Vagus nerve stimulation (VNS) was approved in 1997 by the US Food and Drug Administration (FDA) [1] as an invasive neuromodulator approach for the treatment of epilepsy in anti-epileptic drug (AED) resistant subjects. As the vagus nerve (VN) innervates many organs, it is candidate for many new potentially therapeutically relevant applications of selective neurostimulation.

The VN (like many other large nerves in the human body) is composed by multiple functional units assembling many myelinated A- and B- axons of different diameters combined with small unmyelinated C-fibers. Hereafter, VNS approaches for therapeutically relevant applications require approaches providing high fiber selectivity. Electrode arrays with optimized stimulation waveforms can be used to provide, in theory, such selectivity. Computational models that feature simplified or realistic VN models embedded in realistic human anatomical models along realistic trajectories, together with electrophysiological models of axonal fibers capturing the electric-neuronal interaction, are fundamental for the computationally assisted formulation of new VNS protocols, the design of electrode arrays, the optimization of stimulation waveforms, and the prediction of setup-specific axonal fiber recruitment.

Functionalized VN models, featuring head models, nerve trajectories with an arbitrary numbers of electrophysiological axonal models, can now be created in Sim4Life with the recently added T-NEURO feature in combination with electromagnetic (EM) simulations in the low-frequency range.

 

Cross-sectional 2D VN models that feature, e.g., epineurium, perineurium, and fascicles, can be created from medical images or scratched in Sim4Life (see Figure top) with the graphical user interface (GUI).  3D models of the VN can be created, for example, by extruding realistic 2D nerve cross sections along user-defined trajectories (see Figure middle), or along anatomical nerve trajectories within computational human models (see Figure bottom) Electrode geometries can be imported in Sim4life as CAD files or created as parameterized model objects even using available templates entities (helical, spiral, etc.).

Sim4Life’s electro-quasi-static current dominated (EQSCD) solver can be used to set up low frequency EM simulations for either homogeneous or anisotropic dielectric tissue parameters. Electrode voltages may be assigned as Dirichlet boundary conditions.
Sim4Life’s post-processing tools permit the analysis and visualization of exposure-related quantities such as E-field distribution, input currents at electrodes as well as neurostimulation-related quantities as Eigenvalues and Eigenvectors of the E-field Jacobian to identify regions of neurostimulation on the basis of the ‘activation function concept’ [6].

 

Sim4Life provides multiple options for data visualization (slice and surface view, vector field view and streamline, etc.) including the calculation of E-field related integrals (i.e., flux integrator), the visualization or animation of transmembrane voltages or current profiles. These features can be also used for the visualization of customized post-pro quantities derived from python script (e.g., compound action potentials).

The activation function, predictor of the site of neurostimulation, can be visualized along the axonal geometries (see Figure top). The titration sensor provides threshold E-fields for spike initiation, time and location of spike initiation and permits to derive fiber recruitment curves (Figure bottom).

All post-processing results can be exported for further analysis in MATLAB  or Excel. Python scripts and the Sweeper tool can be used to customize optimization procedures aimed, for example, at identifying steering parameters for selective stimulation (e.g. recruitment of either A-, B-, or C- fibers) or to optimize electrodes geometry.