U.S. patent application number 15/965344 was filed with the patent office on 2019-02-28 for sacral nerve stimulation.
The applicant listed for this patent is Medtronic, Inc.. Invention is credited to David A. Dinsmoor, Xin Su.
Application Number | 20190060647 15/965344 |
Document ID | / |
Family ID | 65436438 |
Filed Date | 2019-02-28 |
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United States Patent
Application |
20190060647 |
Kind Code |
A1 |
Su; Xin ; et al. |
February 28, 2019 |
SACRAL NERVE STIMULATION
Abstract
In some examples, a method including determining a chronaxie of
evoked threshold motor responses from electrical stimulation
delivered to a sacral nerve of a patient; and delivering, based on
the determined chronaxie, electrical stimulation therapy,
configured to treat a patient condition, to the sacral nerve having
a pulse width at or near the identified chronaxie, wherein the
delivered electrical stimulation is configured to inhibit
contraction of at least one a bladder or bowel of the patient.
Inventors: |
Su; Xin; (Plymouth, MN)
; Dinsmoor; David A.; (North Oaks, MN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Medtronic, Inc. |
Minneapolis |
MN |
US |
|
|
Family ID: |
65436438 |
Appl. No.: |
15/965344 |
Filed: |
April 27, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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62553018 |
Aug 31, 2017 |
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62583254 |
Nov 8, 2017 |
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62583814 |
Nov 9, 2017 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61B 5/202 20130101;
A61N 1/0514 20130101; A61N 1/36031 20170801; A61N 1/36139 20130101;
A61N 1/36171 20130101; A61N 1/0553 20130101; A61N 1/36007 20130101;
A61N 1/3606 20130101; A61N 1/36175 20130101 |
International
Class: |
A61N 1/36 20060101
A61N001/36; A61N 1/05 20060101 A61N001/05 |
Claims
1. A method comprising: determining a chronaxie of evoked threshold
motor responses from electrical stimulation delivered to a sacral
nerve of a patient; and delivering, based on the determined
chronaxie, electrical stimulation therapy configured to treat a
patient condition to the sacral nerve having a pulse width at or
near the identified chronaxie, wherein the delivered electrical
stimulation is configured to inhibit contraction of at least one a
bladder or bowel of the patient.
2. The method of claim 1, wherein determining the chronaxie of the
evoked threshold motor responses from the electrical stimulation
delivered to the sacral nerve of the patient comprises: delivering
electrical stimulation at a plurality of different pulse widths to
the sacral nerve; determining a threshold amplitude of the
electrical stimulation that evokes a motor response at each
respective pulse width of the plurality of pulse widths; and
determining the chronaxie based on the respective threshold
amplitudes and corresponding respective pulse widths of the
plurality of pulse widths.
3. The method of claim 2, wherein determining the threshold
amplitude of the electrical stimulation that evokes the motor
response at each respective pulse width of the plurality of pulse
widths comprises determining the threshold amplitude of the
electrical stimulation that evokes the motor response at each
respective pulse width of the plurality of pulse widths based on
input from the patient.
4. The method of claim 2, wherein determining the threshold
amplitude of the electrical stimulation that evokes the motor
response at each respective pulse width of the plurality of pulse
widths comprises determining the threshold amplitude of the
electrical stimulation that evokes the motor response at each
respective pulse width of the plurality of pulse widths based on
sensed EMG indicating the motor response of the patient.
5. The method of claim 1, wherein determining the chronaxie of
evoked threshold motor responses from electrical stimulation
delivered to the sacral nerve of the patient comprises determining
the chronaxie of evoked threshold motor responses from electrical
stimulation delivered to the sacral nerve of the patient based on
received input from the patient.
6. The method of claim 1, further comprising detecting a voiding
the at least one of the bowel or the bladder of the patient, and
wherein delivering, based on the determined chronaxie, the
electrical stimulation therapy configured to treat the patient
condition to the sacral nerve having the pulse width at or near the
identified chronaxie comprises delivering, based on the determined
chronaxie and in response to the detection of the voiding of the at
least one of the bowel or the bladder of the patient, the
electrical stimulation therapy configured to treat the patient
condition to the sacral nerve having the pulse width.
7. The method of claim 1, wherein delivering, based on the
identified chronaxie, electrical stimulation therapy configured to
treat a patient condition to the sacral nerve having a pulse width
at or near the identified chronaxie comprises delivering electrical
stimulation therapy configured to treat a patient condition to the
sacral nerve having the pulse width within about 50% of the
identified chronaxie.
8. The method of claim 1, wherein delivering, based on the
identified chronaxie, electrical stimulation therapy configured to
treat a patient condition to the sacral nerve having a pulse width
at or near the identified chronaxie comprising delivering
electrical stimulation therapy configured to treat a patient
condition to the sacral nerve having the pulse width within about
50 microseconds of the identified chronaxie.
9. The method of claim 1, wherein a frequency of the electrical
stimulation is approximately 10 hertz.
10. The method of claim 1, wherein the pulse width of the
electrical stimulation is approximately 62 microseconds to
approximately 74 microseconds.
11. The method of claim 1, wherein the pulse width of the
electrical stimulation is approximately 70 microseconds.
12. The method of claim 1, wherein a frequency of the electrical
stimulation therapy is fixed.
13. A medical device system comprising: an electrical stimulation
generator configured to deliver electrical stimulation to a sacral
nerve site of a patient; and a processor configured to determine a
chronaxie of evoked threshold motor responses from electrical
stimulation delivered to a sacral nerve of a patient, and control
the electrical stimulation generator to deliver, based on the
determined chronaxie, electrical stimulation therapy configured to
treat a patient condition to the sacral nerve having a pulse width
at or near the identified chronaxie, wherein the delivered
electrical stimulation is configured to inhibit contraction of at
least one a bladder or bowel of the patient.
14. The system of claim 13, wherein the processor is configured to:
control the electrical stimulation generator to deliver electrical
stimulation at a plurality of different pulse widths to the sacral
nerve; determine a threshold amplitude of the electrical
stimulation that evokes a motor response at each respective pulse
width of the plurality of pulse widths; and determine the chronaxie
based on the respective threshold amplitudes and corresponding
respective pulse widths of the plurality of pulse widths.
15. The system of claim 14, wherein the processor is configured to
determine the threshold amplitude of the electrical stimulation
that evokes the motor response at each respective pulse width of
the plurality of pulse widths based on input from the patient.
16. The system of claim 14, wherein the processor is configured to
determine the threshold amplitude of the electrical stimulation
that evokes the motor response at each respective pulse width of
the plurality of pulse widths based on sensed EMG indicating the
motor response of the patient.
17. The system of claim 13, wherein the processor is configured to
determine the chronaxie of evoked threshold motor responses from
electrical stimulation delivered to the sacral nerve of the patient
based on received input from the patient.
18. The system of claim 13, wherein the processor is configured to
detect a voiding the at least one of the bowel or the bladder of
the patient, and control the electrical stimulation generator to
deliver, based on the determined chronaxie and in response to the
detection of the voiding of the at least one of the bowel or the
bladder of the patient, the electrical stimulation therapy
configured to treat the patient condition to the sacral nerve
having the pulse width.
19. The system of claim 13, wherein the processer is configured to
control the electrical stimulation generator to deliver delivering
electrical stimulation therapy configured to treat a patient
condition to the sacral nerve having the pulse width within about
50% of the identified chronaxie.
20. The system of claim 13, wherein the processer is configured to
control the electrical stimulation generator to deliver electrical
stimulation therapy configured to treat a patient condition to the
sacral nerve having the pulse width within about 50 microseconds of
the identified chronaxie.
21. The system of claim 13, wherein a frequency of the electrical
stimulation is approximately 10 hertz.
22. The system of claim 13, wherein the pulse width of the
electrical stimulation is approximately 62 microseconds to
approximately 74 microseconds.
23. The system of claim 13, wherein the pulse width of the
electrical stimulation is approximately 70 microseconds.
24. The system of claim 13, wherein a frequency of the electrical
stimulation therapy is fixed.
25. A method comprising delivering electrical stimulation therapy
configured to treat a patient condition to a sacral nerve having a
pulse width of approximately 60 microseconds to approximately 80
microseconds, and an amplitude and frequency that does not evoke a
motor response but does inhibit contraction of at least one a
bladder or bowel of the patient.
Description
[0001] This application claims the benefit of U.S. Provisional
Patent Application Nos. 62/553,018, filed Aug. 31, 2017, 62/583,254
filed Nov. 8, 2017, and 62/583,814, filed Nov. 9, 2017. The entire
content of each of these applications is incorporated herein by
reference.
TECHNICAL FIELD
[0002] The disclosure relates to medical devices and, more
particularly, to medical devices that may be configured to deliver
electrical stimulation.
BACKGROUND
[0003] Urinary and fecal incontinence (e.g., an inability to
control bladder and bowel function, respectively) are problems that
afflict people of all ages, genders, and races. Various muscles,
nerves, organs and conduits within the pelvic floor cooperate to
collect, store and release bladder and bowel contents. A variety of
disorders may compromise urinary tract and bowel performance, and
contribute to incontinence. Many of the disorders may be associated
with aging, injury, or illness.
[0004] Urinary incontinence, such as, urgency incontinence, may
originate from disorders of portions of the peripheral or central
nervous system which control the bladder micturition reflex. Nerve
disorders may also lead to overactive bladder activities and/or may
prevent proper triggering and operation of the bladder.
Furthermore, urinary incontinence may also result from improper
communication between the nervous system and the urethra.
SUMMARY
[0005] Devices, systems, and techniques for managing urinary
incontinence, fecal incontinence and/or other patient conditions
using sacral nerve stimulation (also referred to as sacral
neuromodulation or electrical stimulation of the sacral nerve) are
described in this disclosure. In some examples, the disclosure
relates to techniques for identifying efficient and preferred pulse
widths for the electrical stimulation based on the chronaxie of
threshold motor responses evoked by delivery of stimulation to a
sacral nerve. For example, the chronaxie of electrical stimulation
delivered to a sacral nerve site that evokes a threshold motor
response may be identified for a patient. Electrical stimulation
therapy that does not evoke a motor response but does inhibit
contraction of at least one of the bladder or the bowel of the
patient may then be delivered to the patient to treat a patient
condition using a pulse width at or near the identified chronaxie.
