U.S. patent application number 14/026854 was filed with the patent office on 2014-01-09 for electrical stimulation therapy to promote gastric distention for obesity management.
This patent application is currently assigned to Medtronic, Inc.. The applicant listed for this patent is Medtronic, Inc.. Invention is credited to Jiande Chen, Elizabeth D. Firestone, Roland C. Maude-Griffin, Warren L. Starkebaum.
Application Number | 20140012348 14/026854 |
Document ID | / |
Family ID | 42110936 |
Filed Date | 2014-01-09 |
United States Patent
Application |
20140012348 |
Kind Code |
A1 |
Starkebaum; Warren L. ; et
al. |
January 9, 2014 |
ELECTRICAL STIMULATION THERAPY TO PROMOTE GASTRIC DISTENTION FOR
OBESITY MANAGEMENT
Abstract
The disclosure is directed to techniques for delivering
electrical stimulation therapy to support obesity management. The
electrical stimulation therapy is configured to cause at least
partial gastric distention. Gastric distention tends to induce a
sensation of fullness and thereby discourages excessive food intake
by the patient. The electrical stimulation therapy may be delivered
to the gastrointestinal tract of the patient by electrodes deployed
by one or more implantable leads coupled to an electrical
stimulator. The electrical stimulator delivers stimulation pulses
having a pulse width in a range found to be effective in causing
gastric distention.
Inventors: |
Starkebaum; Warren L.;
(Plymouth, MN) ; Chen; Jiande; (Houston, TX)
; Firestone; Elizabeth D.; (St. Paul, MN) ;
Maude-Griffin; Roland C.; (Edina, MN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Medtronic, Inc. |
Minneapolis |
MN |
US |
|
|
Assignee: |
Medtronic, Inc.
Minneapolis
MN
|
Family ID: |
42110936 |
Appl. No.: |
14/026854 |
Filed: |
September 13, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
12715993 |
Mar 2, 2010 |
8538532 |
|
|
14026854 |
|
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|
61157068 |
Mar 3, 2009 |
|
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61244431 |
Sep 21, 2009 |
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Current U.S.
Class: |
607/40 |
Current CPC
Class: |
A61F 5/0026 20130101;
A61N 1/36007 20130101 |
Class at
Publication: |
607/40 |
International
Class: |
A61F 5/00 20060101
A61F005/00 |
Claims
1. A method comprising: generating a plurality of electrical
stimulation pulses with a pulse width of approximately 1 to
approximately 10 milliseconds; and applying, using at least one
processors, the plurality of electrical stimulation pulses to a
gastrointestinal tract of a patient to promote weight loss.
2. The method of claim 1, wherein applying the plurality of
electrical stimulation pulses to the gastrointestinal tract of the
patient to promote weight loss comprises applying the plurality of
electrical stimulation pulses to a stomach of the patient to
promote weight loss.
3. The method of claim 2, wherein applying the plurality of
electrical stimulation pulses to the stomach of the patient to
promote weight loss comprises applying the plurality of electrical
stimulation pulses to at least one of a lesser or greater curvature
of the stomach of the patient to promote weight loss.
4. The method of claim 2, wherein applying the plurality of
electrical stimulation pulses to the stomach of the patient to
promote weight loss comprises applying the plurality of electrical
stimulation pulses to a pylorus of the patient to promote weight
loss.
5. The method of claim 1, wherein applying the plurality of
electrical stimulation pulses to the gastrointestinal tract of the
patient to promote weight loss comprises applying the plurality of
electrical stimulation pulses to the gastrointestinal tract of the
patient to induce a sensation of fullness.
6. The method of claim 1, wherein applying the plurality of
electrical stimulation pulses to the gastrointestinal tract of the
patient to promote weight loss comprises applying the plurality of
electrical stimulation pulses to the gastrointestinal tract of the
patient to reduce food intake.
7. The method of claim 1, applying the plurality of electrical
stimulation pulses to the gastrointestinal tract of the patient to
promote weight loss comprises applying the plurality of electrical
stimulation pulses to the gastrointestinal tract of the patient to
induce a sensation of at least one of satiety and nausea.
8. The method of claim 1, wherein applying the plurality of
electrical stimulation pulses to a gastrointestinal tract of the
patient comprises applying the plurality of electrical stimulation
pulses to a gastrointestinal tract of the patient according to a
duty cycle.
9. The method of claim 8, wherein the duty cycle is defined such
that the plurality of electrical stimulation pulses are applied to
the gastrointestinal tract of the patient substantially
continuously.
10. The method of claim 8, wherein the duty cycle is defined such
that the plurality of electrical stimulation pulses are applied to
the gastrointestinal tract of the patient greater than
approximately 20% ON.
11. The method of claim 8, wherein the duty cycle is defined such
that the plurality of electrical stimulation pulses are applied to
the gastrointestinal tract of the patient greater than
approximately 40% ON.
12. The method of claim 8, wherein the duty cycle is defined such
that the plurality of electrical stimulation pulses are applied to
the gastrointestinal tract of the patient greater than
approximately 50% ON.
13. The method of claim 1, further comprising detecting, using the
at least one processor, an indication of food intake by the
patient, and wherein applying the plurality of electrical
stimulation pulses to the gastrointestinal tract of the patient to
promote weight loss comprises applying the plurality of electrical
stimulation pulses to the gastrointestinal tract of the patient
based at least in part on the detection of the indication of food
intake.
14. The method of claim 1, further comprising detecting, using the
at least one processor, gastric contraction by the patient, and
wherein applying the plurality of electrical stimulation pulses to
the gastrointestinal tract of the patient to promote weight loss
comprises applying the plurality of electrical stimulation pulses
to the gastrointestinal tract of the patient based at least in part
on the detection of the gastric contraction.
15. The method of claim 1, further comprising detecting, using the
at least one processor, gastric nerve potentials by the patient,
and wherein applying the plurality of electrical stimulation pulses
to the gastrointestinal tract of the patient to promote weight loss
comprises applying the plurality of electrical stimulation pulses
to the gastrointestinal tract of the patient based at least in part
on the detection of the gastric nerve potentials.
16. The method of claim 1, wherein the plurality of electrical
stimulation pulses are activated for application to the
gastrointestinal tract of the patient for a selected time.
17. The method of claim 16, wherein the selected time coincides
with a sleep time of the patient.
18. The method of claim 16, wherein the selected time coincides
with a meal time of the patient.
19. The method of claim 16, wherein the selected time coincides
with a physical activity time of the patient.
20. An implantable gastric stimulator comprising: an electrical
stimulation pulse generator configured to generate a plurality of
electrical stimulation pulses with a pulse width of approximately 1
to approximately 10 milliseconds; and at least one processor
configured to apply, via one or more electrodes coupled to the
pulse generator, the plurality of electrical stimulation pulses to
a gastrointestinal tract of a patient to promote weight loss.
Description
[0001] This application is a continuation of U.S. application Ser.
No. 12/715,993, filed on Mar. 2, 2010, which claims the benefit of
U.S. Provisional Application No. 61/157,068, entitled, "ELECTRICAL
STIMULATION THERAPY TO PROMOTE GASTRIC DISTENTION FOR OBESITY
MANAGEMENT," and filed on Mar. 3, 2009, and U.S. Provisional
Application No. 61/244,431, entitled, "WAVEFORMS FOR ELECTRICAL
STIMULATION THERAPY," and filed on Sep. 21, 2009, the entire
contents of each application being incorporated herein by
reference.
TECHNICAL FIELD
[0002] The invention relates to implantable medical devices and,
more particularly, implantable medical devices for obesity
management.
BACKGROUND
[0003] Obesity is a serious health problem for many people.
Patients who are overweight often have problems with mobility,
sleep, high blood pressure, and high cholesterol. Some other
serious risks also include diabetes, cardiac arrest, stroke, kidney
failure, and mortality. In addition, an obese patient may
experience psychological problems associated with health concerns,
social anxiety, and generally poor quality of life.
[0004] Certain diseases or conditions can contribute to additional
weight gain in the form of fat, or adipose tissue. However, healthy
people may also become overweight as a net result of excess energy
consumption and insufficient energy expenditure. Reversal of
obesity is possible but difficult. Once the patient expends more
energy than is consumed, the body will begin to use the energy
stored in the adipose tissue. This process will slowly remove the
excess fat from the patient and lead to better health. Some
patients require intervention to help them overcome their obesity.
In these severe cases, nutritional supplements, prescription drugs,
or intense diet and exercise programs may not be effective.
[0005] Surgical intervention is a last resort treatment for some
obese patients who are considered morbidly obese. One common
surgical technique is the Roux-en-Y gastric bypass surgery. In this
technique, the surgeon staples or sutures off a large section of
the stomach to leave a small pouch that holds food. Next, the
surgeon severs the small intestine at approximately mid length and
attaches the distal section of the small intestine to the pouch
portion of the stomach. This procedure limits the amount of food
the patient can ingest to a few ounces, and limits the amount of
time that ingested food may be absorbed through the shorter length
of the small intestine. While this surgical technique may be very
effective, it poses significant risks of unwanted side effects,
malnutrition, and death.
[0006] Electrical stimulation therapy is an alternative to surgical
intervention, and may be effective in treating obesity either alone
or in combination with diet and exercise. For electrical
stimulation therapy, a patient is fitted with an implanted
electrical stimulator that delivers electrical stimulation pulses
to the patient's stomach via electrodes carried by one or more
leads. The electrical stimulation therapy may be configured to
induce a sensation of fullness or nausea in the patient, thereby
discouraging excessive food intake. In addition, in some cases, the
electrical stimulation therapy may be configured to decrease
gastric motility so that caloric absorption is reduced. Hence,
electrical stimulation therapy may be effective in causing weight
loss, by discouraging food intake and/or reducing caloric
absorption.
SUMMARY
[0007] In general, the invention is directed to techniques for
delivering electrical stimulation therapy to support obesity
management. The electrical stimulation therapy is configured to
cause at least partial gastric distention. Gastric distention tends
to induce a sensation of fullness, i.e., satiety, and thereby
discourages excessive food intake by the patient. The electrical
stimulation therapy may be delivered to the gastrointestinal tract
of the patient by electrodes deployed by one or more implantable
leads coupled to an external or implantable electrical
stimulator.
[0008] The electrical stimulator delivers stimulation pulses having
a pulse width found to be effective in causing gastric distention.
In addition, the pulse width may be selected to promote battery
longevity in the implantable electrical stimulator. The pulse width
also may be selected to avoid or reduce undesirable side effects.
Hence, in some examples, the pulse width may be selected to balance
effectiveness in causing gastric distention, power conservation,
and avoidance or reduction of undesirable side effects.
[0009] In one example, the disclosure is directed to a method
comprising generating a plurality of pulse bursts, each of the
pulse bursts having a duration of greater than approximately 100
milliseconds, wherein each of the pulse bursts includes a plurality
of pulses, each of the pulses having a pulse width of approximately
2 milliseconds to approximately 20 milliseconds, and applying the
plurality of pulse bursts to a gastrointestinal tract of a patient
to cause gastric distention.
[0010] In another example, the disclosure is directed to an
implantable gastric stimulator comprising an electrical stimulation
pulse generator configured to generate a plurality of pulse bursts,
each of the pulse bursts having a duration of greater than
approximately 100 milliseconds, wherein each of the pulse bursts
includes a plurality of pulses, each of the pulses having a pulse
width of approximately 2 milliseconds to approximately 20
milliseconds, and one or more electrodes, coupled to the pulse
generator, configured to apply the plurality of pulse bursts to a
gastrointestinal tract of a patient to cause gastric
distention.
[0011] In another example, the disclosure is directed to a
computer-readable storage medium comprising instructions that, upon
execution, cause a processor to control an electrical stimulation
pulse generator to generate a plurality of pulse bursts, each of
the pulse bursts having a duration of greater than approximately
100 milliseconds, wherein each of the pulse bursts includes a
plurality of pulses, each of the pulses having a pulse width of
approximately 2 milliseconds to approximately 20 milliseconds, and
apply, via one or more electrodes, the plurality of pulse bursts to
a gastrointestinal tract of a patient to cause gastric
distention.
[0012] In another example, the disclosure is directed to a device
comprising means for generating a plurality of pulse bursts, each
of the pulse bursts having a duration of greater than approximately
100 milliseconds, wherein each of the pulse bursts includes a
plurality of pulses, each of the pulses having a pulse width of
approximately 2 milliseconds to approximately 20 milliseconds, and
means for applying the plurality of pulse bursts to a
gastrointestinal tract of a patient to cause gastric
distention.
