as well as a description of the adaptation of this model for tDCS. Then, the numerical methods used to implement the multiscale tDCS model are described. Next, an overview of computational tools that we utilized is presented. Finally, the numerical experiments that were performed are described.
2.1. Bidomain Model
Modeling each cell in the brain and head is not computationally feasible; the bidomain model is based on a volume averaging approach, where the value at a point in a tissue is treated as an average over a minuscule, multicellular region around the point [25]. The bidomain model, as its name implies, models two domains, namely, the intracellular and extracellular spaces. Each of these domains is considered continuous within the brain, and they are insulated from each other by the cell membrane. Transcellular electric current is possible via ion channels in the cell membrane, and the transmembrane electric potential is defined to be the difference between intracellular and extracellular electric potentials, .
The bidomain model is given by the following system of partial differential equations for points in the brain, : where is the extracellular electric potential and is the transmembrane voltage. Note that, in this formulation, has been eliminated with the substitution of ; if desired, can be computed at any point in the domain using . and represent the intracellular and extracellular tissue conductivity tensor fields, respectively. In addition, is the cell membrane surface to volume ratio and is the cell membrane capacitance. is the total ionic current between the intracellular and extracellular domains, across the cell membrane. Equation (4), which characterizes the electrophysiological state of the neurons, can be represented by a single equation or by a system of ordinary differential equations (ODEs) [25].
Equations (2)–(4) are defined in the brain. Outside of the brain tissue, the scalp, skull, and cerebrospinal fluid are modeled as a passive conductor with the Laplace equation (1). In this extracerebral domain, neurons and other electrically responsive cells are not present, and so only the extracellular domain exists. Thus, the intracellular current is confined to the brain; this condition is enforced by requiring that the outflow of intracellular current from the brain into the extracerebral region equals zero: where is the surface boundary of the brain.
Extracellular electric field continuity at the interface between the brain and extracerebral domain is preserved by requiring that and are continuous over . To simplify notation, for the remainder of this paper will be represented simply as .
2.2. tDCS Adaptation
To make the bidomain model suitable for tDCS applications, two specific areas need to be addressed. First, the boundary conditions on the scalp must model tDCS administration. Second, cellular models that emulate neuron electrodynamics are necessary. The result of this adaptation is our multiscale tDCS model.
2.2.1. Boundary Conditions
On the surface of the head, there are three separate boundary conditions needed to model tDCS. First, current delivered via tDCS anode electrodes is implemented by the nonhomogeneous Neumann boundary condition where is the inward current at points on the boundary positioned under the anode electrode(s). Second, the cathode electrodes are given by the homogeneous Dirichlet condition for points on the boundary covered by the cathode electrode(s). All other points on the scalp surface are presumed insulated, and so the outward normal component of the current at these points must equal zero:
2.2.2. Cell Model
Simulating single neuron transmembrane voltage dynamics was accomplished with the FitzHughNagumo (FHN) model [26]:where is again the transmembrane voltage and is a state variable that controls transmembrane voltage repolarization. Here, the threshold voltage is defined as + , and is the difference between peak and resting membrane voltages, . We used , , , , and , as proposed by FitzHugh [26] with the coefficients scaled for seconds. This implementation of the FHN model allows us to define and , which we set to −0.07 V and 0.04 V, respectively. Figure 1 displays an AP response of the FHN model when given an applied current for .
The PDE system (2)–(4) and this cell model couple through the the righthand side of (2) and (9a). Also, when using the FHN model with the bidomain model, (4) is represented by the single state equation (9b).
2.3. Numerical Implementation
The multiscale tDCS model was solved with a Godunov operator splitting scheme [25]. The solution algorithm consists of the following two steps.(1)Solve the ODE system: for , and and are known. Let denote the partial solution of at step .(2)Solve the PDE system: for , , and boundary conditions are specified in Sections 2.1 and 2.2.
The result is numerical solutions of and at time step . This fractional step method decouples the nonlinear ODEs from the PDEs. This is advantageous since the ODE system can then be evaluated more frequently than the PDEs during periods of rapid transmembrane voltage change, that is, AP spiking, without having to also solve the computationally intensive PDE system. In addition, this Godunov splitting scheme is numerically stable and computationally efficient [27].
The ODE system in step is solved with Heun’s method [28]. The PDE system in step is solved as a coupled system, discretizing in time with the implicit Euler method, and in space with the finite element method [29]. The resulting finite element formulation yields the following system of equations in block matrix form [25]: where the th and th entries are given by and and are the unknown transmembrane and electric potentials that together form the solution that we seek. Here, and are finite element basis functions over the discretized domain.
The linear system (12) is solved by the conjugate gradient method [30] preconditioned with the following block preconditioner [29]: where and are incomplete LU (ILU) factorizations [31] of and , respectively.
