Clinical Neurophysiology 115 (2004) 589–595

www.elsevier.com/locate/clinph

Electric field and stimulating influence generated by deep brain

stimulation of the subthalamic nucleus
Cameron C. McIntyrea,*, Susumu Morib, David L. Shermanc, Nitish V. Thakorc, Jerrold L. Viteka
a
Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA
b
Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
c
Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Accepted 28 October 2003

Abstract
Objective: The goal of this project was to develop a quantitative understanding of the volume of axonal tissue directly activated by deep
brain stimulation (DBS) of the subthalamic nucleus (STN).
Methods: The 3-dimensionally inhomogeneous and anisotropic tissue medium surrounding DBS electrodes complicates our
understanding of the electric field and tissue response generated by the stimulation. We developed finite element computer models to
address the effects of DBS in a homogeneous isotropic medium, and a medium with tissue conductivity properties derived from human
diffusion tensor magnetic resonance data. The second difference of the potential distribution generated in the tissue medium was used as a
predictor of the volume of tissue supra-threshold for axonal activation.
Results: The model predicts that clinically effective stimulation parameters (2 3 V; 0.1 ms; 150 Hz) result in activation of large diameter
(5.7 mm) myelinated axons over a volume that spreads outside the borders of the STN. The shape of the activation volume was dependent on
the strong dorsal-ventral anisotropy of the internal capsule, and the moderate anterior-posterior anisotropy of the region around zona incerta.
Conclusions: Small deviations (, 1 mm) in the electrode position within STN can substantially alter the shape of the activation volume as
well as its spread to neighboring structures.
Significance: STN DBS represents an effective treatment for medically refractory movement disorders such as Parkinson’s disease.
However, stimulation induced side effects such as tetanic muscle contraction, speech disturbance and ocular deviation are not uncommon.
Quantitative characterization of the spread of stimulation will aid in the development of techniques to maximize the efficacy of DBS.
q 2004 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
Keywords: Finite element model; Subthalamic nucleus; Diffusion tensor; Conductivity tensor

1. Introduction remains elusive (Vitek, 2002; McIntyre and Thakor, 2002).

High frequency deep brain stimulation (DBS) of the
thalamus or basal ganglia represents an effective clinical
technique for the treatment of essential tremor and
Parkinson’s disease (PD) (Benabid et al., 1996; Obeso
et al., 2001). In addition, multiple pilot studies have begun
to examine the utility of DBS for dystonia (Vercueil et al.,
2001), epilepsy (Hodaie et al., 2002), and obsessive-
compulsive disorder (Gabriels et al., 2003). However,
understanding of the therapeutic mechanisms of action
* Corresponding author. Department of Biomedical Engineering,
Cleveland Clinic Foundation, 9500 Euclid Ave ND20, Cleveland, OH
44195, USA. Tel.: þ1-216-445-3264; fax: þ 1-216-444-9198.
E-mail address: mcintyre@bme.ri.ccf.org (C.C. McIntyre).
1388-2457/$30.00 q 2004 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.clinph.2003.10.033
In turn, it is unclear what stimulation parameters, electrode
geometries, and electrode locations are optimal for the
present or future uses of DBS technology.
The subthalamic nucleus (STN) represents the most
common target for DBS technology. Clinically effective
STN DBS for PD has typically been achieved with
electrode contacts in the anterior-dorsal STN (Voges et al.,
2002; Saint-Cyr et al., 2002; Starr et al., 2002; Hamel et al.,
2003; Yelnik et al., 2003). One limitation of STN DBS is
the low threshold for side effects such as tetanic muscle
contraction, speech disturbances and ocular deviation
(Krack et al., 2002; Tamma et al., 2002). Highly
anisotropic fiber tracks surround the STN and activation
of these tracks has been implicated in many of the side
590 C.C. McIntyre et al. / Clinical Neurophysiology 115 (2004) 589–595
effects associated with DBS. However, our limited under-
standing of the neural response to DBS and the 3-
dimensionally anisotropic tissue medium that surround
the electrodes makes predicting the volume of tissue
influenced by DBS challenging.