In this manner, the electrical stimulation therapy may be more
efficient in terms of energy or power consumption compared to
electrical stimulation therapy delivered to a patient with a
greater pulse width.
[0006] In one example, the disclosure is directed to a method
comprising determining a chronaxie of evoked threshold motor
responses from electrical stimulation delivered to a sacral nerve
of a patient; and delivering, based on the determined chronaxie,
electrical stimulation therapy, configured to treat a patient
condition, to the sacral nerve having a pulse width at or near the
identified chronaxie, wherein the delivered electrical stimulation
is configured to inhibit contraction of at least one a bladder or
bowel of the patient.
[0007] In another example, the disclosure is directed to a medical
device system comprising an electrical stimulation generator
configured to deliver electrical stimulation to a sacral nerve site
of a patient; and a processor configured to determine a chronaxie
of evoked threshold motor responses from electrical stimulation
delivered to a sacral nerve of a patient, and control the
electrical stimulation generator to deliver, based on the
determined chronaxie, electrical stimulation therapy configured to
treat a patient condition to the sacral nerve having a pulse width
at or near the identified chronaxie, wherein the delivered
electrical stimulation is configured to inhibit contraction of at
least one a bladder or bowel of the patient
[0008] In another example, the disclosure is directed to a method
comprising delivering electrical stimulation therapy configured to
treat a patient condition to a sacral nerve having a pulse width of
approximately 60 microseconds to approximately 80 microseconds, and
an amplitude and frequency that does not evoke a motor response but
does inhibit contraction of at least one a bladder or bowel of the
patient.
[0009] The details of one or more aspects of the disclosure are set
forth in the accompanying drawings and the description below.
BRIEF DESCRIPTION OF DRAWINGS
[0010] FIG. 1 is a conceptual diagram illustrating an example
therapy system that delivers stimulation therapy to a patient to
manage a patient condition such as, e.g., incontinence.
[0011] FIG. 2 is a conceptual diagram illustrating another example
therapy system that delivers stimulation therapy to a patient to
manage a patient condition such as, e.g., incontinence.
[0012] FIG. 3 is a functional block diagram illustrating an example
configuration of the implantable medical device (IMD) of the
systems shown in FIGS. 1 and 2.
[0013] FIG. 4 is a functional block diagram illustrating an example
configuration of the external programmer of the systems shown in
FIGS. 1 and 2.
[0014] FIG. 5 is a flow diagram illustrating an example technique
for delivering stimulation therapy to a patient to manage urinary
incontinence.
[0015] FIG. 6 is a plot of an example strength-duration curve for
sacral nerve stimulation showing the chronaxie for an evoked motor
response threshold.
[0016] FIGS. 7 to 11B relate to first and second sheep studies that
are described further below.
[0017] FIGS. 12A to 14B relate to a rat study that is described
further below.
DETAILED DESCRIPTION
[0018] As described above, devices, systems, and techniques for
managing incontinence (bladder incontinence and/or fecal
incontinence) of a patient and/or other patient conditions via
electrical stimulation of the sacral nerve are described in this
disclosure. The electrical stimulation therapy may include delivery
of electrical stimulation to one or more sacral nerve sites via a
medical device. Such electrical stimulation may be used to modify
pelvic function to treat various patient conditions (e.g., urinary
incontinence and fecal incontinence) by inhibiting contraction of
the bladder and/or bowel. Although the present disclosure describes
application of electrical stimulation using an IMD, the devices,
systems, and techniques of the present disclosure may also be
implemented in an external medical device that applies electrical
stimulation via implanted or external electrodes.
[0019] Examples of the disclosure are primarily described with
regard to managing incontinence. In other examples, the electrical
stimulation may be delivered to a patient to manage other patient
conditions by inhibiting contraction of the bladder and/or bowel
without evoking motor response, e.g., of the bladder and/or
bowel.
[0020] A medical device may deliver sacral nerve stimulation
therapy to inhibit bladder contraction and/or bowel contraction of
a patient. Contraction may refer to muscle contractions within the
bladder or bowel. In the case of the bladder, contraction may
include contraction of the detrusor muscle or other muscle in the
bladder of a patient. Such bladder contraction may result in a
physiologically significant event, such as, e.g., the voiding of
urine from the bladder (either voluntary or involuntary), or urge
incontinence. Bladder contraction may include reflex contraction,
or unwanted or pathological bladder contraction including both
voiding and non-voiding contractions, such as, contractions causing
urge incontinence. In the case of the bowel of a patient, bowel
contraction may include bowel contraction that results in fecal
voiding, either on a voluntary or involuntary basis. In some
examples, the sacral nerve stimulation therapy delivered to the
patient may inhibit bladder and/or bowel contraction by modulating
nerve signals (e.g., sacral nerve signals). In some examples, the
stimulation delivered to the patient to inhibit bladder contraction
may define an intensity below an evoked motor response threshold of
the stimulated nerve site, e.g., such that the stimulation does not
result in a muscle evoked potential. The pulse width is an
important parameter in determining the stimulation intensity
required to activate nerve fibers with sacral nerve stimulation. As
the pulse width increases, the minimum stimulation intensity needed
for nerve excitation decreases.
[0021] In accordance with some examples of the disclosure, a
medical device may deliver sacral nerve stimulation to a patient
having a pulse width determined based on the chronaxie of evoked
threshold motor responses from electrical stimulation of the sacral
nerve site. The chronaxie refers to the minimum amount of time
needed to stimulate a muscle or nerve site for electrical
stimulation with an intensity (e.g., current amplitude or voltage
amplitude) twice the value of the lowest intensity with indefinite
pulse duration that stimulates the muscle or nerve (i.e., the
rheobase). FIG. 6 is a strength-duration plot in terms of pulse
width and amplitude showing an evoked motor response curve 40 for
electrical stimulation of, e.g., a sacral nerve. The evoked motor
response curve 40 represents the threshold intensity required to
evoke a motor response with electrical stimulation for various
different stimulation durations (e.g., pulse widths). For the plot
in FIG. 6, amplitude A.sub.1 is the rheobase 46 and pulse width
P.sub.2 is the chronaxie 44.
[0022] In some examples, sacral nerve stimulation having a pulse
width much greater than the chronaxie may be delivered to a patient
to treat a patient disorder such as incontinence, e.g., by
inhibiting contraction of the bladder and/or bowel with the sacral
nerve stimulation. In some examples, such electrical stimulation
may have a pulse duration of approximately 210 microseconds
(.mu.s). However, while such therapy may beneficially inhibit
contraction of the bladder and/or bowel, it has been found that
delivery of electrical stimulation with a pulse width at or near
the chronaxie may provide for therapeutically effective stimulation
comparable to electrical stimulation delivered at greater pulse
widths but with reduced energy or power consumption.
[0023] As will be described further below, as one example, an
optimal or otherwise preferential stimulus pulse width for sacral
neuromodulation based on chronaxie of motor responses to third
sacral foramen (S3) sacral nerve stimulation in sheep was
identified in a sheep study. In the sheep study, the
electromyography responses to sacral nerve stimulation with
different stimulation pulse widths were randomly examined using
variable intensities from 0.1 V to 10 V. The experimental data
suggest that a similar motor response may be evoked in the external
anal sphincter (EAS) at pulse widths much shorter (e.g., about 62
.mu.s to about 74 .mu.s) than the 210 .mu.s used with sacral
neuromodulation, in some cases. The use of shorter pulse widths
translates directly to increased energy savings in a
neurostimulator or other medical device configured to deliver
electrical stimulation to a patient (compared to electrical
stimulation having a greater pulse width) while still providing
therapeutically effective stimulation to treat incontinence.
[0024] Additionally, as will be described below, the threshold
difference between activation of different nerve fibers having
different diameters is influenced by the pulse width of electrical
stimulation. Shorter pulse widths will increase the differences in
evoked motor threshold (T.sub.mot) from different diameters of
nerve fibers. The average recruited nerve fiber diameter decreases
(.about.20%) when the stimulus pulse-width increases from 0.01 ms
to 1 ms. The threshold difference between large and small nerve
fibers increases along with the increase in the relative distance
between the stimulating electrode and the nerve fibers. Thus,
preferential activation of large nerve fibers over small fibers can
be more pronounced with a shorter PW stimulation especially when
the electrode is placed farther from the nerve roots. Accordingly,
some examples of the disclosure employing relatively shorter pulse
widths based on chronaxie of motor responses may provide for
therapeutically effective stimulation while also reducing the
likelihood of patient discomfort due to increased fiber selectivity
preferential to larger fibers and reduced discomfort with short PW
nerve stimulation.
[0025] Accordingly, some examples of the disclosure utilize a
medical device configured to deliver electrical stimulation with a
fixed pulse width of, e.g., about 60 .mu.s to about 80 .mu.s (e.g.
70 .mu.s). The electrical stimulation may also have a fixed
frequency of about 10 Hz, which may be the optimal or otherwise
preferential frequency for neuromodulation of bladder function.
One, and the only in some instances, adjustable parameter may be
stimulation intensity, which would provide effective nerve
stimulation and simple operation the medical device system. Such an
example technique may be prescreened on chronaxie for patients who
have no neuropathology conditions.
[0026] Some examples of the disclosure may include techniques in
which the stimulation pulse width could be programed for
neuromodulation based on individual patient's response to S3 nerve
stimulation or other sacral nerve sites. For example, the chronaxie
may vary based on condition of the nerve system of the patients and
pulse width may be adjusted based on the response (e.g., motor
response sensed via electromyography (EMG), patient sensation
(e.g., tingle) and the like) to the delivered stimulation and may
be also the outcome (readout) of diseases (looped control for
example). This method may be useful for patients who have
neuropathology conditions.
[0027] FIGS. 1-4 illustrate one example of a medical device system
that may be employed to perform example techniques of this
disclosure. However, other medical device systems may also employ
the techniques of the disclosure.
[0028] FIG. 1 is a conceptual diagram illustrating an example
therapy system 10 that delivers electrical stimulation therapy to
the sacral nerve of patient 14 to manage a patient condition of
patient 14 (e.g., urinary incontinence or fecal incontinence).