[0013] In an additional example, the disclosure provides a method
comprising generating a long electrical stimulation pulse
approximated by a plurality of short electrical stimulation pulses,
and applying the long electrical stimulation pulse to a
gastrointestinal tract of a patient to cause gastric
distention.
[0014] In another example, the disclosure provides an implantable
gastric stimulator comprising an electrical stimulation pulse
generator that generates a long electrical stimulation pulse
approximated by a plurality of short electrical stimulation pulses,
and one or more electrodes, coupled to the pulse generator, that
apply the long electrical stimulation pulse to a gastrointestinal
tract of a patient to cause gastric distention.
[0015] In an additional example, the disclosure provides a method
comprising generating an electrical stimulation pulse that both
modulates gastric smooth muscle activity and acts through vagal
afferent pathways, and applying the electrical stimulation pulse to
a gastrointestinal tract of a patient.
[0016] In another example, the disclosure provides an implantable
gastric stimulator comprising an electrical stimulation pulse
generator that generates an electrical stimulation pulse that both
modulates gastric smooth muscle activity and acts through vagal
afferent pathways, and one or more electrodes, coupled to the pulse
generator.
[0017] In various examples, the disclosure may provide one or more
advantages. For example, delivery of electrical stimulation therapy
with a pulse width in a range of greater than or equal to
approximately 1 millisecond, more preferably greater than or equal
to approximately 1.5 milliseconds and, still more preferably
greater than or equal to approximately 2 milliseconds may be
effective in promoting gastric distention, e.g., to discourage
excessive food intake by a patient and promote weight loss. A pulse
width in a range of approximately 1 milliseconds to approximately
50 milliseconds, more preferably in a range of approximately 1.5
milliseconds to approximately 10 milliseconds, more preferably
approximately 2 milliseconds to approximately 10 milliseconds, and
even more preferably approximately 2 to 5 milliseconds, may be
effective in causing gastric distention while promoting better
power conservation. Electrical stimulation therapy with pulse
widths in the above ranges may be more effective in conserving
battery resources, relative to larger pulse widths, increasing
longevity of an implanted electrical stimulation device. In
addition, relative to larger pulse widths, electrical stimulation
therapy having pulse widths in the ranges described above may be
more effective in avoiding or reducing adverse side effects in the
patient, which can detract from overall therapy and quality of
life.
[0018] The details of one or more examples of the invention are set
forth in the accompanying drawings and the description below. Other
features, objects, and advantages of the invention will be apparent
from the description and drawings, and from the claims.
BRIEF DESCRIPTION OF DRAWINGS
[0019] FIG. 1 is a schematic diagram illustrating an implantable
gastric stimulation system.
[0020] FIG. 2 is a block diagram illustrating exemplary components
of an implantable gastric stimulator.
[0021] FIG. 3A is a graph illustrating gastric distention response
to electrical stimulation therapy with different pulse widths.
[0022] FIG. 3B is another graph illustrating gastric distention
response to electrical stimulation therapy with different pulse
widths.
[0023] FIG. 4 is a flow diagram illustrating a method for
delivering electrical stimulation having a pulse width selected to
cause substantial gastric distention.
[0024] FIG. 5A is a graph illustrating an example of an electrical
stimulation pulse train for treating obesity using a short pulse
train to approximate a long pulse.
[0025] FIG. 5B is a graph illustrating the short pulse train in
FIG. 5A in greater detail.
[0026] FIG. 6 is a bar graph depicting the mean change in balloon
volume for three isoenergetic variants of gastric electrical
stimulation (GES) during both stimulation and recovery in lean
canines.
[0027] FIG. 7 is a graph comparing the balloon volumes resulting
from the application of the three isoenergetic variants of GES,
beginning from a pre-GES baseline, and continuing through GES and
recovery in lean canines.
[0028] FIG. 8A is a graph illustrating an example of an electrical
stimulation pulse train for treating obesity using a pattern of a
long pulse followed by a train of short pulses.
[0029] FIG. 8B is a graph illustrating the short pulses of FIG. 6B
in greater detail.
[0030] FIG. 9 is a bar graph depicting the mean change in balloon
volume for three isoenergetic variants of GES, during both
stimulation and recovery after stimulation in lean canines.
[0031] FIG. 10 is a graph comparing the balloon volumes resulting
from the application of the three isoenergetic variants of GES,
beginning from a pre-GES baseline, and continuing through GES and
recovery in lean canines.
[0032] FIG. 11 is a bar graph comparing the reduction in antral
pressure using a long pulse GES setting and the combination GES
setting during both application of GES and during recovery in lean
canines.
[0033] FIG. 12 is a graph depicting the mean antral pressure as a
percentage of change from the baseline period mean over a period of
30 minutes, including the GES period and the recovery period using
a long pulse setting and a combination pulse setting in lean
canines.
[0034] FIG. 13 is a bar graph depicting the food intake in mean
grams per day for sham GES, a long pulse setting, and a combination
pulse setting in obese rats.
[0035] FIG. 14 is a graph comparing the mean food intake in grams
using sham GES, a long pulse setting, and a combination setting
over seven days in lean canines.
[0036] FIG. 15 is a bar graph depicting the food intake in mean
grams per day for sham GES, a short pulse setting, a long pulse
setting, and a combination setting in obese rats.
[0037] FIG. 16 is a bar graph depicting gastric volume in mean
milliliters when GES treatment is off and when using a combination
setting treatment in obese rats.
[0038] FIG. 17 is a bar graph depicting the mean percentage of
gastric emptying at 90 min with 95% Cl when GES is off and when
using a combination GES setting stimulation pulses in obese
rats.
[0039] FIG. 18 is a graphic depicting the correlation between GES
induced reductions of food intake and gastric volume following GES
treatment in obese rats.
[0040] FIGS. 19A and 19B are plots illustrating example waveforms
that represent example series of electrical stimulation for
delivery to a patient.
DETAILED DESCRIPTION
[0041] In general, the invention is directed to techniques for
delivering electrical stimulation therapy to support obesity
management. The techniques may be embodied, for example, in an
electrical stimulation method, an electrical stimulation device, or
an electrical stimulation system. The electrical stimulation
therapy is configured to cause at least partial gastric distention.
In particular, the electrical stimulation therapy is delivered with
stimulation pulses having a pulse width in a range found to be
effective in causing gastric distention. In addition, the pulse
width range may be selected to promote battery longevity in the
implantable electrical stimulator. The pulse width also may be
selected to avoid or reduce undesirable side effects in the
patient. Hence, in some examples, the pulse width may be selected
to balance effectiveness in causing gastric distention, power
conservation, and avoidance or reduction of undesirable side
effects.
[0042] As an example, the stimulation pulses may have a pulse width
greater than or equal to approximately 2 milliseconds. In other
examples, an electrical stimulator delivers stimulation pulses with
a pulse width in a range of approximately 2 milliseconds to
approximately 20 milliseconds. In further examples, the pulse width
is in a range of approximately 2 milliseconds to approximately 10
milliseconds, more preferably approximately 2 milliseconds to 5
milliseconds.
[0043] Electrical stimulation having stimulation pulses with pulse
widths in the above ranges may be effective in causing gastric
distention and thereby discouraging excessive food intake and
promoting weight loss while promoting better power conservation. In
addition, electrical stimulation therapy with pulse widths in the
above ranges may be more effective in conserving battery resources,
relative to larger pulse widths, thereby increasing operational
longevity of an implanted electrical stimulation device. In
addition, relative to larger pulse widths, electrical stimulation
therapy having pulse widths in the ranges described above may be
more effective in avoiding or reducing adverse side effects in the
patient. Examples of side effects caused by larger pulse widths
include tremor, nausea, vomiting, pain and abdominal
discomfort.
[0044] FIG. 1 is a schematic diagram illustrating an implantable
stimulation system 10. System 10 is configured to deliver
electrical stimulation therapy to support obesity management. The
electrical stimulation therapy is configured to cause at least
partial gastric distention. Gastric distention generally refers to
relaxation and expansion of a portion of the gastrointestinal
tract, such as the stomach or small intestine. For purposes of
illustration, the disclosure will generally focus on application of
electrical stimulation therapy to the stomach, although stimulation
may be applied elsewhere in the gastrointestinal tract.
[0045] As shown in FIG. 1, system 10 may include an implantable
stimulator 12 and an external module 14, both shown in conjunction
with a patient 16. Ordinarily, patient 16 is a human patient, as
indicated in the example of FIG. 1. Stimulator 12 includes a pulse
generator that generates electrical stimulation pulses. In some
examples, system 10 may further include a drug delivery device that
delivers drugs or other agents to the patient for obesity therapy.
One or more implantable leads 18, 20 carry the electrical
stimulation pulses from implanted stimulator 12 to stomach 22. In
other examples, stimulator 12 may be an external stimulator coupled
to percutaneously implanted leads. As a further example, stimulator
12 may be formed as an RF-coupled system in which an external
controller provides both control signals and inductively coupled
power to an implanted pulse generator.
[0046] Leads 18, 20 each include one or more electrodes 24, 26 for
delivery of the electrical stimulation pulses to stomach 22.
Although the electrical stimulation pulses may be delivered to
other areas within the gastrointestinal tract, such as the
esophagus, duodenum, small intestine, or large intestine, delivery
of stimulation pulses to stomach 22 will generally be described in
this disclosure for purposes of illustration. In the example of
FIG. 1, electrodes 24, 26 are placed in lesser curvature 23 of
stomach 22. For example, electrodes 24, 26 may be placed in lesser
curvature 23 approximately 1 centimeter (cm) to approximately 5 cm
from the pylorus. Alternatively, or additionally, electrodes 24, 26
could be placed in the greater curvature of stomach 22. For
example, electrodes 24, 26 may be placed in the greater curvature
approximately 1 centimeter (cm) to approximately 5 cm from the
pylorus.
[0047] Gastric distention tends to induce a sensation of fullness
and thereby discourages excessive food intake by the patient. The
therapeutic efficacy of gastric electrical stimulation in managing
obesity depends on the stimulation parameters and stimulation
target. Electrical stimulation may have mechanical, neuronal and/or
hormonal effects that result in a decreased appetite and increased
satiety. In turn, decreased appetite results in reduced food intake
and weight loss. Gastric distention, in particular, causes a
patient to experience a sensation of satiety due to expansion of
the stomach, biasing of stretch receptors, and signaling fullness
to the central nervous system.
[0048] For patient 16 to lose weight, patient 16 must have a net
energy such that energy expended is greater than or equal to energy
consumed. Diet and exercise play a role in reducing energy
consumption. As an alternative or supplement to diet and exercise,
stimulator 12 delivers stimulation pulses to the gastrointestinal
tract to cause gastric distention. Gastric distention tends to
induce a sensation of fullness, and serves to limit food intake by
patient 16. Implantable stimulator 12 is configured to deliver
stimulation pulses having a pulse width in a range found to be
particularly effective in causing gastric distention while
promoting battery longevity in the implantable electrical
stimulator.
[0049] In one example, for example, stimulator 12 delivers
stimulation pulses with a pulse width selected to promote gastric
distention. As an example, the stimulation pulses delivered by
stimulator 12 may have a pulse width greater than or equal to
approximately 2 milliseconds. In other examples, an electrical
stimulator delivers stimulation pulses with a pulse width in a
range of approximately 2 milliseconds to approximately 50
milliseconds. In further examples, the pulse width is in a range of
approximately 2 milliseconds to approximately 10 milliseconds, more
preferably approximately 2 milliseconds to 5 milliseconds.
[0050] The pulse widths in the ranges identified above have been
found to be long enough to cause substantial gastric distention.
However, the pulse widths are selected to be sufficiently short so
that excessive power consumption and adverse patient side effects
may be avoided or reduced. In addition, diminishing gains in
therapeutic effect may be perceived by patient 16 as the pulse
widths become larger. Hence, the pulse width may be selected to
balance therapeutic efficacy with reduced power consumption and
side effects.
[0051] Patient 16 may be successfully treated with stimulation
pulses having a range between 1 millisecond and 50 milliseconds.
However, patient 16 may receive less efficacious therapy with pulse
widths as low as 1 millisecond. In addition, larger pulse widths
greater than or equal to 10 milliseconds may cause adverse effects
to the patient that may be effective to treat obesity but detract
from the patient's quality of life. Example adverse effects may
include tremor, nausea, vomiting, gastrointestinal disorders, or
other undesirable effects. Moreover, larger pulse widths generally
result in a higher rate of power consumption.