2.4. Computational Tools
Several of the multiscale tDCS numerical simulations are performed on a threedimensional grid derived from human MRI data. The SimNIBS software package [32] provides the associated computational grid; it is a highquality tetrahedral mesh of the scalp, skull, CSF, GM, and WM. Gmsh [33] supported mesh visualization and supplied grid file conversion to a format supported by Diffpack (http://www.diffpack.com/) [34]. Figure 2 displays portions of the computational mesh used in the threedimensional simulations.
(a) Head boundary of mesh
(b) WM and GM portion of mesh
Finite element solutions were performed with Diffpack. An anisotropic conductivity tensor field for the brain region of the MRIderived mesh is generated by SimNIBS and stored in a Matlab [35] binary data file; the Matlab engine was invoked and utilized in our C++ code to access these tensor data at run time. The ODE solver (Heun’s method) was implemented in C++, and the operator splitting scheme was performed with Diffpack. In addition, the block coefficient matrix (12) and block preconditioner (14) were implemented with Diffpack. Results were exported to VTK format and visualized with ParaView (http://www.paraview.org/).
2.5. Multiscale tDCS Numerical Experiments
Numerical experiments were contrived to examine the following four properties:(1)action potential conduction velocity;(2)tDCS electric potential;(3)tDCS electric current and field;(4)tDCSinduced transmembrane voltage increase.
Experiments were run with a global timestep ms. The ODE system was solved more frequently with a time step ms. At each time step, the system of (12) was solved using the conjugate gradient method preconditioned with a relaxed ILU block matrix (14), with relaxation parameter [31] for both the and blocks. A relative residual convergence monitor of was used, where is the norm of the initial residual, and is the norm of the residual of the th iteration. The convergence tolerance was set to . In all experiments, the parameter was set to , and was set to [36].
The multiscale tDCS model was assessed and validated against several two and threedimensional numerical experiments. The following subsections describe each of these.
2.5.1. TwoDimensional Experiments
Figure 3 displays the geometry used for twodimensional experiments. It is constructed with concentric annuli to simulate the overlapping and embedded nature of head and cerebral tissues. The innermost region, emulating the white matter of the brain, is a circle with radius = 40 mm. Surrounding this region, four annuli are positioned with outer radii equal to 50, 70, 90, and 100 mm, which emulate the GM, CSF, skull, and scalp tissues, respectively. To simulate the interwoven nature of the CSF with the GM and WM, a 10 mm thick CSF strip extends horizontally through the center of the geometry, providing a passage for CSF through the GM and WM. This prototypical domain allows us to observe and comprehensively assess action potential conduction, electric potential, and electric field simulation results throughout the entire domain.
Isotropic extracellular conductivities were assigned to different tissues: skin = 0.465, skull = 0.010, CSF = 1.654, GM = 0.276, and WM = 0.126, each with units S/m [37], and an intracellular conductivity value of 0.1 S/m was used in the GM and WM. Each experiment included 10,000 linear triangular finite elements.
Individual twodimensional experiments are described in the following paragraphs. Action potential conduction: an AP centered at (), encompassing a circular region with radius = 2.5 mm, was simulated for ms. Total simulation time is 100 ms. tDCS was not administered and so the homogeneous Neumann boundary condition was imposed on the entire scalp surface. This experiment is used to ensure the biological legitimacy of the multiscale model’s AP conduction velocity and in doing so verifies that appropriate parameter values were selected. This experiment is also used to examine the electric potential, , produced by the AP. tDCS electric potential and field: models of tDCS based on the Laplace equation (1) accurately quantify tDCS electric potentials and fields [11, 14]. Therefore, to validate the multiscale model, its electric potential and electric field simulation results are compared to those produced by (1). These comparisons are performed using two simulations. First, tDCS was simulated with the anode and cathode electrodes positioned at () and (), respectively. Electrode size is 10 mm, and the anode electric current magnitude was set to 1.0 mA (see Section 2.2.1) at . No AP was artificially initiated; that is, (9a), and simulation duration is 100 ms. This numerical experiment was repeated with a different electrode configuration, placing the anode electrode at () and the cathode at (). This electrode arrangement was selected to provide substantive differences from the first arrangement. First, the electric current entry via the anode does not neighbor the central CSF channel, as is the case with the first electrode configuration. Second, the current exit at the cathode electrode is as distant from the central CSF channel as possible in this twodimensional domain. In addition, the anode and cathode are on opposite sides of the CSF channel in the second configuration.