Therapy system 10 includes an implantable medical device (IMD) 16,
which is coupled to leads 18, 20, and 28, sensor 22, and external
programmer 24. IMD 16 may deliver the electrical stimulation
therapy to a sacral nerve of patient 14 to inhibit bladder
contractions or bowel contractions. As described herein, the pulse
width of the electrical stimulation therapy may be selected based
on the chronaxie determined for the electrical stimulation
delivered to the sacral nerve of patient 14, e.g., using an
electrical stimulation having a pulse width at or near the
chronaxie and an amplitude and frequency that does not results in
an evoked motor response but does inhibit bladder contractions or
bowel contractions. For ease of description, system 10 is primarily
described with regard to treatment of a patient condition, such as
urinary incontinence, by delivering therapy to inhibit bladder
contraction. However, system 10 may also be employed to treat other
conditions, such as fecal incontinence by delivering therapy to
inhibit bowel contraction.
[0029] IMD 16 provides electrical stimulation therapy to patient 14
by generating and delivering electrical stimulation signals to a
target therapy site by lead 28 and, more particularly, via
electrodes 29A-29D (collectively referred to as "electrodes 29")
disposed proximate to a distal end of lead 28. For example, IMD 16
may deliver sacral nerve stimulation to patient 14 to inhibit
bladder contraction following a bladder contraction, e.g., a
contraction associated with a voiding event. In some examples, IMD
16 may delivery the stimulation to patient 14 based on, e.g.,
sensor data and/or patient input. As one example, IMD 16 may detect
a bladder contraction based on sensor data and then deliver sacral
nerve stimulation based on the detected bladder contraction. As
another example, patient 14 may use external programmer 24 to
provide patient input to IMD 16, e.g., indicating an increased
probability of unintentional voiding, and IMD 16 may deliver the
stimulation to patient 14 to inhibit bladder contraction based on
the patient input.
[0030] IMD 16 may be surgically implanted in patient 14 at any
suitable location within patient 14, such as near the pelvis. In
some examples, the implantation site may be a subcutaneous location
in the side of the lower abdomen or the side of the lower back or
upper buttocks. IMD 16 has a biocompatible housing, which may be
formed from titanium, stainless steel, a liquid crystal polymer, or
the like. The proximal ends of leads 18, 20, and 28 are both
electrically and mechanically coupled to IMD 16 either directly or
indirectly, e.g., via a respective lead extension. Electrical
conductors disposed within the lead bodies of leads 18, 20, and 28
electrically connect sense electrodes (not shown) and stimulation
electrodes, such as electrodes 29, to a therapy delivery module
(e.g., a stimulation generator) within IMD 16. In the example of
FIG. 1, leads 18 and 20 carry electrodes 19A, 19B (collectively
referred to as "electrodes 19") and electrodes 21A, 21B
(collectively referred to as "electrodes 21"), respectively. As
described in a further detail below, electrodes 19 and 21 may be
positioned for sensing an impedance of bladder 12, which may
decrease as the volume of urine within bladder 12 increases.
[0031] One or more medical leads, e.g., leads 18, 20, and 28, may
be connected to IMD 16 and surgically or percutaneously tunneled to
place one or more electrodes carried by a distal end of the
respective lead at a desired sacral nerve site. In FIG. 1, leads 18
and 20 are placed proximate to an exterior surface of the wall of
bladder 12 at first and second locations, respectively. Electrodes
29 of the common lead 28 may deliver stimulation to the same or
different nerves. In other examples of therapy system 10, IMD 16
may be coupled to more than one lead that includes electrodes for
delivery of electrical stimulation to different stimulation sites
within patient 14, e.g., to target different nerves.
[0032] In the example shown in FIG. 1, leads 18, 20, 28 are
cylindrical. Electrodes 19, 21, 29 of leads 18, 20, 28,
respectively, may be ring electrodes, segmented electrodes or
partial ring electrodes. Segmented and partial ring electrodes each
extend along an arc less than 360 degrees (e.g., 90-120 degrees)
around the outer perimeter of the respective lead 18, 20, 28. In
examples, one or more of leads 18, 20, 28 may be, at least in part,
paddle-shaped (i.e., a "paddle" lead) and include pad electrodes
positioned on a distal paddle surface.
[0033] In some examples, one or more of electrodes 19, 21, 29 may
be cuff electrodes that are configured to extend at least partially
around a nerve (e.g., extend axially around an outer surface of a
nerve). Delivering stimulation via one or more cuff electrodes
and/or segmented electrodes may help achieve a more uniform
electrical field or activation field distribution relative to the
nerve, which may help minimize discomfort to patient 14 that
results from the delivery of stimulation therapy.
[0034] The illustrated numbers and configurations of leads 18, 20,
and 28 and electrodes carried by leads 18, 20, and 28 are merely
exemplary. Other configurations, i.e., number and position of leads
and electrodes, are possible. For example, IMD 16 may be coupled to
additional leads or lead segments having one or more electrodes
positioned at different locations in the pelvic region of patient
14. The additional leads may be used for delivering stimulation
therapies to respective stimulation sites within patient 14 or for
monitoring one or more physiological parameters of patient 14. In
an example in which the target therapy sites for the stimulation
therapies are different, IMD 16 may be coupled to two or more
leads, e.g., for bilateral or multi-lateral stimulation. As another
example, IMD 16 may be coupled to a fewer number of leads, e.g.,
just lead 28.
[0035] In some examples, IMD 16 may deliver stimulation therapy
based on patient input. In some examples, patient 14 may provide
patient input using external programmer 24 or by tapping over IMD
16 when IMD 16 includes a motion sensor that is responsive to
tapping. Using programmer 24, patient 14 may provide input to IMD
16 that indicates an urge felt by the patient, a leakage incident
experienced by the patient, an imminent voiding event predicted by
the patient, or a voluntary voiding event to be undertaken by the
patient. In this way, therapy system 10 provides patient 14 with
direct control of stimulation therapy.
[0036] In the illustrated example of FIG. 1, IMD 16 determines an
impedance through bladder 12, which varies as a function of the
contraction of bladder 12, via electrodes 19 and 21 on leads 18 and
20, respectively. In the example shown in FIG. 1, IMD 16 determines
bladder impedance using a four-wire (or Kelvin) measurement
technique. In other examples, IMD 16 may measure bladder impedance
using a two-wire sensing arrangement. In either case, IMD 16 may
transmit an electrical measurement signal, such as a current,
through bladder 12 via leads 18 and 20, and determine bladder
impedance based on the measurement of the transmitted electrical
signal.
[0037] In the example four-wire arrangement shown in FIG. 1,
electrodes 19A and 21A and electrodes 19B and 21B, may be located
substantially opposite each other relative to the center of bladder
12. For example, electrodes 19A and 21A may be placed on opposing
sides of bladder 12, either anterior and posterior or left and
right. In FIG. 1, electrodes 19 and 21 are shown placed proximate
to an exterior surface of the wall of bladder 12. In some examples,
electrodes 18 and 21 may be sutured or otherwise affixed to the
bladder wall. In other examples, electrodes 19 and 21 may be
implanted within the bladder wall. To measure the impedance of
bladder 12, IMD 16 may source an electrical signal, such as
current, to electrode 19A via lead 18, while electrode 21A via lead
20 sinks the electrical signal. IMD 16 may then determine the
voltage between electrode 19B and electrode 21B via leads 18 and
20, respectively. IMD 16 determines the impedance of bladder 12
using a known value of the electrical signal sourced and the
determined voltage.
[0038] In the example of FIG. 1, IMD 16 also includes a sensor 22
for detecting changes in the contraction of bladder 12. Sensor 22
may be, for example, a pressure sensor for detecting changes in
bladder pressure, electrodes for sensing pudendal or sacral
afferent nerve signals, or electrodes for sensing urinary sphincter
EMG signals, or any combination thereof. In examples in which
sensor 22 is a pressure sensor, the pressure sensor may be a remote
sensor that wirelessly transmits signals to IMD 16 or may be
carried on one of leads 18, 20, or 28 or an additional lead coupled
to IMD 16. In examples in which sensor 22 includes one or more
electrodes for sensing afferent nerve signals, the sense electrodes
may be carried on one of leads 18, 20, or 28 or an additional lead
coupled to IMD 16. In examples in which sensor 22 includes one or
more sense electrodes for generating a urinary sphincter EMG, the
sense electrodes may be carried on one of leads 18, 20, or 28 or
additional leads coupled to IMD 16. In any case, in some examples,
IMD 16 may control the delivery of electrical stimulation based on
input received from sensor 22. For example, IMD 16 may initiate the
delivery of stimulation to inhibit the contract of bladder 12 when
the sensor 22 indicates an increase in the probability of an
involuntary voiding event of patient 14, such as when an increase
in bladder pressure is detected by sensor 22.
[0039] In other examples, sensor 22 may comprise a patient motion
sensor that generates a signal indicative of patient activity level
or posture state. In some examples, IMD 16 controls the delivery of
stimulation therapy to patient 14 based on sensed patient activity
level or posture state. For example, a patient activity level that
is greater than or equal to a threshold may indicate that there is
an increase in urgency and/or an increase in the probability that
an incontinence event will occur, and accordingly, IMD 16 may
provide electrical stimulation based on the patient activity
level.
[0040] As an additional example, patient 14 may be more prone to an
incontinence event when patient 14 is in an upright posture state
compared to a lying down posture state. Accordingly, in some
examples, IMD 16 may control the delivery of electrical stimulation
to patient based on the patient posture state determined based on a
signal generated by sensor 22.
[0041] As another example, sensor 22 may generate a signal
indicative of patient motion and IMD 16 or programmer 24 may
determine whether patient 14 voluntarily voided based on a pattern
in the patient motion signal associated with a voluntary voiding
event alone or in combination with other sensed parameters (e.g.,
bladder impedance).
[0042] System 10 includes an external programmer 24, as shown in
FIG. 1. In some examples, programmer 24 may be a wearable
communication device, handheld computing device, computer
workstation, or networked computing device. Programmer 24 may
include a user interface that receives input from a user (e.g.,
patient 14, a patient caretaker or a clinician). The user interface
may include a keypad and a display (e.g., an LCD display). The
keypad may take the form of an alphanumeric keypad or a reduced set
of keys associated with particular functions of programmer 24.