[0052] For these reasons, patient 16 may be successfully treated
with stimulation having pulse widths within a smaller range. For
example, patient 16 may be successfully treated with stimulation
having a pulse width between approximately 2 milliseconds and 20
milliseconds, between approximately 2 milliseconds and 10
milliseconds, and between approximately 2 milliseconds and 5
milliseconds. Pulse widths of 2 milliseconds and greater may be
able to target excitable tissue with strength-duration
characteristics not captured with pulse widths smaller than 2
milliseconds in some patients. However, in some cases, patient 16
may perceive adverse side effects with pulse widths substantially
greater than or equal to approximately 5 milliseconds. Also, pulse
widths greater than or equal to approximately 5 milliseconds may
provide diminishing, additional therapeutic benefit over smaller
pulse widths less than approximately 5 milliseconds. Accordingly,
in these cases, patient 16 may be effectively treated with
stimulation pulses having a pulse width between 2 milliseconds and
5 milliseconds, thereby balancing therapeutic efficacy, reduction
in adverse side effects, and reduction in power consumption.
[0053] Battery longevity in an implantable stimulator is a
paramount concern. Implantation of stimulator 12 in patient 16
requires surgery. Similarly, surgery is required for explanation of
stimulator 12 in the event battery resources are exhausted, as well
as for re-implantation of a replacement stimulator. To reduce the
number of surgical operations, and associated pain, recovery time,
and risks, it is desirable to preserve battery resources to the
extent possible while ensuring therapeutic efficacy. Because
shorter pulse widths may reduce power consumption while increasing
battery longevity, delivery of stimulation pulses in particular
pulse width ranges described in this disclosure may achieve
therapeutic efficacy in causing gastric distention while promoting
battery longevity.
[0054] With further reference to FIG. 1, at the outer surface of
stomach 22, e.g., along the lesser curvature 23, leads 18, 20
penetrate into tissue such that electrodes 24 and 26 are positioned
to deliver stimulation to the stomach. As mentioned above, the
parameters of the stimulation pulses generated by stimulator 12 are
selected to distend stomach 22 and thereby induce a sensation of
fullness, i.e., satiety. In some examples, the parameters of the
stimulation pulses also may be selected to induce a sensation of
nausea. In each case, the induced sensation of satiety and/or
nausea may reduce a patient's desire to consume large portions of
food. Again, the stimulation pulses may be delivered elsewhere
within the gastrointestinal tract, either as an alternative to
stimulation of lesser curvature 23 of stomach 22, or in conjunction
with stimulation of the lesser curvature of the stomach. For
example, electrodes 24, 26 may be placed in lesser curvature 23
approximately 1 centimeter (cm) to approximately 5 cm from the
pylorus. As one example, stimulation pulses could be delivered to
the greater curvature of stomach 22. For example, electrodes 24, 26
may be placed in the greater curvature approximately 1 centimeter
(cm) to approximately 5 cm from the pylorus.
[0055] The pulse width may be selected so that electrical
stimulation, when applied, causes at least a twenty-five percent
increase in gastric volume relative to a baseline gastric volume,
preferably at least a fifty percent increase in gastric volume,
more preferably at least a seventy-five percent increase in gastric
volume, and still more preferably at least a one-hundred percent
increase in gastric volume. The increase in gastric volume may be
measured relative to a baseline gastric volume, such as a
preprandial (pre-meal) gastric volume, and may be measured within a
selected area of the gastrointestinal tract. For example, the
gastric volume may be measured within the stomach if electrical
stimulation is applied to the stomach. Alternatively, the baseline
and stimulation-induced gastric volume may be measured elsewhere
within the gastrointestinal tract.
[0056] In addition to pulse width, the stimulation pulses are
defined by other parameters including current or voltage amplitude,
pulse rate, and duty cycle. In some examples, stimulation
parameters may further include electrode combinations and
polarities in the event leads 18, 20 provide multiple electrode
positions. As an illustration, in addition to a pulse width in the
ranges identified above, stimulator 12 may generate stimulation
pulses having a current amplitude in a range of approximately less
than 1 milliamp (mA) to approximately 20 mA, preferably
approximately 1 mA to approximately 15 mA. The pulse rate of the
stimulation pulses may be in a range of approximately 2 Hz to 90
Hz, more preferably approximately 2 Hz to 40 Hz, and more
preferably approximately 5 Hz to 25 Hz. As described below, a
substantial amount of distention may be produced for a pulse width
of approximately 2 ms in combination with a pulse rate of
approximately 40 Hz.
[0057] In addition, stimulator 12 may deliver the stimulation
pulses with a duty cycle of approximately 50% ON/50% OFF,
preferably 20% ON/80% OFF, and more preferably 100% ON/0% OFF. Duty
cycle generally refers to the percentage of time that stimulator 12
is delivering stimulation pulses versus the percentage of time
during which the stimulator is idle. During ON time, stimulator 12
delivers pulses according to a set of parameters such as amplitude,
pulse rate and pulse width. During OFF time, stimulator 12 does not
deliver stimulation pulses to patient 16. In addition, the duty
cycle may include multiple levels of delivering stimulation and not
delivering stimulation. For example, the duty cycle may include the
amount of time pulses are delivered and the amount of time pulses
are not delivered to patient 16 when the stimulator 12 is ON.
Additionally, a higher level duty cycle includes the amount of time
stimulator 12 is ON and OFF. In this manner, example stimulation
therapy may have duty cycles that describe when stimulator 12 is ON
and OFF in addition to cycles that describe the amount of time
pulses are delivered to patient 16 during the ON period.
[0058] As one illustration, to cause gastric distention, stimulator
12 may deliver stimulation pulses with a pulse current amplitude of
approximately 1 to 15 mA, a pulse width of approximately 2 to 10
milliseconds (ms), a pulse rate of approximately 1 to 60 Hz, and a
duty cycle of approximately 25% ON/75% OFF. As another
illustration, stimulator 12 may deliver stimulation pulses with an
amplitude of approximately 3 to 6 mA, a pulse width of
approximately 2 to 5 milliseconds (ms), a pulse rate of
approximately 20 to 50 Hz, and a duty cycle of approximately 40%
ON/60% OFF. In each case, stimulator 12 will cause substantial
gastric distention and a sensation of fullness, resulting in
reduced food intake and, ultimately, weight loss.
[0059] Implantable stimulator 12 may be constructed with a
biocompatible housing, such as titanium, stainless steel, or a
polymeric material, and is surgically implanted within patient 16.
The implantation site may be a subcutaneous location in the side of
the lower abdomen or the side of the lower back. Stimulator 12 is
housed within the biocompatible housing, and includes components
suitable for generation of electrical stimulation pulses.
Stimulator 12 may be responsive to an external module 14 that
generates control signals to adjust stimulation parameters.
Although stimulator 12 is illustrated as implanted in the example
of FIG. 1, in other examples, stimulator 12 may be an external
stimulator coupled to percutaneous leads for either trial
stimulation or chronic stimulation. As a further example,
stimulator 12 may be formed as an RF-coupled system in which an
external controller provides both control signals and inductively
coupled power to an implanted pulse generator.
[0060] Electrical leads 18 and 20 are flexible and include one or
more internal conductors that are electrically insulated from body
tissues and terminated with respective electrodes 24 and 26 at the
distal ends of the respective leads. The leads may be surgically or
percutaneously tunneled to stimulation sites on stomach 22. The
proximal ends of leads 18 and 20 are electrically coupled to the
pulse generator of stimulator 12 via internal conductors to conduct
the stimulation pulses to stomach 22 via electrodes 24, 26.
[0061] Leads 18, 20 may be placed into the muscle layer or layers
of stomach 22 via an open surgical procedure, or by laparoscopic
surgery. Leads also may be placed in the mucosa or submucosa by
endoscopic techniques or by an open surgical procedure. Electrodes
24, 26 may form a bipolar pair of electrodes. Alternatively,
stimulator 12 may carry a reference electrode to form an "active
can" arrangement, in which one or both of electrodes 24, 26 are
unipolar electrodes referenced to the electrode on the pulse
generator. The housing of implantable stimulator 12 may itself
serve as a reference electrode. A variety of polarities and
electrode arrangements may be used. Each lead 18, 20 may carry a
single electrode or an array of electrodes, permitting selection of
different electrode combinations and polarities among the leads for
delivery of stimulation.
[0062] In addition to pulse width, as discussed above, the
stimulation pulses delivered by implantable stimulator 12 are
characterized by other stimulation parameters such as a voltage or
current amplitude and pulse rate. Pulse width and the other
stimulation parameters may be fixed, adjusted in response to sensed
physiological conditions within or near stomach 22, or adjusted in
response to patient or physician input entered via external module
14. For example, in some examples, patient 16 may be permitted to
adjust stimulation amplitude, pulse width, or pulse rate and turn
stimulation on and off via external module 14.
[0063] External module 14 transmits instructions to stimulator 12
via wireless telemetry. Accordingly, stimulator 12 includes
telemetry electronics to communicate with external module 14.
External module 14 may be a small, battery-powered, portable device
that accompanies patient 16 throughout a daily routine. External
module 14 may have a simple user interface, such as a button or
keypad, and a display or lights. External module 14 may be a
hand-held device configured to permit activation of stimulation and
adjustment of stimulation parameters.
[0064] Alternatively, external module 14 may form part of a larger
device including a more complete set of programming features
including complete parameter modifications, firmware upgrades, data
recovery, or battery recharging in the event stimulator 12 includes
a rechargeable battery. External module 14 may be a patient
programmer, a physician programmer, or a patient monitor. In some
examples, external module 14 may be a general purpose device such
as a cellular telephone, a wristwatch, a personal digital assistant
(PDA), or a pager.
[0065] In some examples, system 10 may include multiple implantable
stimulators 12 or multiple leads 18, 20 to stimulate a variety of
regions of stomach 22. Stimulation delivered by the multiple
stimulators may be coordinated in a synchronized manner, or
performed without communication between stimulators. Also, the
electrodes may be located in a variety of sites on the stomach, or
elsewhere in the gastrointestinal tract, dependent on the
particular therapy or the condition of patient 12.
[0066] Electrodes 24, 26 carried at the distal ends of lead 18, 20,
respectively, may be attached to the wall of stomach 22 in a
variety of ways. For example, the electrode may be formed as a
gastric electrode that is surgically sutured onto the outer wall of
stomach 22 or fixed by penetration of anchoring devices, such as
hooks, barbs or helical structures, within the tissue of stomach
22. Also, surgical adhesives may be used to attach the electrodes.
In some cases, the electrodes 24, 26 may be placed in the lesser
curvature 23 on the serosal surface of stomach 22, within the
muscle wall of the stomach, or within the mucosal or submucosal
region of the stomach. For example, electrodes 24, 26 may be placed
in lesser curvature 23 approximately 1 centimeter (cm) to
approximately 5 cm from the pylorus. Alternatively, or
additionally, electrodes 24, 26 may be placed in the greater
curvature of stomach 22 such that stimulation is delivered to the
greater curvature. For example, electrodes 24, 26 may be placed in
the greater curvature approximately 1 centimeter (cm) to
approximately 5 cm from the pylorus.
[0067] In some examples, system 10 may include multiple implantable
stimulators 12 to stimulate a variety of regions of stomach 22 or a
variety of different regions in the gastrointestinal tract.
Stimulation delivered by the multiple stimulators may be
coordinated in a synchronized manner, or performed independently
without communication between stimulators. As an example, one
stimulator may control other stimulators by wireless telemetry, all
stimulators may be controlled by external module 14, or the
stimulators may act autonomously subject to parameter adjustment or
download by external module 14.
[0068] FIG. 2 is a block diagram illustrating implantable
stimulator 12 in greater detail in accordance with an example of
the invention. In the example of FIG. 2, stimulator 12 includes
pulse generator 28, processor 30, memory 32, wireless telemetry
interface 34 and power source 36. In some examples, stimulator 12
may generally conform to the Medtronic Itrel 3 Neurostimulator,
manufactured and marketed by Medtronic, Inc., of Minneapolis, Minn.
However, the structure, design, and functionality of stimulator 12
may be subject to wide variation without departing from the scope
of the invention as broadly embodied and described in this
disclosure.
[0069] Processor 30 controls pulse generator 28 by setting and
adjusting stimulation parameters such as pulse amplitude, pulse
rate, pulse width and duty cycle. Processor 30 may be responsive to
parameter adjustments or parameter sets received from external
module 14 via telemetry interface 34. Hence, external module 14 may
program stimulator 12 with different sets of operating parameters.
In some examples, pulse generator 28 may include a switch matrix.
Processor 30 may control the switch matrix to selectively deliver
stimulation pulses from pulse generator 28 to different electrodes
38 carried by one or more leads 18, 20. In some examples,
stimulator 12 may deliver different stimulation programs to patient
16 on a time-interleaved basis with one another.
