Neuromodulation: Technology at the Neural Interface

Received: February 15, 2016 Accepted: March 7, 2016

(onlinelibrary.wiley.com) DOI: 10.1111/ner.12438

Parameters of Spinal Cord Stimulation

and Their Role in Electrical Charge Delivery:
A Review
Jonathan P. Miller, MD*; Sam Eldabe, MD, FRCA†; Eric Buchser, MD‡;
Lisa M. Johanek, PhD§; Yun Guan, MD, PhD¶; Bengt Linderoth, MD, PhD**
Objective: All spinal cord stimulation (SCS) parameters (amplitude, pulse width, frequency) influence the interaction of stimula-
tion with the nervous system and impact the delivery of charge. Regardless of the stimulation pattern, there are certain crucial
elements related to dose, and a basic fundamental knowledge of the parameters used to administer the therapy is fundamentally
important.
Methods: This paper reviews basic concepts of energy delivery in neurostimulation (amplitude, pulse width, and frequency) and
introduces the concept of the duty cycle and charge per sec as another way to characterize stimulation patterns.
Results: Results from recent clinical publications indicate that an important aspect of the therapy may be the total charge deliv-
ery over a period of time. Viewed in this way, rate of charge delivery may be analogous to dosage of medication, and SCS
parameters that use different duty cycles may exert distinct therapeutic effects by allowing different amounts of energy to be
delivered to neural tissue with less sensory percept or even none at all.
Conclusions: The basic parameters of amplitude, pulse width, and frequency have important implications for the delivery of
charge in SCS. Modern programming strategies require an understanding of charge delivery for conventional SCS therapy as well
as new therapies such as 10 kHz and burst SCS.

Keywords: Charge, mechanisms, programming

Conflict of Interest: Drs. Buchser, Guan, and Eldabe have received research funding from Medtronic. Dr. Eldabe has done consult-
ing work for Medtronic Europe. Dr. Johanek is an employee of Medtronic. Dr. Linderoth serves as a consultant for Medtronic, St.
Jude Medical Boston Scientific, and Elekta AB. Dr. Miller serves as a consultant for Medtronic Neuromodulation. Dr. Buchser serves
as a consultant for Medtronic Switzerland.

INTRODUCTION
Since its introduction in 1967, spinal cord stimulation (SCS) has
had a transformative effect on the treatment of chronic neuropathic
pain. Contemporary theories of pain transmission in the spinal cord
described a “gating mechanism” where the activation of large-
diameter fibers modulated pain perception; therefore, the mecha-
nisms of SCS were framed primarily in terms of axonal activation (1).
However, research has suggested that the mechanisms of action of
SCS are substantially more complex. SCS produces local alteration of
wide-dynamic-range neuron excitability, facilitation of physiological
inhibitory mechanisms, and changes in activity of a number of neu-
rotransmitters, especially GABA, but also glutamate, adenosine, ace-
tylcholine, substance P, CGRP, BDNF, bradykinin, and others (2–4). In
addition, orthodromic activation of dorsal column fibers may acti-
vate descending serotonergic pathways from brainstem centers as
well as alter pain processing in the cerebrum (5–8). Furthermore, dis-
tinct pain syndromes with individual patterns of pathological neuro-
nal hyperexcitability may respond differently to SCS (3,4).
Stimulation parameters have been investigated and manipulated
for years to optimize pain therapy. The wide range of frequencies
used in commercially available SCS devices have been explored for
(up to 1400 Hz) (11,12). The clinical effects of various pulse widths
have also been examined (13,14). Programming strategies have
often considered parameters as separate and discrete variables, and
Address correspondence to: Jonathan Miller, MD, FAANS, FACS, University Hospi-
tals Case Medical Center, 11100 Euclid Ave, Cleveland, OH 44106, USA. Email:
jonathan.miller@uhhospitals.org
* Functional and Restorative Neurosurgery Center and Department of
Neurological Surgery, Case Western Reserve University School of Medicine,
University Hospitals Case Medical Center, Cleveland, OH, USA;
†
The James Cook University Hospital, Middlesbrough, UK;
‡
Anaesthesia and Pain Management Services at the Neuromodulation Centre,
Hospital de Morges, Morges, Switzerland;
§
Department of Medical Affairs, Medtronic, PLC, Minneapolis, MN, USA;
¶
Department of Anesthesiology/Critical Care Medicine, The Johns Hopkins
University School of Medicine, Baltimore, MD, USA; and
** Functional Neurosurgery, Department of Clinical Neuroscience, Karolinska
Institutet, Stockholm, Sweden
For more information on author guidelines, an explanation of our peer review
process, and conflict of interest informed consent policies, please go to http://
www.wiley.com/WileyCDA/Section/id-301854.html
Source(s) of financial support: No funding was received in the drafting of this
1

various indications, in low (<5 Hz) (9,10) and high-frequency ranges manuscript.