Programmer 24 can additionally or alternatively include a
peripheral pointing device, such as a mouse, via which a user may
interact with the user interface. In some examples, a display of
programmer 24 may include a touch screen display, and a user may
interact with programmer 24 via the touch screen display. It should
be noted that the user may also interact with programmer 24 and/or
IMD 16 remotely via a networked computing device.
[0043] Patient 14 may interact with programmer 24 to control IMD 16
to deliver the stimulation therapy, to manually abort the delivery
of the stimulation therapy by IMD 16 while IMD 16 is delivering the
therapy or is about to deliver the therapy, or to inhibit the
delivery of the stimulation therapy by IMD 16, e.g., during
voluntary voiding events. Patient 14 may, for example, use a keypad
or touch screen of programmer 24 to cause IMD 16 to deliver the
stimulation therapy, such as when patient 14 senses that a leaking
episode may be imminent. In this way, patient 14 may use programmer
24 to control the delivery of the stimulation therapy "on demand,"
e.g., when extra stimulation therapy is desirable.
[0044] Patient 14 may interact with programmer 24 to terminate the
delivery of the stimulation therapy during voluntary voiding events
or to modify the type of stimulation therapy that is delivered
(e.g., to control IMD 16 to deliver stimulation therapy to help
patient 14 voluntarily void in examples in which patient 14 has a
urinary retention disorder). That is, patient 14 may use programmer
24 to enter input that indicates the patient will be voiding
voluntarily. When IMD 16 receives the input from programmer 24, IMD
16 may suspend delivery the stimulation therapy for a predetermined
period of time, e.g., two minutes, to allow the patient to
voluntarily void, or switch to a different type of stimulation
therapy to help patient 14 voluntarily void.
[0045] A user, such as a physician, technician, surgeon,
electrophysiologist, or other clinician, may also interact with
programmer 24 or another separate programmer (not shown), such as a
clinician programmer to communicate with IMD 16. Such a user may
interact with a programmer to retrieve physiological or diagnostic
information from IMD 16. The user may also interact with a
programmer to program IMD 16, e.g., select values for the
stimulation parameter values of the therapy cycle with which IMD 16
generates and delivers electrical stimulation and/or the other
operational parameters of IMD 16. For example, the user may use
programmer 24 to retrieve information from IMD 16 regarding the
contraction of bladder 12 and voiding events. As another example,
the user may use programmer 24 to retrieve information from IMD 16
regarding the performance or integrity of IMD 16 or other
components of system 10, such as leads 18, 20, and 28, or a power
source of IMD 16.
[0046] In some examples, patient 14 or other user may interact with
programmer 24 to instruct IMD 16 to identify a pulse width for the
delivered electrical stimulation based on the determined chronaxie
for the stimulation nerve site and/or assist IMD 16 in determining
such a chronaxie, e.g., by providing input via programmer 24
identifying the motor threshold for stimulation at a given pulse
width, e.g., based on patient 14 sensation of the activation by the
electrical stimulation.
[0047] IMD 16 and programmer 24 may communicate via wireless
communication using any techniques known in the art. Examples of
communication techniques may include, for example, low frequency or
radiofrequency (RF) telemetry, but other techniques are also
contemplated. In some examples, programmer 24 may include a
programming head that may be placed proximate to the patient's body
near the IMD 16 implant site in order to improve the quality or
security of communication between IMD 16 and programmer 24.
[0048] In some examples, IMD 16 controls the delivery of
stimulation to inhibit bladder contraction based on patient input
from programmer 24 and/or sensor data (e.g., generated by sensor
22). Sensor data may include measured signals relating to urinary
incontinence, e.g., bladder impedance, bladder pressure, pudendal
or sacral afferent nerve signals, a urinary sphincter EMG, or any
combination thereof. As another example, sensor data may include,
and IMD 16 may deliver stimulation therapy in response to, measured
signals relating to a patient activity level or patient posture
state. In some instances, sensor data may be indicative of an
increased probability of an occurrence of an involuntary voiding
event.
[0049] Bladder contraction may be less likely immediately after a
voiding event and/or the possibility of an involuntary voiding
event may be relatively low immediately after a voiding event.
Therefore, the delivery of stimulation to inhibit bladder
contraction may not be necessary to prevent or at least minimize
the possibility of an involuntary voiding event during the time
period immediately following the occurrence of a voluntary or
involuntary voiding event. In contrast, bladder contraction may be
more likely as time passes since the last voiding event and/or the
possibility of an involuntary voiding event may increase as time
passes since the last voiding event. Accordingly, IMD 16 may
delivery stimulation to inhibit bladder contraction only after a
period of time has passed since the last voiding event. For
example, IMD 16 may be configured to deliver electrical stimulation
to inhibit bladder contraction only after fill level of the bladder
is determined to be above a threshold level (e.g., some fill level
associated with a high probability of an involuntary voiding
event).
[0050] FIG. 2 is conceptual diagram illustrating another example
therapy system 30 that delivers stimulation therapy to manage,
e.g., urinary incontinence or other condition of patient 14.
Therapy system 30 includes a distributed array of electrical
stimulators, referred to herein as microstimulators 32A-32D
(collectively referred to as "microstimulators 32"), in addition to
IMD 16, leads 18, 20, and 28, sensor 22, and programmer 24.
Microstimulators 32 are configured to generate and deliver
electrical stimulation therapy to patient 14 via one or more
electrodes. Microstimulators 32 have a smaller size than IMD 16,
and are typically leadless.
[0051] IMD 16 may deliver electrical stimulation therapies to
patient 14 via microstimulators 32. For example, IMD 16 may
communicate wirelessly with microstimulators 32 via wireless
telemetry to control delivery of the stimulation therapies via
microstimulators 32. In the example of FIG. 2, microstimulators 32
are implanted at different target stimulation sites. For example,
microstimulators 32A and 32B may be positioned to stimulate a
different set of nerves than microstimulators 32C and 324D. As an
example, microstimulators 32A and 32B may target sacral nerves,
while microstimulators 32C and 32D target the pudendal nerve. In
other examples, microstimulators 32 may be implanted at various
locations within the pelvic floor region, e.g., at different
positions in proximity to the sacrum to target different nerves
within the pelvic region. The illustrated number and configuration
of microstimulators 32 is merely exemplary. Other configurations,
i.e., number and position of microstimulators, are possible.
[0052] Systems 10 and 30 shown in FIGS. 1 and 2, respectively, are
merely examples of therapy systems that may provide a stimulation
therapy to manage urgency and/or urinary incontinence. Systems with
other configurations of leads, electrodes, and sensors are
possible. Additionally, in other examples, a system may include
more than one IMD.
[0053] FIG. 3 is a functional block diagram illustrating example
components of IMD 16. In the example of FIG. 3, IMD 16 includes
sensor 22, processor 50, therapy delivery module 52, impedance
module 54, memory 56, telemetry module 58, and power source 60.
[0054] Therapy delivery module 52 generates and delivers electrical
stimulation under the control of processor 50. In particular,
processor 50 controls therapy delivery module 52 by accessing
memory 56 to selectively access and load therapy programs into
therapy delivery module 52. Therapy delivery module 52 generates
and delivers electrical stimulation according to the therapy
programs. In some examples, therapy delivery module 52 generates
therapy in the form of electrical pulses. In other examples,
therapy delivery module 52 may generate electrical stimulation in
the form of continuous waveforms.
[0055] Patient 14 may provide patient input to IMD 16 using
programmer 24 or another device, or directly via IMD 16. For
example, patient 14 may provide patient input to IMD 16 using
sensor 22 when sensor 22 includes a motion sensor that is
responsive to tapping (e.g., by patient 14) on skin superior to IMD
16. When sensor 22 includes a motion sensor that is responsive to
tapping, upon detecting the pattern of tapping that indicates a
particular patient input, processor 50 may determine that the
patient input was received.
[0056] Regardless of whether patient input is received from
programmer 24 or other device, the patient input may indicate an
urge felt by patient 14, a leakage incident experienced by patient
14, an imminent voiding event predicted by patient 14, a voluntary
voiding event undertaken by patient 14 or other information that
may affect the timing or intensity level of stimulation delivered
by IMD 16.
[0057] In the example of FIG. 3, therapy delivery module 52 is
electrically coupled to a single lead 28, and therapy delivery
module 52 delivers electrical stimulation to a tissue site of
patient 14 via selected electrodes 29A-29D carried by lead 28. A
proximal end of lead 28 extends from the housing of IMD 16 and a
distal end of lead 28 extends to one or more target therapy sites
proximate a sacral nerve. In other examples, therapy delivery
module 52 may deliver electrical stimulation with electrodes on
more than one lead and each of the leads may carry one or more
electrodes. The leads may be configured as axial leads with ring
electrodes and/or paddle leads with electrode pads arranged in a
two-dimensional array. Additionally, or alternatively, the leads
may include segmented and/or partial ring electrodes. The
electrodes may operate in a bipolar or multi-polar configuration
with other electrodes, or may operate in a unipolar configuration
referenced to an electrode carried by the device housing or "can"
of IMD 16. In yet other examples, such as system 30 shown in FIG. 2
that includes microstimulators 32, processor 50 may act as a
"master" module that controls microstimulators to deliver
stimulation at target therapy sites. In other examples, however,
one of microstimulators 32 may act as a master module or
microstimulators 32 may be self-controlled.
[0058] In some examples, processor 50 controls therapy module 52 to
deliver the stimulation therapy to patient 14 based on signals
received from impedance module 54, sensor 22, or patient input
received via telemetry module 58. In the example shown in FIG. 3,
processor 50 monitors bladder impedance to detect bladder
contractions based on signals received from impedance module 54.