[0070] Memory 32 stores instructions for execution by processor 30,
including operational commands and programmable parameter settings.
Memory 32 may include one or more memory modules constructed, e.g.,
as random access memory (RAM), read-only memory (ROM), non-volatile
random access memory (NVRAM), electrically erasable programmable
read-only memory (EEPROM), and/or FLASH memory. Processor 30 may
access memory 32 to retrieve instructions for control of pulse
generator 28 and telemetry interface 34, and may store information
in memory 32, such as operational information.
[0071] Wireless telemetry in stimulator 12 may be accomplished by
radio frequency (RF) communication or proximal inductive
interaction of implantable stimulator 12 with external module 14
via telemetry interface 34. Processor 30 controls telemetry
interface 34 to exchange information with external module 14.
Processor 30 may transmit operational information and receive
stimulation parameter adjustments or parameter sets via telemetry
interface 34. Also, in some examples, stimulator 12 may communicate
with other implanted devices, such as stimulators or sensors, via
telemetry interface 34.
[0072] Power source 36 delivers operating power to the components
of implantable stimulator 12. Power source 36 may include a battery
and a power generation circuit to produce the operating power. In
some examples, the battery may be rechargeable to allow extended
operation. Recharging may be accomplished through proximal
inductive interaction between an external charger and an inductive
charging coil within implantable stimulator 12. In other examples,
an external inductive power supply may transcutaneously power
implantable stimulator 12 whenever stimulation therapy is to
occur.
[0073] Implantable stimulator 12 is coupled to electrodes 38, which
may correspond to electrodes 24 and 26 illustrated in FIG. 1, via
one or more leads 18, 20. Implantable stimulator 12 provides
stimulation therapy to the gastrointestinal tract of patient 16.
Pulse generator 28 includes suitable pulse generation circuitry for
generating a voltage or current waveform with a selected amplitude,
pulse width, pulse rate, and duty cycle. In general, as described
in this disclosure, the stimulation pulses generated by pulse
generator 28 are formulated with pulse widths suitable to cause
substantial gastric distention without excessive consumption of
power provided by power source 36.
[0074] FIG. 3A is a graph illustrating gastric distention response
to electrical stimulation therapy with different pulse widths. In
FIG. 3A, the vertical axis represents the amount of gastric
distention caused by different sets of stimulation pulse parameters
in terms of preprandial (i.e., pre-meal) gastric volume in cubic
centimeters (cc). The horizontal axis shows application of
different stimulation parameter sets with substantially constant
amplitude, pulse rate and duty cycle values, but varying pulse
width values.
[0075] The results shown in FIG. 3A are from a canine study. To
measure gastric distention, a gastric cannula with an attached
balloon was placed in the proximal stomach via a percutaneous
gastric port, approximately 10 centimeters (cm) proximal to the
pylorus. The balloon was coupled to a barostat to measure gastric
distention, e.g., as described in Yong Lei et al., Effects and
Mechanisms of Implantable Gastric Stimulation on Gastric Distention
in Conscious Dogs, Obesity Surgery, 15, pages 528-533, 2005.
[0076] With stimulation OFF, the baseline preprandial gastric
volume was approximately 95 cc. In the graph, MDP refers to minimum
distending pressure, which is the pressure just above the native
abdominal pressure. With stimulation ON, gastric distention induced
by electrical stimulation resulted in a gastric volume of
approximately 120 cc upon application of stimulation pulses with a
pulse amplitude of 5 milliamps (mA), pulse width of 0.21
milliseconds (210 microseconds), pulse rate of 40 Hz, and a duty
cycle of 2 seconds ON and 3 seconds OFF (i.e., duty cycle of 40% ON
and 60% OFF).
[0077] Gastric distention induced by electrical stimulation
resulted in an increased gastric volume of approximately 110 cc
upon application of stimulation pulses with a pulse amplitude of 5
milliamps (mA), pulse width of 0.45 milliseconds (450
microseconds), pulse rate of 40 Hz, and a duty cycle of 2 seconds
ON and 3 seconds OFF (i.e., duty cycle of 40% ON and 60% OFF).
Gastric distention induced by electrical stimulation resulted in an
increased gastric volume of approximately 80 cc upon application of
stimulation pulses with a pulse amplitude of 5 milliamps (mA),
pulse width of 1.0 milliseconds, pulse rate of 40 Hz, and a duty
cycle of 2 seconds ON and 3 seconds OFF (i.e., duty cycle of 40% ON
and 60% OFF).
[0078] Notably, for a pulse width of 2 milliseconds, with a pulse
amplitude of 5 milliamps (mA), pulse rate of 40 Hz, and a duty
cycle of 2 seconds ON and 3 seconds OFF (i.e., duty cycle of 40% ON
and 60% OFF), the gastric distention induced by electrical
stimulation resulted in an increased gastric volume of
approximately 180 cc. The approximate 180 cc volume caused by the 2
ms pulse width resulted in an increase in gastric volume of almost
100% relative to the baseline gastric volume of approximately 95
cc. Accordingly, as shown in FIG. 3A, assuming common amplitudes,
pulse rates and duty cycles, different pulse widths appear to have
different impacts on the degree of gastric stimulation induced by
electrical stimulation. In particular, to achieve more substantial
gastric distention, it is desirable to increase the pulse width to
a value greater than or equal to 1 millisecond (ms). More
particularly, a more substantial degree of gastric distention was
observed with a pulse width of 2 ms.
[0079] To avoid excessive power consumption, however, it is
generally undesirable to apply stimulation pulses with very large
pulse widths. Therefore, in accordance with an example of the
invention, stimulator 12 may be configured, programmed, or
otherwise constructed to deliver stimulation pulses with pulse
widths selected to cause substantial gastric distention without
consuming excessive amounts of power. As an example, the
stimulation pulses delivered by stimulator 12 may have a pulse
width greater than or equal to approximately 2 milliseconds. In
other examples, an electrical stimulator delivers stimulation
pulses with a pulse width in a range of approximately 2
milliseconds to approximately 10 milliseconds. In further examples,
the pulse width is in a range of approximately 2 milliseconds to 5
milliseconds.
[0080] Although higher pulse widths, e.g., 300 milliseconds, may
cause as much or even more distention than pulse widths in the
ranges described in this disclosure, the resulting power
consumption is excessive, undermining device longevity due to the
need for premature battery replacement. In addition, larger pulse
widths may be more difficult to produce using existing electrical
stimulation devices. Instead, larger pulse widths may require
substantial redesign of pulse generator circuitry, which is
generally undesirable. Further, larger pulse widths may cause
undesirable adverse effects in patient 16 that prevent the overall
therapy from being efficacious. Possible adverse effects may
include tremors, nausea, vomiting, and/or other gastrointestinal
changes. Various examples of the invention may provide a balance
between therapeutic efficacy, power consumption, and pulse
generator complexity.
[0081] Stimulator 12 may be configured to operate in either a
voltage control mode or a current control mode. In a current
control mode, a substantially constant current amplitude may be
maintained for the pulses. For example, a constant current
amplitude of approximately 5 mA is described in some of the
examples in this disclosure. In a voltage control mode, a
substantially constant voltage amplitude may be maintained for the
pulses. For example, an appropriate voltage corresponding to
approximately 5 mA can be determined by measuring the impedance of
the leads and electrodes, and computing the voltage as
voltage=current.times.impedance. Hence, stimulator 12 may deliver
constant current or constant voltage stimulation pulses. As further
illustration, example stimulation may be delivered over a 500 ohm
impedance in patient 16. In this example, one example may include a
voltage range between 0.5 Volts (V) and 10V. In another example,
the voltage range may be between 1V and 5V. In an additional
example, the voltage range may be between 1.5V and 3V. These
voltage ranges may be applicable to constant current amplitude
examples or constant voltage examples.
[0082] Gastric stimulation has been shown to invoke a gastric
distention response. Short pulse width (PW) stimulation results in
a modest gastric distention response (GDR), while very wide pulse
width stimulation results in maximal gastric distention response,
but excessive power consumption. It is presumed that the GDR/PW
curve has a sigmoid shape, which may allow for determination of the
lowest power settings to invoke a desired GDR response.
[0083] In some examples, pulses may be delivered in bursts of
pulses during the ON portion of the duty cycle. The pulse train may
be delivered in a variety of different modes, such as a continuous
mode, an asynchronous burst mode, or a synchronous burst mode. In a
continuous mode, the pulse train is delivered relatively
continuously over an active period in which stimulation is "ON." In
an asynchronous burst mode, the pulse train is delivered in
periodic bursts during the active period. The continuous mode and
asynchronous burst mode may be considered open loop in the sense
that they do not rely on synchronization with sensed events.
[0084] In a synchronous burst mode, the pulse train is delivered in
bursts that are synchronized with a sensed event, such as a sensed
physiological condition such as gastric contraction. In this sense,
the synchronous burst mode may be viewed as a closed loop approach.
For example, leads 18, 20 or different leads may carry one or more
sensors, such as sense electrodes, piezoelectric electrodes, strain
gauge sensors, accelerometers, pressure sensors, ultrasonic sensors
or the like. Such sensors may sense physiological one or more
conditions, such as gastric contractions, gastric nerve potentials,
or gastric pressure, that indicate the intake of food. In response,
stimulator 12 may activate stimulation to cause gastric distention
and thereby discourage the intake of excessive amounts of food.
Sensing may occur continuously, periodically, or intermittently, as
therapy dictates. Information relating to the sensed conditions may
be stored in memory within stimulator 12 or external module 14 for
retrieval and analysis at a later time.
[0085] The active period for delivery of stimulation pulses each
mode may be full-time, part-time, or subject to patient control.
The active period is different from a duty cycle. The duty cycle
applies during an active period, and represents the time that the
stimulation is ON versus the time the stimulation is OFF during the
active period. During an inactive period, no stimulation is
delivered. For part-time activation, the stimulation may be
activated for selected parts of the day. The selected parts of the
day may coincide with meal times, physical activity times, sleep
times, or other selected times, and be controlled using a clock
within stimulator 12 or external module 14.
[0086] Additionally, or alternatively, patient 16 may control
stimulator 12 via external module 16 to activate delivery of
stimulation pulses, e.g., when the patient 16 intends to ingest a
meal. Also, in some examples, patient 16 may be permitted to adjust
one or more stimulation parameters such as amplitude, pulse width,
pulse rate, or duty cycle, and turn stimulation on and off. In
other cases, if the patient lacks sufficient discipline or capacity
to effectively activate and adjust stimulation, stimulator 12 may
operate without substantial patient intervention.
[0087] FIG. 3B is another graph illustrating gastric distention
response to electrical stimulation therapy with different pulse
widths, pulse amplitudes, and stimulation duty cycles. In FIG. 3B,
the vertical axis represents change in preprandial (i.e., pre-meal)
gastric volume caused by different sets of stimulation pulse
parameters in terms of gastric volume in milliliters. The
horizontal axis represents the width of the stimulation pulse in
milliseconds (ms). With stimulation ON, gastric distention induced
by electrical stimulation resulted in a gastric volume of
approximately 61 milliliters upon application of stimulation pulses
with a pulse amplitude of 5 milliamps (mA), pulse width of 0.21
milliseconds (210 microseconds), and a duty cycle of 2 seconds ON
and 3 seconds OFF (i.e., duty cycle of 40% ON and 60% OFF).
Changing only the pulse width of the stimulation to 0.45
milliseconds resulted in a gastric volume of approximately 50
milliliters. Changing only the pulse width of the stimulation to
1.0 millisecond resulted in a gastric volume of approximately 54
milliliters. Changing only the pulse width of the stimulation to
2.0 milliseconds resulted in a gastric volume of approximately 107
milliliters. Changing only the pulse width of the stimulation to
4.0 milliseconds resulted in a gastric volume of approximately 166
milliliters.
[0088] Referring still to FIG. 3B, gastric distention induced by
electrical stimulation resulted in a gastric volume of
approximately 194 milliliters upon application of stimulation
pulses with a pulse amplitude of 6 milliamps (mA), pulse width of
4.0 milliseconds, and a duty cycle of 2 seconds ON and 2 seconds
OFF (i.e., duty cycle of 50% ON and 50% OFF). Notably, gastric
distention induced by electrical stimulation resulted in a gastric
volume of approximately 232 milliliters upon application of
stimulation pulses with a pulse amplitude of 6 mA, pulse width of
4.0 milliseconds, and a continuous duty cycle (i.e., 100% ON and 0%
OFF).
[0089] FIG. 4 is a flow diagram illustrating a method for
delivering electrical stimulation having a pulse width selected to
cause substantial gastric distention. As shown in FIG. 4, the
method may include generating electrical stimulation pulses with
pulse widths selected to cause gastric distention (40). As
described in this disclosure, the stimulation pulses may have a
pulse width greater than or equal to approximately 2 milliseconds.