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 MILLER ET AL.
Figure 1. The characteristics of electrical pulses. a. The stimulation pulse is
defined by the amplitude and pulse width. The charge per pulse (in nanocou-
lombs) is the product of the amplitude (mA) and the pulse width (ms). The fre-
quency defines how often pulses occur, typically in Hertz or pulses per sec. b.
Stimulation pulse shapes can differ depending on whether they are biphasic,
current-controlled, or voltage-controlled.
less consideration has been given to how these variables interact to
modulate pain pathways within the nervous system.
With the recent focus on new frequencies and waveforms in the
SCS field, such as 10 kHz (15–17) and burst stimulation (18–20), there
is a growing appreciation for the impact of energy delivery on the
nervous system. However, there is also a critical need to understand
how the energy is being delivered. A developing concept focuses
on the combination of stimulation parameters and their resulting
charge delivery. When all parameters are considered together, stimu-
lation can be characterized by “charge over time,” which can be
delivered through various dosing strategies. Conventional SCS
“doses” therapy with a high “charge per pulse.” In contrast, a dosing
strategy using higher frequencies and/or wider pulse widths pro-
duces a more consistent dose of energy, providing higher “charge
per second.” Thus, stimulation parameters can be characterized as
having a low or high “concentration of current,” and the delivery of
energy could be characterized as involving low or high “dose.”
The purpose of this paper is to review basic concepts of charge
delivery in SCS for a clinical readership and discuss the ways parame-
ters might interact in order to relieve neuropathic pain. A review of
modern programming strategies is provided, where charge delivery
in conventional SCS therapy is compared with therapies such as
10 kHz and burst SCS.
SCS PARAMETERS
Amplitude and Pulse Width
The basic unit of electrical stimulation in neuromodulation is the
“pulse” (Fig. 1). The pulse consists of a sustained delivery of a spe-
cific amount of current amplitude (measured in milliamperes, mA)
for a specific amount of time (pulse width, measured in microsec-
onds, ls). Each pulse is followed by an equal flow of current in the
opposite direction to balance charge and safeguard against
electrode-tissue interface damage due to chemical reactions that
might result from buildup of charge (Fig. 1b). The “recharge” pulse
can be active (producing a biphasic appearance) or passive (bal-
anced but asymmetric); in most SCS systems, charge balancing
2
occurs after each individual pulse and in a passive manner. In
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Figure 2. Depiction of the strength-duration curve for neuronal activation.
The gray lines represent hypothetical curves for different axon types or popula-
tions. Under ideal conditions the threshold for generation of an action poten-
tial will follow a hyperbolic curve of the shape of f(x) 5 1/x, called the
“strength-duration curve.” The strength-duration curve demonstrates that nar-
row pulse widths require high amplitudes to activate a neuron, while wider
pulse widths need lower amplitudes.
voltage-controlled systems, amplitude is prescribed as a potential
difference (measured in volts, V) applied to the electrode surface, in
which case the actual flow of current will be dependent upon
impedance at the electrode-tissue interface, whereas current-
controlled systems deliver a prescribed current, thus allowing the
voltage to vary with impedance. As long as the impedance is stable
over time there is no known clinical difference between constant-
voltage and constant-current systems (21). Furthermore, the effects
of spinal cord movement and cerebral spinal fluid thickness have
been shown to have a greater impact on required stimulation ampli-
tude than impedance (22–25). Current is defined as the flow of
charge, such that 1 mA is equal to the flow of 1 millicoulomb (mC)
of electric charge in one sec. If the function of current over time
Ð is
defined as I, the charge per pulse (in coulombs) is calculated as I dt
across the time period of the pulse. Assuming the amplitude is con-
stant during the pulse, this will be exactly the same as the product
of the amplitude and pulse width (Fig. 1). In other words, multiply-
ing the amplitude (in mA) by the pulse width (in ls) will provide a
value for the charge per pulse (in nanocoulombs).
At SCS frequencies most commonly used in clinical practice (e.g.
40–100 Hz), the threshold for neural activation will be approximately
proportional to the charge per pulse. Therefore, the threshold for
generation of an action potential will typically follow a hyperbolic
curve of the shape of f(x) 5 1/x, called the “strength-duration curve”
(Fig. 2), in which the value amplitude multiplied by pulse width (i.e.,
the charge per pulse) is the same at all points along the curve. The
strength-duration curve demonstrates that narrow pulse widths
require high amplitudes to activate a neuron or axon, while wider
pulse widths need lower amplitudes. In vivo, each individual axon
will have its own strength-duration curve based on size, myelination,
and distance from the stimulation source. The concept of the
strength-duration curve has been demonstrated in studies testing
activation of spinal cord axons in animal models (26), and in patients
implanted with SCS systems (13,14).
The strength-duration curve for dorsal column fibers can be
established in SCS patients by determining the amplitude needed
 SCS PARAMETERS AND CHARGE DELIVERY

Figure 3. Properties of the action potential and strength duration curve. a. Stimuli can depolarize the neural membrane away from its resting membrane potential.
An action potential is generated when the stimulus depolarizes the neuron to its action threshold level. b. A schematic of the strength-duration curve illustrates that
both pulse width and amplitude play a role in neuronal activation. Stimuli below the strength-duration curve will be subthreshold for neural activation. Stimuli
above the strength duration curve will activate neurons and result in an action potential.

