Review
For reprint orders, please contact reprints@future-drugs.com
CONTENTS
Deep brain stimulation
Modeling the neural
response to
extracellular stimulation
Characterizing the neural
response to therapeutic DBS
Expert commentary
Five-year view
Key issues
Financial disclosure
References
Affiliations
†
Author for correspondence
Department of Biomedical
Engineering, Cleveland Clinic
Foundation, 9500 Euclid Avenue,
ND20, Cleveland,
OH 44195, USA
Tel.: +1 216 445 3264
Fax: +1 216 444 9198
mcintyc@ccf.org
KEYWORDS:
depression, dystonia, epilepsy,
essential tremor, neuromodulation,
neurostimulation,
obsessive–compulsive disorder,
Parkinson’s disease,
Tourette’s syndrome
www.future-drugs.com
Computational analysis of
deep brain stimulation
Cameron C McIntyre†, Svjetlana Miocinovic and Christopher R Butson
Chronic, high-frequency electrical stimulation of subcortical brain structures (deep brain
stimulation [DBS]) is an effective clinical treatment for several medically refractory
neurological disorders. However, the clinical successes of DBS are tempered by the limited
understanding of the response of neurons to applied electric fields and scientific definition
of the therapeutic mechanisms of DBS remains elusive. In addition, it is presently unclear
which electrode designs and stimulation parameters are optimal for maximum therapeutic
benefit and minimal side effects. Detailed computer modeling of DBS has recently
emerged as a powerful technique to enhance our understanding of the effects of DBS and
to create a virtual testing ground for new stimulation paradigms. This review summarizes
the fundamentals of neurostimulation modeling and provides an overview of some of the
scientific contributions of computer models to the field of DBS. We then provide a
prospective view on the application of DBS-modeling tools to augment the clinical utility of
DBS and to design the next generation of DBS technology.
Expert Rev. Med. Devices 4(5), 615–622 (2007)
Deep brain stimulation 50% improvement in clinical ratings of motor
Over the last 20 years, deep brain stimulation symptoms in appropriately selected patients [5].
(DBS) has evolved from an experimental tech- However, DBS typically requires highly trained
nique to a well-established therapy for a range of and experienced clinical oversight to achieve
medically refractory neurological disorders [1]. maximal therapeutic benefit in each patient [6].
To date, the most effective application of DBS A team of neurosurgeons, neurophysiologists,
technology has been in the treatment of move- neurologists, radiologists, psychiatrists, nurses
ment disorders, such as Parkinson’s disease, and engineers is required to provide all of the
essential tremor and dystonia. Thalamic DBS expertise necessary for a comprehensive DBS
has virtually replaced ablative lesions of the tha- program. Consequently, DBS can be an expen-
lamus for the treatment of essential tremor [2]. sive proposition for the patient, as well as the
DBS of the subthalamic nucleus (STN) or glo- hospital. Therefore, development of techniques
bus pallidus internus (GPi) has largely replaced to optimize the clinical implementation of
pallidotomy in the treatment of the cardinal DBS represents an important and necessary
motor features of Parkinson’s disease (tremor, step forward for this medical technology.
rigidity and bradykinesia) [3]. GPi DBS has Crucial steps toward the optimization of DBS
recently emerged as an effective therapy for will be to improve scientific and clinical under-
dystonia [4]. In addition, multiple studies are standing of the effects and therapeutic mecha-
currently examining the utility of DBS for epi- nisms of electrical stimulation of the brain.
lepsy, obsessive–compulsive disorder, Tourette’s Experimental neurophysiologists have been
syndrome and depression. addressing the science of extracellular stimula-
The clinical outcomes of DBS are a testa- tion of neurons for decades [7,8]. Furthermore,
ment to the efficacy of the current device tech- the fundamental purpose of DBS is to modulate
nology, surgical implantation techniques and pathological neural activity with applied electric
clinical programming strategies. DBS for fields. However, many clinicians implementing
movement disorders can provide more than a DBS technology do not have a quantitative
10.1586/17434440.4.5.615 © 2007 Future Drugs Ltd ISSN 1743-4440 615
McIntyre, Miocinovic & Butson
understanding of the neural response to manipulation of the var-
ious stimulation parameters. This problem is compounded by
the typical lack of visual reference of the DBS electrode location
relative to the underlying neuroanatomy while stimulation
parameter adjustments are performed. Guidelines do exist on
stimulation parameter settings that are typically effective [9], but
it is unfeasible to clinically evaluate each of the thousands of
stimulation parameter combinations that are possible. As a result,
the therapeutic benefit achieved with DBS is strongly dependent
on the surgical placement of the DBS electrode and the intuitive
skill of the clinician performing the stimulation parameter selec-
tion. In addition, application of DBS technology to disorders,
