CLINICAL NEUROENGINEERING: PART 2

Electrical Stimulation
as Therapy for
Neurological Disorders
The Basics of Implantable Neurological Stimulators
EYEWIRE

BY ROY L. TESTERMAN,
MARK T. RISE, AND
PAUL H. STYPULKOWSKI

his article outlines the basics of implantable neurological stimulators (INSs) and electrodes. Mechanisms of
neural stimulation relevant to the clinician are
reviewed, including the activating function, strengthduration relationship, and strength-distance relationship as well as safety considerations including safe charge and
charge density levels. Clinical examples are taken from spinal
cord stimulation (SCS) for pain and deep brain stimulation
(DBS) for movement disorders such as essential tremor and
Parkinsons disease.

Hardware Basics: Implantable Neurological

Stimulators and Electrodes

Neurostimulation is a clinical tool used to treat various

neurological disorders, including chronic pain, urinary
incontinence, and movement disorders. The particular therapeutic application determines which structures within the
central or peripheral nervous system are targeted for stimulation. Independent of the specific therapy, there are a
number of basic principles that have been developed to
guide the use of neurostimulation systems in a safe and
effective manner. A number of those fundamental principles and their application to clinical practice are reviewed
in subsequent sections.
The primary components of a neurostimulation system
include the implantable neurostimulator (INS) and at least one
electrode array (or lead). Current generations of neurostimulators are programmed by the clinician after implantation
using a physician programmer. The programmer communicates with the implanted electronics using pulse-width- and/or
pulse-interval-modulated encoding of an inductively coupled
carrier frequency. The coded instructions are sent to the
implanted device, and the values of the various stimulation
parameters can be modified. Depending upon the specific
device, the clinician has a range of stimulation parameters that
can be adjusted, including the number of channels of stimulation, the electrode configuration, electrode polarity, stimulus
amplitude, pulse width, and rate.
Some neurostimulators include multiple stimulation output
channels, defined as a single source of current/voltage pulses
with a common set of parameters, i.e., the same pulse width,
frequency, and amplitude. These devices allow the selection of
74 IEEE ENGINEERING IN MEDICINE AND BIOLOGY MAGAZINE

multiple independent electrodes to be associated with each

stimulus channel. Those electrodes selected to be on may be
programmed to be positive (an anode) or negative (a cathode).
By convention, there are two basic types of electrode configurations, referred to as monopolar and bipolar stimulation. Of
course, for current to flow, it is necessary that there be at least
two electrodes, a positive anode and a negative cathode. In
monopolar stimulation there is an electrode, usually a cathode
of relatively small surface area located near the nervous tissue
to be stimulated, and a distant positive electrode, usually with a
larger surface area. Typically, the sealed titanium case of the
neurostimulator electronics package is used as the positive
anode when performing monopolar stimulation. When performing bipolar stimulation, both the positive and negative
electrodes are in or near the nervous tissue targeted for stimulation. For some therapy applications, more than two electrodes
can be activated in tripolar, quadripolar, etc. configurations.
Various stimulators are designated as constant voltage or
constant current if their output impedances are low or high,
respectively. Independent of stimulator design, the typical output parameters that are clinically relevant include stimulus
amplitude, pulse width, and rate (or frequency). In general,
stimulus amplitude and pulse width influence the spatial
extent of the effective stimulation field as these parameters
directly control the excitation process for neural tissue, while
stimulus frequency plays more of a role in therapy effectiveness based on the temporal pattern of activity delivered to the
nervous system.
Typical stimulus parameters employed for DBS for movement disorders are in the range of 24 V (or 24 mA for a
typical DBS electrode impedance of 1,000
), 90180 s
pulse width, and 100185 Hz. These parameters can be
adjusted over a fairly wide range (e.g., 010.5 V, 60450 s,
2250 Hz) depending upon the specific therapy application.
Finally, some models of neurostimulators include patient
programmers, which communicate with the implanted neurostimulator and allow patients to adjust selected parameters
within a limited range of values prescribed by the physician.
This gives the patient an opportunity to make adjustments to
the stimulation parameters as required to manage his/her
therapy or to turn the device on and off. Sample devices
described are illustrated in Figure 1.
0739-5175/06/$20.002006IEEE

SEPTEMBER/OCTOBER 2006

Mechanisms of Stimulation in Clinical Applications

The reader is referred to review articles by Ranck [1], Durand

[2], Tehovnik [3], Holsheimer [4], or Kuncel and Grill [5] and
the book by Agnew and McCreery [6] for more complete
information on the biophysics of neural stimulation. However,
several general rules or guidelines derived from these studies
are useful to the clinician.
The first pertains to the order of recruitment of nervous tissue. In general, the following rules hold for most applications
of neurostimulation: 1) nerve cells further away from the electrode will be less likely to be stimulated; 2) axons will be stimulated at lower stimulation amplitudes than nerve cell bodies;
3) larger axons will respond to lower stimulus amplitudes than
will smaller axons; and 4) axons with branching processes will
be more easily activated than those without branching.
The Activating Function

With regard to the excitation process, the orientation of nerve

cells relative to the electric field is very important. The second
spatial derivative of voltage along the axis of the axon determines if a neuron is activated (Figure 2). This second derivative has been named the activating function by Rattay [7]. This
means that 1) stimulation applied parallel to a nerve fiber is
more effective than stimulation applied perpendicular to the
fiber, and 2) a uniform electric field is ineffective. These facts
were verified almost 80 years ago by Rushton [8].