For example, processor 50 may determine an impedance value based on
signals received from impedance module 54, and a particular
impedance value may be associated with a bladder contraction (e.g.,
based on data obtained during a programming period). Therapy module
52 may deliver electrical stimulation therapy to patient 14 based
on detection of bladder contraction using impedance module 54. For
example, therapy module 52 may deliver electrical stimulation to
inhibit bladder contraction in response to detection of an
impedance value that indicates that the likelihood of a bladder
contraction is increasing in order to address a possible increase
likelihood of unintentional voiding. In other examples, therapy
module 52 may deliver electrical stimulation to inhibit bladder
contraction in response to detection of an impedance value (e.g., a
low impedance value) that indicates that the bladder is filling in
order to address a possible increase in the likelihood of
unintentional voiding. In still other examples, a high impedance
value may indicate that the bladder is empty, for example, after a
voiding event.
[0059] In the example of FIG. 3, impedance module 54 includes
voltage measurement circuitry 62 and current source 64, and may
include an oscillator (not shown) or the like for producing an
alternating signal, as is known. In some examples, as described
above with respect to FIG. 1, impedance module 54 may use a
four-wire, or Kelvin, arrangement. As an example, processor 50 may
periodically control current source 64 to, for example, source an
electrical current signal through electrode 19A and sink the
electrical current signal through electrode 21A. Impedance module
54 may also include a switching module (not shown) for selectively
coupling electrodes 19A, 19B, 21A, and 21B to current source 64 and
voltage measurement circuitry 62. Voltage measurement circuitry 62
may measure the voltage between electrodes 19B and 21B. Voltage
measurement circuitry 62 may include sample and hold circuitry or
other suitable circuitry for measuring voltage amplitudes.
Processor 50 determines an impedance value from the measured
voltage values received from voltage measurement circuitry 52.
[0060] Processor 50 may delivery stimulation to inhibit bladder
contraction based on signals received from sensor 22 in addition
to, or instead of, impedance module 54. In examples in which sensor
22 includes a pressure sensor, processor 50 may determine a bladder
pressure value based on signals received from the pressure sensor.
Processor 50 may determine whether contractions of bladder 12 are
indicative an imminent incontinence event, for example, based on
comparison of the sensed pressure to a pressure threshold that
indicates an imminent event. For example, processor 50 may detect
an imminent incontinence event when the sensed pressure is greater
than the pressure threshold. Accordingly, in some examples, therapy
delivery module 52, under control of processor 50, may deliver
electrical stimulation to inhibit bladder contraction when sensed
pressure is greater than the pressure threshold.
[0061] In examples in which sensor 22 includes a motion sensor,
processor 50 may determine a patient activity level or posture
state based on a signal generated by sensor 22. For example,
processor 50 may determine a patient activity level by sampling the
signal from sensor 22 and determining a number of activity counts
during a sample period, where a plurality of activity levels are
associated with respective activity counts. In one example,
processor 50 compares the signal generated by sensor 22 to one or
more amplitude thresholds stored within memory 56, and identifies
each threshold crossing as an activity count.
[0062] Processor 50 may determine a patient posture state based on
a signal from sensor 22 using any suitable technique. In one
example, a posture state may be defined as a three-dimensional
space (e.g., a posture cone or toroid), and whenever a posture
state parameter value, e.g., a vector from a three-axis
accelerometer of sensor 22 resides within a predefined space,
processor 50 indicates that patient 14 is in the posture state
associated with the predefined space.
[0063] Certain posture states or activity levels may be associated
with a higher incidence of incontinence events. For example,
patient 14 may have less control of the pelvic floor muscles when
occupying an upright posture state or when patient 14 is in a
highly active state (e.g., as indicated by a stored activity count
or a threshold activity signal value). Thus, detection of these
activity levels or posture states may be triggers for the delivery
of stimulation therapy. For example, therapy delivery module 52
may, under control of processor 50, deliver electrical stimulation
when sensed activity levels or patient posture indicates an
increased probability that an incontinence event may occur.
[0064] The threshold values stored in memory 56 may be determined
using any suitable technique. In some examples, the threshold
values may be determined during implantation of IMD 16 or during a
trial period in a clinician's office following the implant
procedure. For example, a clinician may record impedance values
during involuntary voiding events and use the recorded impedance
values or values calculated based on the recorded values as
threshold values. These threshold values may be adapted over time
based on patient input, e.g., via external programmer 24. As an
example, patient 14 may indicate, via programmer 24, when an
involuntary voiding event takes place. When the patient input is
received, processor 50 may determine an impedance value during the
event or immediately prior to the event based on signals received
from impedance module 54. A new threshold value may be determined
using this impedance value. For example, the threshold value stored
may be a running average of impedance values measured during
involuntary voiding events.
[0065] In some examples, IMD 16 includes impedance sensing module
54 and not sensor 22, while in other examples IMD 16 includes
sensor 22 but not impedance sensing module 54. Moreover, in some
examples, sensor 22 and/or impedance sensing module 54 may be
physically separate from IMD 16. Physically separate sensors may be
useful in examples in which either sensor 22 and/or impedance
sensing module 54 sense one or more physiological parameters at a
location that is not accessible by IMD 16 or difficult to access by
IMD 16.
[0066] Processor 50 may control therapy delivery module 52 to
deliver stimulation therapy based on patient input received via
telemetry module 58. Telemetry module 58 includes any suitable
hardware, firmware, software or any combination thereof for
communicating with another device, such as programmer 24 (FIG. 1).
Under the control of processor 50, telemetry module 58 may receive
downlink telemetry, e.g., patient input, from and send uplink
telemetry to programmer 24 with the aid of an antenna, which may be
internal and/or external. Processor 50 may provide the data to be
uplinked to programmer 24 and the control signals for the telemetry
circuit within telemetry module 58, and receive data from telemetry
module 58.
[0067] Processor 50 may control telemetry module 58 to exchange
information with medical device programmer 24. Processor 50 may
transmit operational information and receive stimulation programs
or stimulation parameter adjustments via telemetry module 58. Also,
in some examples, IMD 16 may communicate with other implanted
devices, such as stimulators, control devices, or sensors, via
telemetry module 58.
[0068] The processors described in this disclosure, such as
processor 50 and processing circuitry in impedance module 54 and
other modules, may be one or more digital signal processors (DSPs),
general purpose microprocessors, application specific integrated
circuits (ASICs), field programmable logic arrays (FPGAs), or other
equivalent integrated or discrete logic circuitry, or combinations
thereof. The functions attributed to processors described herein
may be provided by a hardware device and embodied as software,
firmware, hardware, or any combination thereof. In some examples,
the processing circuitry of impedance module 54 that determines an
impedance based on a measured voltage and/or current of a signal
may be the same microprocessor, ASIC, DSP, or other digital logic
circuitry that forms at least part of processor 50.
[0069] Memory 56 stores instructions for execution by processor 50,
in addition to therapy cycles. In some examples, memory 56 store
patient parameter information, such as information generated by
impedance module 54 and/or sensor 22. For example, information
related to measured impedance and determined posture may be
recorded for long-term storage and retrieval by a user, or used by
processor 50 for adjustment of stimulation parameters, such as
amplitude, pulse width, and frequency (e.g., pulse rate). Memory 56
may include separate memories for storing instructions, electrical
signal information, programs, and other data.
[0070] In addition to the stimulation pulse widths described
herein, example ranges of electrical stimulation parameters that
may be used in the electrical stimulation therapy include amplitude
(voltage amplitude or current amplitude) and frequency (e.g., pulse
rate). In some example, the amplitude may be between approximately
0.1 volts and 50 volts, such as between approximately 0.5 volts and
20 volts, or between approximately 0.1 volt and 10 volts. In other
embodiments, a current amplitude may be defined as the biological
load in the voltage that is delivered. For example, the range of
current amplitude may be between approximately 0.1 milliamps (mA)
and 50 mA. In some examples, the frequency may be between about 0.5
Hz and about 500 Hz, such as between about 1 Hz and about 250 Hz,
between about 1 Hz and about 20 Hz, or about 10 Hz.
[0071] As described herein, the stimulation parameters may define
an electrical stimulation therapy with an intensity below a motor
threshold of the target tissue being stimulation at a given pulse
width and frequency. For example, the stimulation may have an
intensity just below the motor threshold such that the stimulation
does result in a motor evoked potential in the stimulated tissue
but still inhibits contraction of at least one a bladder or bowel
of the patient. The pulse width for the delivered electrical
stimulation may be selected based on the chronaxie identified for
patient 12, e.g., for a particular nerve site.
[0072] Memory 56 may include any volatile, non-volatile, magnetic,
or electrical media, such as a random access memory (RAM),
read-only memory (ROM), non-volatile RAM (NVRAM),
electrically-erasable programmable ROM (EEPROM), flash memory, and
the like. Memory 56 may store program instructions that, when
executed by processor 50, cause IMD 16 to perform the functions
ascribed to IMD 16 herein.
[0073] Power source 60 delivers operating power to the components
of IMD 16. Power source 60 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 IMD 16. In other examples, an external
inductive power supply may transcutaneously power IMD 16 whenever
stimulation therapy is to occur.
[0074] FIG. 4 is a functional block diagram illustrating example
components of external programmer 24. While programmer 24 may
generally be described as a hand-held computing device, the
programmer may be a notebook computer, a cell phone, or a
workstation, for example. As illustrated in FIG. 4, external
programmer 24 may include a processor 70, memory 72, user interface
74, telemetry module 76, and power source 78. Memory 72 may store
program instructions that, when executed by processor 70, cause
processor 70 to provide the functionality ascribed to programmer 24
throughout this disclosure.
[0075] In some examples, memory 72 may further include therapy
cycles defining stimulation therapy, similar to those stored in
memory 56 of IMD 16. The therapy cycles stored in memory 72 may be
downloaded into memory 56 of IMD 16. Memory 72 may include any
volatile, non-volatile, fixed, removable, magnetic, optical, or
electrical media, such as RAM, ROM, CD-ROM, hard disk, removable
magnetic disk, memory cards or sticks, NVRAM, EEPROM, flash memory,
and the like. Processor 70 can take the form one or more
microprocessors, DSPs, ASICs, FPGAs, programmable logic circuitry,
or the like, and the functions attributed to processor 70 herein
may be embodied as hardware, firmware, software or any combination
thereof.