for paresthesia perception and discomfort thresholds, at increasing
pulse width (27,28). The resulting “therapeutic window” may guide
SCS programming for amplitude and pulse width to optimize pain
relief while minimizing discomfort. Amplitude impacts the number
of fibers recruited, and results in a perceived increase or decrease in
the intensity and/or area of paresthesia sensation. Pulse width is typ-
ically considered a secondary factor in controlling energy delivery,
but an increase in this parameter may also recruit a larger number
of fibers. Computer models have shown that increasing pulse width
may result in broader paresthesia coverage by recruiting a larger
number and smaller diameter Ab-fibers (29).
An understanding of the strength-duration curve also demon-
strates how substantial current could be delivered to an axon with-
out necessarily producing an action potential. When the stimulation
is below the activation threshold for a neuron, the neuron may
locally depolarize, but no action potentials generated. Furthermore,
large amounts of charge could be administered at the extreme ends
of the curve (with narrow or wide pulse width), still remaining below
threshold and avoiding the development of intense paresthesia
(Fig. 3). Therefore, stimulation targeted at the dorsal columns may
be subthreshold with respect to neuronal activation, and subpercep-
tion with respect to the patient’s experience, even though large
amounts of charges are delivered. Being below the firing threshold
of the dorsal column fibers, no action potentials are generated and
no clear sensory effects (paresthesia) are likely to be produced (30).
Frequency
The parameter of frequency (number of pulses per sec) can also
be adjusted to optimize patient therapy (Fig. 1). SCS rates have his-
torically been in the range of 40–100 Hz (31), which produce pares-
thesia (in combination with a relevant charge per pulse) and are
associated with relatively low energy consumption. For example, in
a study involving 171 patients, the average rate selected by the
patients was 62.7 6 54.2 Hz (range 8–200 Hz) (31). However, for a
number of electrical stimulation therapies including SCS, there is evi-
dence that frequency can be an important determinant for activat-
stimulation and electro-acupuncture, low rate therapy (2–10 Hz) acti-
vates l-opioid receptor pathways, whereas high rate therapy
(100 Hz) likely activates endogenous d-opioid systems instead
(32–35). Investigation of SCS therapy has likewise demonstrated
very different neurochemical effects at different frequencies. Low-
frequency stimulation (4–60 Hz) engages various degrees of endog-
enous opioid release where the low frequency might release trans-
mitters binding to l-opioid receptors while 60 Hz instead might
relate to activation of the d-opioid system (36). Frequencies around
50 Hz activate dorsal horn GABAergic neurons but also interneurons
that use other transmitters such as acetylcholine and adenosine
(37–40), serotoninergic cells in the rostoventromedial medulla
(5,6,41), and nuclei in the locus coeruleus region containing norepi-
nenphine (42,43). At much higher rates, other effects are seen. For
example, 500 Hz induces greater peripheral blood flow changes
than lower SCS frequencies (44), and 1000 Hz produces changes in
the conduction properties of afferent sensory neurons at a lower
intensity than 50 Hz stimulation (45).
Frequency influences how often a neuron fires in response to a
stimulus. Typical action potential duration for somatosensory fibers,
including the refractory period, is about 5 milliseconds (ms). This
means that neurons can better entrain (one action potential per one
stimulus) at low frequencies. Each pulse above the activation thresh-
old is able to induce a distinct action potential and neurons will fire
together in a synchronous manner (Fig. 4). Different types of neu-
rons will have different entrainment properties. In general, many
neurons fire at rates less than 200 Hz (46–49) and could therefore
likely entrain electrical stimulation around 200 Hz and below. How-
ever, there is evidence that sensory neurons can fire in response to
higher frequency pulse trains. In one study of high-frequency SCS in
sheep, it was shown that dorsal column axons were able to entrain
to a 900 Hz stimulus (50). As the rate was increased from about
1.7 kHz to 13.7 kHz clusters of fibers initially responded synchro-
nously but, by the tenth stimulus, neurons began to “drop out” as
demonstrated by lower compound action potential amplitudes. The
proportion of dorsal column fibers activated by stimulation reached
3

ing specific pain-relieving mechanisms. In transcutaneous electrical a steady state of 20–40% within 250 pulses at these kilohertz

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frequencies. Thus, a consistent number of neurons do in fact fire to
each supra-threshold stimulation pulse, but a different “cluster” of
axons is responsible for the compound action potential generated
for each pulse (50). The percentage of activated axons at any point
in time will depend on the charge delivered as well as the depolari-
zation and refractory period state. Figure 4b depicts a schematic
illustration of asynchronous firing, with two hypothetical neurons
responding to different pulses within the electrical stimulation train.
Action potentials are generated in response to some but not all
stimulation pulses, resulting in a “pseudo-random” or stochastic acti-
vation pattern.
When discussing neural mechanisms, the frequency cannot be
considered independently of pulse width and amplitude (Table 1);
all stimulation parameters are related. For example, since frequency
is inversely related to the length of the cycle period, it will dictate
the possible pulse widths. As frequency increases, the time available
to complete a pulse cycle decreases: A stimulus at 100 Hz completes
a cycle in 10 ms, at 1000 Hz in 1 ms, and at 10,000 Hz in 0.1 ms.
Amplitude must also be considered with frequency and pulse width
when discussing the physiological mechanisms of stimulation. In the
well-established neural mechanisms of SCS frequency mentioned
above, amplitudes were set at levels either tested or assumed to be
high enough for action potential activation in dorsal column axons.
The putative mechanisms of frequencies in the kilohertz range (for
example, 10,000 Hz) will vary depending on the amplitude. For
example, high intensity kilohertz stimulation results in a complete
but reversible block of neural impulses (51). The literature discussing
high frequency alternating current (HFAC) is abundant (51–58), and
studies suggest that before being blocked, axons are first depolar-
ized and activated (also called an on-set response; for review see Kil-
gore and Bhadra, 2014). The peripheral nerve blocking effect was
illustrated in a paper by Cuellar at al., 2013, which reported that
wide dynamic range (WDR) neurons decrease their firing when
HFAC is administered (59). In this study the investigators applied
high amplitude HFAC directly to the dorsal root, where it acted simi-
larly to a local anesthetic conduction block and effectively prevented
impulse transmission in primary afferent neurons. Action potentials
generated from electrical and mechanical hindpaw stimulation were
stopped at the point of the HFAC block at the dorsal root; therefore,
the WDR neurons had no activating input and remained silent.
In summary, the charge-per-pulse (i.e., strength-duration curve)
determines whether neurons and axons will be activated, and fre-
quency impacts how often a single axon may fire and which neuro-
nal mechanisms are engaged. Charge per pulse, frequency, and the
recovery properties of axons all play a role in whether the axons
depolarize, and subsequently, whether they entrain to each pre-
sented stimulus or fire in a more stochastic manner.

10KHz AND BURST SCS

Figure 4. A schematic of neuronal responses to hypothetical stimuli. a. Fre-
quency of an electrical stimulus will influence how often a neuron fires an
action potential. At lower frequencies, assuming the stimulus is above activa-
tion threshold, a neuron may respond to each stimulation impulse with an
action potential. The schematic shows four electrical stimulation pulses and
four resulting action potentials. b. As frequency increases, a neuron is less likely
to entrain to each electrical stimulus. The schematic picture shows two hypo-
thetical neurons, one responding to every other stimulation pulse, one firing
an action potential to every third stimulus. In a population of neurons, the
result of higher rate of stimulation, above activation threshold, is stochastic or
“pseudo-random” firing.
Recent clinical investigations focusing on the stimulation wave-
form have helped to emphasize the importance of energy delivery
in neuromodulation therapies (60). One paradigm being used is a
10 kHz frequency with a pulse width at 30 ms and amplitude typi-
cally 1–5 mA (15). Hypotheses about the mechanism of neuromodu-
lation induced by using this waveform have varied; some thoughts
that have been suggested include 1) temporal summation, where
multiple pulses build on each other to achieve neuronal activation;
2) depolarization blockade, where propagating action potentials are

Table 1. Description of SCS Parameters and Considerations for Neural Mechanisms.