One fundamental step toward understanding the neural
response to DBS is characterizing the electric field
generated by the stimulating electrodes. The electric field
is dependent on the shape of the electrode and the electrical
conductivity of the tissue medium (McIntyre and Grill,
2001, 2002). DBS electrodes are 3-dimensional structures
and the tissue conductivity of the central nervous system
(CNS) is both inhomogeneous (dependent on location) and
anisotropic (dependent on direction). The tissue inhom-
ogeneity and anisotropy surrounding the electrode can alter
the shape of the electric field and the subsequent neural
response to stimulation (Grill, 1999). Therefore, we
employed diffusion tensor imaging to estimate the electrical
conductivity tensor of the tissue medium surrounding DBS
electrodes (Tuch et al., 2001). We incorporated the tissue
conductivity data into finite element models (FEM) tailored
to accurately represent the structure of the clinical DBS
electrode and surrounding tissue medium. We then used
these models to predict the volume of tissue likely to be
affected by typical stimulation parameters (1 –3 V; 0.1 ms;
150 Hz).
2. Methods
We developed 3-dimensional finite element models of
the Medtronic 3387 DBS lead (Medtronic, Inc., Minneapo-
lis, MN). We examined two representations of the
surrounding tissue electrical properties. One model utilized
a homogenous isotropic tissue conductivity of 0.3 S/m
(Sances and Larson, 1975), while the other explicitly
represented the anisotropy of the tissue with conductivity
tensors (s) derived from diffusion tensor magnetic
resonance images. In both models, a 0.2 mm thick sheath
of encapsulation tissue (Haberler et al., 2000) with a
conductivity of 0.15 S/m (Grill and Mortimer, 1994)
surrounded the electrode shaft. The model was implemented
using 231,404 elements in a commercially available soft-
ware package FEMLAB 2.3 (COMSOL Inc., Burlington,
MA). The model boundary was determined by a
100 £ 100 £ 100 mm3 cube that surrounded the electrode.
The boundary was set to 0 V, and the electrode contact set to
the stimulus voltage. The potential distribution (Ve)
generated in the tissue medium was calculated from the
Laplace equation:
7 · s7Ve ¼ 0;
with a Good Broyden iterative solver and an algebraic
multigrid preconditioner. Doubling the density of the mesh
or doubling the distance of the boundary from the electrode
(i.e. the size of the tissue box) generated a potential
distribution that differed by , 2% when compared to the
default model.
Diffusion tensor imaging (DTI) characterizes the diffu-
sional behavior of water in tissue on a voxel-by-voxel basis
in terms of a matrix quantity from which the diffusion
coefficient can be obtained corresponding to any direction in
space (Basser et al., 1994; Le Bihan et al., 2001). The work
of Tuch et al. (2001) provided the framework for obtaining
the electrical conductivity tensor of a tissue medium from
the diffusion tensor (D). The hypothesized relationship
between electrical conductivity and water diffusion in tissue
is prompted by the observation that in a structured medium
the two processes are related through mutual respect for the
boundary conditions imposed by the tissue geometry. In
turn, s was directly solved for at each voxel using a simple
linear transform of D:
s ¼ ðse =de ÞD;
where se is the effective extracellular conductivity and
de is the effective extracellular diffusivity. The ratio of
(se/de ¼ 0.736 (S 2 s)/mm2) was determined from exper-
imental and empirical data (Tuch et al., 2001; Haueisen
et al., 2002).