Fig. 1. Neurostimulator and lead systems used for spinal cord

stimulation to treat chronic pain. (Medtronic, Inc.). The Itrel 3
and Synergy are neurostimulators. The Synergy EZ is a patient
programmer. Percutaneous extradural spinal leads (top
right) and extradural surgical leads (bottom right) are shown.

Strength-Distance Relationship

Nerve cells near the electrode are more likely to be activated

than neurons located farther away. The experimental data
from the literature [9] suggest that strength-distance relationship is given by

Electrodes
Current

Ith = a + kD2 ,

(1)

where Ith is the threshold current, D is the distance from the electrode, a can be interpreted as the threshold when the electrode is
in direct contact with the neural element, and k is the strengthdistance constant. This constant is actually a function of many
parameters, including electrode size, pulse width, tissue impedance, nerve fiber size, and the nerve membrane properties.

Single Fiber
Nerve Bundle
(a)
Ve

rm
x

Strength-Duration Relationship

Stimulus amplitude and pulse width interact strongly to determine stimulus threshold. This interaction is defined by the
strength-duration relationship. This relationship is often
described by an empirical equation, such as that developed by
Weiss [10]:



Tch
,
(2)
Ith = Irh 1 +
PW
where Ith is the threshold current, Irh is the rheobase current,
PW is the pulse width, and Tch is the chronaxie.
A number of studies have shown that the characteristics of
the strength-duration curve varies depending upon the neuronal substructure being activated (axon versus dendrite versus cell body) as well as the relative size of the structure
(e.g., larger axons can be excited with narrower pulse widths
than smaller axons). Recent studies in human subjects suggest that DBS therapy is mediated via the activation of large,
myelinated axons near the active electrode(s). The
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n1 re x

re x

cm x

re x

im x
n
rm
x
x
cm

rm
x

n+1 re x
le
cm x
li

Vi

ri x

ri x

Ie at node n = imn x =
imn

ri x

ri x
x

Ven1+Ven+12Ven
re x

2
1 Ve = 1 E = 1 J
re x2 re x re x

(b)
Fig. 2. (a) Nerve fibers can be modeled as (b) electrical
cables. External values have subscript e, and internal values
have subscript i. Nerve membrane impedances have subscript m. The current entering a node of the nerve fiber is proportional to the second derivative of the external voltage,
Ve , along the nerve. (Conventional) current passing out of
the nodes depolarize the fiber. Therefore, action potentials
are usually initiated at Nodes of Ranvier near the cathode.

SEPTEMBER/OCTOBER 2006

75

researchers based these conclusions upon the strength-duration relationship measured for the stimulus parameters
required to attain the desired clinical effect [11][15].
Quantitatively, large nerve fibers have lower rheobase values
and smaller chronaxies than small fibers do. This means that
large nerve fibers are stimulated more easily than small fibers.
Interaction of Stimulus Amplitude, Pulse Width,
and Frequency

The interactions of stimulus amplitude and pulse width are

largely independent of the stimulus frequency (within the
range used clinically) and are dominated by the fundamental properties of the tissue near the electrode. On the other
hand, the frequency component is largely mediated through
its influence on the activity within the overall neural network. Therefore, frequency effects are much more dependent on the particular therapy. Changes in frequency are
generally less effective than changes in amplitude or pulse
width in producing clinically measurable effects. Optimal
stimulus frequency ranges, if they exist at all, are extremely
broad [16].
Safety Issues: Current and Charge Density

Early electrical stimulators used unidirectional pulses (i.e.,

monophasic waveforms). However, Lilly [17] determined
that the repeated exposure of tissue to direct current could
have a deleterious effect. He proposed using a stimulus
pulse that had two phases of current flow, resulting in zero
net flow of charge. Charge-balanced stimulation pulses have
become the standard method of delivering stimulation puls-

es to excitable tissue in clinical applications. Most commercial stimulators use some version of rectangular biphasic
(positive and negative) pulses.
Charge-balanced pulses alone are not enough to assure safe
stimulation. A number of publications over the past 30 years
have summarized the current understanding of safe electrical stimulation parameters for electrodes in contact with neural
tissue. Seminal studies by the Huntington Group [6], [18]
found that charge density interacted synergistically with
charge per phase to determine the threshold of stimulationinduced neural injury in cat cortex. This interaction occurred
over a wide range of both parameters. Shannon [19] analyzed
these data and found that the boundary between safe and
unsafe charge injections at different charge and charge density
levels can be approximated by the equation
log D = k log Q,