Description Considerations for neural mechanisms

Amplitude Current delivered  Amplitude and pulse width (charge per pulse) are required to activate neurons.
(milliamperes, mA)  Axon characteristics (size, myelination) and distance from stimulus will influence activation.
 Charge per pulse at the target is lower than the charge at the electrode.
Pulse width Duration of pulse  Amplitude and pulse width (charge per pulse) are required to activate neurons.
(microseconds, ls)  Axon characteristics (size, myelination) and distance from stimulus will influence activation.
 Charge per pulse at the target is lower than the charge at the electrode.
Frequency Number of pulses  Defines the number of pulses delivered in the waveform.
(Hertz, Hz)  Inversely related to the pulse width.
 Neuronal properties define whether the neuron will entrain to each pulse.
 With moderate-high amplitude, high frequency may induce axonal blocking mechanisms.
Duty cycle Amount of “on time”  May be a consideration for nonactivating or subthreshold neuronal mechanisms
(Percent of time)
4

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Table 2. Comparison of Reported Parameters Used for 10 kHz SCS, Burst SCS, and Conventional/Tonic SCS.
10 kHz*
(Minimum–Maximum)
Amplitude (mA) 1.6–3.8
Frequency (Hz) 10,000
Pulse width (ms) 30
Charge per pulse (mC) 0.05–0.11
Duty cycle (% on time) 30%
Charge per second (mC/sec) 480–1,140
Possible interaction with Low charge per pulse
neurons unlikely to activate fibers or
neurons.
High charge per second may
modulate.
Comparison of stimulation waveform characteristics between 10 kHz, burst and tonic spinal cord stimulation.
*Average minimum and maximum parameters reported in Kapural et al., 2015 (15) Calculations characterize the minimum and maximum possible charge
per pulse, duty cycle, and charge per second based on the reported values.
†
Parameters reported in De Ridder et al., 2010 (20).
‡
Average frequency delivered in burst stimulation (5 pulses * 40 Hz).
blocked by the high frequency stimulation; and 3) desynchroniza-
tion, where kilohertz stimulation results in pseudo-spontaneous or
stochastic neuronal activity (51,61). All of these hypotheses rely on
neuronal activation. Clinically a case series with 10 kHz SCS suggests
pain can be relieved for durations up to two years (16,17). However,
no clinical manifestation of either neuronal blockade or stimulation
has been reported to accompany pain relief in these cohorts and
computational studies (61) indicate that that the first two hypothe-
ses above are less probable.
A second waveform being studied is a “burst” pattern. This has
arbitrarily been chosen as a series of five 1000 ms pulses at a pulse
frequency 500 Hz followed by a single repolarization pulse, with
each train repeated at 40 Hz (19,62). Burst stimulation is proposed to
provide a signal that is more similar and relevant to endogenous
activation patterns in the nervous system. Indeed, neurons responsi-
ble for encoding aspects of pain signaling from peripheral neurons
(63–65) and the thalamus (66–68) have been reported to fire in
bursting patterns. While this is an interesting hypothesis, it is not
clear how the stimulation pattern alters on-going bursting activity in
the pain pathways. Clinically, burst stimulation has been shown to
produce pain relief in a number of small RCTs and prospective stud-
ies (19,20,69,70).
Interestingly, both 10 kHz and the burst paradigm have been
reported to produce pain relief without paresthesia in the majority
of patients. Paresthesia is the sensation that results from activation
of sensory-specific dorsal column fibers (71), so absence of paresthe-
sia suggests that stimulation is not activating dorsal column Ab
fibers (61,72,73). However, the typical hypotheses explaining the
effects of 10 kHz and burst rely on neuronal activation, and the
hypothesis of 10 kHz-induced conduction block has been criticized.
A NEW MODEL: LOW CHARGE PER PULSE,
GREATER CHARGE PER SECOND
A different and potentially more rational way to characterize stim-
ulation paradigms is according to the total charge delivered per unit
time, or “charge per second.” The charge per sec is calculated by
determining the charge per pulse and multiplying this by the num-
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SCS PARAMETERS AND CHARGE DELIVERY
“Burst”† Tonic*
(Minimum–Maximum)
0.6 3.6–8.5
200‡ 39–77
1000 347–591
0.6 1.2–5.0
20% 1.4–4.6%
120 49–387
Low charge per pulse High charge per pulse likely
unlikely to activate fibers or to activate dorsal column
neurons. fibers.
High charge per second may Modulation is also possible.
modulate.
ber of pulses delivered in 1 sec. This concept was first described in a
report of burst SCS in order to compare it to conventional stimula-
tion (20). Although the charge per pulse was lower in burst mode
(0.654 lC) compared with the 40–50 Hz tonic SCS mode (1.03 lC),
the charge delivery over time (charge per sec, called “energy/second”
in that paper) was considerably higher (130.8 lC/sec for the burst
mode vs. 47.7 lC/sec for the tonic mode).
Higher charge delivery could be accomplished by increasing
amplitude; therefore, increasing the charge per pulse. Studies assess-
ing the effects of SCS in rodent behavior models or spinal neuron
physiology, demonstrated that at conventional frequencies (50–
60 Hz) higher amplitudes results in better reversal of nociceptive
behaviors (74–76). Thus, increasing amplitude is one method to
deliver more overall charge (both charge per pulse and charge per
sec). However, this method could surpass the sensory threshold
(strength-duration curve), and lead to discomfort; therefore, this
strategy is not possible in all clinical applications.
Another way to increase charge delivery is to use lower ampli-
tude, but use wider pulse widths and/or higher frequency. Indeed, a
common feature of high charge delivery per unit time emerges
when considering the 10 kHz and burst waveforms. Instead of
increasing amplitude with potential production of an uncomfortable
sensation, these strategies use the extremes of pulse width on the
strength duration curve to deliver large amounts of charge to the
spinal cord without discomfort or even a perceptible sensation
(Table 2). Burst stimulation, using what may be functionally equiva-
lent to a very wide pulse width at low amplitudes, delivers charge
per sec reported to be 2.5–3 times higher than that achievable using
conventional stimulation patterns (20). Likewise, 10 kHz SCS, using