such as epilepsy, dystonia, depression and obsessive–compulsive
disorder, are especially problematic because the beneficial effects
of stimulation can take weeks to months to manifest. Further-
more, it remains unclear what stimulation paradigms are optimal
for these different disorders. Therefore, a synergistic combination
of clinical experience and scientific knowledge is needed to ena-
ble a more efficacious application of DBS technology to patients.
We propose that computational modeling can be a powerful tool
to augment this process.
Modeling the neural response to extracellular stimulation
The electric field generated by DBS is a three-dimensionally com-
plex phenomenon that is distributed throughout the brain [10,11].
This field is applied to the complex 3D geometry of the sur-
rounding neural processes (i.e., axons and dendrites). The
response of an individual neuron to the applied field is related to
the second derivative of the extracellular potential distribution
along each neural process [12,13]. In turn, each neuron (or neural
process) surrounding the electrode will be subject to both depo-
larizing and hyperpolarizing effects from the stimulation [14,15]. A
neuron can be either activated or suppressed in response to extra-
cellular stimulation in different ways and in different neural
processes depending on its positioning with respect to the elec-
trode and the stimulation parameters. In general, three classes of
neurons can be affected by the stimulation: local cells, afferent
inputs and fibers of passage. Local cells represent neurons that
have their cell body in close proximity to the electrode. Afferent
inputs represent neurons that project axon terminals to the
region of the electrode and whose axon terminals make synaptic
connections with local cells. Fibers of passage represent neurons
where both the cell body and axon terminals are far from the
electrode, but the axonal process of the neuron traces a path that
comes in close proximity to the electrode.
Experimental measurements indicate that local cells, afferent
inputs and fibers of passage have similar thresholds for activa-
tion [7]. In addition, local cells can be excited directly by the stim-
ulus and/or have their excitability indirectly altered via activation
of afferent inputs that make synaptic connections on their den-
dritic arbor [16]. Neural modeling allows for simultaneous study of
the effects of stimulation on all the different types of neurons sur-
rounding the electrode. In addition, models provide a highly con-
trolled environment to study the effects of stimulation on neural
activity, something that is difficult to achieve experimentally.
616
However, the strengths of modeling are tempered by the necessary
simplifications made in any reasonable model. In turn, modeling
should be coupled as closely as possible to experimental work,
allowing for a synergistic analysis of results.
The modeling techniques used presently to predict the neural
response to extracellular stimulation date back to McNeal [12],
who was the first to integrate an electric field model and multi-
compartment cable model to predict action potential generation
(FIGURE 1). This technique has become an important research tool
in neurostimulation device development [17–20]. In general, mode-
ling the excitation of neurons relies on representing the neural
membrane with multiple compartments of electrical circuits.
Each compartment consists of a conductance (Gm[n]), or group
of conductances that represent different ion channel types, in par-
allel with a membrane capacitance (Cm[n]) [21]. These individual
neural compartments are then connected in series by resistors that
represent the intracellular conductance (Gi[n]) [22]. The extracel-
lular potential (Ve[n]) generated by the electrode can then be
applied at each compartment of the neuron to predict the neural
response to the stimulus. The membrane current at compartment
n is equal to the sum of the incoming axial currents and the sum
of the capacitive and ionic currents through the membrane:
Cm[n](dVm[n]/dt) + Ii[n] =
Gi[n – 1](Vi[n – 1] – Vi[n] + Ve[n – 1] – Ve[n]) +
Gi[n](Vi[n + 1] – Vi[n] + Ve[n + 1] – Ve[n])
The transmembrane voltage at each compartment (Vm[n]) is
defined by the difference between the intracellular (Vi[n]) and
extracellular (Ve[n]) potentials (FIGURE 1) [12]. With the addition of
nonlinear ion channels to each neural compartment, this type of
modeling can be computationally intensive. However, this level of
detail is often necessary to accurately capture the spatiotemporal
response of a neuron to extracellular stimulation.
Ve[n-1] Ve[n] Ve[n+1]
Gm[n] Cm[n]
Vi[n-1] Vi[n] Vi[n+1]
Gi[n-1] Gi[n]
Figure 1. Multicompartment cable model of extracellular stimulation.
Electrical network representation of a neural process consists of conductances
representing the tramsmembrane ion channels (Gm[n]), the membrane
capacitance (Cm[n]) and the intracellular conductances connecting different
compartments (Gi[n]). The extracellular potential (Ve[n]) generated in the tissue
medium by an electrode can be applied to the cable to predict the neural
response to the stimulus.
Adapted from McNeal [12].
Expert Rev. Med. Devices 4(5), (2007)

