IOP PUBLISHING JOURNAL OF NEURAL ENGINEERING J. Neural Eng. 4 (2007) 107–119 doi:10.1088/1741-2560/4/2/011 Assessing the direct effects of deep brain stimulation using embedded axon models Stamatios N Sotiropoulos and Peter N Steinmetz Brain Modeling Laboratory, Harrington Department of Bioengineering, Mail Code 9709, ASU Main Campus, Tempe, AZ 85287, USA E-mail: soti0003@umn.edu and Peter.Steinmetz@asu.edu Received 7 August 2006 Accepted for publication 16 February 2007 Published 28 March 2007 Online at stacks.iop.org/JNE/4/107 Abstract To better understand the spatial extent of the direct effects of deep brain stimulation (DBS) on neurons, we implemented a geometrically realistic finite element electrical model incorporating anisotropic and inhomogenous conductivities. The model included the subthalamic nucleus (STN), substantia nigra (SN), zona incerta (ZI), fields of Forel H2 (FF), internal capsule (IC) and Medtronic 3387/3389 electrode. To quantify the effects of stimulation, we extended previous studies by using multi-compartment axon models with geometry and orientation consistent with anatomical features of the brain regions of interest. Simulation of axonal firing produced a map of relative changes in axonal activation. Voltage-controlled stimulation, with clinically typical parameters at the dorso-lateral STN, caused axon activation up to 4 mm from the target. This activation occurred within the FF, IC, SN and ZI with current intensities close to the average injected during DBS (3 mA). A sensitivity analysis of model parameters (fiber size, fiber orientation, degree of inhomogeneity, degree of anisotropy, electrode configuration) revealed that the FF and IC were consistently activated. Direct activation of axons outside the STN suggests that other brain regions may be involved in the beneficial effects of DBS when treating Parkinsonian symptoms. 1. Introduction Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been used extensively for treatment of advanced stages of Parkinson’s disease [1–3]. The mechanism by which DBS produces clinical benefit, however, remains uncertain [4]. Understanding the mechanism of DBS is an important step to improving stimulator devices and also to applying high frequency stimulation to other diseases [5, 6]. However, the several types of neuronal effects that may be induced by STN stimulation make understanding this mechanism difficult. Neurons can be affected directly by the stimulating field or can be indirectly affected trans-synaptically in the neuronal network. Furthermore, both short-term [7] and long-term effects [8] occur. A key issue to gain insight into the mechanisms of DBS is to determine which brain regions are directly immediately affected by the electric stimulus and whether only the target nucleus or other regions too are affected. Indirect effects will then originate from these directly affected regions of the brain. One approach to this issue is to apply physical principles to model the effects of electric fields within the brain. These effects are governed by the second spatial difference of the field’s electric potential, known as the activating function [9], which has been used in computer models to predict the volume of activated tissue [10, 11]. However, coupling the stimulation-evoked electric field to multi-compartment neuron models provides a more precise prediction of activated neurons [12, 13] and will be used throughout the models described here. Multi-compartment models of whole cells can be implemented and studied through computer simulations. However, the large number of anatomical and electrophysiological parameters needed for such models makes them difficult to constrain, particularly given the limited number of ultrastructural and physiological studies for the regions of interest in primates [14–17]. Since axons are more excitable than cell bodies and dendritic fields [18, 19], and are thought to be the main target processes of DBS [20, 21], we focus here on the firing of axons evoked by the electric field during DBS. Models of axons alone 1741-2560/07/020107+13$30.00 © 2007 IOP Publishing Ltd Printed in the UK 107