10,000 low amplitude 30 ms duration pulses, is reported to deliver
about 10 times more charge per sec as compared to more conven-
tional programming parameters (Table 2) (15). Thus, burst and
10 kHz stimulation patterns differ from conventional SCS, where the
former may employ more charge per sec, and the latter, more
charge per pulse.
All pulse patterns have a certain percentage of time in which the
signal is active and delivering energy. This proportion of “on” vs.
“off” time, termed “duty cycle,” can be used to characterize and
5
compare pulse patterns. Since duty cycle is a function of frequency
 MILLER ET AL.
Figure 5. Methods to determine the charge per sec. a. The charge per sec
can be considered as adding up the charge per pulse over a period of time.
The charge per pulse is calculated from the amplitude 3 pulse width. Assum-
ing a constant (patterned) series of pulses, the frequency of the stimulation
provides the number of pulses per one sec. Therefore the charge per sec is the
amplitude 3 frequency 3 pulse width. b. The charge per sec is influenced by
the duty cycle of the pulse series. Assuming a constant (nonpatterned) series
of pulses, the duty cycle is the amount of time the stimulus is presented (“on”)
over the total period, from the first pulse to the beginning of the next pulse
(“period”). The more time the stimulation is “on,” the more opportunity there is
to deliver charge. Higher duty cycles allow for higher charge delivery.
and pulse width (Fig. 5b), patterns with diverse frequency and pulse
width can be compared with this metric. For example, the duty cycle
of a 30 ms pulse at 10 kHz is 30%; the duty cycle of a 200 ms pulse at
1000 Hz is 20%; the duty cycle of a 500 ms pulse at 500 Hz is 25%. In
contrast, the duty cycle of a 400 ms pulse at 50 Hz, typical for con-
ventional SCS, is only 2% (Table 3). Higher duty cycles increase the
proportion of “on time” stimulation, resulting in the ability to deliver
more charge over time. Duty cycle can be increased by increasing
the frequency, increasing the pulse width, or combinations of both.
Examples of how pulse width and frequency influence pulse duty
cycle are shown in Figure 6. The duty cycle helps to define how
often charge is being delivered.
Delivering charge through a high duty-cycle strategy has three
potential implications for SCS therapy and mechanisms. First, it pro-
vides terminology to discuss charge delivery beyond the individual
parameters of amplitude, frequency, and pulse width. The terminol-
ogy of “charge per second” can be equated to a “dose” of electrical
energy, and depending on the parameters, the dose may appear to
be relatively “low” or “high.” Thus, the electrical energy can be
delivered similarly to a medication, with various dosing strategies.
Any stimulation setting can, in analogy with pharmaceutical ther-
apy, be characterized by its concentration (duty cycle) and dose
(charge per sec) and rate of delivery (current amplitude). These
terms provide a way to describe features of stimulation not immedi-
ately apparent when considering amplitude, frequency, and pulse
width in isolation.
Second, the introduction of a high duty cycle may impact how
patients perceive the therapy. Higher duty cycles may allow the use
of a relatively low amplitude for each individual pulse, and pain
6
relief without paresthesia may be possible since charge delivered by
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Table 3. The Role of Frequency and Pulse Width in the Generation
of Duty Cycles.
Duty cycle Frequency (Hz) Pulse width (ms)
20% 1000 200
20% 200 1000
20% 500 400
10% 100 1000
10% 200 500
2% 50 400
2% 100 200
Duty cycle calculations. Duty cycle is a characteristic of any stimulation
waveform, and multiple combinations of frequency and pulse width
can result in identical duty cycles. A duty cycle of 2% is achieved with
more conventional programming parameters, and could be consid-
ered a “lower dose” option. In contrast, higher frequencies and wider
pulse widths enable higher duty cycles, or a “higher dose” option.
each pulse remains below the threshold for sensory activation
according to the strength-duration curve for stimulation perception.
In other words, because of the higher duty cycle, more energy can
be delivered over time without the need to increase amplitude. This
leads into the third point. What are the spinal mechanisms that
allow for modulation of pain processing with low charge per pulse,
without the activation of dorsal column axons?
Thus, the high duty cycle charge delivery option opens a discus-
sion around the putative neural mechanisms that respond differ-
ently to different forms of charge delivery. Furthermore, the limits of
“low” and “high” duty cycle have yet to be determined. The next
section will summarize research that has adjusted duty cycle to help
define “high” duty cycle or “high” charge, and present possible
hypotheses for modulation of spinal cord neuronal structures with-
out direct activation of dorsal column fibers.
TITRATION OF “CHARGE PER SEC”
Duty cycle and charge over time represent additional ways to
characterize energy delivery during SCS, although there is limited
evidence to support this dosing strategy. Clinical and pre-clinical
titration studies may provide some insights. For example, a study
investigating parameters related to burst demonstrated that
patients retain their pain-relieving benefits when the duty cycle is
halved (18). In this study, the pulse width within the 5-pulse burst
was decreased from 1000 ms to 500 ms (Fig. 7), changing the overall
duty cycle from 20% to 10% without altering the total number of
pulses per sec. Assuming that the current was similar in both para-
digms (although not reported), the rate of charge delivery would
also be halved. Thus, duty cycles of 20% and 10% produced similar
outcomes; however, the lower threshold needed for the effects of
burst remain unclear.
In contrast, increasing charge by increasing the duty cycle may be
important for certain neuronal mechanisms. The parameters influ-
encing higher charge delivery included pulse frequency, pulse
width, and amplitude. Using a rodent model of neuropathic pain,
Crosby et al., 2015, found that the charge per burst was influential
for the inhibitory effect on rat WDR neuron firing (73). The authors
report that more neuronal inhibition was observed as the charge
per burst increased. Additional evidence for overall charge was
reported by Song et al., 2015. SCS delivered by monophasic and
 SCS PARAMETERS AND CHARGE DELIVERY