The DTI data was acquired with a 1.5 T Philips Gyroscan
NT using a single-shot echo-planar imaging (EPI) sequence
with the SENSE parallel imaging scheme (SENSitivity
Encoding, reduction factor R ¼ 2.5) (Jones et al., 1999;
Bammer et al., 2002). The imaging matrix was 96 £ 96 with
a field of view of 240 £ 240 mm, which was zerofilled to
256 £ 256. Axial slices of 2.5 mm thickness were acquired
parallel to the anterior-posterior commissure line. The
diffusion weighting was encoded along 30 independent
orientations and the b-value was 700 s/mm2. The dorsal
STN was located in axial slices based on stereotactic
coordinates and co-registration with the Schlatlenbrand and
Bailey (1959) brain atlas (Fig. 1B). We extracted the DTI
data from the 10 £ 10 mm region that surrounded our
electrode location in the STN (2 mm ventral, 10 mm lateral,
and 1 mm posterior to the mid-commissural point
(Saint-Cyr et al., 2002; Hamel et al., 2003)). We then
transformed the diffusion tensors to conductivity tensors,
incorporated the conductivity tensors into co-registered
subdomains in the FEM, and solved for the potential
distribution generated in the tissue medium by DBS.
3. Results
We compared the electric field of a theoretical point
source, a DBS electrode in an isotropic medium, and a
DBS electrode in an anisotropic medium representative of
the STN and surrounding tissue structures. Fig. 1 shows the
potential distribution (Ve) generated in the tissue medium
for each of these models as well as the second difference of
the potential (D2Ve) evaluated at 0.5 mm increments
along different directions (i.e. D2Ve ¼ Ve[n þ 0.5 mm]
 C.C. McIntyre et al. / Clinical Neurophysiology 115 (2004) 589–595 591

Fig. 1. Potential distribution (Ve) and its second difference (D2Ve) generated by DBS electrodes. (A) Comparison of a monopolar point source (21 mA, left
column), monopolar DBS (21 V, middle two columns), and bipolar DBS (^1 V, right column) in an isotropic medium. The top row shows Ve over a 10 £ 10
mm2 area. The middle row shows D2Ve evaluated along the vertical direction relative to the displayed plane. The bottom row shows D2Ve evaluated along the
direction perpendicular to the displayed plane. Positive D2Ve is representative of a depolarizing influence and negative D2Ve is representative of a
hyperpolarizing influence. D2Ve values .20 and ,220 mV are clipped to provide better resolution of the values of interest. (B) DBS in an anisotropic
medium representative of the STN and surrounding tissue structures. The right panels of the top row shows the volume ratio (l1l2l3 / [(l1 þ l2 þ l3)/3]3),
a scalar that quantifies the degree of anisotropy in each voxel based on the eigenvalues (l1, l2, l3) of the diffusion tensor, for the entire axial slice (far right) and
the 10 £ 10 region that was used in the finite element model (middle right). The representative location in the Schlatlenbrand and Bailey (1959) brain atlas is
overlayed for reference. The left panels of the top row shows Ve generated from a 21 V stimulus (middle left), and D2Ve evaluated along the direction
perpendicular to the displayed plane for a 21 V stimulus (far left). The bottom row shows D2Ve for a 23 V stimulus with the electrode located in the anterior-
dorsal STN (far left), 1 mm anterior (middle left), 1 mm medial (middle right), and 1 mm lateral (far right).
592 C.C. McIntyre et al. / Clinical Neurophysiology 115 (2004) 589–595
þ Ve[n 2 0.5 mm] 2 2*Ve[n ]). The D2Ve along indivi-
dual neuronal processes induces transmembrane currents
that result in direct polarization of the neuron by the
applied electric field (Rattay, 1986). D2Ve has both positive
and negative components along any given direction,
resulting in regions of both depolarization (positive
D2Ve) and hyperpolarization (negative D2Ve) in neurons
surrounding the electrode (Fig. 1).