In other examples, an electrical stimulator delivers stimulation
pulses with a pulse width in a range of approximately 2
milliseconds to approximately 10 milliseconds, more preferably
approximately 2 milliseconds to 5 milliseconds. The method may
further include applying the stimulation pulses to the
gastrointestinal tract to cause gastric distention (42), e.g., via
one or more electrodes carried by one or more implantable leads.
The electrical stimulation pulses may be applied to the stomach, or
to other areas within the gastrointestinal tract, such as the
esophagus, duodenum, small intestine, or large intestine.
[0090] Gastric distention may generally refer to as an increase in
gastric volume or a relaxation in gastric muscle tone. Hence, a
volumetric change associated with gastric distention may be
indicative of a state or relaxation of gastric muscle tone. In
general, in accordance with this disclosure, gastric distention,
increase in gastric volume and relaxation of gastric muscle tone
may be used interchangeably to generally refer to a relative state
of contraction or relaxation of the stomach muscle.
[0091] The state of contraction or relaxation of the stomach muscle
may be evaluated using a device called a balloon barostat. The
Distender Series II.TM., manufactured by G&J Electronics, Inc.,
Toronto, Ontario, Canada, is an example of a balloon barostat
system that may be used to diagnose certain gastric motility
disorders. Using this system, a balloon is inserted into the
stomach, and inflated to a pressure just above the abdominal
pressure, referred to the minimum distending pressure. The barostat
is configured so that the pressure in the balloon is maintained at
a constant pressure. If the state of contraction of stomach muscle
decreases, i.e., the state of relaxation of the stomach muscle
increases, then the balloon volume will increase. A decrease in the
state of stomach muscle contraction, if measured under conditions
of constant balloon pressure, indicates a change in gastric muscle
tone, i.e., gastric muscle relaxation, and is sometimes referred to
as a change in gastric distention, gastric volume, or gastric tone.
More particularly, a decrease in muscle contraction corresponds to
an increase in muscle relaxation and promotes distention in terms
of an increase in gastric volume using balloon barostat
evaluation.
[0092] FIG. 5A is a graph illustrating an example waveform for
treating obesity in accordance with the disclosure. Rather than use
a long pulse to provide electrical stimulation, a short pulse burst
may be used to approximate or simulate a long pulse, as in FIG. 5A.
A long pulse, low frequency gastric electrical stimulation (GES)
paradigm effectively modulates gastric smooth muscle activity,
while a short pulse, high frequency GES paradigm may act primarily
through vagal afferent pathways. A combination of these GES
paradigms, given their distinct effects, has larger effects on
gastric tone than either alone.
[0093] For reference, a long pulse may be characterized as having a
pulse width greater than approximately 100 milliseconds and less
than approximately 600 milliseconds, and a short pulse may be
characterized as having a pulse width greater than approximately 2
milliseconds and less than approximately 20 milliseconds.
Additionally, a low frequency may be characterized as having a
pulse rate in a range between approximately 0.1 hertz (Hz) and
approximately 1 Hz, and a high frequency may be characterized as
having a pulse rate of greater than approximately 2 Hz and less
than approximately 200 Hz.
[0094] In FIG. 5A, one example of a short pulse burst used to
approximate a long pulse is depicted. The y-axis of FIG. 5A
represents the pulse voltage amplitude of the waveform comprising a
plurality of pulse bursts in volts and the x-axis represents time
in seconds. A plurality of pulse bursts 100 is shown including 3
pulse bursts 110, 120, 130, each having a pulse voltage amplitude
of approximately 6 volts. In FIG. 5A, pulse bursts 110, 120, 130
are separated by approximately 4 seconds, and begin at
approximately 1 second, 5 seconds, and 9 seconds, respectively,
from the start of a sequence. Each pulse burst 110, 120, 130 may be
used to approximate a 300 millisecond ("long") pulse having a pulse
rate of approximately 0.25 Hz.
[0095] It should be noted that that the waveform depicted in FIG.
5A is charged balanced. Charge balance may generally refer to the
property of the net charge of two or more stimulation pulses being
approximately equal to zero. For example, when a pair of single
phase pulses having opposite polarity are substantially charged
balanced, the charge of the first pulse substantially offsets the
charge of the second pulse such that the net charge of the pulses
is substantially zero. Graphically, in terms of two pulses having
opposite polarity, charge balance implies that the net area under
the amplitude vs. time curve is zero. In general, charge balance
may be desirable for limiting electrochemical reactions on the
surface of the stimulation electrodes that can cause corrosion of
the electrodes, formation of noxious compounds at the stimulation
site, and transfer of electrode material into the surrounding
tissue. As seen in FIG. 5A, pulse trains 110, 120, and 130 are
charge balanced because the area defined by each of pulse trains
110, 120, and 130 is equal to the area below 0 volts between each
of pulse trains 110, 120, and 130.
[0096] Gastric electrical stimulation (GES) may refer to
stimulation of the stomach, as well as stimulation of other regions
within the gastrointestinal tract (e.g., small intestine).
[0097] FIG. 5B is a graph depicting a short pulse burst (e.g., 110,
120, 130) of FIG. 5A in greater detail. The y-axis of FIG. 5B
represents the pulse voltage amplitude of the pulse burst in volts
and the x-axis represents time in milliseconds. In FIG. 5B, thirty
pulses (forming, for example one of short pulse bursts 110, 120,
130 of FIG. 5A) having a pulse width of approximately 10
milliseconds, a pulse voltage amplitude of approximately 6 volts,
and a 2 millisecond interpulse interval between pulses, are
depicted. The pulse burst begins at approximately 75 milliseconds
and ends at approximately 430 milliseconds.
[0098] Waveform 100 shown in FIG. 5A is just one example of a
plurality of pulse bursts that may be used to promote gastric
distention in accordance with the disclosure. As will be described
in more detail below, parameters of the pulse bursts and waveform
may be varied within certain operating ranges to produce desirable
effects.
[0099] Short pulses bursts used to approximate or simulate a long
pulse may have larger effects on gastric tone than either short
pulses or long pulses alone. In a canine study, the effect of long
pulse, low frequency stimulation was compared to the effect of
short pulse burst approximation of long pulse stimulation and very
short pulse burst approximation of long pulse stimulation. A very
short pulse burst is a subset of a short pulse burst. The combined
treatments described below are hybrids of long pulse, low frequency
GES and short pulse, high frequency GES in which long pulses (e.g.
a stimulation pulse having a pulse width of about 400 milliseconds)
are approximated by isoenergetic short pulse bursts.
[0100] Platinum-iridium wire electrodes were implanted in the
gastric antrum of 10 canine subjects. A gastric cannula was also
implanted for balloon barostat measurements of gastric distension.
Percutaneous lead wires and an external pulse generator were used
to deliver 3 isoenergetic (600 .mu.C/s) variants of GES: a long
pulse setting having a pulse width of 400 milliseconds and a pulse
rate of 0.25 Hz; a short pulse burst setting having a pulse width
of 10 milliseconds, a pulse rate of 83 Hz, and a duty cycle of 0.48
seconds ON and 3.52 seconds OFF that replaced each long pulse of
400 milliseconds with a train of forty 10-millisecond pulse bursts;
and, a very short pulse burst setting having a pulse width of 1
millisecond, a pulse rate of 500 Hz, and a duty cycle of 0.8
seconds ON and 3.2 seconds OFF that replaced each long pulse of 400
milliseconds with a train of four-hundred 1-millisecond pulses. The
pulse current amplitude was generated by a constant current source
and fixed at 6 milliamps (mA) for long pulses, short pulse bursts,
and very short pulse bursts. The pulse voltage amplitude was
approximately 6 volts.
[0101] Results of the study are shown graphically in FIGS. 6 and 7.
In FIG. 6, the mean change in balloon volume, as an indication of
amount of distension, is depicted for each of the 3 isoenergetic
variants of GES described above, during both stimulation and
recovery in lean canines. From left to right during the stimulation
portion as well as the recovery portion, the change in balloon
volume is depicted for the very short pulse burst setting, the long
pulse setting, and the short pulse burst setting. As seen in FIG.
6, the change in balloon volume is greater after application of the
short pulse burst setting than either the long pulse or very short
pulse burst settings.
[0102] FIG. 7 graphically compares the balloon volumes resulting
from the application of the 3 isoenergetic variants of GES
described above, beginning from a pre-GES baseline, and continuing
through GES and recovery in lean canines. In FIG. 7, the y axis
represents the balloon volume in milliliters and the x-axis
represents time in minutes. Relative to pre-GES baseline levels,
gastric distention induced by electrical stimulation caused volume
increases by approximately 108 ml upon application of stimulation
pulses with a pulse width of 400 milliseconds and a pulse rate of
0.25 Hz. Relative to pre-GES baseline levels, gastric distention
induced by electrical stimulation increased by approximately 78 ml
under application of stimulation pulses that approximated each long
pulse of 400 milliseconds with a train of 400 1 millisecond pulses,
each of the 400 pulses having a pulse width of 1 millisecond, a
pulse rate of 500 Hz, and a duty cycle of 0.8 seconds ON and 3.2
seconds OFF.
[0103] Notably, under application of stimulation pulses that
approximated each long pulse of 400 milliseconds with forty 10
millisecond pulses, each of the 40 pulses having a pulse width of
approximately 10 milliseconds, a pulse rate of 83 Hz, and a duty
cycle of 0.48 seconds ON and 3.52 seconds OFF, gastric distention
induced by electrical stimulation increased by approximately 285 ml
relative to pre-GES baseline levels. The approximate 285 ml volume
increase caused by a series of pulse bursts, where each pulse burst
consisted of 40 pulses having a pulse width of 10 milliseconds to
approximate a 400 ms pulse width, resulted in a gastric distention
response more than 2.5 times larger than that achieved by applying
stimulation pulses with an actual pulse width of 400 milliseconds
and a pulse rate of 0.25 Hz. The train of 400 1 millisecond pulses,
with each of the 400 pulses having a pulse width of 1 millisecond,
a pulse rate of 500 Hz, and a duty cycle of 0.8 seconds ON and 3.2
seconds OFF, was significantly less effective than either the
stimulation pulses with an actual pulse width of 400 milliseconds
and a pulse rate of 0.25 Hz or the train of forty 10 millisecond
pulses to approximate a 400 millisecond pulse rate, each of the 40
pulses having a pulse width of 10 milliseconds. Thus, a hybrid
version of GES that combines elements of long pulse-low frequency
and short pulse-high frequency stimulation paradigms may be more
effective than long pulse GES in inducing gastric distension.
Combining GES modalities that alter acute gastrointestinal (GI)
function via differing pathways may be one means for improving the
efficacy of GES as a treatment for obesity or gastroparesis.
[0104] Of course, the specific example described above with respect
to the canine study is only one example of an electrical
stimulation waveform using a plurality of short pulse bursts, with
each short pulse burst approximating a long pulse, for treating
obesity. The stimulation waveform and the pulse bursts are not
limited to the specific parameters described above. Rather,
implantable stimulator 12 is configured to deliver stimulation
pulses using stimulation parameters within certain operating
ranges.
[0105] In some examples, for example, stimulator 12 may be
configured to deliver stimulation pulses with interpulse intervals
in a range of approximately 200 microseconds to approximately 2
milliseconds, and more preferably approximately 500 microseconds to
approximately 2 milliseconds. In some examples, stimulator 12
delivers stimulation pulses at a frequency such that the interpulse
intervals are less than 2 milliseconds. In each case, the
interpulse interval generally refers to the time between successive
pulses, e.g., the time between the fall of one pulse and the rise
of the next pulse.
[0106] In some examples, stimulator 12 delivers stimulation pulses
with pulse widths within a range of approximately 2 milliseconds to
approximately 20 milliseconds. In other examples, the pulse width
is in a range of approximately 2 milliseconds to approximately 10
milliseconds. And in further examples, the pulse width is in a
range of approximately 2 milliseconds to approximately 5
milliseconds.
[0107] In one example, stimulator 12 delivers stimulation pulses
with a pulse current amplitude in a range between approximately
less than 1 milliamp and approximately 20 milliamps. In other
examples, the pulse current amplitude is in a range between
approximately 1 milliamps and approximately 15 milliamps. In
further examples, the pulse current amplitude is in a range between
approximately 5 milliamps and approximately 9 milliamps.