2.5.2. ThreeDimensional Experiments
Threedimensional experiments were conducted on an MRIderived volume mesh. Figure 2 displays portions of the mesh used in these simulations. Extracellular conductivities of the scalp, skull, and CSF were isotropic and set to 0.465 , 0.010 , and 1.654 , respectively [37]. Anisotropic extracellular conductivities of the GM and WM portions of the brain were used; this tensor field is provided by the SimNIBS software package (see Section 2.4). The intracellular conductivity for the brain region was set to 0.1 .
Three separate electrode montages were selected for the threedimensional simulations (see Table 1). Each montage is specified using the international 1020 system [38]. Transcranial direct current stimulation applied with montage 1 has shown to enhance motor sequence learning [39], for example. This montage is known to target the motor cortex region ipsilateral to the anode electrode [40]. Montage 2 has been utilized in a host of biomedical research studies involving motor skills and also enhances neural tissue excitability in the motor cortex ipsilateral to the anode [38]. Montage 3 has been shown to improve gait and bradykinesia in patients with Parkinson’s disease [3]. However, the regions of the brain and the mechanisms by which tDCS enhances motor performance in these individuals remain unclear. Neurostimulation research suggests that stimulation of the primary motor cortex is a catalyst for motorskill improvement [3, 41]. In addition, other research studies verify that electrical stimulation to the subthalamic nucleus (STN) and substantia nigra (SN) greatly improves motor performance in Parkinson’s disease patients [42–46].

In all montages, the anode electric current magnitude was set to 1.0 mA (see Section 2.2.1) at and the surface area of each electrode is approximately 25 cm^{2} [3, 39]. Numerical experiments were run for 100 ms, and no APs were forced; that is, (9a). The head geometry is comprised of approximately 1.1 million linear tetrahedra finite elements.
Again, the Laplace equation (1) accurately models tDCS electric potentials and fields [11, 14]. For each montage, the multiscale model is validated by comparing its scalp surface electric potential simulation results against those generated by Laplace equationbased simulations. A similar comparison is performed with the tDCS electric current and field. Then, the multiscale model’s ability to predict the areas of the brain that become more excitable from tDCS treatments administered with these three montages is verified. This is accomplished by examining the transmembrane voltage increase in those regions of the brain known to become more excitable from tDCS. For montages 1 and 2, the motor cortex ipsilateral to the anode is examined, and for montage 3 the motor cortex and the STN and SN regions are inspected (see Table 1).
3. Results and Discussion
3.1. TwoDimensional Simulations
3.1.1. Action Potential Conduction
Transmembrane voltage results for the AP numerical experiment described in Section 2.5.1 are presented in Figure 4. Figure 4(a) shows the start of the AP. By time ms, AP dispersion is quite noticeable (Figure 4(b)). The conduction velocity is approximately 2.0 . This value is on the lower end of normal neural conduction velocities [47]; however, average AP speed varies among individuals and testing conditions [48]. In addition, the conduction velocity can easily be adjusted in the model by changing , or . Further, alternative neuron models possess different AP transmembrane voltage upstroke rates that will affect conduction velocity [25].
(a) Transmembrane voltage at time ms
(b) Transmembrane voltage at time ms
Figure 5 displays the electric potential, , produced from the AP. Figure 5(a) shows throughout the entire twodimensional domain at ms. Variability in the electric potential due to the inhomogeneous extracellular conductivities is noticeable. Figure 5(b) displays electric potential timecourse plots, for points at the center of the domain and surface boundary that intersect each Cartesian axis. The curves representing the points that intersect the axis, namely, () and (), are similar due to their symmetry with respect to the AP. However, all other curves show variability due to their spacial separation and tissue conductivity inhomogeneity.
(a) Electric potential at time ms
(b) Electric potential timecourse plots at five points in the domain
These electric potential results are of the same order of magnitude as those reported by Szmurło et al. [22]. Further, they are several orders of magnitude lower than those produced during tDCS sessions [37]. These results are consistent with the observation that head surface electric potential measurements are dominated by the tDCS electric current with negligible impact from AP conduction [49].
This numerical experiment confirms that the selected parameter set produces biologically reasonable action potential results. Conduction speeds are appropriate and the electric potential resulting from an AP is consistent with previous research reports. In the following sections, the multiscale model is validated when tDCS is administered.
3.1.2. tDCS Administration
First Electrode Configuration. Electric potential simulation results for the Laplace equationbased model and the multiscale model are presented in Figure 6. The electric potential of the Laplace model (Figure 6(a)) closely resembles the multiscale model’s electric potential at both ms (Figure 6(b)) and ms (Figure 6(c)). The electric potential difference between these two times has minuscule change. For ms, the electric potential stabilizes, and no visible differences were observed throughout the remainder of the simulation.