Figure 6. Methods to increase duty cycle. A. Duty cycle can be incerased by increasing the stimulus pulse width. As pulse width is increased, the stimulus “on”
time in a given period will increase. b. Duty cycle can also be increased by increasing frequency. As the frequency increases, the time “off” decreases. Both of these
methods would allow for the opportunity for higher charge delivery.

Figure 7. Titrating parameters in a burst stimulus. a. The schematic shows a series of burst pulses delivered at a 40 Hz rate. The burst frequency is 500 Hz and each
stimulus has a pulse width of 1000 ms. b. A similar burst schematic is shown with a 40 Hz stimulation rate. In this scenario, when the burst frequency increased to
1000 Hz, the pulse width simultaneously decreased to 500 ms. Assuming the same amplitude in (a) and (b), the overall charge delivery in scenario (b) would be half
of that in scenario (a) and duty cycle decreased from 20% to 10%.

biphasic pulses of two different pulse widths was studied in a rodent
model of neuropathic pain. Reversal of neuropathic pain behavior
was similar in those groups of animals with identical frequency and
pulse width, regardless of pulse shape. The authors conclude that
the amount of electric charge transfer was a critical factor for the
effect—not the pulse shape per se (77).
Frequency also impacts the amount of charge delivery over a
time period. Two pre-clinical studies have tested kilohertz SCS in a
dose-responsive manner in rodent models of neuropathic pain
(45,78). “High frequency” ranging from 500 Hz to 10 kHz resulted in
similar changes in behavior associated with mechanical paw with-
drawal thresholds. Amplitudes were set at 40% or 80% of motor
threshold, which was defined with a stimulus of 4 Hz at 200 ms. In
both studies, 1 kHz and 10 kHz using the same pulse width (24 ms)
achieve the same behavior response with 50 Hz (24 ms) stimulation,
a higher amplitude (80% of motor threshold) was required (75).
Hence, the 50 Hz stimulation delivered twice as much charge per
pulse, but 1 kHz and 10 kHz delivered higher charge per sec.
To better understand how rodent studies align with clinical appli-
cation, Song et al., 2014, attempted to determine the amplitudes
that generated a perception in the rodents (78). They performed
careful behavioral video-monitoring of the rodent response to stim-
ulation while in a darkened room under infrared light. Under these
conditions, the sensory threshold was reported to be around
40–50% of motor threshold (defined as above). This is consistent
with the observations of Shechter et al., 2013, who reported in their
supplemental information that sensory threshold was thought to be
around 50% of motor threshold (45). Thus, higher frequencies
7

produced similar effects at 40% of motor threshold. However, to (500 Hz, 1 kHz, 10 kHz) produce reversal of pain behaviors at lower