[0076] User interface 74 may include a button or keypad, lights, a
speaker for voice commands, and a display, such as a liquid crystal
(LCD). In some examples the display may be a touch screen. As
discussed in this disclosure, processor 70 may present and receive
information relating to stimulation therapy via user interface 74.
For example, processor 70 may receive patient input via user
interface 74. The patient input may be entered, for example, by
pressing a button on a keypad or selecting an icon from a touch
screen. Patient input may include, but is not limited to, input
that indicates an urge felt by the patient, a leakage incident
experienced by the patient, an imminent voiding event predicted by
the patient, or a voluntary voiding event to be undertaken by the
patient.
[0077] Telemetry module 76 supports wireless communication between
IMD 16 and external programmer 24 under the control of processor
70. Telemetry module 76 may also be configured to communicate with
another computing device via wireless communication techniques, or
direct communication through a wired connection. Telemetry module
76 may be substantially similar to telemetry module 58 described
above, providing wireless communication via an RF or proximal
inductive medium. In some examples, telemetry module 76 may include
an antenna, which may take on a variety of forms, such as an
internal or external antenna. An external antenna that is coupled
to programmer 24 may correspond to a programming head that may be
placed over IMD 16.
[0078] Examples of local wireless communication techniques that may
be employed to facilitate communication between programmer 24 and
another computing device include RF communication according to IEEE
802.11 or Bluetooth specification sets, infrared communication,
e.g., according to an IrDA standard, or other standard or
proprietary telemetry protocols. In this manner, other external
devices may be capable of communicating with programmer 24 without
needing to establish a secure wireless connection.
[0079] In some cases, it may be desirable for IMD 16 to decrease
the frequency of stimulation or even suspend the delivery of the
stimulation configured to inhibit bladder contractions of patient
14 when patient 14 needs to void. In some examples, patient 14 may
interact with programmer 24 (or directly with IMD 16 as described
above) to control IMD 16 to withhold the stimulation that is
intended to inhibit bladder contractions. Patient 14 may indicate
an intent to void via user interface 74, and processor 70 may
implement a blanking interval through communication of the
indication to IMD 16 via telemetry module 76. For example,
processor 70 may transmit a command signal to IMD 16 that indicates
IMD 16 should temporarily suspend delivery of the stimulation
therapy in response to command signal. In some cases, this may
permit voluntary voiding by patient 14.
[0080] In other examples, IMD 16 may automatically determine when
patient 14 is attempting to voluntary void, e.g., based on a
voiding signature of an EMG signal indicative of bladder activity
or based on bladder pressure or contraction. In such examples, IMD
16 may automatically suspend the delivery of electrical stimulation
therapies to permit patient 14 to voluntary void. In some cases,
suspension of stimulation by IMD 16 is not necessary to facilitate
voiding, and stimulation may occur substantially simultaneously
with the voluntary voiding. For example, the bladder volume will
eventually increase to a level to trigger strong bladder
contractions that prevails over the stimulation therapy to allow
voiding.
[0081] Power source 78 delivers operating power to the components
of programmer 24. Power source 78 may include a battery, for
example a rechargeable battery. Recharging may be accomplished by
using an alternating current (AC) outlet or through proximal
inductive interaction between an external charger and an inductive
charging coil within programmer 24.
[0082] FIG. 5 is a flow diagram of an example technique for
delivering electrical stimulation to a sacral nerve of patient. For
ease of description, the technique will be described as being
performed by medical device system 10 of FIGS. 1-4. In some
examples, the technique of FIG. 5 may be implemented as a set of
instructions executable by processor 50 and stored by memory 56 of
IMD 16 or a memory of another device. While processor 50 and memory
56 are primarily referred to throughout the description of FIG. 5,
in other examples, a processor of another device (e.g., programmer
24) may perform any part of the techniques described herein,
including the technique shown in FIG. 5, alone or in combination
with another device. Although FIG. 5 is described with regard to
system 10 of FIG. 1, other systems and devices employing the
technique of FIG. 5 are contemplated.
[0083] In accordance with the example of FIG. 5, system 10 may
identify the chronaxie for electrical stimulation delivered to the
sacral nerve of patient 14 from IMD 16 that evokes a threshold
motor response (82). Any suitable technique may be used to identify
the chronaxie for electrical stimulation delivered to the sacral
nerve of patient via IMD 16. In the example of FIG. 5, IMD 16,
under the control of processor 50, may deliver electrical
stimulation to the sacral nerve via one or more of electrodes 29 at
plurality of different pulse widths while keeping the frequency
constant (80). For each pulse width, the threshold intensity of the
stimulation that evokes a motor response may be determined, e.g.,
by ramping/stepping up the amplitude of the stimulation from some
nominal amount until a motor response is evoked by the stimulation
(80). The evoked threshold motor response may be detected using any
suitable technique including, e.g., based on a EMG signal and/or
accelerometer signal sensed via sensor 22, local pulsation, patient
feedback indicating sensation of a motor response or other
sensation such as tingle, which may occur earlier than an evoked
motor response, and the like. Patient feedback may be input by
patient 14 or clinician via programmer 24. For example, patient 14
may provide input indication a sensation corresponding to
activation of nerve fibers as a result of electrical stimulation at
a set pulse width while the amplitude of the stimulation is
ramped/stepped up. Such a process may be repeated at a plurality of
difference pulse width (e.g., as a fixed frequency) to identify the
chronaxie for the electrical stimulation delivered to the sacral
nerve of patient 14.
[0084] Processor 50 and/or 70 may then determine the chronaxie for
the electrical stimulation delivered to the sacral nerve based on
the determined thresholds for each of the pulse widths. In one
example, processor 50 may identify the rheobase for the delivered
electrical stimulation, and then determine the pulse width at which
an amplitude twice the rheobase evoked at threshold evoked motor
response. In some examples, the described "test" stimulation
therapy at a plurality of different pulse widths may be used to
generate a plot similar to the strength-duration plot show in FIG.
6, and the chronaxie of the stimulation may be determined using the
generated plot. For example, using a set of data points identifying
a response thresholds for various pulse widths, the chronaxie and
rheobase may be calculated with a non-linear fit to
Y=(Y.sub.0-N.sub.S)*exp.sup.(-K*X)+N.sub.S, where Y is the EMG
response (assessed either visually or via the EAS electrodes), X is
the pulse width, Y.sub.0 is the initial value, N.sub.S is the
rheobase, and K is the inverse of the chronaxie. However, other
techniques may be utilized to determine the chronaxie in a manner
that is specific to patient 14, e.g., rather than estimating the
chronaxie based on deliver of similar stimulation to one or more
other patients.
[0085] IMD 16 may then be programmed using programmer 24 to deliver
electrical stimulation to the sacral nerve of patient 14 with a
pulse width at or near the identified chronaxie (84) to treat
incontinence or other disorder of patient 14. For example, the
pulse width may be within about 50%, about 40%, about 30%, about
20%, about 10%, about 5%, or about 1% of the identified chronaxie.
As another example, the pulse with may be within at least one of
about 50 microseconds, about 40 microseconds, about 30
microseconds, about 20 microseconds, about 10 microseconds, about 5
microseconds, or about 1 microsecond of the identified chronaxie.
The frequency (e.g., pulse rate) of the sacral nerve stimulation
may be the same or substantially similar to the frequency of the
"test" stimulation to identify the chronaxie. The amplitude of the
sacral nerve stimulation may be just below the threshold that
evokes a motor response at the defined pulse width and frequency.
In this manner, the sacral nerve stimulation may inhibit the
contraction of the bladder and/or bowel of patient 14 without
evoking a motor response.
[0086] The technique of FIG. 5 may be performed during a
programming session (e.g., an initial programming session after the
implantation of IMD 16) and/or periodically throughout the chronic
delivery of sacral nerve stimulation to treat patient 16 to
re-determine the chronaxie of the stimulation, which may change
over time. For example, the re-determination may occur periodically
based on a predetermined schedule and/or based on patient input
(e.g., when patient 16 believes that the sacral nerve stimulation
therapy is no longer effectively treating the patient
condition).
[0087] The techniques described in this disclosure may be
implemented in hardware, software, firmware, or any combination
thereof. In particular, the techniques may be implemented in a
hardware device, such as a wireless communication device or network
device, either of which may include software and/or firmware to
support the implementation. For portions implemented in software,
the techniques may be realized in part by a computer-readable
medium comprising program code containing instructions that, when
executed, performs one or more of the methods described above. In
this case, the computer readable medium may comprise RAM (e.g.,
synchronous dynamic random access memory (SDRAM)), ROM, NVRAM,
EEPROM, FLASH memory, magnetic or optical data storage media, and
the like.
[0088] The program code may be executed by one or more processors,
such as one or more DSPs, general purpose microprocessors, ASICs,
FPGAs, or other equivalent integrated or discrete logic circuitry.
In this sense, the techniques are implemented in hardware, whether
implemented entirely in hardware or in hardware such as a processor
executing computer-readable code. Accordingly, the term
"processor," as used herein may refer to any of the foregoing
structure or any other structure suitable for implementation of the
techniques described herein.
EXPERIMENTAL RESULTS
[0089] Multiple studies were carried out to evaluate one or more
aspects of example of the disclosure. Those studies are described
below. However, the disclosure is not limited by the studies or the
corresponding description.
Study One--Motor Responses to S3 Sacral Nerve Stimulation in
Sheep
[0090] One object of the first sheep study was to characterize the
strength-duration (SD) response of external anal sphincter (EAS)
activation as assessed both visually and with EMG in response to
the third sacral foramen (S3) sacral neuromodulation (SNM). SNM at
the S3 is an FDA-approved therapy for urinary urge incontinence,
urgency-frequency and fecal incontinence. In some examples, a
recommended pulse width for SNM is 210 .mu.s, but the SD response
from S3 SNM has not been fully elucidated. A positive motor
response in the EAS can be a candidate predictor for clinical
efficacy.
Methods
[0091] Four adult female Polypay sheep were used for this study.