(a) Laplacebased model
(b) tDCS multiscale model; ms
(c) tDCS multiscale model; ms
Figure 7 displays the tDCS electric fields for the Laplace and multiscale models. Multiscale model results are shown at ms, but they are essentially identical at all times. Differences between the models’ electric current densities and fields are virtually indistinguishable. The tendency of the electric field to shunt the skull is due to the low conductivity of this tissue, and this produces an increased current density exiting the edges of the anode and entering the edges of the cathode [11]. In addition, the portion of the electric current that penetrates the skull has high affinity for the highly conductive CSF.
(a) Laplacebased model
(b) Multiscale model; ms
Second Electrode Configuration. Figures 8 and 9 display electric potential and electric field results for both models with tDCS delivered with the second electrode configuration. The multiscale simulation results again match the Laplacebased simulation results very closely. Electric field shunting is again present as well as the resulting areas of higher current density at the borders of the electrodes. Perhaps more visible in this electrode configuration is the propensity of the current to gravitate towards CSF regions of the domain (Figure 9). Similar to the first configuration, electric potential, current, and field results of the multiscale model were essentially identical at all time steps.
(a) Laplacebased model
(b) Multiscale model; ms
(a) Laplacebased model
(b) Multiscale model; ms
These two experiments demonstrate that the multiscale tDCS model can accurately compute electric potentials and fields when tDCS is administered. In the next section these validations are continued. In addition, the ability of the multiscale model to accurately identify regions of the brain that are electrically excited by tDCS is also demonstrated.
3.2. ThreeDimensional Simulations
3.2.1. Montage 1
Figure 10 displays the electric potential and field results of the multiscale model simulated with the montage 1 electrode configuration (see Table 1). Maximum and minimum surface potential coincide with electrode location (Figure 10(a)). Figure 10(b) illustrates the electric current and field within a coronal crosssection through the C3 and C4 electrodes, viewed from the posterior. Curvilinear electric field lines within the cerebral tissue due to the interwoven CSF and GM and WM tissues are visible.
(a) Electric potential on head surface; viewing perspective is from directly above the head with the nasion facing downward
(b) Electric current density and field stream lines from coronal crosssection taken through the anode and cathode electrode centers; viewing perspective is from the posterior
The shunting of the electric field along the scalp and skull is noticeable in Figure 10(b), resulting in regions of higher current density at the electrode edges, similar to the twodimensional simulation results (see Section 3.1). Further, electric potential, current, and field results are essentially the same at all time steps, as was observed in the twodimensional experiments. These results are in agreement with simulation results produced by Laplace equationbased models.
Figure 11 displays transmembrane voltage results for this montage. A sagittal crosssection through the motor cortex ipsilateral to the anode electrode and perpendicular to the primary electric field direction was taken. Viewing perspective is from the left side of the head with the head facing left. The arrows (Figure 11(a)) locate the motor cortex, which is the area of the brain expected to have increased excitability from tDCS (see Table 1). Results are displayed for = 1, 10, 25, 50, and ms. The increased sensitivity of neural tissue to generate action potentials was quantified as a percentage with the following formula: where mV and mV, given the parameters used with the FHN cell model (see Section 2.2.2). This formula provides a measure of the degree to which neural tissue has increased from its resting membrane potential to become more susceptible to firing action potentials.
(a) = 1 ms
(b) = 10 ms
(c) = 25 ms
(d) = 50 ms
(e) = 100 ms
After 1 ms of tDCS administration (Figure 11(a)), increases in resting potential are noticed throughout the cerebral tissue, most notably in the motor cortex. At time = 10 ms (Figure 11(b)), AP sensitivity in portions of the motor cortex has increased by approximately 8%. By 25 ms (Figure 11(c)), the effects of tDCS are quite visible. Again the greatest increase in sensitivity is achieved in the motor cortex, with the majority of this region having values over 5% and portions exceeding 10%. After 25 ms, the membrane potential begins to repolarize (Figure 11(d)). This process is slow, and by the end of the simulation (Figure 11(e)), resting membrane potential is still elevated in the motor cortex.
3.2.2. Montage 2
Montage 2 electric potential and electric field results are presented in Figure 12. Maximum and minimum surface potential again coincide with anode and cathode electrode placement, respectively (Figure 12(a)). The current density and direction are viewed from a plane intersecting the anode and cathode centers (Figure 12(b)). The electric field shunts along the skull, as was observed in montage 1, again resulting in higher current magnitudes at the borders of the electrodes. Wavelike electric field lines through the interwoven CSF, GM, and WM are also visible. These results are in agreement with those generated by Laplace equationbased models.