(3)

where D is the charge density in coulombs per centimeter

squared per phase (C/cm2 /phase) and Q is the charge in
C/phase. The boundary occurs at approximately k = 1.85.
More conservative values that lie entirely within the safe area
for cortical stimulation (for example, k = 1.7) are sometimes
used (Figure 3). Note that the charge density in (3) is average
charge density. No quantitative information exists concerning
the distribution of damage over the electrode-tissue interface.
As an example, the Medtronic Model 3387 DBS leads have
electrode surface areas of 6 mm2 . Then log D < 1.7 log Q
for charge values less than about 1.8 C/phase, and a corresponding charge density limit of about 30 C/cm2 /phase.

Safe Stimulation Regions

100000

Charge Density (C/cm2 phase)

10000
100 m2
1000 m2
0.01 mm2
0.1 mm2
1 mm2
6 mm2 (3387)

1000

100

12 mm2 (3487)
k= 1.7
McCreey90 No Damage
McCreery90 Damage

10

McCreery94 No Damage
McCreery94 Damage

0.1

0.01
0.001

0.01

0.1

10

100

Charge (C/phase)

Fig. 3. Log-log nomograph of charge versus charge density. The trajectory of charge versus charge density will fall on straight
lines determined by electrode surface area as shown. The 6-mm2 line represents the surface area of the Medtronic Model 3387
DBS electrodes. The 12-mm2 line represents the surface area of the Medtronic Model 3487 SCS electrodes. The heavy blue line
(k = 1.7) separates the safe from unsafe areas, as determined by the cat cortex data (red) (3), [18], [19]. Equation (3) does
not hold for data obtained from the cochlear nucleus at higher frequencies with smaller surface area (green) [20].

76 IEEE ENGINEERING IN MEDICINE AND BIOLOGY MAGAZINE

SEPTEMBER/OCTOBER 2006

This is the source of Medtronics recommendation that maximum stimulus levels not exceed 30 C/cm2 /phase in DBS
applications.
This method of estimating safe stimulation levels cannot, however, be applied universally for all applications of
electrical stimulation. For example, the experimental findings for microelectrodes placed in the cochlear nucleus
[20] do not conform to (3). Another example is the
extradural stimulation of the spinal cord (discussed in the
next section), where the intervening cerebrospinal fluid
shunts most of the stimulus current away from the cord.
Modeling studies show that less than 10% of the current
reaches the target neural tissue in this application of neurostimulation [21].
Clinical Examples

In this article, space does not permit the discussion of the

many therapeutic uses of electrical stimulation. However, two
prominent examples will be reviewed: spinal cord stimulation
(SCS) for pain treatment and deep brain stimulation (DBS) for
movement disorders.
Spinal Cord Stimulation
for Pain Relief

Deep Brain Stimulation for Movement Disorders

Essential tremor (ET) and Parkinsons disease (PD) are two

extremely disabling movement disorders. In severe cases, surgical treatments involving lesions to specific regions of the
brain have been historically performed. For ET, the target has
been the ventral intermediate nucleus of the thalamus (Vim).
For Parkinsons disease, lesions have been placed in the basal
ganglia, usually the internal portion of the globus pallidus
(GPi). In order to verify the target during surgery, acute electrical stimulation is used to test for a clinical response. In the
course of performing these tests, it was found that high-frequency stimulation (greater than 100 pulses/s) often alleviated
the underlying symptoms. This led Benabid et al. [16], [25] to
investigate chronic deep brain stimulation (DBS) as a nondestructive alternative in the treatment of ET. They found that
88% of their initial patients had complete or substantial relief.
Furthermore, the side effects were mild and could be eradicated by reduction or elimination of stimulation. This reversibility and adaptability made thalamic stimulation preferable to
thalamotomy.
Similarly, stimulation of the GPi has been shown to reduce
the symptoms of Parkinsonism. After animal models of PD
had shown overactivity of the excitatory neurons from the subthalamic nucleus (STN) to GPi, Limousin et al. [26] decided
to stimulate the STN directly in patients. This successful treatment was the first demonstration in human beings of the role
played by the STN in PD. The STN is now the target of choice
for treatment of PD.
The mechanism of DBS therapy is the subject of intensive
investigation. It was originally thought that DBS caused a
reversible lesion, since the clinical results were similar to
those of surgical lesions. However, accumulating data from
a variety of studies do not support this view [27][29].
Increasingly, electric field modeling, neural cell modeling,
and neural network simulation are being used to explore the