During extracellular stimulation of the CNS, axonal
elements represent the most excitable components of
neurons surrounding the electrode (Nowak and Bullier,
1998a,b; McIntyre and Grill, 1999, 2000). Evaluation of
D2Ve can provide qualitative predictions on the likelihood
of neural activation by extracellular sources (Rattay, 1986;
Warman et al., 1992; Moffitt et al., 2003). Therefore, to
provide a quantitative reference to the D2Ve data in Fig. 1
we used the 5.7 mm diameter myelinated axon model from
McIntyre et al. (2002) to draw correlations between axonal
threshold and D2Ve. A Dx of 0.5 mm was used in evaluating
D2Ve as this distance represents the internodal spacing of
the 5.7 mm fiber. Fifty axons oriented parallel to the
electrode shaft were randomly positioned in the tissue
medium surrounding the electrode and D2Ve was calculated
for threshold stimulation (Fig. 2). This analysis revealed that
for a 150 Hz train of cathodic stimuli 0.1 ms in duration a
D2Ve . 12 mV always generated propagating action
potentials at the stimulus frequency and when the axon
was further than 3 mm from the electrode a D2Ve . 8 mV
was sufficient for activation (Fig. 2). In addition, the axon
model never exhibited block of firing during 2 3 V; 0.1 ms;
150 Hz stimulation for any of the positions examined.
Fig. 2. Voltage distance relationship of large diameter axons during DBS.
Threshold stimulus amplitude was calculated for fifty 5.7 mm diameter
myelinated axons (see McIntyre et al. (2002) for model specifics) to follow
a 150 Hz train of 0.1 ms duration pulses as a function of their distance from
the DBS electrode. The axons were randomly positioned in the tissue
medium and oriented parallel to the electrode shaft. The second difference
of the potential distribution (Dx ¼ 0.5 mm) at threshold was calculated for
each axon along its path length and at the point in axial plane that slices
through the center of the stimulating contact (i.e. [D2Ve perpendicular, DBS
axial] in Fig. 1A).
We evaluated D2Ve along several directions relative to
the electrode (Fig. 1). The red/blue of D2Ve vertical (middle
row in Fig. 1A) represent regions of depolarization/
hyperpolarzation that would be generated in neural elements
running vertically in the displayed plane (i.e. up/down the
page). D2Ve perpendicular (bottom row of Fig. 1A)
represents regions of depolarization/hyperpolarization that
would be generated in neural elements running perpendicu-
lar to the displayed plane (i.e. into/out of the page). D2Ve
always results in both positive and negative regions in the
tissue medium, however, example results from D2Ve
perpendicular (bottom row of Fig. 1A) only show
depolarizing effects. In these examples, hyperpolarizing
effects still exist in the tissue medium, but because of the 3D
nature of the stimulation they are not within the field of
view. Coupled comparison of [D2Ve vertical, DBS axial]
and [D2Ve perpendicular, DBS coronal] or [D2Ve perpen-
dicular, DBS axial] and [D2Ve vertical, DBS coronal] show
orthogonal planes through the center of the electrode
contact where D2Ve has been evaluated along the same
direction relative to the electrode and can give a sense of the
3D stimulation effects. The model results show that
monopolar 2 1 V stimuli resulted in activation of large
diameter axons within , 2.5 mm radius surrounding the
electrode contact (Figs. 1A and 2). Bipolar stimulation
generated a more complex pattern of depolarization/
hyperpolarization, but did not dramatically alter the volume
of tissue supra-threshold for activation of large diameter
axons (Fig. 1A).
The incorporation of tissue electrical properties repre-
sentative of the STN and surrounding structures resulted in
distortion of Ve and D2Ve generated by DBS as compared to
the isotropic case (Fig. 1B). The strong dorsal-ventral
anisotropy of the internal capsule (IC) limited stimulation
anterior and lateral to the electrode. The moderate anterior-
posterior anisotropy of the region around zona incerta (ZI)
extended stimulation posterior to the electrode. Increasing
the stimulus amplitude to 2 3 V resulted in a volume of
activation that was more dependent on the tissue anisotropy
and spread outside the borders of the STN. In addition,
medial-lateral and/or anterior-posterior variation in the
electrode location within STN directly altered the shape
and volume of activation (Fig. 1B). Electrodes positioned
near the anterior and/or lateral borders of the STN exhibited
strong activation of IC, while electrodes located in the
medial STN resulted in the largest overall volume of
activation and limited activation of IC. These results show
that minor changes (1 mm) in the electrode location within
the dorsal STN can have substantial effects on the neural
response to DBS.