[0108] In some examples, stimulator 12 delivers stimulation pulses
with a pulse voltage amplitude in a range between approximately 3
volts and approximately 12 volts. In other examples, the pulse
voltage amplitude is in a range between approximately 4 volts and
approximately 10 volts. In further examples, the pulse voltage
amplitude is in a range between approximately 5 volts and
approximately 8 volts.
[0109] In one example, stimulator 12 delivers stimulation pulses at
a pulse rate such that the interpulse interval is in a range of
approximately 200 microseconds to approximately 2 milliseconds. The
interpulse interval is the time from the trailing edge of one pulse
to the leading edge of the next pulse. The frequency is the inverse
of the period, which is the sum of the pulse width and the
interpulse interval. Because the period is the time from the
leading edge of one pulse to the leading edge of the next, it
includes the pulse width and the interpulse interval. By way of
example, for pulses with a 2 millisecond pulse width and a 2
millisecond interpulse interval, the period is 4 milliseconds and
the frequency is 1/(4 milliseconds), or about 250 Hz. In other
examples, the frequency range of pulses may be between
approximately 2 Hz and approximately 90 Hz. In other examples, the
frequency range may be between approximately 2 Hz and approximately
40 Hz. In some examples, the frequency range may be between
approximately 5 Hz and approximately 25 Hz.
[0110] As mentioned above, a short pulse burst may be used to
approximate or emulate a long pulse. Because long pulses typically
have pulse widths greater than 100 milliseconds, e.g., between
approximately 100 milliseconds and approximately 600 milliseconds,
the short pulse burst approximation of the long pulse may also have
a duration of between approximately 100 milliseconds and
approximately 600 milliseconds. In some examples, stimulator 12
delivers short pulse burst approximations having a duration between
approximately 200 milliseconds and approximately 550 milliseconds.
In further examples, stimulator 12 delivers short pulse burst
approximations having a duration between approximately 300
milliseconds and approximately 500 milliseconds.
[0111] In some examples, a short pulse burst may be delivered as an
isoenergetic plurality of bursts in order to approximate the energy
delivered by a long pulse. As such, any duty cycle may be chosen
that results in a short pulse burst delivering approximately the
same energy as a long pulse. Thus, the duty cycle of the short
pulse width pulse burst may be chosen based on the long pulse that
is being approximated. In some examples, each short pulse burst has
a pulse rate of approximately 5 Hz to approximately 50 Hz.
[0112] FIG. 8A is a graph illustrating another example of an
electrical stimulation waveform for treating obesity in accordance
with the disclosure. Rather than using long pulses alone to provide
electrical stimulation, a pattern of a long pulse followed by a
short pulse burst followed by a long pulse followed by a short
pulse bursts, etc. may be used, as seen in FIG. 8A. In some
examples, the pattern may repeat. In this example, a short pulse
burst is delivered between successive long pulses. A long pulse,
low frequency GES paradigm effectively modulates gastric smooth
muscle activity, while a short pulse, high frequency GES appears to
act primarily through vagal afferent pathways. A combination of
these GES paradigms, given their distinct effects, may result in
greater food intake and acute gastrointestinal (GI) effects than
either modality alone.
[0113] A long pulse may be characterized as having a pulse width
greater than approximately 100 milliseconds and less than
approximately 600 milliseconds, and a short pulse may be
characterized as having a pulse width greater than approximately 1
millisecond and less than approximately 20 milliseconds. In some
examples, stimulator 12 delivers long pulses with each long pulse
having a pulse width in the range of approximately 100 milliseconds
to approximately 600 milliseconds. In other examples, the pulse
width is in a range of approximately 200 milliseconds to
approximately 550 milliseconds. In further examples, the pulse
width in the range of approximately 300 milliseconds to
approximately 500 milliseconds. In some examples, stimulator 12
delivers short stimulation pulses with pulse widths within a range
of approximately 2 milliseconds to approximately 20 milliseconds.
In other examples, the pulse width is in a range of approximately 2
milliseconds to approximately 10 milliseconds. And in further
examples, the pulse width is in a range of approximately 2
milliseconds to approximately 5 milliseconds.
[0114] Additionally, a low frequency may be characterized as having
a pulse rate in a range between approximately 0.1 Hz and
approximately 1 Hz, and a high frequency may be characterized as
having a pulse rate of greater than approximately 2 Hz and less
than approximately 200 Hz. In other examples, a low frequency pulse
rate is in a range of approximately 0.15 Hz to approximately 0.8
Hz. In further examples, a low frequency pulse rate is in a range
of approximately 0.2 Hz to approximately 0.4 Hz. In some examples,
the high frequency pulse rate is in a range of approximately 25 Hz
to approximately 100 Hz. In other examples, the high frequency
pulse rate is in a range of approximately 30 Hz to approximately 90
Hz.
[0115] In one example, the short pulse burst is delivered between a
range of approximately 1 second and approximately 20 seconds. In
other examples, the short pulse burst is delivered between a range
of approximately 5 seconds and approximately 15 seconds. In some
examples, the short pulse bursts is delivered between a range of
approximately 10 seconds and approximately 12 seconds.
[0116] In FIG. 8A, the y-axis represents the pulse voltage
amplitude of the pulse train in volts and the x-axis represents
time in seconds. Electrical stimulation waveform 200 includes long
pulses 210, 220, 230, each with a pulse width of approximately 300
milliseconds, a pulse voltage amplitude of approximately 6 volts,
and long pulses being separated by approximately 4 seconds.
Electrical stimulation waveform 200 further includes short pulse
bursts 240, 250, each having a pulse voltage amplitude of
approximately 6 volts, following long pulses 210, 220,
respectively. Short pulse burst 240 begins at approximately 2.6
seconds and short pulse burst 250 begins at approximately 6.6
seconds. Each pulse burst 240, 250 may have a pulse width of
approximately 4 milliseconds, a pulse rate of approximately 40 Hz,
and a duty cycle of approximately 2 seconds ON and 2 seconds
OFF.
[0117] FIG. 8B depicts the pulses that form short pulse burst 240,
250 of FIG. 8A in more detail. The y-axis represents the pulse
voltage amplitude of the pulse burst in volts and the x-axis
represents time in milliseconds. In FIG. 8B, 4 pulses 260, 270,
280, 290 are depicted with each pulse having a pulse width of
approximately 4 milliseconds, an interpulse interval of
approximately 20 milliseconds, and a pulse voltage amplitude of
approximately 6 volts.
[0118] Electrical stimulation waveform 200 shown in FIG. 8A is just
one example of a waveform including a plurality of pulse bursts
between long pulses that may be used to promote gastric distention
in accordance with the disclosure. As will be described in more
detail below, parameters of the stimulation pulses and pulse bursts
may be varied within certain operating ranges to produce desirable
effects.
[0119] As mentioned above, a combination of long pulse, low
frequency GES and short pulse, high frequency GES paradigms may
have greater food intake and acute gastrointestinal (GI) effects
than either modality alone. In a canine study, the effect of long
pulse, low frequency stimulation was compared to the effect of
short pulse, high frequency pulse trains alone, and the combination
of long pulse, low frequency and short pulse, high frequency pulse
trains. Platinum-iridium wire electrodes were implanted in the
gastric antrum of 10 canine subjects. A gastric cannula was also
implanted for balloon barostat measurements of GD and monitoring of
antral motility (AM) via manometric catheter. Percutaneous lead
wires and an external pulse generator were used to deliver 3
variants of GES: a long pulse setting having a pulse width of 400
milliseconds and a pulse rate of 0.25 Hz; a short pulse burst
setting with each pulse of the pulse burst having a pulse width of
4 milliseconds, a pulse rate of 40 Hz, and a duty cycle of 2
seconds ON and 2 seconds OFF; and a combination setting that
combines a long pulse setting and a short pulse burst setting,
having a long pulse with pulse width of 400 milliseconds and a
pulse rate of 0.25 Hz and a short pulse burst with each pulse of
the pulse burst having a pulse width of 4 milliseconds, a pulse
rate of 40 Hz, and a duty cycle of 2 seconds ON and 2 seconds OFF,
with long pulses centered between short pulse trains. Gastric
distention was measured under all 3 settings while AM and food
intake were measured under the long pulse and combination settings.
Pulse amplitude was fixed at 6 mA in the gastric distention and
food intake studies, and at 8 mA during AM testing.
[0120] Results of the study are shown graphically in FIGS. 9 and
10. In FIG. 9, the mean change in balloon volume is depicted for
each of the 3 isoenergetic variants of GES described above, during
both stimulation and recovery after stimulation in lean canines.
From left to right during the stimulation portion as well as the
recovery portion, the change in balloon volume is depicted for the
long pulse setting, the short pulse burst setting, and the
combination of long and short pulse burst setting. As seen in FIG.
9, the mean change in balloon volume is greater after application
of the combination setting than either the long pulse setting or
the short pulse burst settings.
[0121] FIG. 10 compares the balloon volumes resulting from the
application of the 3 isoenergetic variants of GES described above,
beginning from a pre-GES baseline, and continuing through GES and
recovery in lean canines. In FIG. 10, the y axis represents the
balloon volume in milliliters and the x-axis represents time in
minutes. Relative to pre-GES baseline levels, gastric distention
induced by electrical stimulation increased by approximately 108 ml
upon application of stimulation pulses with a pulse width of 400
milliseconds and a pulse rate of 0.25 Hz. Relative to pre-GES
baseline levels, gastric distention induced by electrical
stimulation increased by approximately 195 ml upon application of
stimulation pulses with a pulse width of 4 milliseconds, a pulse
rate of 40 Hz, and a duty cycle of 2 seconds ON and 2 seconds
OFF.
[0122] Notably, under application of the combination setting
stimulation pulses having a long pulse with a pulse width of 400
milliseconds and a pulse rate of 0.25 Hz and a short pulse burst
with each pulse of the pulse burst having a pulse width of 4
milliseconds, a pulse rate of 40 Hz, and a duty cycle of 2 seconds
ON and 2 seconds OFF, with long pulses centered between short pulse
bursts, gastric distention induced by electrical stimulation
increased by approximately 285 ml relative to pre-GES baseline
levels. In some examples, the long pulses are not centered between
short pulse bursts. Rather, the long pulses are offset between
short pulse bursts. In one example, there may be more time between
the trailing edge of a short pulse burst and the leading edge of a
long pulse than between the trailing edge of the long pulse and the
leading edge of the next short pulse burst. In another example,
there may be less time between the trailing edge of a short pulse
burst and the leading edge of a long pulse than between the
trailing edge of the long pulse and the leading edge of the next
short pulse burst.
[0123] FIG. 11 graphically compares the reduction in antral
pressure using a long pulse GES setting and the combination GES
setting during both application of GES and during recovery in lean
canines. As seen in FIG. 11, relative to stimulation pulses having
a pulse width of 400 milliseconds and a pulse rate of 0.25 Hz
alone, the combination setting produced a greater reduction in mean
postprandial antral pressure relative to pre-GES levels (12.5 mmHg
vs. 6.5 mmHg). During the recovery period, mean postprandial antral
pressure remained significantly higher for the combination
setting.
[0124] FIG. 12 graphically depicts the mean antral pressure as a
percentage of change from the baseline period mean over a period of
30 minutes, including the GES period and the recovery period in
lean canines. As seen in FIG. 12, the combination setting produced
a greater percentage change in mean antral pressure from the
baseline period mean than the long pulse GES setting.
[0125] FIG. 13 depicts the food intake in mean grams per day for
sham GES, the long pulse setting, and the combination pulse setting
in obese rats. The phrase "sham GES" indicates that alligator clip
wires were attached to external leads as though GES was to be
delivered, but GES was never activated. Again, in the study, a long
pulse setting refers to a pulse having a pulse width of 400
milliseconds and a pulse rate of 0.25 Hz. A short pulse burst
setting refers to a pulse burst with each pulse of the pulse burst
having a pulse width of 4 milliseconds, a pulse rate of 40 Hz, and
a duty cycle of 2 seconds ON and 2 seconds OFF. And, a combination
setting refers to the combination of a long pulse setting and a
short pulse burst setting, having a long pulse with pulse width of
400 milliseconds and a pulse rate of 0.25 Hz and a short pulse
burst with each pulse of the pulse burst having a pulse width of 4
milliseconds, a pulse rate of 40 Hz, and a duty cycle of 2 seconds
ON and 2 seconds OFF, with long pulses centered between short pulse
bursts. Relative to stimulation pulses having a pulse width of 400
milliseconds and a pulse rate of 0.25 Hz alone (long pulses), the
combination setting produced greater reduction in food intake (289
grams vs. 344 grams, or 29% vs. 16%) relative to sham-GES control
treatment (409 grams).