(a) Electric potential on head surface
(b) Electric current density and field stream lines in a plane intersecting the anode and cathode electrode centers; head is facing towards the left
Figure 13 displays the transmembrane voltage results for montage 2. A slice longitudinal through the motor cortex ipsilateral to the anode, approximately perpendicular to the primary electric field path, was taken. Viewing perspective is from the left posterior of the head, with the head facing left. The arrows (Figure 13(a)) locate the motor cortex ipsilateral to the anode, the expected region of increased action potential sensitivity. Results are displayed for = 1, 10, 20, and ms.
(a) = 1 ms
(b) = 10 ms
(c) = 20 ms
(d) = 50 ms
The multiscale simulation predicts an increase in transmembrane voltage in the motor cortex after 1 ms of tDCS treatment (Figure 13(a)), and AP sensitivity increases near 7% are visible at 10 ms (Figure 13(b)). The maximum increase in resting membrane voltage for this montage occurs at 20 ms (Figure 13(c)). Repolarization occurs for ms and is quite observable at 50 ms ( Figure 13(d)).
Montages 1 and 2 possess similar transmembrane voltage trends in the motor cortex region. The simulations predict that montage 1 will, however, increase the resting membrane voltage in this region approximately 1.5 times that of montage 2. This phenomena can be explained by the fact that the electric current distribution with montage 1 is more confined to this locality due to the closer proximity of its electrodes to each other and to the motor cortex [11]. Supporting this explanation is the observation that tDCS medical research studies fundamentally use montage 1 with motor cortex specific applications, whereas montage 2 is also utilized in other treatment focuses [38].
3.2.3. Montage 3
Figure 14 displays surface potential and electric field simulation results for the third montage. The patient’s left mastoid is shown; an identical cathode is positioned over the contralateral mastoid. The electric current and field are displayed in a crosssection through the centers of the anode and left mastoid cathode. Once again, the current reaches maximal values at electrode edges, and both skulldivergent and convoluted cerebral electric field lines are present. These results are consistent with those generated by Laplacebased models.
(a) Electric potential on head surface
(b) Electric current density and field stream lines in a plane intersecting the anode and cathode electrode centers; head is facing towards the left
Based on the research communities’ suggestion that motor cortex stimulation enhances mobility and movement capabilities in Parkinson’s disease patients (see Section 2.5.2), we first examined the increase in transmembrane voltage in this region (Figure 15). A plane through the left primary motor cortex was taken; viewing perspective is from the rear. The motor cortex is indicated by the arrows (Figure 15(a)), and results are displayed for = 1, 10, 20, and 50 ms.
(a) = 1 ms
(b) = 10 ms
(c) = 20 ms
(d) = 50 ms
Increases in motor cortex excitability are observable at 10 ms (Figure 15(b)) and reach maximal values at 20 ms (Figure 15(c)). Repolarization begins after this time and is noticeable at 50 ms (Figure 15(d)). Although an increase in the resting membrane potential of the motor cortex is visible throughout this simulation, the increase is low when compared to the previous two montages. Specifically, AP sensitivity increases do not exceed 2.0%, which is less than 50% attained by montage 2 and less than 25% attained by montage 1.
Next, the increase in membrane resting potential in the subthalamic nucleus and substantia nigra regions (Figure 16) were examined, due to results from deep brain stimulation research affirming that electrically stimulating these regions yields enhanced motor abilities (see Section 2.5.2). A coronal slice through the STN and SN regions is shown, viewed from the posterior. Results are again displayed for = 1, 10, 20, and 50 ms.
(a) = 1 ms
(b) = 10 ms
(c) = 20 ms
(d) = 50 ms
Resting membrane voltage increases in these regions are much larger than those seen in the motor cortex, with AP sensitivity values comparable to those attained with montages 1 and 2. After 1 ms of tDCS administration, AP sensitivity increases in the STN and SN regions are observable (Figure 16(a)). By 10 ms (Figure 16(b)), AP sensitivity in these regions is approaching 4 percent. Maximal increases occur once again at 20 ms (Figure 16(c)), and after 20 ms membrane voltage begins to repolarize (Figure 16(d)).
These threedimensional numerical experiments further validate the multiscale model’s ability to accurately compute the electric potentials and currents generated during tDCS treatments. In addition, using an MRIderived head geometry and anisotropic tissue conductivities, the ability of the multiscale model to identify regions in the brain that have elevated resting membrane potentials during tDCS treatments with three realworld electrode configurations has been shown.
4. Conclusions
We have presented a novel, multiscale model of tDCS that couples the mathematics of this procedure to neuronal functioning. The model has been validated against several test cases with comparisons to existing simulations and medical research results. In all of these experiments, the multiscale model accurately simulates tDCS electric potentials and electric fields. We verified the model’s ability to correctly identify those areas of the brain known to be electrically stimulated by specific, realworld tDCS electrode montages. Further, we demonstrated the model’s medical applicability with simulations on a threedimensional head geometry, derived from MRI data, with anisotropic and inhomogeneous tissue conductivities.