4. Discussion
DBS represents an effective clinical therapy for move-
ment disorders; however, our limited understanding of
 C.C. McIntyre et al. / Clinical Neurophysiology 115 (2004) 589–595
the effects of stimulation on the underlying neural tissue
hinders future advancement of this technology. The electric
field generated by DBS electrodes, using therapeutic
stimulation parameters, is capable of directly activating a
large volume of tissue (Figs. 1 and 2). Our results show that
the stimulating effect of the field will spread outside the
borders of the dorsal STN and can result in activation of
axonal elements in the ZI, fields of Forel (H2), and IC (Fig.
1B). In agreement with these model predictions, clinical
stimulation amplitudes in the range of 2 3 V are often
capable of inducing side effects associated with activation
of the corticospinal and corticobulbar tracts of the IC (Krack
et al., 2002; Tamma et al., 2002; Ashby et al., 1999). Our
models suggest that the low threshold side effects of IC
stimulation can be avoided with electrode locations slightly
(, 1 mm) medial and/or posterior to the clinical target of the
anterior-dorsal STN (Voges et al., 2002; Saint-Cyr et al.,
2002; Starr et al., 2002; Hamel et al., 2003; Yelnik et al.,
2003). However, given the intrinsic error in the DBS
implantation procedure it is not presently possible to
position the electrode with sub-millimeter accuracy relative
to the patient specific neuroanatomy (Zonenshayn et al.,
2000). In addition, it is unclear if the spread of stimulation
outside the borders of STN to ZI and H2 is beneficial or
detrimental to clinical outcome. Therefore, the results of
this study act only as a guide to the spread of stimulation and
are not intended to alter present DBS implantation
procedures.
While this study provides quantitative results on the
effects of DBS that would be difficult to achieve
experimentally, there exist two important limitations in
our models that should be noted. First, we used electrostatic
analysis and the resolution of our diffusion tensor based
tissue conductivities was on the order of 1 mm. In general,
CNS tissue has a small reactive component that results in
limited increases in conductivity at higher frequencies
(Ranck, 1963), and micro-inhomogeneities exist on scales
smaller than 1 mm (Le Bihan et al., 2001). Second, neural
activation that results from applied fields is more appro-
priately predicted by directly coupling the field data to
multi-compartment cable models of individual neurons
(McNeal, 1976). Our goal was to develop a simplified
estimation of the volume of tissue supra-threshold for
activation that could be derived directly from the field data.
By evaluating D2Ve in a plane containing the electrode
contact one can visualize the spatial characteristics of the
depolarizing influence of the field (Fig. 1). We then
explicitly calculated the D2Ve necessary to activate large
diameter axons (8 mV for large electrode-to-axon distances)
as a worst-case scenario to address the spread of stimulation
(Fig. 2). This simplified estimation of the spatial extent of
DBS on large diameter axons has an associated error of
several hundred micrometers (Fig. 2). However, given the
large volume tissue affected by DBS (Fig. 1) the error is
relatively small, especially with high stimulus amplitudes
(Fig. 2). Nonetheless, our model of STN DBS represents
593
a significant improvement over previous attempts to
characterize the spatial extent of stimulation using empirical
observations and models that ignored the tissue electrical
properties and electrode geometry (Ranck, 1975; Wu et al.,
2001).
Extracellular stimulation generates a complex electric
field in the tissue medium that is applied to the underlying
neural processes as a distribution of extracellular potentials.