The age of the sheep ranged from 18 to 39 months (mean: 31 months)
with weights ranging from ranging from 64 to 92 kilograms (kg)
(mean: 78 kg). A pair of sensing electrodes, with inter-electrode
distance of about 1 cm were implanted in the EAS at the three and
nine o'clock positions. The lead bodies were tunneled cranially and
exteriorized. A two cm skin incision was made in the perineum
lateral to the tail, and subcutaneous tissue was dissected until
the EAS was palpated. Two foramen needle introducers were passed
from just lateral to the vulva dorsally, through the EAS, and out
the subcutaneous tissue dissection plane. The sensing electrodes
(Medtronic Model 431, 35 cm length, Medtronic Inc., Minneapolis,
Minn., USA) were passed into each introducer. The introducers were
removed and the electrodes were sutured into the EAS.
[0092] Tined, quadripolar electrode leads (Medtronic Model 3889)
were implanted bilaterally in the S3 foramina. The lead bodies were
tunneled cranially and exteriorized. Concurrent electrical
stimulation during lead placement was used to assess the best
placement. The final lead placement was chosen based on lowest
stimulation threshold seen in the EAS.
[0093] Variable intensity (0.1V to 10V), 10 Hz stimulation was
delivered unilaterally to electrodes 3(-) & 0(+) for 10 to 300
.mu.s pulse widths. Balanced, biphasic stimulation was delivered
with a Biopac STM100C (Biopac Systems, Inc., Goleta, Calif., USA).
A 100 .mu.s inter-phase interval was present between the cathodic
and anodic phases. In two sheep, the SD curves were assessed
independently from both pairs of S3 leads. In another sheep, two
sets of SD curves were collected from the same lead on different
days.
[0094] EMG was collected from the two bipolar pairs in the EAS to
assess EAS contraction. Biopac EMG100C sense amplifiers were used.
The HP pole was 10 Hz, the LP pole was 5 kHz, gain was 2000, and
the sampling rate was 25 kHz. EAS contraction was also assessed
visually.
Results and Discussion
[0095] SD response thresholds were plotted against the cathodic
pulse width. The chronaxie and rheobase were calculated with a
non-linear fit to Y=(Y.sub.0-N.sub.S)*exp.sup.(-K*X)+N.sub.S, where
Y is the EMG response (assessed either visually or via the EAS
electrodes), X is the pulse width, Y.sub.0 is the initial value,
N.sub.S is the rheobase, and K is the inverse of the chronaxie. All
data was expressed as mean.+-.standard error of mean. The EMG
area-under-the curve (AUC) for three different pulse widths (10
.mu.s, 60 .mu.s and 210 .mu.s) was also plotted as a function of
stimulation amplitude.
[0096] FIG. 8A is the plot of SD curves for both the EMG and
visually assessed EAS contraction threshold. The chronaxie and
rheobase for the EMG assessed SD curves was 62.03.+-.0.001 .mu.s
and 0.48.+-.0.29V. The chronaxie and rheobase for the visually
assessed SD curves was 74.35.+-.0.001 .mu.s and 0.48.+-.0.12V,
respectively. The amplitude required to evoke an EAS contraction
with 10 .mu.s cathodic pulses as assessed both with EMG and
visually was 1.62.+-.0.22V and 1.85.+-.0.39V, respectfully. FIG. 8B
is the plot of EMG area-under-the curve (AUC) for three different
pulse widths (10 .mu.s, 60 .mu.s and 210 .mu.s) as a function of
stimulation amplitude.
[0097] Based on the results, the chronaxie for EAS activation in
response to S3 SNM in normal physiology sheep was determined to be
significantly lower than the standard 210 .mu.s pulse width used
clinically. It was unknown if SNM at shorter pulse widths has
equivalent clinical efficacy to that at 210 .mu.s.
Study Two--Sacral Neuromodulation in Sheep
[0098] One object of the second sheep study was to characterize the
EMG responses of the EAS to different pulse widths (PWs) of S3 SNM
in anesthetized and awake sheep. Quadripolar tined leads were
implanted adjacent to the S3 nerve root bilaterally to deliver SNM
and two pairs of intramuscular leads were placed on either side of
the EAS for EMG sensing. The EMG responses to SNM with different
PWs (ranging from 0.03 milliseconds (ms) to 0.3 ms) were examined
using variable intensities from 0.1 V to 5 V.
Methods
[0099] Fourteen S3 nerve roots from seven adult, female Polypay
sheep (two roots per sheep) were used for the study. The animals
ranged in age from 18 to 39 months (mean: 31 months) and weight
from 64 to 92 kg (mean: 78 kg) at time of implant. The sheep were
prepped with intramuscular morphine (0.5 mg/kg), induced with
intravenous propofol, and maintained on isoflurane. To deliver S3
neuromodulation, Medtronic Model 3889 tined quadripolar leads (28
cm length) were inserted through the left and right side of the
sacral foramen, respectively. The S3 foramina were identified under
fluoroscopic guidance and electrical stimulation was used to verify
appropriate motor responses of perianal, tail, or bellows
contractions with minimal leg contractions. The final lead
placement was chosen based on the stimulation threshold for motor
response at the designated location with the lowest stimulation
voltage. The leads were tunneled to separate sub-dermal pockets
cranially and anchored at the externalization site.
[0100] FIG. 7 is a flowchart summarizing a trial schedule for the
sheep study. In all seven sheep, EMG responses were recorded
initially under anesthesia of propofol and isoflurane, and a couple
of weeks later in an awake condition. Sacral nerve stimulation was
delivered with a stimulator, which was connected to the externally
tunneled quadripolar lead. The stimulator parameters were bipolar
10 Hz, and electrodes 3 and 0 as the cathode and anode,
respectively. Pulse widths and stimulation amplitudes were swept
through various values to develop threshold-PW curves.
[0101] Response thresholds were obtained from both visual detection
(T.sub.visual) and EMG waveform analysis against the stimulus
intensity. T.sub.visual was determined by the stimulation intensity
which triggered the first visible appearance of a motor response to
ascending intensity of consecutive 10 Hz stimuli and further
confirmed by disappearance of motor response to decreasing
stimulation intensity. The evaluated parameters of EMG response
include threshold (T.sub.EMG) and the area under the curve (AUC,
represented by mV-msec) of integrated and calculated EMG action
potentials. Responses to stimulation on each nerve root were
plotted against the voltage intensity on a semilogarithmic scale.
The T.sub.EMG of each individual response was defined as the
intensity at which evoked potentials were distinguished from basal
activity in the EMG detection window and increased to at least
three ascending intensities of consecutive 10 Hz stimuli.
[0102] To assess the effect of PW on motor function, T.sub.visualS
or T.sub.EMGS were plotted against PW. The chronaxie and rheobase
were calculated according to the equation
Y=(Y.sub.0-N.sub.S)*exp.sup.(-K*X)+N.sub.S, where Y is threshold
response, X is the pulse width, and Y.sub.0 is the threshold value
when the pulse width is close to zero. N.sub.S is the rheobase (the
intensity needed for excitation with a very long or infinite
pulse). K is the rate constant in inverse units of pulse width. The
half-life (chronaxie) equals the ln(2) divided by K. The value of
threshold charge (voltage*PW) to different PWs were compared using
analysis of variance (ANOVA).
Results and Discussion
[0103] The EMG responses from ipsilateral EAS (I.sub.EAS) and
contralateral EAS (C.sub.EAS) were compared. The EMG responses from
I.sub.EAS appeared significantly stronger than that from C.sub.EAS.
The late component EMGs from the C.sub.EAS tended to be more
sensitive to a lower intensity of nerve stimulation in awake sheep.
The strength-duration responses from the I.sub.EAS as ascertained
visually and with EMG in anesthetized and awake sheep were fitted
with a monoexponential nonlinear regression. The resulting time
constants (chronaxie) were of 0.05 ms (n=6), and 0.04 ms (n=6) and
0.04 ms (n=8), respectively.
[0104] FIGS. 9A and 9B are plots summarizing the stimulus-response
functions of two components of EMG activities from I.sub.EAS and
C.sub.EAS to graded intensities of the SNM (i.e.,
intensity-response) in anaesthetized (FIG. 9A) and awake conditions
(FIG. 9B). The EMG responses were larger in amplitude as the
stimulation intensity was increased. The I.sub.EAS EMGs appeared
significantly stronger than C.sub.EAS in anesthetized condition
(p<0.05, two-way ANOVA, Bonferroni post-test, FIG. 9A). In the
conscious condition, the I.sub.EAS EMGs remained significantly
stronger than C.sub.EAS EMGs. In addition, the second component of
C.sub.EAS EMG occurred sensitive to SNM, with a higher response
amplitude.
[0105] FIG. 10A is a plot summarizing the response thresholds from
either visual detection (T.sub.visual) or EMG waveform analysis
from the ipsilateral EAS (T.sub.EMG) against the stimulus PW to
demonstrate the minimal stimulation required to activate the S3
nerve at a given PW in anaesthetized and conscious conditions. The
solid curves are monoexponential nonlinear regression fits and
gives time constants of 0.05 ms (95% CI: 0.03-0.08, n=6), and 0.04
ms (95% CI: 0.03-0.06, n=6) and 0.04 ms (95% CI: 0.02-0.11, n=8),
respectively. The rheobase values were 0.39.+-.0.05 V, 0.42.+-.0.03
V, and 0.70.+-.0.14 V, respectively. The maximal values to minimal
PW were 1.53.+-.0.16 V, 1.57.+-.0.11 V and 3.74.+-.0.70 V,
respectively.
[0106] FIG. 10B summarized the activation charge threshold (mV*ms)
to different PW stimulation. One-way ANOVA demonstrated
significantly lower charge values (more efficient) to shorter PWs
of 0.03 ms, 0.06 ms or 0.09 ms in comparison to longer
(.gtoreq.0.24 ms) PWs (p<0.05, Bonferroni post-test's post
test).
[0107] FIGS. 11A and 11B are plots summarizing the
stimulus-response function of increased EMG activities from the EAS
when the PWs were 0.03 ms, 0.06 mn, 0.12 ms and 0.21 ms in
anesthetized (FIG. 11A) and awake conditions (FIG. 11B). EMG
response was stronger as the stimulation intensity increased. This
effect is significantly greater to longer PW stimulations (FIG.
11B, e.g. 0.21, 0.12 ms) than that produced by short PW stimulation
(e.g. 0.03 ms, p<0.05, repeated measures ANOVA).