Characterizing the neural response to therapeutic DBS
Recently, our group has focused on coupling computational
models of DBS to experimental and/or clinical measurements
of DBS. Traditionally, computer models of electrical stimula-
tion have been used to develop qualitative hypotheses to
address generalized phenomenon. However, the prospect of
making quantitative predictions on the effects of DBS on a
subject-specific basis posed new challenges that required the
development of new techniques.
Early finite-element models (FEMs) of the electric field gen-
erated by DBS relied on numerous assumptions (e.g., electro-
static homogeneous isotropic volume conductor models) that
were well accepted in the 1990s. The first computer models of
DBS were created by Roy Testerman at Medtronic Inc., and
soon thereafter academic researchers began to investigate the
electric fields generated by DBS [10,23–29]. However, these early
efforts suffered from significant limitations by ignoring some or
all of the following:
• The actual stimulus waveform generated by DBS implanted
pulse generators [30,31]
• The capacitance of the electrode–tissue interface [30]
• The impedance of the electrode–tissue interface [32]
• The 3D anisotropy and heterogeneity of the tissue
medium [10,11,29]
Over the last few years, our group, and others, have demon-
strated that each of these issues substantially impacts the mag-
nitude and shape of the electric field generated by DBS. Con-
sequently, efforts to develop quantitative predictions on the
effects of DBS require anatomically and electrically accurate
electric field models.
Characterizing the electric field is only the first step in simulat-
ing DBS on a subject-specific basis. The fundamental purpose of
DBS is to modulate neural activity; therefore, prediction tech-
niques are needed to estimate the neural response to the applied
electric field. Typically, this is accomplished with a McNeal-type
model, as described previously. Recently, we used such an
approach to investigate neural activation during therapeutic
DBS of the subthalamic region in parkinsonian, nonhuman pri-
mates (FIGURE 2) [33]. The general model system integrated three
fundamental components:
• The anatomical model
• The electric field model
• The neural-activation model
The anatomical model was a histological reconstruction of the
monkey-specific DBS electrode location in the subthalamic
region. The electric field model was a FEM of the monkey DBS
electrode, and the neural activation model coupled populations
of multicompartment cable neuron models to the electric field
model to predict action potential generation.
The model predicted that, when stimulating STN projec-
tion neurons with DBS, action potential initiation always
took place in the myelinated axon of the STN neuron
(FIGURE 2). This resulted in an interesting phenomenon where
www.future-drugs.com
Deep-brain stimulation models
the soma and axon of the same neuron could exhibit dramati-
cally different firing patterns. Dominant globus pallidus
externus inhibitory afferents converge primarily on the cell
body and proximal dendrites of STN neurons [34]. As dis-
cussed previously, afferent inputs (i.e., axon terminals) can be
directly activated by DBS [35]. In our simulations, the pres-
ence of stimulation-induced GABAA synaptic input inhibited
somatic firing while the axon fired in a ratio of almost 1:1
with the stimulation frequency (FIGURE 2) [33]. Similar results
were noted previously in a model of thalamic DBS [26], and
this model prediction reconciles seemingly contradictory
experimental results on DBS that show inhibition of somatic
firing in the stimulated nucleus [36], but changes in the neural
activity of efferent nuclei consistent with activation of the
stimulated nucleus [37].
Given the neuroanatomy of the subthalamic region, two
neural populations represent logical candidates as targets for
stimulation: first, STN projection neurons and/or second, GPi
fibers of passage that form the lenticular fasciculus [38]. There-
fore, we created 3D neuron models, based on single-cell stain-
ing studies, of the dendritic and axonal architectures of these
two cell types [33]. Populations of these neuron models, with
anatomically realistic positions, were placed into a model sys-
tem intending to recreate the experimental environment used
in two nonhuman primates implanted with scaled clinical
DBS systems (FIGURE 2). When experimentally defined thera-
peutic stimulation parameters were applied to the model,
axonal activation of both STN neurons and GPi fibers was pre-
dicted. However, only axonal activation of the STN neurons
demonstrated a statistically significant increase in both mon-
key models when comparing clinically effective and ineffective
stimulation (FIGURE 2) [33].
Similar model systems have also been developed to analyze
DBS in human patients (FIGURE 3) [10,11,27,29]. Our most recent
efforts on this front followed the general methodology described
previously through coupling the anatomical model, the electric
field model and the neural-activation model. However, our
human DBS-modeling system used a diffusion–tensor-based
FEM to capture the 3D tissue anisotropy and heterogeneity that
surrounds DBS electrodes [10]. Furthermore, the neural-activa-
tion model was generalized to enable definition of a total vol-
ume of tissue activated (VTA), derived from the response of
myelinated axons to the applied electric field [20]. We used this
model system to analyze the effects of subthalamic DBS in a
patient with Parkinson’s disease [11]. Quantitative measurements
of bradykinesia (during a finger-tapping exercise) and rigidity
(passive joint impedance) were evaluated over a range of stimu-
lation parameter settings and correlated with the predicted acti-
vation of surrounding anatomical structures (FIGURE 3). Stimula-
tion through electrode contacts that provided therapeutic
benefit generated VTAs that intersected the thalamus, STN,
zona incerta and fields of Forel. However, the common anatom-
ical region associated with improvements in both rigidity and
bradykinesia was found when stimulating zona incerta/fields of
Forel, a tissue region associated with the lenticular fasciculus.
617
McIntyre, Miocinovic & Butson