As derived from the cable equation, the second derivative of
the extracellular potentials along each process will produce
both transmembrane and axial currents that will be
distributed throughout the neuron (Rattay, 1986; Warmen
et al., 1992). In turn, each neuron exposed to the applied
field will experience both inward and outward transmem-
brane currents and regions of depolarization and hyperpol-
arization. These theoretical predictions have been verified in
numerous experimental preparations demonstrating the
differences between anodic, cathodic, and bipolar stimu-
lation on the ability to both activate and block neural
activity with extracellular stimulation (Basser and Roth,
2000).
Analysis of the effects of DBS is complicated by our
limited understanding of the response of neurons surround-
ing the electrode to the applied fields. Addressing the effects
of high frequency DBS presents investigators with a
paradox of how stimulation (traditionally thought to activate
neurons) can result in similar therapeutic outcomes as
lesioning target structures in the thalamus or basal ganglia.
In turn, there exist two general philosophies on the effects of
DBS: (1) DBS generates a functional ablation by suppres-
sing or inhibiting the structure being stimulated; or (2) DBS
results in activation patterns in the stimulated network that
override pathological network activity. The results of this
study support the latter by showing with detailed models
and therapeutically effective stimulation parameters that
axonal elements are activated over a large volume of tissue
surrounding the electrode.
In support of our conclusions, experimental investigation
on the effects of STN DBS has implicated activation of large
diameter fiber tracks with therapeutic stimulation par-
ameters (Ashby et al., 1999). In addition, previous attempts
to predict the volume of tissue affected by DBS, utilizing
current-density calculations, have suggested that axonal
elements would be activated over 2.5 mm radius of the
electrode contact with a 2 3 V stimulus (Wu et al., 2001).
However, current-density is not directly related to the neural
response to stimulation and has a non-uniform distribution
on DBS electrode contacts (McIntyre and Thakor, 2002). A
scaled version of the derivative of the current-density, D2Ve,
represents a value that more accurately quantifies the
stimulating influence of the electric field (McNeal, 1976;
Rattay, 1986). Using D2Ve in combination with tissue
electrical properties derived from DTI we predict that 2 3V
STN DBS can activate axonal elements in STN, ZI, H2, and
IC spreading as far as 4 mm from the electrode contact
(Fig. 1B). Furthermore, the anisotropic tissue properties
594 C.C. McIntyre et al. / Clinical Neurophysiology 115 (2004) 589–595
surrounding STN as well as the electrode location within
STN directly affect the size and shape of the activated
volume of tissue.
Acknowledgements
This work was supported by a fellowship from Medtronic
Inc. and a grant from the American Parkinson’s Disease
Association.
References
Ashby P, Kim YJ, Kumar R, Lang AE, Lozano AM. Neurophysiological
effects of stimulation through electrodes in the human subthalamic
nucleus. Brain 1999;122:1919–31.
Bammer R, Auer M, Keeling SL, Augustin M, Stables LA, Prokesch RW,
Stollberger R, Moseley ME, Fazekas F. Diffusion tensor imaging using
single-shot SENSE-EPI. Magn Reson Med 2002;48:128–36.
Basser PJ, Roth BJ. New currents in electrical stimulation of excitable
tissues. Annu Rev Biomed Eng 2000;2:377 –97.
Basser PJ, Mattiello J, LeBihan D. MR diffusion tensor spectroscopy and
imaging. Biophys J 1994;66:259–67.
Benabid AL, Pollak P, Gao D, Hoffmann D, Limousin P, Gay E, Payen I,
Benazzouz A. Chronic electrical stimulation of the ventralis inter-
medius nucleus of the thalamus as a treatment of movement disorders.
J Neurosurg 1996;84:203 –14.
Gabriels L, Cosyns P, Nuttin B, Demeulemeester H, Gybels J. Deep brain
stimulation for treatment-refractory obsessive-compulsive disorder:
psychopathological and neuropsychological outcome in 3 cases. Acta
Psychiatr Scand 2003;107:275–82.