To our knowledge, this paper presents the first multiscale model and simulations of tDCS, which effectively couples cellularlevel functionality with tDCS treatment conditions. In addition, our simulation implementation strategies provide an intersection between the tDCS simulation and computational neuroscience communities. In the future, we plan to enhance the fidelity of our simulations with more robust, locationspecific neuron models. We also plan to investigate alternative electrode configurations and the numerical methods that most efficiently execute these simulations.
Conflict of Interests
The authors declare that there is no conflict of interests regarding the publication of this paper.
Acknowledgments
The authors would like to acknowledge the financial support received from Virginia Tech’s Open Access Subvention Fund and the entire inuTech team for their assistance with Diffpack.
References
 P. S. Boggio, L. P. Khoury, D. C. S. Martins, O. E. M. S. Martins, E. C. de Macedo, and F. Fregni, “Temporal cortex direct current stimulation enhances performance on a visual recognition memory task in Alzheimer disease,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 80, no. 4, pp. 444–447, 2009. View at: Publisher Site  Google Scholar
 P. S. Boggio, C. A. Valasek, C. Campanhã et al., “Noninvasive brain stimulation to assess and modulate neuroplasticity in Alzheimer's disease,” Neuropsychological Rehabilitation, vol. 21, no. 5, pp. 703–716, 2011. View at: Publisher Site  Google Scholar
 D. H. Benninger, M. Lomarev, G. Lopez et al., “Transcranial direct current stimulation for the treatment of Parkinson's disease,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 81, no. 10, pp. 1105–1111, 2010. View at: Publisher Site  Google Scholar
 P. S. Boggio, R. Ferrucci, S. P. Rigonatti et al., “Effects of transcranial direct current stimulation on working memory in patients with Parkinson's disease,” Journal of the Neurological Sciences, vol. 249, no. 1, pp. 31–38, 2006. View at: Publisher Site  Google Scholar
 U. G. Kalu, C. E. Sexton, C. K. Loo, and K. P. Ebmeier, “Transcranial direct current stimulation in the treatment of major depression: a metaanalysis,” Psychological Medicine, vol. 42, no. 9, pp. 1791–1800, 2012. View at: Publisher Site  Google Scholar
 F. Fregni, P. S. Boggio, M. A. Nitsche, S. P. Rigonatti, and A. PascualLeone, “Cognitive effects of repeated sessions of transcranial direct current stimulation in patients with depression,” Depression and Anxiety, vol. 23, no. 8, pp. 482–484, 2006. View at: Publisher Site  Google Scholar
 G. Schlaug, V. Renga, and D. Nair, “Transcranial direct current stimulation in stroke recovery,” Archives of Neurology, vol. 65, no. 12, pp. 1571–1576, 2008. View at: Publisher Site  Google Scholar
 S. Hesse, A. Waldner, J. Mehrholz, C. Tomelleri, M. Pohl, and C. Werner, “Combined transcranial direct current stimulation and robotassisted arm training in subacute stroke patients: an exploratory, randomized multicenter trial,” Neurorehabilitation and Neural Repair, vol. 25, no. 9, pp. 838–846, 2011. View at: Publisher Site  Google Scholar
 T. Neuling, S. Wagner, C. H. Wolters, T. Zaehle, and C. S. Herrmann, “Finiteelement model predicts current density distribution for clinical applications of tDCS and tACS,” Frontiers in Psychiatry, vol. 3, article 83, 2012. View at: Publisher Site  Google Scholar
 F. Gasca, L. Marshall, S. Binder, A. Schlaefer, U. G. Hofmann, and A. Schweikard, “Finite element simulation of transcranial current stimulation in realistic rat head model,” in Proceedings of the 5th International IEEE/EMBS Conference on Neural Engineering (NER ’11), pp. 36–39, Cancun, Mexico, May 2011. View at: Publisher Site  Google Scholar