Interestingly, while rigidity improved in a

A B roughly monotonic fashion with increases
1V
in stimulus voltage magnitude, bradykinesia
a had an optimal voltage. While this data was
40 mV
1 ms
reported for only one patient, the combined
analysis of our human and nonhuman pri-
b
mate DBS models suggests that multiple
mV stimulation target areas exist within the sub-
c
thalamic region and this hypothesis is sup-
D P
ported by numerous anatomical studies on
M the location of therapeutic DBS electrode
d
contacts [39–41]. A prospective, multipatient
study, using our DBS-modeling technology,
is currently underway to examine this issue
C 136 Hz DBS
in more detail.

40 mV 50 ms Expert commentary
a
To date, DBS computer models have pro-
d
vided a relatively minor contribution to the
overall field of DBS. However, a critical
mass of scientific investigators and clinical
D
researchers are beginning to realize the
100
potential value of computational modeling
90 STN neurons
% neurons affected

80 in augmenting the analysis of DBS experi-

GPi fibers
70 mental results, as well as its predictive
60 power for the design of new stimulation
50 Monkey
40 R7160
paradigms. In turn, there is great potential
30 for computational modeling to play a more
20 prominent role in the scientific and clinical
D P 10 analysis of DBS. In addition, a growing
M 0
Ineffective Effective number of appropriately trained individu-
(1.4 V) (1.8 V) als (e.g., mathematicians, computer scien-
100
90 Monkey tists and engineers) are finding their way
% neurons affected

80 R370 into the field of DBS and beginning to

70 make novel contributions. However, real
60 advances in the field will require real inter-
50
action between basic science, computer sci-
40
ence and clinical neurology/neurosurgery.
30
20 Leaders in each of these respective areas will
D P
10 need to reach out to each other, and this
M will undoubtedly generate exciting new
0
Ineffective Effective
(2 V) (3 V)
research ideas and directions.

Figure 2. Modeling deep brain stimulation in the parkinsonian monkey. (A) 3D reconstruction of the
Five-year view
DBS electrode location in the neuroanatomy (STN: light gray volume; GPi: dark gray volume) and the DBS Clinical application of DBS models
polarization of a 3D STN neuron model; (B) Lowercase letters indicate location in the STN neuron where The consensus within the clinical and indus-
the transmembrane voltage was recorded (a: soma; b: first node of Ranvier; c: 30th node of Ranvier; trial neuromodulation communities is that
d: 50th node of Ranvier). The action potential initiated in the axon and propagated toward the cell body
DBS will continue to grow over the next
and axonal terminals in the globus pallidus. The traces in the top row represent the stimulus voltage
waveform applied to the neuron; (C) Trains of DBS suppressed somatic firing, but enhanced axonal 5 years, especially in the treatment of neu-
output; (D) 3D pictures show STN neuron axons (top) and GPi fibers (bottom) activated (red) by clinically ropsychiatric disorders. DBS is an attractive
effective DBS in monkey R7160. Graphs display the percentage of neurons activated for monkeys R7160 therapy for a variety of reasons. DBS allows
(top) and R370 (bottom) during clinically ineffective and clinically effective DBS, averaged over three for bilateral procedures without high inci-
randomized populations.
dence of side effects, the side effects associ-
Adapted with permission from Miocinovic et al. [33].
DBS: Deep brain stimulation; GPi: Globus pallidus internus; STN: Subthalamic nucleus. ated with stimulation are reversible and DBS
allows for customization of the therapy to