Grill WM. Modeling the effects of electric fields on nerve fibers: influence
of tissue electrical properties. IEEE Trans Biomed Eng 1999;46:
918– 28.
Grill WM, Mortimer JT. Electrical properties of implant encapsulation
tissue. Ann Biomed Eng 1994;22:23–33.
Haberler C, Alesch F, Mazal PR, Pilz P, Jellinger K, Pinter MM,
Hainfellner JA, Budka H. No tissue damage by chronic deep brain
stimulation in Parkinson’s disease. Ann Neurol 2000;48:372– 6.
Hamel W, Fietzek U, Morsnowski A, Schrader B, Herzog J, Weinert D,
Pfister G, Muller D, Volkmann J, Deuschl G, Mehdorn HM. Deep brain
stimulation of the subthalamic nucleus in Parkinson’s disease:
evaluation of active electrode contacts. J Neurol Neurosurg Psychiatry
2003;74:1036–46.
Haueisen J, Tuch DS, Ramon C, Schimpf PH, Wedeen VJ, George JS,
Belliveau JW. The influence of brain tissue anisotropy on human EEG
and MEG. Neuroimage 2002;15:159– 66.
Hodaie M, Wennberg RA, Dostrovsky JO, Lozano AM. Chronic anterior
thalamus stimulation for intractable epilepsy. Epilepsia 2002;43:
603– 8.
Jones DK, Horsfield MA, Simmons A. Optimal strategies for measuring
diffusion in anisotropic systems by magnetic resonance imaging. Magn
Reson Med 1999;42:515 –25.
Krack P, Fraix V, Mendes A, Benabid AL, Pollak P. Postoperative
management of subthalamic nucleus stimulation for Parkinson’s
disease. Mov Disord 2002;17(Suppl.):188–97.
Le Bihan D, Mangin JF, Poupon C, Clark CA, Pappata S, Molko N,
Chabriat H. Diffusion tensor imaging: concepts and applications.
J Magn Reson Imaging 2001;13:534–46.
McIntyre CC, Grill WM. Excitation of central nervous system neurons by
non-uniform electric fields. Biophys J 1999;76:878 –88.
McIntyre CC, Grill WM. Selective microstimulation of central nervous
system neurons. Ann Biomed Eng 2000;28:219–33.
McIntyre CC, Grill WM. Finite element analysis of the current-density and
electric field generated by metal microelectrodes. Ann Biomed Eng
2001;29:227–35.
McIntyre CC, Grill WM. Extracellular stimulation of central neurons:
influence of stimulus waveform and frequency on neuronal output.
J Neurophysiol 2002;88:1592–604.
McIntyre CC, Thakor NV. Uncovering the mechanisms of deep brain
stimulation for Parkinson’s disease through functional imaging, neural
recording, and neural modeling. Crit Rev Biomed Eng 2002;30:249 –81.
McIntyre CC, Richardson AG, Grill WM. Modeling the excitability of
mammalian nerve fibers: influence of after potentials on the recovery
cycle. J Neurophysiol 2002;87:995–1006.
McNeal DR. Analysis of a model for excitation of myelinated nerve.
IEEE Trans Biomed Eng 1976;23:329– 37.
Moffitt MA, McIntyre CC, Grill WM. Prediction of nerve stimulation
thresholds: limitations of linear models. IEEE Trans Biomed Eng 2003;
(in press).
Nowak LG, Bullier J. Axons, but not cell bodies, are activated by electrical
stimulation in cortical gray matter. I. Evidence from chronaxie
measurements. Exp Brain Res 1998a;118:477– 88.
Nowak LG, Bullier J. Axons, but not cell bodies, are activated by electrical
stimulation in cortical gray matter. II. Evidence from selective
inactivation of cell bodies and axon initial segments. Exp Brain Res
1998b;118:489–500.
Obeso JA, Olanow CW, Rodriguez-Oroz MC, Krack P, Kumar R, Lang AE.