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V Neuromodulation 2016; ••: ••–••
 MILLER ET AL.
and presumably subliminal amplitude (40% motor threshold), while
conventional 50 Hz SCS reversed pain behaviors at 80–90% of motor
threshold. Although higher frequencies resulted in higher duty
cycles, these studies found similar reversal of pain behaviors for
500 Hz, 1 kHz, and 10 kHz. Thus, there may be a ceiling effect of neu-
ronal inhibition by increasing the duty cycle.
Although multiple combinations of frequency and pulse width
can have similar duty cycles, it is unclear how much these parame-
ters influence outcomes. Schu et al., 2014 compared burst stimula-
tion to subparesthetic tonic stimulation at 500 Hz. The duty cycle of
the burst stimulus was 20%, while the 500 Hz tonic stimulation was
given at an average duty cycle around 18.5% (the average pulse
width was 370.8 ms). While the overall charge delivery was higher in
the tonic 500 Hz mode, the burst mode was reported to produce
better outcomes in terms of pain relief (79). Therefore, the manner
by which charge is delivered may influence the outcome, and the
interplay between overall amplitude, charge, and pattern may play a
significant role in activating pain-relieving mechanisms.
There are limitations when comparing various parameters in a
clinical setting, and potential confounding factors on patient
response should be considered. For example, a prospective random-
ized and placebo-controlled clinical study was conducted by Perru-
choud et al., 2013, comparing sham stimulation to 5 kHz (60 ms) SCS
and with amplitudes below paresthesia threshold (80). This study
demonstrated a strong placebo effect and a marginal advantage of
5 kHz over sham stimulation that was neither statistically nor clini-
cally significant. The authors discuss carry over effects and patient
expectation as possible confounding factors.
Many of the studies on stimulation patterns have been conducted
in animal models, and it is important to recognize the limitations
when applying the findings to clinical translation. For example, per-
ception threshold cannot be precisely determined in rodent models
and the size of the animal and SCS lead may influence how much
energy is transmitted to the spinal cord. Even so, these parameter
titration studies suggest there is much more to understand about
the way parameters engage specific mechanisms and how fre-
quency and pulse width interplay with each other in optimal “high
charge” scenarios.
HYPOTHESES ON MECHANISMS
Mechanistic differences are emerging between conventional, low
frequency and high charge per sec stimulation. In a rodent model,
low frequency 50 Hz stimulation reduced WDR neuron activity, while
1000 Hz stimulation did not (45). In contrast, both 50 Hz and
1000 Hz modulated action potential condition (seen as a decrease in
compound action potential response after SCS); however, only 1000
Hz was able to produce this modulation at a low amplitude. In addi-
tion, low and high frequency stimulation differ in modulating non-
mechanical thermal pain. Only conventional 50 Hz stimulation, not
10 kHz, was able to reverse heat- and cold-induced pain behaviors
in a rodent model of neuropathic pain (78). A report using quantita-
tive sensory testing in SCS patients observed differential effects of
conventional and 1000 Hz SCS. The authors reported that high fre-
quency stimulation increased sensory thresholds for mechanical
stimuli and pressure pain vs. low frequency stimulation, but had no
effect on thermal detection and on thermal pain thresholds (81).
The mechanisms of SCS have previously focused on activation of
dorsal column fibers (2,3). However, the charge per pulse delivered
with 10 kHz and burst stimulation likely remains below activation
8
threshold, and Ab dorsal column fiber activation in response to the
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V Neuromodulation 2016; ••: ••–••
stimulation pulses would be unlikely (72,78). If the underlying mech-
anisms are not driven by activing neurons, what are the other possi-
bilities? And if the mechanism underlying pain relief does not rely
on activation, are there are other parameter sets that can engage
this same mechanism? In the section below we present two hypoth-
eses on how weak electrical fields applied to the spinal cord might
modulate dorsal column fibers and potentially modulate the pain
system.
Bifurcation or Branch Point Blocking
A study conducted in a leech ganglion preparation showed that a
weak (subfiring threshold) electrical field applied over the axonal
bifurcation, or branch point, of a sensory neuron caused failure of
axonal propagation (82). The strength of the branch point failure
was dependent on the strength of the electrical field. Propagation
through branch points may be critical for learning, neural plasticity,
and information processing (83). Bifurcation points are a common
characteristic of dorsal column neurons: As Ab afferent fibers project
through the dorsal columns, collateral axons branch off the main
axon and synapse with dorsal horn circuitry (84,85). Dorsal column
fibers are responsible for signaling proprioception and mechanosen-
sation. However, evidence exists that ectopic activity in Ab-fibers
may modulate neuropathic pain (86). The mechanisms of pain relief
based on this model are still unclear, but may involve modulation of
abnormal endogenous Ab-fiber activity induced by peripheral nerve
injury. Perhaps a mechanism of electrical modulation around the
branch point is to filter ectopic Ab-fiber activity (87), preventing
abnormal action potential interaction with spinal circuitry within the
dorsal horn. In their rodent model of neuropathic pain, Shechter
et al., 2013, compared the ability of 50 Hz and 1000 Hz to modulate
the size of a compound action potential recorded from a peripheral
nerve before and after SCS. At the lower intensity, only 1000 Hz con-
ditioning stimulation of the dorsal columns decreased the size of
Aa/b waveform from the pre-stimulation baseline (45). The authors
conclude that the underlying mechanism for this finding remains to
be determined, but the results are consistent with the hypothesis
that high rate, low charge per pulse, stimulation may lead to
changes in conduction properties, which may include conduction
failure at afferent fiber bifurcation points.
Modulation of Neural Networks
The ability of neural networks to synchronize and desynchronize
has largely been studied in certain brain regions such as the hippo-
campus. The synchronized activity of cortical networks generates
weak electrical fields which can be detected by electroencephalog-
raphy. These endogenous electrical fields can be perturbed or
modulated by weak exogenous fields delivered by invasive or nonin-
vasive approaches (88). An interesting line of investigation has been
focused on the ability of weak electrical fields to influence neuronal
synchronization, and recent studies have demonstrated that influ-
encing the membrane voltage by application of external electric
fields can modulate spike timing and network coherence (89,90).
The delivery of weak electrical fields may also result in alteration,
obliteration, or refinement of endogenous oscillations that impact
the perception of pain. It is unknown whether pain-relevant oscilla-
tory activity is found in the dorsal horn of the spinal cord where
much of the circuitry responsible for pain processing is located;
however, chronic back pain has been shown to produce oscillatory
activity which can be detected in brain regions such as the medial
prefrontal cortex (91). Preliminary computational modeling suggests
that weak electrical fields can reach the dorsal horn of the spinal
 SCS PARAMETERS AND CHARGE DELIVERY

cord, where they could influence synaptic nerve endings and den-
drites. Furthermore, high duty cycle paradigms may allow for the
dorsal horn circuitry to be under influence of such fields for longer
periods of time (92).
The overall excitability of neural network pools could also be
modulated by electrical fields. Dorsal horn neurons show hyperexcit-
ability and some develop spontaneous activity after nerve injury, a
central mechanism for ongoing pain and hyperalgesia (93). Similarly,
motor neuron pools in the ventral horn can become hyperexcitable
after spinal cord injury—largely considered to be due to a significant
decrease of descending inhibitory influences. Computational model-
ing of the ventral horn has suggested that electrical fields could
suppress the excitability of motor neurons by modulating the mag-
nitude of dendritic persistent inward currents (94). Therefore, weak
electrical fields may exert inhibition on neurons that are in a hyper-
active state. Similar to that observed on motor neurons, the weak
exogenous electrical field may also exert different effects on inactive
dorsal horn neurons (e.g., na€ıve) and those already sensitized and
active after injury.