618 Expert Rev. Med. Devices 4(5), (2007)

 Deep-brain stimulation models

target and trajectory. Intraoperatively, stereo-

0.18 tactic microdrive coordinates and MER data
A C

Mechanical impedance
Rigidity can be entered, enabling real-time interactive
visualization of the electrode location in 3D
0.14
relative to the surrounding neuroanatomy
and neurophsyiology. Furthermore, the neu-
0.10 rosurgeon can use the combination of ana-
tomical (MRI/CT/3D brain atlas), neuro-
physiological (MER) and electrical (DBS
0.06 VTA) data to optimize the placement of the
0 1 2 3 4 5 DBS electrode prior to permanent implanta-
B Stimulus voltage (V) tion (FIGURE 4) [42].
160
Power spectrum peak
Once the DBS electrode has been
D
Bradykinesia implanted, the device must be programmed
120
by a clinician to define stimulation parame-
80 ter settings that provide therapeutic benefit.
Clinical estimates suggest that 18–36 h per
40 patient are necessary to program and assess
DBS patients with current techniques [45].
0 Much of this time is dedicated to balancing
2V stimulation
0 1 2 3 4 5 the stimulation with medication adjust-
Stimulus voltage (V)
ments, and plasticity in the nervous system.
However, several hours are commonly dedi-
Figure 3. Patient-specific model of deep brain stimulation. (A) 3D brain atlas (thalamus: yellow
volume; subthalamic nucleus: green volume) warped to fit the patient MRI; (B) Deep brain stimulation cated to an initial parameter search to iden-
electrode (gray with pink contacts) and the volume of tissue activated (red volume) for a -2V, 0.06 ms, tify the electrode contact that provides the
130 Hz stimulus train through contact 2; (C) Rigidity measurements as a function of stimulation voltage best therapeutic benefit [9]. In an attempt to
through contact 2 (decrease indicates an improvement); (D) Bradykinesia measurements as a function of decrease the time and skill needed for this
voltage through contact 2 (increase indicates an improvement).
process, we developed a postoperative stimu-
Adapted from Butson et al. [11].
lation parameter selection software tool
the individual patient needs over time via alteration of the stimu- (StimExplorer) [46]. Starting from the Cicerone patient-specific
lation parameters. Furthermore, DBS does not destroy tissue, model, StimExplorer uses VTA predictions and volume-based
allowing patients to potentially benefit from emerging restorative optimization algorithms to define a theoretically optimal stimu-
therapies. However, defining the optimal surgical placement for lation parameter setting (FIGURE 4). The optimization algorithm
the DBS electrode and programming DBS devices for maximal relies on quantitative definition of specific regions of activated
clinical benefit can be a difficult and time-consuming process tissue associated with therapeutic benefit and side effects, and is
that typically requires highly trained and experienced clinical therefore specific to both the given anatomical nucleus where
staff to achieve acceptable results. In addition, current DBS elec- the electrode is implanted and the disease state of the patient.
trode designs and stimulation pulsing paradigms were derived These theoretically optimal settings can represent the start point
empirically and are probably not optimal. However, advances in of clinical programming of the DBS device, thereby focusing the
scientific knowledge will soon allow for the reengineering of DBS clinical customization of DBS to an anatomically and electrically
technology to maximize clinical outcomes, and we see great logical parameter space [46].
opportunities for computational modeling to augment the future Another area that may benefit from computational modeling is
surgical and clinical application of DBS. the design of the DBS electrode. The current clinical DBS elec-
Stereotactic neurosurgery and neurophysiological micro- trode design (four cylindrical contacts in a linear array) was cre-
electrode recording (MER) techniques used in DBS implantation ated approximately 20 years ago without knowledge of several
procedures are typically performed without visualization tools neurostimulation principals that have only recently been eluci-
that could improve data management. To address these limit- dated. In turn, a unique opportunity exists to design DBS elec-
ations, we developed a Microsoft Windows-based software tool trodes that are customized to the anatomical and electrical con-
(Cicerone) that enables interactive 3D visualization of coregis- straints of the stimulation target [20,47]. The underlying
tered MRIs, CT scans, 3D brain atlases, MER data and DBS assumption of such an exercise is that by improving the engineer-
electrode(s) with the VTA as a function of the stimulation para- ing design of clinical DBS devices it will be possible to improve
meters (FIGURE 4) [42]. This software system, or other similar sys- therapeutic outcome. Recently, we performed a theoretical analy-
tems [43,44], are examples of how DBS models could be used in sis of the impact of changes in the DBS electrode geometry on
the future to augment the DBS surgical procedure. Preoperative the VTA [20]. Our results suggest that the VTA size and shape
planning can allow for definition of the stereotactic anatomical that can be manipulated with a great deal of flexibility by simple

www.future-drugs.com 619
McIntyre, Miocinovic & Butson

hypothesized that stimulation-induced neu-

A B ral activity may represent a noise source that
disrupts pathological bursting behavior of the
parkinsonian basal ganglia and, in turn,
improves the information transfer from the
basal ganglia to the cortex [48]. This concept
has been supported by additional theoretical
analyses [50], and computational studies are
beginning to look into alternative closed-loop
stimulation paradigms that should be more
cost effective in terms of power consumption
than traditional high-frequency open-loop
stimulation [49,51]. However, clinical enthusi-
C D asm for these predictions is tempered by the
lack of physiological realism or experimental
validation of the currently available basal gan-
glia network models. In turn, simultaneous
in vivo multielectrode experimental record-
ings of basal ganglia neural activity in the nor-
mal, disease and DBS states is of fundamental
importance for expanding our understanding
of biological network interactions. Addition-
ally, this experimental data is necessary to ena-
ble accurate parameterization of network
models. With advances in modeling technol-
Figure 4. Deep brain stimulation software tools. (A & B) Cicerone enables microelectrode recording
data (thalamus: yellow dots; white matter: white dots; subthalamic nucleus: green dots; substantia nigra
ogy and growing pools of experimental data, a
pars reticulate: red dots) and possible deep brain stimulation electrode positions to be viewed in realistic goal for the next 5 years is synergistic
stereotactic space with the MRI and anatomical nuclei (thalamus: yellow volume; subthalamic nucleus: interaction between systems neurophysiolo-
green volume); (C & D) StimExplorer provides a target volume of stimulation (black volume) and allows gists and computational neuroscientists to
for definition for a theoretically optimal stimulation parameter setting that maximizes volume of tissue quantitatively define network activity patterns
activated coverage and minimizes volume of tissue activated spread out of the target.
Adapted from Miocinovic et al. [42] and Butson et al. [46].
that are responsible for various pathological
symptoms. The network model systems that
modifications to the cylindrical DBS electrode design. In turn, a will result from this type of interaction will undoubtedly be able to
realistic goal for the future is to develop theoretically optimal define experimentally testable hypotheses on novel stimulation
DBS electrode designs for specific anatomical targets that are techniques that could vastly improve DBS technology.
based on scientific principals.