[0126] FIG. 14 graphically compares the mean food intake in grams
using sham GES, the long pulse setting, and the combination setting
over seven days in lean canines Treatment using the stimulation
pulses described above occurred from Tuesday through Friday,
followed by a washout period from Saturday through Monday. As seen
in FIG. 14, the combination setting resulted in a smaller food
intake than either the long pulse setting or the sham GES, with the
results of the combination setting remaining stable over the
treatment period. Interestingly, during the washout period, the
results of sham GES, the long pulse setting, and the combination
setting converge on Monday to the sham GES results that were seen
on Friday. The convergence may indicate a "wire effect" resulting
from the attachment of the wire leads to the subjects on
Monday.
[0127] When combined, long pulse GES and short pulse GES may act
additively to enhance acute GI and food intake responses to GES.
Combining GES modalities that alter feeding via differing pathways
such as vagal nerve afferent pathways and smooth muscle fiber
stimulation may be one method for improving the efficacy of GES as
an obesity treatment.
[0128] Of course, the specific example described above with respect
to the canine study is only one example of an electrical
stimulation waveform having a repeating pattern of a long pulse
followed by a short pulse burst followed by a long pulse followed
by a short pulse burst, etc. that may be used to treat obesity. The
stimulation waveform is not limited to the specific stimulation
parameters described above. Rather, implantable stimulator 12 is
configured to deliver stimulation pulses using stimulation
parameters within certain operating ranges.
[0129] In some examples, stimulator 12 delivers short pulses
(forming a short pulse burst) with each pulse having a pulse width
in a range of approximately 2 milliseconds to approximately 20
milliseconds. In other examples, the pulse width is in a range of
approximately 2 milliseconds to approximately 10 milliseconds. In
further examples, the pulse width is in a range of approximately 2
milliseconds to approximately 5 milliseconds.
[0130] In one example, stimulator 12 delivers short pulses at a
pulse rate in range of approximately 2 Hz to approximately 90 Hz.
In other examples, the pulse rate is in a range of approximately 2
Hz to approximately 40 Hz. In further examples, the pulse rate is
in a range of approximately 5 Hz to approximately 25 Hz.
[0131] In some examples, stimulator 12 delivers long pulses with
each long pulse having a pulse width in the range of approximately
100 milliseconds to approximately 600 milliseconds. In other
examples, the pulse width is in a range of approximately 200
milliseconds to approximately 550 milliseconds. In further
examples, the pulse width in the range of approximately 300
milliseconds to approximately 500 milliseconds.
[0132] In one example, stimulator 12 delivers long pulses at a
pulse rate in range of approximately 0.1 Hz to approximately 1 Hz.
In other examples, the pulse rate is in a range of approximately
0.15 Hz to approximately 0.8 Hz. In further examples, the pulse
rate is in a range of approximately 0.2 Hz to approximately 0.4
Hz.
[0133] In some examples, stimulator 12 delivers stimulation pulses
with a pulse current amplitude in a range between approximately
less than 1 milliamp and approximately 20 milliamps. In other
examples, the pulse current amplitude is in a range between
approximately 1 milliamp and approximately 15 milliamps. In further
examples, the pulse current amplitude is in a range between
approximately 5 milliamps and approximately 9 milliamps.
[0134] In other examples, stimulator 12 delivers stimulation pulses
with a pulse voltage amplitude in a range between approximately 3
volts and approximately 12 volts. In other examples, the pulse
voltage amplitude is in a range between approximately 4 volts and
approximately 10 volts. In further examples, the pulse voltage
amplitude is in a range between approximately 5 volts and
approximately 8 volts.
[0135] In one example, stimulator 12 delivers short pulse bursts
for a duration between approximately 0.5 seconds and approximately
20 seconds. In one example, the pulse burst is delivered between a
range of approximately 5 seconds and approximately 15 seconds. In
some examples, the short pulse burst is delivered between a range
of approximately 10 seconds and approximately 12 seconds. The
duration of the short pulse burst may be dependent upon the pulse
rate of the long pulses. That is, it may be desirable for
stimulator 12 to complete delivery of the short pulse burst before
delivering the next long pulse. In some examples, however, the
delivery of the short pulse burst and long pulses may overlap. For
example, separate electrode pairs may be used to deliver short
pulse bursts and long pulses, thereby allowing a long pulse to be
delivered while short pulse bursts are still being delivered, or
short pulse bursts to be delivered while a long pulse is still
being delivered.
[0136] In some examples, stimulator 12 delivers short pulse bursts
immediately following long pulses, with approximately zero delay
between long and short pulse bursts. Or, in other examples, there
may be a delay between a trailing edge of the long pulse and a
rising edge of the short pulse burst. The delay between the
trailing edge of the long pulse and the rising edge of the short
pulse burst is a function of the duty cycle of the short pulses.
The delay may be extended as long as necessary, so long as the
short pulse burst finishes before the next long pulse begins.
However, in some examples, the delivery of the short pulse bursts
and long pulses may overlap, as mentioned above. In some examples,
the short pulse bursts may be centered between the long pulses. In
other examples, however, the short pulse bursts may immediately
follow the long pulse with approximately zero delay. In further
examples, the long pulse may immediately follow the short pulse
burst with approximately zero delay.
[0137] In some examples, the interval between the trailing edge of
the long pulse and the rising edge of the short pulse burst may be
in a range between approximately 0 seconds and approximately 10
seconds. In other examples, the interval between the trailing edge
of the long pulse and the rising edge of the short pulse burst may
be in a range between approximately 500 milliseconds and
approximately 1 second.
[0138] In some examples, the interval between the trailing edge of
the short pulse burst and the rising edge of the long pulse may be
in a range between approximately 0 seconds and approximately 10
seconds. In other examples, the interval between the trailing edge
of the short pulse burst and the rising edge of the long pulse may
be in a range between approximately 500 milliseconds and
approximately 1 second.
[0139] In one example, a short pulse burst with each pulse of the
short pulse burst having a pulse width of 4 milliseconds may be
used in combination with a long pulse having a 400 millisecond
pulse width.
[0140] In another study, an obese rat model was used to test
whether combining a long pulse, low frequency GES paradigm with a
short pulse, high frequency GES paradigm produces a large reduction
in food intake than either alone. Using 20 obese male
Sprague-Dawley rats (aged 16-17 weeks, mean weight: 568 grams,
range: 485-684 grams), the effect of long pulse, low frequency
stimulation was compared to the effect of short pulse, high
frequency pulse trains alone, and the combination of long pulse,
low frequency and short pulse, high frequency pulse trains. The
combination of long pulse, low frequency and short pulse, high
frequency pulse trains is similar to the electrical stimulation
waveform shown and described above with respect to FIGS. 8A and
8B.
[0141] During the study, platinum-iridium electrodes were implanted
in the gastric antrum of the rat subjects. Lead wires were
externalized on the subjects' backs for connection to an external
pulse generator. The subjects were acclimated to feed for 2 hours
per day in a restrainer to allow GES delivery during feeding. The
subjects received 5 days of each treatment in randomized order,
separated by 2 day washouts. The treatments included the following:
sham GES; a long pulse setting having a pulse width of 400
milliseconds, a pulse rate of 0.25 Hz, and a pulse amplitude of 6
mA; a short pulse burst setting with each pulse of the pulse burst
having a pulse width of 4 milliseconds, a pulse rate of 40 Hz, a
duty cycle of 2 seconds ON and 2 seconds OFF, and a pulse amplitude
of 6 mA; and, a combination setting that combines a long pulse
setting and a short pulse burst setting, having a long pulse with
pulse width of 400 milliseconds, a pulse rate of 0.25 Hz, and a
pulse amplitude of 6 mA and a short pulse burst with each pulse of
the pulse burst having a pulse width of 4 milliseconds, a pulse
rate of 40 Hz, a duty cycle of 2 seconds ON and 2 seconds OFF, and
a pulse amplitude of 6 mA. At necropsy, the rats were randomized
(n=9-10 per group) to receive sham GES or GES using the combination
setting for 90 minutes before sacrifice and after a 2.5 gram solid
meal. Harvested stomachs were used to measure gastric volume and
emptying effects of the GES using the combination setting.
[0142] FIG. 15 depicts the food intake in mean grams per day for
sham GES, the short pulse setting, the long pulse setting, and the
combination setting in obese rats. Relative to the sham GES (19.8
grams), mean daily food intake induced by electrical stimulation
was reduced 26.7% to 14.5 grams upon application of stimulation
pulses with a short pulse burst setting with each pulse of the
pulse burst having a pulse width of 4 milliseconds, a pulse rate of
40 Hz, a duty cycle of 2 seconds ON and 2 seconds OFF, and a pulse
amplitude of 6 mA. Relative to the sham GES, mean daily food intake
induced by electrical stimulation was reduced by 29.8% to 13.9
grams upon application of stimulation pulses with a long pulse
setting having a pulse width of 400 milliseconds, a pulse rate of
0.25 Hz, and a pulse amplitude of 6 mA.
[0143] Notably, under application of the combination setting
stimulation pulses having a long pulse with pulse width of 400
milliseconds, a pulse rate of 0.25 Hz, and a pulse amplitude of 6
mA and a short pulse burst with each pulse of the pulse burst
having a pulse width of 4 milliseconds, a pulse rate of 40 Hz, a
duty cycle of 2 seconds ON and 2 seconds OFF, and a pulse amplitude
of 6 mA, mean daily food intake induced by electrical stimulation
was reduced by 39.3% to 12.0 grams relative to the sham GES. Also,
although feeding suppression was greater under application of the
combination setting stimulation pulses than under application of
either the long pulse stimulation setting or short pulse
stimulation setting alone, feeding suppression did not differ
across the long pulse stimulation setting or short pulse
stimulation setting alone treatments.
[0144] FIG. 16 graphically depicts gastric volume in mean
milliliters when GES treatment is off and using a combination
setting treatment in obese rats. After 90 minutes of application of
the combination GES setting stimulation pulses having a long pulse
with pulse width of 400 milliseconds, a pulse rate of 0.25 Hz, and
a pulse amplitude of 6 mA and a short pulse burst with each pulse
of the pulse burst having a pulse width of 4 milliseconds, a pulse
rate of 40 Hz, a duty cycle of 2 seconds ON and 2 seconds OFF, and
a pulse amplitude of 6 mA, post-mortem gastric volume was higher
(6.8 ml) than after sham GES (4.2 ml).
[0145] FIG. 17 graphically depicts the mean percentage of gastric
emptying at 90 min with 95% Cl when GES is off and when using the
combination GES setting stimulation pulses in obese rats. After 90
minutes of application of the combination GES setting stimulation
pulses, test meal emptying was lower (50.2%) than after sham GES
(69.8%).
[0146] FIG. 18 is a graphic depicting the correlation between GES
induced reductions of food intake and gastric volume following GES
treatment in obese rats. FIG. 18 depicts the percentage food intake
(y-axis) compared to the gastric volume (x-axis) in milliliters in
obese rats. The graph shows the correlation between changes in food
intake from sham-GES control levels under the combination GES
setting treatment during the food intake cross-over experiment with
post-mortem gastric volume in 10 rats from the cross-over study
sample that received 90 minutes of combination GES setting
treatment just before sacrifice. These 10 rats had significantly
higher mean post-mortem gastric volumes (6.8 ml vs. 4.2 ml) than
the 9 remaining cross-over study rats who were assigned to receive
only sham-GES during the 90 minutes before necropsy. This
difference reflects the gastric distension induced by active GES
treatment. The scatter plot of FIG. 18 shows that the degree of
GES-induced gastric distension, which is reflected in total gastric
volume, correlates with the food intake effect of GES, with food
intake suppression tending to be greater in rats with greater
gastric volume. The correlation suggests that gastric distension
may be a useful acute response marker for the food intake reduction
efficacy of GES treatments, and may also be part of the mechanism
by which GES reduces food intake. As compared to the preceding
cross-over study, higher gastric volume application of the
combination GES setting stimulation pulses was associated with a
larger food intake reduction using the combination setting
treatment, while gastric emptying did not correlate significantly
with food intake response. Combining GES modalities that alter
feeding via differing pathways may be one means for improving the
efficacy of GES as an obesity treatment. Exaggeration of the
receptive gastric distension response to food intake may be one
mechanism by which GES inhibits feeding.
[0147] Of course, the specific example described above with respect
to the obese rat study is only one example of an electrical
stimulation pulse train having a repeating pattern of a long pulse
followed by a short pulse burst followed by a long pulse followed
by a short pulse burst, etc. that may be used to treat obesity. The
electrical stimulation waveform is not limited to the specific
stimulation parameters described above. Rather, implantable
stimulator 12 is configured to deliver stimulation pulses using
stimulation parameters with certain operating ranges. The ranges of
stimulation parameters are substantially similar to those described
above with respect to the canine study described immediately above
in which the effect of long pulse, low frequency stimulation was
compared to the effect of short pulse, high frequency pulse trains
alone, and the combination of long pulse, low frequency and short
pulse, high frequency pulse trains.