FUTURE OPPORTUNITIES: STOCHASTIC

FIRING, TONIC, AND PATTERN
Electrical stimulation is defined by the basic elements of ampli-
tude, pulse width, and frequency. However, these parameters can
be varied, resulting in new electrical stimulation patterns. The pat-
tern should not be viewed alone, but in combination with all the
parameters, which have been discussed above. While this review
has focused on assessment of the parameters in terms of charge
delivery, it is important to recognize that other aspects of the stimu-
lation waveform, such as pattern and pulse shape, might engage
unique neural mechanisms. Different elements of a neuron (e.g.,
axons, soma, dendrites, spines) may be differentially impacted by an
imposed electrical field. From many possible neuronal mechanisms,
the bias toward one or another is influenced by the relationship
between the applied field properties (e.g., intensity, frequency,
polarity, pattern, and direction). Already being discussed in the liter-
ature for peripheral nerve stimulation are particular patterns of stim-
ulation that appear to generate various and specific tactile
sensations (95), with similar applications for SCS that alter the sensa-
tion of paresthesia (96). As more patterns and variations emerge, it is
important that all the parameters are clearly reported to clarify the
Figure 8. Hypothetical neuronal responses to a pulse series. a. A series of
commonalities and differences. pulses, for example in a burst mode, which is subactivation threshold for neu-
The manner in which stimulation parameters are combined and rons, may produce partial depolarization of neurons, but no corresponding
delivered are important for investigating mechanisms of action and action potentials. Neurons will not entrain to a series of subthreshold pulses.
the subsequent desired clinical outcomes. For example, the mecha- b. As the stimulation gets closer to the activation threshold for neurons, more
neurons may respond to the stimulus. Since this particular stimulus holds the
nism of high amplitude kilohertz frequency is not likely to be the
recharging phase until the end of the series, to the neurons, it likely looks like a
same as low amplitude kilohertz frequency (61). Asynchronous firing long depolarizing pulse. Therefore, action potentials may be elicited at the
is thought to occur once frequencies exceed the ability of neurons beginning, but not during the entire stimulus train. c. The most effective way
to entrain to the stimulation. Therefore, one hypothesis is that high to elicit a firing pattern in a neuron is with a stimulus which is above activation
threshold for the neuron and allows time for the neuron to repolarize after
frequency SCS evokes an asynchronous firing mechanism. It is possi-
each stimulus is presented. In this schematic, an action potential response is
ble that asynchronous firing of dorsal column neurons may lead to a elicited in response to each electrical pulse.
change of perceived sensation. For example, in the auditory system,
there is suggestion that desynchronized firing can modulate percep-
tion. The desynchronization of firing of clusters of auditory neurons sal column fibers are activated a logical assumption is that the
can be obtained by ultra-high frequency neural input, and this patient would perceive some altered sensation.
appears to scramble or disrupt the “message effect” in a previously Similarly, bursting or “irregular firing” patterns likely do have rele-
syncronized cluster firing (97). During SCS, the sensory experience or vant effects on the nervous system. However, is the mechanism of
perception by the patient is likely different depending on how the low amplitude burst the same as high amplitude burst? Publications
9

axons fire with different patterns or rates, yet if even a subset of dor- describing the programming for burst SCS state that patients are

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V Neuromodulation 2016; ••: ••–••
 MILLER ET AL.
“programmed in a supine position and amplitude is increased until
paresthesias are elicited. Subsequently, the amplitude is decreased
to an amplitude below paresthesia perception level” (19). This
description suggests that the therapy is set to an intensity below
activation threshold for the dorsal column fibers. The programming
methodology and low amplitude pulses suggest that neurons may
not entrain or fire action potentials in response to each pulse in the
burst series (Fig. 8a). In addition to the stimulation intensity, the
location of the recovery pulse could play a role in how neurons
would respond to a burst stimulus. Unlike the earlier description of
recharge occurring after each pulse, the recharge phase for this par-
ticular burst pattern is initiated at the end of the five pulses (Fig. 8b).
Therefore, a train or series of pulses with immediate recharge would
look slightly different from this pattern. In particular, neurons may
be more likely to entrain to a stimulus that allows recovery time
after each pulse (Fig. 8c).
When evaluating the possible mechanisms underlying a pattern,
it will be important to understand all parameters, understand com-
monalities and overlaps, and to determine the key aspects for each
stimulation pattern that are influencing the therapeutic effects.
CONCLUSION
SCS involves delivery of energy to neural tissue and requires an
effective dose to reach the critical neural targets to obtain the
desired pain relieving effect. Regardless of the stimulation pattern,
there are certain crucial elements related to dose, and a basic funda-
mental knowledge of the parameters used to administer the therapy
is fundamentally important. This paper reviews basic concepts of
energy delivery in neurostimulation (amplitude, pulse width, and fre-
quency) and introduces the concept of the duty cycle and charge
per sec as another way to characterize stimulation patterns.
The historical view of SCS mechanisms has typically considered
the electrical stimulation pulse as the key mechanism for activat-
ing dorsal column Ab fibers and subsequently engaging mecha-
nisms responsible for pain relief. However, the concept of duty
cycle and “charge per second” allows an appreciation of the elec-
trical charge delivery itself as the therapy analogous to the process
of “medicine delivery.” Electrical energy may be viewed as the
medication that is titrated to produce optimal pain relief. The indi-
vidual electrical pulse may have the additional effect of paresthe-
sia that is proportional to quantity of medicine administered with
each dose (charge per pulse). Providing smaller doses at more fre-
quent intervals to administer the same or greater total amount of
medication may lessen the effects of paresthesia or allow for none
at all. In this model, the parameters of current, pulse width, and
frequency are tightly related: Just as the combination of drug
amount (i.e., milligrams) and the delivery rate (i.e., twice daily)
determines the dose of medicine required to reach a therapeutic
plasma concentration, the electrical “dose” delivered is a combina-
tion of duty cycle and current delivery. While the precise mecha-
nisms that underlie the clinical benefits of SCS still remain to be
fully elucidated, conception of the therapy in terms of charge
delivery may lead to a more meaningful discussion and under-
standing of its effects and greater flexibility in its application.
Authorship Statement
Drs. Miller and Johanek drafted the manuscript with substantial
10
input, revision, and critique from Drs. Linderoth, Eldabe, Buchser,
www.neuromodulationjournal.com C 2016 International Neuromodulation Society
V Neuromodulation 2016; ••: ••–••
and Guan. All authors confirm the content and made substantial
contributions to drafting the paper and critical review.
How to Cite this Article:
Miller J.P., Eldabe S., Buchser E., Johanek L. M., Guan Y.,
Linderoth B. 2016. Parameters of Spinal Cord Stimulation
and Their Role in Electrical Charge Delivery: A Review.
Neuromodulation 2016; E-pub ahead of print.
DOI:10.1111/ner.12438.
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