Scientific advances with DBS models Key issues

The exact mechanisms of DBS will continue to be debated over
the next 5 years. A growing consensus in the DBS scientific com-
munity is that its therapeutic mechanisms are rooted in stimula-
tion-induced network activity. In turn, while the last 5 years con-
centrated on the effects of DBS at the level of the individual
neuron, the next 5 years will need to apply these results to under-
stand the effects of DBS on networks of neurons. The fields of
computational neuroscience and dynamical systems have already
developed many of the analytical tools necessary for this step, and
insightful investigators are beginning to use these tools to study
DBS [48–52].
Neurons encode and transmit information in a sequence of
action potentials where the information encoded is related to the
pattern of activity across the neural network. Current DBS meth-
ods use very regular high-frequency stimulation, unlike the dis-
charge activity in most biological neurons. Based on results from
simplified neural network models, Montgomery and Baker
• Deep brain stimulation (DBS) is a powerful clinical tool.
• After approximately 20 years of clinical utility we are only
beginning to understand the effects of DBS on the
nervous system.
• Defining the therapeutic mechanisms of DBS will enable the
design of more efficacious devices.
• Computational modeling will play an important role in
analyzing the effects of DBS, and re-engineering the device
for the future.
• Subject-specific models of DBS can be created that enable
quantitative predictions of the neural activation generated
by the stimulation.
• Software tools can be created to augment the clinical
implementation of DBS technology.