[0148] In one example, the long pulse in the electrical stimulation
pulse train having a repeating pattern of a long pulse followed by
a train of short pulses followed by a long pulse followed by a
train of short pulses, etc. may be approximated using a short pulse
train, as shown and described above with respect to FIGS. 5A-5B,
for example.
[0149] The stimulation pulses described above may be unipolar
pulses (e.g., delivered from a lead electrode and referenced to an
electrode carried or formed by a housing of implantable stimulator
12) or bipolar pulses (e.g., delivered from a lead electrode and
referenced to another electrode on the lead). In addition, the
stimulation pulses described above may be "alternating monophasic
rectangular pulses" or simply "alternating monophasic pulses," as
shown and described below with respect to FIG. 19.
[0150] FIG. 19A is a plot illustrating an example waveform 300
representing an example series of electrical stimulation pulses for
delivery to patient 16. In particular, first stimulation pulse
302a, second stimulation pulse 302b, third stimulation pulse 302c,
and fourth stimulation pulse 302d (collectively "series of
stimulation pulses" 302) are represented by waveform 300. Waveform
300 may be referred to as an "alternating monophasic rectangular
pulses" or "alternating monophasic pulses." Implantable stimulator
12 may generate and deliver gastric electric stimulation to stomach
22 of patient 16 via electrodes 24 and 26 carried on leads 18 and
20 respectively, where the gastric electric stimulation includes
the series of electrical stimulation pulses 302 represented by
waveform 300. In some examples, such electric stimulation may
effectively treat one or more patient conditions, e.g., by
increasing the distension of stomach 22 of patient 16. Although
series of stimulation pulses 302 represented by waveform 300 are
shown to include four stimulation pulses 302a-d, the gastric
electric stimulation generated and delivered to patient 16 by
implantable stimulator 12 may include any number of stimulation
pulses that provide effective treatment to patient 16.
[0151] As represented by waveform 300, implantable stimulator 12
delivers first stimulation pulse 302a, second stimulation pulse
302b, third stimulation pulse 302c, and fourth stimulation pulse
302d in direct succession with one another and in the order listed.
In the series of stimulation pulses 302, each pulse has a polarity
that is opposite of the polarity of the directly preceding pulse
and the directly following pulse. For example, as delivered by
implantable stimulator 12, first stimulation pulse 302a has a first
polarity, which may be either anodic or cathodic, second
stimulation pulse 302b has a polarity opposite from that of first
pulse 302a, third stimulation pulse 302c has a polarity opposite
from that of second stimulation pulse 302b, and so forth.
[0152] As seen in waveform 300 of FIG. 19, a time interval that is
greater than zero separates each respective pulse in the series of
pulses 302. For example, a time interval T(2) greater than zero
separates the trailing edge of first pulse 302a and leading edge of
second pulse 302b. Similarly, a time interval T(3) greater than
zero separates the trailing edge of second pulse 302b and leading
edge of third pulse 302c.
[0153] It should also be noted that pulses 302a-302d of waveform
300 do not form coupled pulse pairs with one another. A coupled
pair of electrical stimulation pulses may include a first
electrical stimulation pulse of one polarity (anodic or cathodic)
followed immediately, or with some fixed delay, by second
electrical stimulation pulse of opposite polarity. When the coupled
pair of electrical stimulation pulses are charge balanced, the
charge of the first pulse is equal to but opposite of that of the
charge of the second pulse. Notably, unlike uncoupled pulses, the
timing of the delivery of two stimulus pulses that are coupled to
one another is fixed. Instead of forming coupled pulse pairs, the
temporal relationship between each individual pulse in the series
of pulses in FIG. 19A is dependent on the stimulation pulse
frequency. In particular, time intervals T(2), T(3) and T(4) depend
on the frequency that the series of pulses are delivered and the
pulse width (PW) of each pulse. If series of pulses 302 are
delivered at an increased frequency while the pulse width is
constant, then time intervals T(2), T(3) and T(4) all decrease.
Conversely, if series of pulses 302 are delivered at a decreased
frequency while the pulse width is constant, then time intervals
T(2), T(3) and T(4) all increase.
[0154] In some examples, time intervals T(2), T(3) and T(4) may be
substantially equal to one another such that pulses 302a-d are
evenly spaced. In other examples, time interval T(2) may be
different than that of time interval T(3) and/or time interval
T(4). However, in each case, time intervals T(2), T(3) and T(4) are
dependent on the frequency at which the series of pulses 302 are
delivered since none of pulses 302a-302d form coupled pulse pairs
(none of time intervals T(2), T(3) and T(4) are fixed). In examples
in which T(2), T(3) and T(4) are approximately equal to one another
and pulses 302a-302d each have approximately the same pulse width,
the pulse frequency of series of pulses 302 may be determined by
the time interval between the leading edge of each pulse, e.g.,
time interval T(1) between first pulse 302a and second pulse 302b.
In some examples, the interpulse interval between directly
successive pulses is not less than the pulse width of the
successive pulses. For example, time interval T(2) may be greater
than or equal to PW1 and PW2. In some examples, the interpulse
intervals defined by the series of pulses 302 (i.e., time intervals
T(2)-T(4)) may be greater than approximately 1 millisecond, such
as, e.g., greater than 2 milliseconds or greater than 10
milliseconds or greater than 50 milliseconds. The interpulse
interval between each of pulses 302a-302d is dependent on the pulse
frequency and pulse width that the series of pulses 302a-302d are
delivered.
[0155] The overall charge of the series of pulses 302 of waveform
300 may be approximately zero. The charge of each pulse is
dependent on the amplitude and pulse width of each respective pulse
of the series of pulses 302. In some examples, the pulse width and
amplitude of each respective pulse 302a-d may be selected such that
the charge of first pulse 302a may be approximately equal to and
opposite of that of the charge of second pulse 302b, and the charge
of third pulse 302c may be approximately equal to and opposite of
that of the charge of fourth pulse 302d. In some examples, each
pulse of the series of pulses 302 may have approximately the same
amplitude and pulse width. In other examples, the pulse width and
amplitude may differ between pulses. In any case, the series of
pulses 302 may be described as charged balanced even though the
first pulse 302a is not followed substantially immediately by a
second pulse 302b with an equal and opposite charge. Instead,
second pulse 302b is delivered after time interval T(2) greater
than zero after the end first pulse 302a.
[0156] As mentioned above, waveform 300 may be referred to as
representing "alternating monophasic rectangular pulses" or simply
"alternating monophasic pulses". The interval between every
successive pulse of opposite polarity in waveform 300 of FIG. 19
may vary with the pulse frequency selected. This is because each
pair of adjacent rectangular pulses with opposite polarity in
waveform 300 are two uncoupled stimulus pulses, rather than some of
the pulses forming coupled pulse pairs. An increase in pulse
frequency for the alternating monophasic waveform 300 will cause
the intervals between successive stimulus pulses of opposing
polarity to decrease in duration, while a decrease in the selected
pulse frequency will cause these intervals between successive
pulses of opposite polarity to increase.
[0157] In accordance with the techniques of this disclosure, short
pulse bursts may be used to approximate or simulate first pulse
302a, third pulse 302c, and so forth, in the manner described above
with respect to FIGS. 5A and 5B. Stimulation parameters that may be
used to generate a short pulse burst were described in detail above
and will not be described again. In some examples, a short pulse
burst may also be used to approximate or simulate second pulse
302b, fourth pulse 302d, and so forth, in the manner described
above with respect to FIGS. 5A and 5B. Or, in other examples,
rather than using a short pulse burst to approximate or simulate
second pulse 302b, fourth pulse 302d, and so forth, each of second
pulse 302b, fourth pulse 302d, and so forth may be a long
pulse.
[0158] FIG. 19B is a plot illustrating an example waveform 304
representing an example series of electrical stimulation pulses for
delivery to patient 16. In particular, first stimulation pulse
306a, second stimulation pulse 306b, third stimulation pulse 306c,
and fourth stimulation pulse 306d (collectively "series of
stimulation pulses" 306) are represented by waveform 304. The
series of pulses 306 of waveform 304 are substantially the same as
the series of pulses 302 of waveform 300 in FIG. 19A. For example,
none of pulses 306a-306d form coupled pulses with each other.
Instead, the temporal relationship between each of 306a-306d is
dependent on the frequency at which the series of pulses 66 is
delivered. In some examples, time intervals T(5), T(6) and T(7) may
be substantially the same, and may vary based on the frequency at
which the series of pulses 306 are delivered to patient 16.
[0159] However, unlike that shown in FIG. 19A, the pulse width and
pulse amplitude of the series of pulses 306 is not the same for
each respective pulse 306a-d. In particular, first pulse 306a and
third pulse 306c have substantially the same amplitude, which is
greater than the amplitude of second pulse 306b and fourth pulse
306d, which also have substantially the same amplitude. Moreover,
the pulse width PW5 of first pulse 306a and pulse width PW7 of
third pulse 306c are substantially the same and less than that of
the pulse width PW6 of second pulse 306b and pulse width PW8 of
fourth pulse 306d, which are also substantially the same as one
another. Despite the difference in pulse widths and pulse
amplitudes, the pulse width and amplitude of each respective pulse
may be selected such that the series of pulses 306 are
substantially charge balanced. For example, first pulse 306a may
have substantially the same but opposite charge from the charge of
second pulse 306b.
[0160] Implantable stimulator 12 may deliver the series of pulses
represented by waveforms 300 and 304 to patient 16, e.g., to
stomach 22, according to any suitable value for each of pulse
width, pulse amplitude, and pulse frequency. In some examples, one
or more of the stimulation parameters may be selected such that the
electrical stimulation delivered by implantable stimulator 12 to
stomach 22 of patient 16 causes the distension of stomach 22 to
increase.
[0161] In some examples, such pulses may be delivered via a
lead-borne electrode (e.g., as a cathode) and an implantable
stimulator housing electrode (can electrode) (e.g., as an anode) in
a unipolar arrangement, or between bipolar or multipolar lead-borne
electrodes. Furthermore, such pulses may be delivered as a
continuous pulse train, or the pulses may be contained in periodic
or aperiodic bursts of multiple pulses, or in periodic or aperiodic
pulse burst envelopes containing multiple pulse bursts. The pulse
bursts may be of the same duration or different durations. In some
examples, implantable stimulator 12 may deliver electrical
stimulation with a burst frequency between approximately 2 and
approximately 15 bursts per minute. In some examples, implantable
stimulator 12 may deliver bursts having a duration of between
approximately 0.1 seconds and approximately 15 seconds.
[0162] In accordance with the techniques of this disclosure, a
short pulse burst may be used to approximate or simulate first
pulse 306a, third pulse 306c, and so forth, in the manner described
above with respect to FIGS. 5A and 5B. Stimulation parameters that
may be used to generate a short pulse burst were described in
detail above and will not be described again. In some examples, a
short pulse burst may also be used to approximate or simulate
second pulse 306b, fourth pulse 306d, and so forth, in the manner
described above with respect to FIGS. 5A and 5B. Or, in other
examples, rather than using a short pulse burst to approximate or
simulate second pulse 306b, fourth pulse 306d, and so forth, each
of second pulse 306b, fourth pulse 306d may be a long pulse.
[0163] The techniques described in this disclosure may be
implemented in hardware, software, firmware or any combination
thereof. For example, various aspects of the techniques may be
implemented within one or more microprocessors, digital signal
processors (DSPs), application specific integrated circuits
(ASICs), field programmable logic arrays (FPGAs), or any other
equivalent integrated or discrete logic circuitry, as well as any
combinations of such components. The term "processor" or
"processing circuitry" may generally refer to any of the foregoing
logic circuitry, alone or in combination with other logic
circuitry, or any other equivalent circuitry.
[0164] When implemented partially in software, the functionality
ascribed to the systems and devices described in this disclosure
may be embodied as instructions on a computer-readable medium such
as random access memory (RAM), read-only memory (ROM), non-volatile
random access memory (NVRAM), electrically erasable programmable
read-only memory (EEPROM), FLASH memory, magnetic media, optical
media, or the like. The instructions are executed to support one or
more aspects of the functionality described in this disclosure.
Even when implemented in software, the functionality described in
this disclosure is implemented in a hardware device, such as a
processor that executes the instructions.
[0165] Various examples of the invention have been described. These
and other examples are within the scope of the following
claims.
* * * * *