 A. Datta, X. Zhou, Y. Su, L. C. Parra, and M. Bikson, “Validation of finite element model of transcranial electrical stimulation using scalp potentials: implications for clinical dose,” Journal of Neural Engineering, vol. 10, no. 3, Article ID 036018, 2013. View at: Publisher Site  Google Scholar
 P. C. Miranda, M. Lomarev, and M. Hallett, “Modeling the current distribution during transcranial direct current stimulation,” Clinical Neurophysiology, vol. 117, no. 7, pp. 1623–1629, 2006. View at: Publisher Site  Google Scholar
 S. K. Kessler, P. Minhas, A. J. Woods, A. Rosen, C. Gorman, and M. Bikson, “Dosage considerations for transcranial direct c urrent stimulation in children: a computational modeling study,” PLoS ONE, vol. 8, no. 9, Article ID e76112, 2013. View at: Publisher Site  Google Scholar
 R. Plonsey and D. B. Heppner, “Considerations of quasistationarity in electrophysiological systems,” The Bulletin of Mathematical Biophysics, vol. 29, no. 4, pp. 657–664, 1967. View at: Publisher Site  Google Scholar
 R. Sadleir, “A bidomain model for neural tissue,” International Journal of Bioelectromagnetism, vol. 12, no. 1, pp. 2–6, 2010. View at: Google Scholar
 E. Mandonnet and O. Pantz, “The role of electrode direction during axonal bipolar electrical stimulation: a bidomain computational model study,” Acta Neurochirurgica, vol. 153, no. 12, pp. 2351–2355, 2011. View at: Publisher Site  Google Scholar
 A. L. Hodgkin and A. F. Huxley, “A quantitative description of membrane current and its application to conduction and excitation in nerve,” The Journal of Physiology, vol. 117, no. 4, pp. 500–544, 1952. View at: Google Scholar
 J. L. Hindmarsh and R. M. Rose, “A model of neuronal bursting using three coupled first order differential equations,” Proceedings of the Royal Society of London Series B: Biological sciences, vol. 221, no. 1222, pp. 87–102, 1984. View at: Publisher Site  Google Scholar
 C. Koch, Methods in Neuronal Modeling: From Ions to Networks, The MIT Press, Cambridge, Mass, USA, 1998.
 W. Ying and C. S. Henriquez, “Hybrid finite element method for describing the electrical response of biological cells to applied fields,” IEEE Transactions on Biomedical Engineering, vol. 54, no. 4, pp. 611–620, 2007. View at: Publisher Site  Google Scholar
 A. AgudeloToro and A. Neef, “Computationally efficient simulation of electrical activity at cell membranes interacting with selfgenerated and externally imposed electric fields,” Journal of Neural Engineering, vol. 10, no. 2, Article ID 026019, 2013. View at: Publisher Site  Google Scholar
 R. Szmurło, J. Starzyński, B. Sawicki, and S. Wincenciak, “Multiscale finite element model of the electrically active neural tissue,” in Proceedings of the International Conference on Computer as a Tool (EUROCON '07), pp. 2343–2348, Warsaw, Poland, September 2007. View at: Publisher Site  Google Scholar
 R. Szmurło, J. Starzyński, B. Sawicki, S. Wincenciak, and A. Cichocki, “Bidomain formulation for modeling brain activity propagation,” in Proceedings of the 12th Biennial IEEE Conference on Electromagnetic Field Computation (CEFC ’06), Miami, Fla, USA, May 2006. View at: Publisher Site  Google Scholar
 D. B. Geselowitz and W. T. Miller III, “A bidomain model for anisotropic cardiac muscle,” Annals of Biomedical Engineering, vol. 11, no. 34, pp. 191–206, 1983. View at: Publisher Site  Google Scholar
 J. Sundnes, G. T. Lines, X. Cai, B. F. Nielsen, K.A. Mardal, and A. Tveito, Computing the Electrical Activity in the Heart, Springer, Berlin, Germany, 2006. View at: MathSciNet
 R. FitzHugh, “Impulses and physiological states in theoretical models of nerve membrane,” Biophysical Journal, vol. 1, no. 6, pp. 445–466, 1961. View at: Publisher Site  Google Scholar
 J. A. Southern, G. Plank, E. J. Vigmond, and J. P. Whiteley, “Solving the coupled system improves computational efficiency of the bidomain equations.,” IEEE transactions on biomedical engineering, vol. 56, no. 10, pp. 2404–2412, 2009. View at: Publisher Site  Google Scholar