620 Expert Rev. Med. Devices 4(5), (2007)


Financial disclosure
Cameron C McIntyre and Christopher R Butson authored
intellectual property related to the content of this article, and
hold company shares in IntElect® Medical Inc.
References
Papers of special note have been highlighted as:
• of interest
•• of considerable interest
1 Perlmutter JS, Mink JW. Deep brain
stimulation. Annu. Rev. Neurosci. 29,
229–257 (2006).
2 Benabid AL, Pollak P, Gao D et al. Chronic
electrical stimulation of the ventralis
intermedius nucleus of the thalamus as a
treatment of movement disorders.
J. Neurosurg. 84(2), 203–214 (1996).
3 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. 345(13), 956–963 (2001).
4 Vidailhet M, Vercueil L, Houeto JL et al.
Bilateral deep-brain stimulation of the
globus pallidus in primary generalized
dystonia. N. Engl. J. Med. 352(5), 459–467
(2005).
5 Walter BL, Vitek JL. Surgical treatment for
Parkinson’s disease. Lancet Neurol. 3(12),
719–728 (2004).
6 Moro E, Poon YY, Lozano AM,
Saint-Cyr JA, Lang AE. Subthalamic
nucleus stimulation: improvements in
outcome with reprogramming. Arch.
Neurol. 63(9), 1266–1272 (2006).
7 Ranck JB. Which elements are excited in
electrical stimulation of mammalian central
nervous system: a review. Brain Res. 98,
417–440 (1975).
• Detailed review of the fundamentals of
electrical stimulation, as pertinent today as
it was in 1975.
8 Tehovnik EJ, Tolias AS, Sultan F,
Slocum WM, Logothetis NK. Direct and
indirect activation of cortical neurons by
electrical microstimulation. J. Neurophysiol.
96(2), 512–521 (2006).
9 Volkmann J, Moro E, Pahwa R. Basic
algorithms for the programming of deep
brain stimulation in Parkinson’s disease.
Mov. Disord. 21(S14), S284–S289 (2006).
10 McIntyre CC, Mori S, Sherman DL,
Thakor NV, Vitek JL. Electric field and
stimulating influence generated by deep
brain stimulation of the subthalamic
nucleus. Clin. Neurophysiol. 115(3),
589–595 (2004).
www.future-drugs.com
This work was supported by grants from the Ohio Biomedical
Research and Technology Transfer Partnership, Wallace H.
Coulter Foundation and National Institutes of Health
(NS047388, NS050449 and NS052042).
11 Butson CR, Cooper SE, Henderson JM,
McIntyre CC. Patient-specific analysis of
the volume of tissue activated during deep
brain stimulation. Neuroimage 34(2),
661–670 (2007).
12 McNeal DR. Analysis of a model for
excitation of myelinated nerve. IEEE Trans.
Biomed. Eng. 23(4), 329–337 (1976).
•• Prepared the original groundwork for
computer models of the neural response to
electrical stimulation.
13 Rattay F. Analysis of models for external
stimulation of axons. IEEE Trans. Biomed.
Eng. 33(10), 974–977 (1986).
14 McIntyre CC, Grill W. Excitation of central
nervous system neurons by nonuniform
electric fields. Biophys. J. 76, 878–888
(1999).
15 Rattay F. The basic mechanism for the
electrical stimulation of the nervous system.
Neuroscience 89(2), 335–346 (1999).
16 Gustafsson B, Jankowska E. Direct and
indirect activation of nerve cells by
electrical pulses applied extracellularly.
J. Physiol. 258(1), 33–61 (1976).
17 Basser PJ, Roth BJ. New currents in
electrical stimulation of excitable tissues.
Annu. Rev. Biomed. Eng. 2, 377–397
(2000).
18 Holsheimer J. Computer modelling of
spinal cord stimulation and its contribution
to therapeutic efficacy. Spinal Cord 36(8),
531–540 (1998).
19 Frijns JH, de Snoo SL, ten Kate JH. Spatial
selectivity in a rotationally symmetric
model of the electrically stimulated cochlea.
Hear. Res. 95(1–2), 33–48 (1996).
20 Butson CR, McIntyre CC. Role of
electrode design on the volume of tissue
activated during deep brain stimulation.
J. Neural Eng. 3(1), 1–8 (2006).
21 Hodgkin AL, Huxley AF. A quantitative
description of membrane current and its
application to conduction and excitation in
nerve. J. Physiol. 117(4), 500–544 (1952).
22 Rall W, Burke RE, Holmes WR, Jack JJ,
Redman SJ, Segev I. Matching dendritic
neuron models to experimental data.
Physiol. Rev. 72(4 Suppl.), S159–S186
(1992).
23 Astrom M, Johansson JD, Hariz MI,
Eriksson O, Wardell K. The effect of
cystic cavities on deep brain stimulation
Deep-brain stimulation models
in the basal ganglia: a simulation-based
study. J. Neural Eng. 3(2), 132–138
(2006).
24 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. 30(4–6),
249–281 (2002).
25 Kuncel AM, Grill WM. Selection of
stimulus parameters for deep brain
stimulation. Clin. Neurophysiol. 115(11),
2431–2441 (2004).
26 McIntyre CC, Grill WM, Sherman DL,
Thakor NV. Cellular effects of deep brain
stimulation: model-based analysis of
activation and inhibition. J. Neurophysiol.
91(4), 1457–1469 (2004).
27 Hemm S, Mennessier G, Vayssiere N,
Cif L, El Fertit H, Coubes P. Deep brain
stimulation in movement disorders:
stereotactic coregistration of two-
dimensional electrical field modeling and
magnetic resonance imaging. J. Neurosurg.
103(6), 949–955 (2005).
28 Wei XF, Grill WM. Current density
distributions, field distributions and
impedance analysis of segmented deep
brain stimulation electrodes. J. Neural Eng.
2(4), 139–147 (2005).
29 Sotiropoulos SN, Steinmetz PN. Assessing
the direct effects of deep brain stimulation
using embedded axon models. J. Neural
Eng. 4(2), 107–119 (2007).
30 Butson CR, McIntyre CC. Tissue and
electrode capacitance reduce neural
activation volumes during deep brain