Activating Function Value (V/m2)

In 1965, Melzack and Wall [22] presented their gate control theory of pain control. This theory proposes that
activity in large cutaneous nerve fibers inhibits the neurons in the dorsal horn of the spinal cord that relay pain
information, preventing pain sensations from being transmitted to higher centers in the brain. Many of these large
cutaneous fibers pass directly into the dorsal columns of
the spinal cord. This led Shealy et al. [23] to perform the
first dorsal column implant for pain control in 1967.
Theories of pain processing have advanced considerably
in the past 40 years, but the underlying assumption
remains that the dorsal column
fibers must be activated to achieve
pain control. Empirically, effective
4000
pain control requires that paresthesia
2
(usually a tingling sensation) must
1
3000
be achieved in the painful region.
This indicates that the dorsal column
2000
fibers innervating the affected
region are being stimulated.
1000
The principles outlined above have
been employed to optimize the spinal
0
stimulating leads. Holsheimer et al. [4],
[11], [12], [21], [24] have led this effort
1000
through the development of electrical
field models of SCS. These models have
2000
validated the activating function principles outlined above. In particular, for a
3000
specific distance between the electrodes
and dorsal columns, there is an optimal
4000
electrode spacing as predicted from the
11109 8 7 6 5 4 3 2 1 0 1 2 3 4 5 6 7 8 9 10 11
activating functions (Figure 4).
Longitudinal Distance (mm)
Activating functions also predict that
electrode arrays oriented transverse to the
cord will have higher stimulus thresholds Fig. 4. Model activating functions for point source electrodes 2.5 mm above the spinal
than arrays oriented parallel to the dorsal cord. Higher-activating function peaks give lower nerve thresholds. The cathode
column fibers. These model predictions (right) is 12 mm from the anode (left) in the plot
for wide-spaced electrodes (Curve
1). The electrodes have the optimum spacing of (3/2) 2.5
= 3 mm in Curve 2.
have been verified clinically [24].
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77

feasibility of various hypotheses. For instance, it appears

that cell axons are almost always stimulated instead of cell
bodies. Furthermore, firing in cell bodies can be blocked,
but the axons of the same cells can be simultaneously activated [28]. These findings are encouraging new ideas about
the function of the nervous system and potentially more
effective clinical treatments as well.
Conclusions

Neural stimulation is becoming more widely used as an

effective clinical tool in the treatment of neurological disorders. This evolution is being spurred by more effective and
reliable hardware and by a more widespread understanding
of the fundamental mechanisms of stimulation. There is an
emerging synergy between the engineering simulation specialist and the clinician. As the applications for neural stimulation continue to grow, this synergy gives hope for better
understanding and better treatments for a large number of
neurological disorders.
Address for Correspondence: Mark T. Rise, Medtronic
Neurological, Medtronic, Inc, Minneapolis, MN 55412 USA.
Phone: +1 763 514 5094. E-mail: mark.turner.rise@
medtronic.com.
Roy L. Testerman received a Ph.D. degree in electrical engineering from the University of Rochester. He has 32 years of
experience with Medtronic, Inc. in biomedical instrumentation
research, testing, and regulatory submissions, specializing in neurological stimulation. He is currently the president of a consulting
business specializing in biomedical stimulation applications.
Mark T. Rise is a distinguished scientist in the emerging therapies group of the neurological business division of Medtronic,
Inc. He has been with Medtronic for over 26 years, primarily in
developing new medical therapies utilizing electrical stimulation of the nervous system. He has been awarded numerous
patents for medical therapies and devices. He is a fellow of the
Bakken Society of Medtronic, Inc. and the American Institute
of Biomedical Engineering (AIMBE). Dr. Rise earned a B.S.
in general science and a masters degree in electrical engineering from the University of Iowa. He received a Ph.D. in biomedical engineering from the University of Minnesota in 1979.
He is a member of the Society for Neuroscience and the
Association for Convulsive Therapy.
Paul H. Stypulkowski is senior director of therapy research and
development for Medtronic Neurological. He is responsible for
the identification and development of new therapy opportunities
in the field of neurological disorders, based upon the application
of Medtronics implantable neurostimulation and drug delivery
technology platforms. He has over 20 years of experience in the
medical device industry with 3M, GN ReSound, and, most
recently, Medtronic and has been involved in the research, development, and commercialization of a number of medical devices,
notably, the first FDA-approved cochlear implant in the United
States and Medtronics recently approved Deep Brain
Stimulation therapy for Parkinsons disease. He holds a Ph.D. in
neurophysiology from the University of Connecticut and has
numerous publications and patents in the neurosciences field.

78 IEEE ENGINEERING IN MEDICINE AND BIOLOGY MAGAZINE

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