 E. Suli, An Introduction to Numerical Analysis, Cambridge University Press, Cambridge, UK, 2003.
 K. A. Mardal, J. Sundes, H. P. Langtangen, and A. Tveito, “Systems of PDEs and block preconditioning,” in Advanced Topics in Computational Partial Differential Equations: Numerical Methods and Diffpack Programming, H. P. Langtangen and A. Tveito, Eds., Lecture Notes in Computational Science and Engineering, pp. 199–236, Springer, Berlin, Germany, 2003. View at: Publisher Site  Google Scholar
 H. A. van der Vorst, Iterative Krylov Methods for Large Linear Systems, Cambridge Monographs on Applied and Computational Mathematics, Cambridge University Press, Cambridge, UK, 2003. View at: MathSciNet
 H. P. Langtangen, Computational Partial Differential Equations: Numerical Methods and Diffpack Programming, Springer, Berlin, Germany, 2003. View at: Publisher Site  MathSciNet
 M. Windhoff, A. Opitz, and A. Thielscher, “Electric field calculations in brain stimulation based on finite elements: An optimized processing pipeline for the generation and usage of accurate individual head models,” Human Brain Mapping, vol. 34, no. 4, pp. 923–935, 2013. View at: Publisher Site  Google Scholar
 C. Geuzaine and J. F. Remacle, “Gmsh: A 3D finite element mesh generator with builtin pre and postprocessing facilities,” International Journal for Numerical Methods in Engineering, vol. 79, no. 11, pp. 1309–1331, 2009. View at: Publisher Site  Google Scholar  MathSciNet
 A. M. Bruaset and H. P. Langtangen, “Diffpack: a software environment for rapid prototyping of PDE solvers,” in Proceedings of the 15th IMACS World Congress on Scientific Computation, Modeling and Applied Mathematics, pp. 553–558, 1997. View at: Google Scholar
 MATLAB, Version 8.2.0.701 (R2013b), The MathWorks, Natick, Mass, USA, 2013.
 R. Szmurlo, J. Starzynski, S. Stanislaw, and A. Rysz, “Numerical model of vagus nerve electrical stimulation,” COMPEL, vol. 28, no. 1, pp. 211–220, 2009. View at: Publisher Site  Google Scholar
 A. Datta, J. M. Baker, M. Bikson, and J. Fridriksson, “Individualized model predicts brain current flow during transcranial directcurrent stimulation treatment in responsive stroke patient,” Brain Stimulation, vol. 4, no. 3, pp. 169–174, 2011. View at: Publisher Site  Google Scholar
 M. A. Nitsche, L. G. Cohen, E. M. Wassermann et al., “Transcranial direct current stimulation: State of the art 2008,” Brain Stimulation, vol. 1, no. 3, pp. 206–223, 2008. View at: Publisher Site  Google Scholar
 E. K. Kang and N.J. Paik, “Effect of a tDCS electrode montage on implicit motor sequence learning in healthy subjects,” Experimental and Translational Stroke Medicine, vol. 3, no. 1, article 4, 2011. View at: Publisher Site  Google Scholar
 M. Okamoto, H. Dan, K. Sakamoto et al., “Threedimensional probabilistic anatomical craniocerebral correlation via the international 10–20 system oriented for transcranial functional brain mapping,” NeuroImage, vol. 21, no. 1, pp. 99–111, 2004. View at: Publisher Site  Google Scholar
 F. Fregni, P. S. Boggio, M. C. Santos et al., “Noninvasive cortical stimulation with transcranial direct current stimulation in Parkinson's disease,” Movement Disorders, vol. 21, no. 10, pp. 1693–1702, 2006. View at: Publisher Site  Google Scholar
 C. W. Hess, “Modulation of corticalsubcortical networks in Parkinson's disease by applied field effects,” Frontiers in Human Neuroscience, vol. 7, article 565, 2013. View at: Publisher Site  Google Scholar
 C. C. Mcintyre and T. J. Foutz, “Computational modeling of deep brain stimulation,” Handbook of Clinical Neurology, vol. 116, pp. 55–61, 2013. View at: Publisher Site  Google Scholar
 D. T. Brocker and W. M. Grill, “Principles of electrical stimulation of neural tissue,” Handbook of Clinical Neurology, vol. 116, pp. 3–18, 2013. View at: Publisher Site  Google Scholar
 A. C. Sutton, W. Yu, M. E. Calos et al., “Deep brain stimulation of the substantia nigra pars reticulata improves forelimb akinesia in the hemiparkinsonian rat,” Journal of Neurophysiology, vol. 109, no. 2, pp. 363–374, 2013. View at: Publisher Site  Google Scholar
 D. Weiss, S. Breit, T. Wächter, C. Plewnia, A. Gharabaghi, and R. Krüger, “Combined stimulation of the substantia nigra pars reticulata and the subthalamic nucleus is effective in hypokinetic gait disturbance in Parkinson's disease,” Journal of Neurology, vol. 258, no. 6, pp. 1183–1185, 2011. View at: Publisher Site  Google Scholar
 A. Siegel, Essential Neuroscience, Lippincott Williams & Wilkins, Philadelphia, Pa, USA, 2006.
 D. S. Stetson, J. W. Albers, B. A. Silverstein, and R. A. Wolfe, “Effects of age, sex, and anthropometric factors on nerve conduction measures,” Muscle and Nerve, vol. 15, no. 10, pp. 1095–1104, 1992. View at: Publisher Site  Google Scholar
 J. Malmivuo and R. Plonsey, Bioelectromagnetism: Principles and Applications of Bioelectric and Biomagnetic Fields, Oxford University Press, New York, NY, USA, 1995.
Copyright
Copyright © 2014 Edward T. Dougherty et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.