stimulation. Clin. Neurophysiol. 116(10),
2490–2500 (2005).
31 Butson CR, McIntyre CC. Differences
among implanted pulse generator
waveforms cause variations in the neural
response to deep brain stimulation. Clin.
Neurophysiol. 118, 1889–1894 (2007).
32 Butson CR, Maks CB, McIntyre CC.
Sources and effects of electrode impedance
during deep brain stimulation. Clin.
Neurophysiol. 117(2), 447–454 (2006).
33 Miocinovic S, Parent M, Butson CR et al.
Computational analysis of subthalamic
nucleus and lenticular fasciculus activation
during therapeutic deep brain stimulation.
J. Neurophysiol. 96, 1569–1580 (2006).
621
McIntyre, Miocinovic & Butson
34 Smith Y, Bolam JP, Von Krosigk M.
Topographical and synaptic organization of
the GABA-containing pallidosubthalamic
projection in the rat. Eur. J. Neurosci. 2(6),
500–511 (1990).
35 Anderson TR, Hu B, Iremonger K,
Kiss ZH. Selective attenuation of afferent
synaptic transmission as a mechanism of
thalamic deep brain stimulation-induced
tremor arrest. J. Neurosci. 26(3), 841–850
(2006).
36 Meissner W, Leblois A, Hansel D et al.
Subthalamic high frequency stimulation
resets subthalamic firing and reduces
abnormal oscillations. Brain 128(Pt 10),
2372–2382 (2005).
37 Hashimoto T, Elder CM, Okun MS, Patrick
SK, Vitek JL. Stimulation of the subthalamic
nucleus changes the firing pattern of pallidal
neurons. J. Neurosci. 23(5), 1916–1923
(2003).
• Electrophysiological study of deep brain
stimulation (DBS) in parkinsonian
nonhuman primates implanted with scaled
clinical DBS systems.
38 Parent M, Parent A. The pallidofugal motor
fiber system in primates. Parkinsonism Relat.
Disord. 10(4), 203–211 (2004).
39 Yelnik J, Damier P, Demeret S et al.
Localization of stimulating electrodes in
patients with Parkinson disease by using a
three-dimensional atlas-magnetic resonance
imaging coregistration method. J. Neurosurg.
99(1), 89–99 (2003).
40 Herzog J, Fietzek U, Hamel W et al. Most
effective stimulation site in subthalamic deep
brain stimulation for Parkinson’s disease.
Mov. Disord. 19(9), 1050–1054 (2004).
41 Plaha P, Ben-Shlomo Y, Patel NK, Gill SS.
Stimulation of the caudal zona incerta is
superior to stimulation of the subthalamic
nucleus in improving contralateral
parkinsonism. Brain 129(Pt 7), 1732–1747
(2006).
622
42 Miocinovic S, Maks CB, Noecker AM,
Butson CR, McIntyre CC. Cicerone: deep
brain stimulation neurosurgical navigation
software system. Acta Neurochir. Suppl.
(Wien) 97, 561–567 (2007).
43 Finnis KW, Starreveld YP, Parrent AG,
Sadikot AF, Peters TM. Three-dimensional
database of subcortical electrophysiology for
image-guided stereotactic functional
neurosurgery. IEEE Trans. Med. Imaging
22(1), 93–104 (2003).
• Groundbreaking example of the integration
of neurophysiology, neurosurgery and
computer science into a clinically relevant
DBS application.
44 D’Haese PF, Cetinkaya E, Konrad PE, Kao
C, Dawant BM. Computer-aided placement
of deep brain stimulators: from planning to
intraoperative guidance. IEEE Trans. Med.
Imaging 24(11), 1469–1478 (2005).
45 Hunka K, Suchowersky O, Wood S,
Derwent L, Kiss ZH. Nursing time to
program and assess deep brain stimulators in
movement disorder patients. J. Neurosci.
Nurs. 37(4), 204–210 (2005).
46 Butson CR, Noecker AM, Maks CB,
McIntyre CC. StimExplorer: deep brain
stimulation parameter selection software
system. Acta Neurochir. Suppl. (Wien) 97,
569–574 (2007).
47 Gimsa U, Schreiber U, Habel B, Flehr J,
van Rienen U, Gimsa J. Matching geometry
and stimulation parameters of electrodes for
deep brain stimulation experiments
– numerical considerations. J. Neurosci.
Methods, 150(2), 212–227 (2006).
48 Montgomery EB, Baker KB. Mechanisms of
deep brain stimulation and future technical
developments. Neurol. Res. 22(3), 259–266
(2000).
49 Tass PA. A model of desynchronizing deep
brain stimulation with a demand-controlled
coordinated reset of neural subpopulations.
Biol. Cybern. 89(2), 81–88 (2003).
50 Rubin JE, Terman D. High frequency
stimulation of the subthalamic nucleus
eliminates pathological thalamic
rhythmicity in a computational model.
J. Comput. Neurosci. 16(3), 211–235
(2004).
51 Feng XJ, Greenwald B, Rabitz H,
Shea-Brown E, Kosut R. Toward closed-
loop optimization of deep brain stimulation
for Parkinson’s disease: concepts and lessons
from a computational model. J. Neural Eng.
4(2), L14–L21 (2007).
52 Montgomery EB. Dynamically coupled,
high-frequency reentrant, non-linear
oscillators embedded in scale-free basal
ganglia–thalamic–cortical networks
mediating function and deep brain
stimulation effects. Nonlinear Studies 11(3),
385–421 (2004).
Affiliations
• Cameron C McIntyre, PhD
Assistant Staff, Cleveland Clinic Foundation,
and, Assistant Professor, Cleveland Clinic Lerner
College of Medicine, Department of Biomedical
Engineering,9500 Euclid Avenue, ND20,
Cleveland, OH 44195, USA
Tel.: +1 216 445 3264
Fax: +1 216 444 9198
mcintyc@ccf.org
• Svjetlana Miocinovic, PhD
Medical Student, Case Western Reserve
University, 10900 Euclid Ave, T401,
Cleveland, OH 44106, USA
Tel.: +1 216 368 3404
Fax: +1 216 368 5295
svjetlana.miocinovic@case.edu
• Christopher R Butson, PhD
Research Associate, Cleveland Clinic
Foundation, 9500 Euclid Ave, ND20,
Cleveland, OH 44195, USA
Tel.: +1 216 445–7856
Fax: +1 216 444 9198
butsonc@ccf.org
Expert Rev. Med. Devices 4(5), (2007)