Deep-brain stimulation of the subthalamic nucleus or the pars interna of
the globus pallidus in Parkinson’s disease. N Engl J Med 2001;345:
956 –63.
Ranck JB. Specific impedance of rabbit cerebral cortex. Exp Neurol 1963;
7:144–52.
Ranck JB. Which elements are excited in electrical stimulation of mam-
malian central nervous system: a review. Brain Res 1975;98:417–40.
Rattay F. Analysis of models for external stimulation of axons. IEEE Trans
Biomed Eng 1986;33:974–7.
Saint-Cyr JA, Hoque T, Pereira LC, Dostrovsky JO, Hutchison WD, Mikulis
DJ, Abosch A, Sime E, Lang AE, Lozano AM. Localization of clinically
effective stimulating electrodes in the human subthalamic nucleus on
magnetic resonance imaging. J Neurosurg 2002;97:1152–66.
Sances A, Larson SJ. Impedance and current density studies. In: Sances A,
Larson SJ, editors. Electroanesthesia: biomedical and biophysical
studies. New York: Academic Press; 1975. p. 114–24.
Schlatlenbrand G, Bailey P. Introduction to stereotaxis with an atlas of the
human brain, 2nd ed. New York: Grune and Stratton Inc; 1959.
Starr PA, Christine CW, Theodosopoulos PV, Lindsey N, Byrd D, Mosley
A, Marks WJ. Implantation of deep brain stimulators into the
subthalamic nucleus: technical approach and magnetic resonance
imaging-verified lead locations. J Neurosurg 2002;97:370–87.
Tamma F, Caputo E, Chiesa V, Egidi M, Locatelli M, Rampini P, Cinnante
C, Pesenti A, Priori A. Anatomo-clinical correlation of intraoperative
stimulation-induced side-effects during HF-DBS of the subthalamic
nucleus. Neurol Sci 2002;23(Suppl. 2):109–10.
Tuch DS, Wedeen VJ, Dale AM, George JS, Belliveau JW. Conductivity
tensor mapping of the human brain using diffusion tensor MRI. Proc
Natl Acad Sci 2001;98:11697–701.
Vercueil L, Pollak P, Fraix V, Caputo E, Moro E, Benazzouz A, Xie J,
Koudsie A, Benabid AL. Deep brain stimulation in the treatment of
severe dystonia. J Neurol 2001;248:695–700.
Vitek JL. Mechanisms of deep brain stimulation: excitation or inhibition.
Mov Disord 2002;17(Suppl. 3):69–72.
Voges J, Volkmann J, Allert N, Lehrke R, Koulousakis A, Freund HJ,
Sturm V. Bilateral high-frequency stimulation in the subthalamic
nucleus for the treatment of Parkinson disease: correlation of
therapeutic effect with anatomical electrode position. J Neurosurg
2002;96:269–79.
Warman EN, Grill WM, Durand D. Modeling the effects of electric fields
on nerve fibers: determination of excitation thresholds. IEEE Trans
Biomed Eng 1992;39:1244–54.
 C.C. McIntyre et al. / Clinical Neurophysiology 115 (2004) 589–595 595

Wu YR, Levy R, Ashby P, Tasker RR, Dostrovsky JO. Does stimulation of
the GPi control dyskinesia by activating inhibitory axons? Mov Disord
2001;16:208 –16.
Yelnik J, Damier P, Demeret S, Gervais D, Bardinet E, Bejjani BP,
Francois C, Houeto JL, Arnule I, Dormont D, Galanaud D, Pidoux B,
Cornu P, Agid Y. Localization of stimulating electrodes in patients
with Parkinson disease by using a 3-dimensional atlas-magnetic
resonance imaging coregistration method. J Neurosurg 2003;99:
89– 99.
Zonenshayn M, Rezai AR, Mogilner AY, Beric A, Sterio D, Kelly PJ.
Comparison of anatomic and neurophysiological methods for sub-
thalamic nucleus targeting. Neurosurgery 2000;47:282–92.