[0108] In the second sheep study, clinical sacral neuromodulation
therapy was mimicked via SNM leads insertion through the S3 sacral
foramen. The evoked EMG responses of the EAS, a physiomarker of
sacral neuromodulation, was measured for different pulse width S3
SNM. The study results demonstrated a 0.04-0.05 ms chronaxie for
this locus of neurostimulation. Accordingly, it was determined that
shorter pulse width SNM may be advantageous owing to minimized
energy consumption from the implantable neurostimulator battery,
versus the 0.21 ms pulse which is generally used as the clinical
standard. Reducing pulse width would be expected to significantly
increase the window between battery replacements. Potential battery
savings manifested by shorter pulse width would provide more
efficient therapy delivery and increased longevity of the
stimulator.
[0109] Based on response threshold and pulse width response curves,
short pulse widths correlate significantly to lower charge values
in comparison to longer pulse widths. Setting the stimulation
intensity close to the chronaxie may allow that shorter pulse
widths reduce the stimulation charge. Pulse width also affects the
relative selectivity of stimulation among different types of nerve
fibers (diameter). Shorter pulse widths will increase the
differences in motor thresholds from different diameters of nerve
fibers. The threshold difference between large and small nerve
fibers increases along with the increase in the relative distance
between the stimulating electrode and the nerve fibers. Thus,
preferential activation of large nerve fibers over small fibers can
be more pronounced with a shorter pulse width stimulation.
Therefore, shorter pulse width stimulation may reduce discomfort
due to higher nerve fiber selectivity compared to the 0.21 ms PW
that is widely used clinically.
Study Three--Spinal Nerve Stimulation of Rats
[0110] One object of the rat study was to investigate the spinal
nerve stimulation (SNS) evoked motor threshold (T.sub.mot) response
across different PWs, and assess a subset of selected stimulation
PWs with respect to bladder reflex contraction (BRC). The study
described the motor threshold (T.sub.mot) responses-PW of SNS at a
range of 0.02 ms to 0.3 ms. When the chronaxie of the T.sub.mot-PW
curve was identified, a subset of PWs (0.03 ms to 0.21 ms) was
tested at the frequency of 10 Hz and individual T.sub.mot intensity
on the micturition reflex in a rat model of isovolumetric bladder
contraction.
Methods
[0111] Wire electrodes were placed under each of the L6 spinal
nerves in anesthetized female Sprague-Dawley rats to produce
bilateral SNS. The rats weighed 200 grams (g) to 300 g (n=46) and
were anesthetized with urethane (two i.p. injections, 4 min apart,
total 1.2 g/kg). The anesthetized rats were maintained at 37
degrees Celsius with a heating pad during the studies and were
euthanized by CO.sub.2 asphyxia upon completion of experimental
procedures.
[0112] To deliver electrical stimulation, a wire electrode was
placed on each side of the L6 spinal nerve. The L6/S1 posterior
processes were exposed after a dorsal midline incision was made
from approximately L3 to S2. The S1 processes were removed and the
L6 nerve trunks localized caudal and medial to the sacroiliac
junction. A wire electrode was placed with bared segments of
teflon-coated, 40-guage, stainless steel wire under each nerve.
Silicone adhesive was then applied to cover the wire around the
nerve, and the skin incision was sutured shut. The electrode was
connected to a Grass S88 stimulator, through a stimulus isolation
unit (SIU-BI, Grass Medical Instruments), and needle electrodes
under the skin of the tail served as the ground.
[0113] SNS evoked hind-toe twitches and/or pelvic floor muscle
contraction. The motor response threshold current (T.sub.mot) was
evaluated across the PW range from 0.02 ms to 0.3 ms of biphasic
pulses (10 Hz) in 11 rats. T.sub.mot was defined as the lowest
intensity to evoke the first, barely discernible, skeletal muscle
contraction. It was determined as the stimulation intensity which
triggered the first visible appearance of motor response to
ascending intensity of consecutive 10 Hz stimuli and further
confirmed by disappearance of motor response to decreasing
stimulation intensity. This procedure was then repeated two more
times for added confirmation.
[0114] In each of the 35 rats in which bladder contraction was
recorded, a cannula (size PE50) was placed into the bladder via the
urethra, and secured with a suture tie. The urethral cannula was
connected via a T-type connector to a pressure transducer of the
data acquisition system (ADInstrument MLT0380D, Colorado Springs,
Colo., USA) and the intravesical pressure signal was put through a
DC amplifier (ADInstrument, ML119). The other end of the T-type
connector was attached to a syringe pump. To induce BRC, saline was
infused into the bladder via the syringe pump at a rate of 0.05 mL
per minute to induce a micturition reflex (defined as bladder
contraction of a magnitude>10 mmHg in the study). The infusion
rate was then lowered to 0.01 mL per minute and continued until 3
to 5 consecutive contractions were established. After initiating
perpetual BRC in this manner, saline infusion was terminated.
[0115] After a 15-min control period, nerve stimulation was applied
for 10 minutes. The T.sub.mot was first determined by 0.1 ms PW
stimulation and further adjusted and confirmed by disappearance
or/and re-appearance of motor response to the tested PW ranging
from 0.03 ms to 0.21 ms. The T.sub.mot was measured on each root
side separately, to allow for potential differences between left
and right nerve roots. Stimulation intensities at a given PW were
then maintained for 10 mins. The BRC was recorded for 20 minutes
post stimulation. Each trial of recording lasted for 45 minutes
including a 15 minutes control, 10 min nerve stimulation, and 20
min post-stimulation. Two trials of the testing were performed with
a random stimulation parameter in 29 rats. The bladder was emptied
after finishing the first trial and BRC was re-established by
saline infusion. The second stimulation was applied at least 40 min
after the first stimulation. A total of 64 trials were studied in
35 rats.
Results and Discussion
[0116] The T.sub.mot response was plotted against PW using a
monoexponential nonlinear regression to elucidate the effect of PW
on motor function. The chronaxie and rheobase were calculated
according to the equation Y=(Y.sub.0-N.sub.S)*exp.sup.(-K*X)+NS,
where Y is T.sub.mot response, X is PW, and Y.sub.0 is T.sub.mot
value when PW is close to 0. NS is the rheobase (that is, the
intensity needed for excitation with a very long or infinite
pulse). K is the rate constant in inverse units of PW. The
half-life (chronaxie) equals the ln(2) divided by K. The value of
T.sub.mot current charge (current*PW) to different PWs were
compared using analysis of variance (ANOVA). Tukey's multiple
comparison post test was used to determine the statistical
significance between individual PW points.
[0117] For effect of PW on BRC, the frequency of BRC were
calculated in 5 minute bins, having three control periods, two
periods during stimulation, and four periods after stimulation. SNS
does not reduce the amplitude of bladder contractions, therefore
only effects on frequency/interval of BRC were studied. All data
were compared to the mean response during the last 5 minutes prior
to stimulation. Mean values of 10-min before, during and post
stimulation were analyzed with Student's paired t-test (Prism 5
GraphPad Software Inc., San Diego, Calif.). The amplitude changes
of inhibitory effects caused by 10 minute SNS to different PWs were
compared using a repeated measures analysis of variance (ANOVA)
with multiple comparisons (Prism 5 GraphPad Software). All data us
expressed as mean.+-.SEM and a value of p<0.05 was considered
statistically significant.
[0118] SNS evoked muscle contraction observed visually and the
muscle contraction became stronger. Additional muscle groups at
more locations were involved as the stimulation intensity was
increased. It was observed that there was no difference in motor
responses between SNS on the left and right nerve roots (n=11,
p>0.05, Two-way ANOVA). The T.sub.mot currents at which first
visible motor contraction occurred with 0.03 ms PW stimulation on
the left and on the right were 0.39.+-.0.12 mA and 0.53.+-.0.14 mA,
respectively.
[0119] FIGS. 12A and 12B summarize data of visual motor threshold
responses to graded pulse-width of bilateral spinal nerve
stimulation (n=22, two nerve roots in 11 rats). FIG. 12A is a plot
summarizing visual T.sub.mot current intensities against
corresponding stimulation PWs. As shown in the plot of FIG. 12A,
the motor thresholds current values lower as the pulse widths are
increased. The monoexponential nonlinear regression analysis gives
chronaxie of 0.04.+-.0.002 ms. The rheobase values were
0.12.+-.0.02 mA. The maximal values to minimal pulse-width were
0.71.+-.0.13 mA. The motor thresholds to shorter PW stimulation of
0.02 ms, 0.03 ms or 0.06 ms were significantly higher in comparison
to longer (.gtoreq.0.18 ms) PWs (0.02 ms vs PW.gtoreq.0.03 ms,
p<0.002; 0.03 ms vs PW.gtoreq.0.06 ms, p<0.002; 0.06 ms vs
PW.gtoreq.0.18 ms, p=0.033, Tukey's post test).
[0120] FIG. 12B is a plot summarizing the activation charge
threshold (T.sub.mot, nC) versus different PW stimulation. One-way
ANOVA demonstrated significantly lower charge values (which may be
more efficient) to shorter PWs of 0.02 ms, 0.03 ms or 0.06 ms in
comparison to longer (.gtoreq.0.15 ms) PWs (0.02 ms or 0.03 ms vs
PW.gtoreq.0.15 ms, p<0.002; 0.06 ms vs 0.15 ms, p=0.033; 0.06 ms
vs PW.gtoreq.0.18 ms, p<0.002, Tukey's post test). Statistical
differences were also obtained for comparisons between other pairs,
0.09 ms vs PW.gtoreq.0.21 ms (p<0.002), 0.12 ms vs
PW.gtoreq.0.27 ms (p<0.002), 0.15 ms vs 0.3 ms (p=0.002), and
0.18 ms vs 0.3 ms (p=0.033).
[0121] FIGS. 13A and 13B are plots of experimental records showing
no significant change in isovolumetric bladder contraction (mmHg)
without electrical stimulation (FIG. 13A), and abolished bladder
contractions to 0.06 ms pulse-width (PW), motor threshold
intensity, 10 Hz of bilateral spinal nerve stimulation (FIG.
13B).
[0122] FIGS. 14A and 14B are plots illustrating the effects of
spinal nerve stimulation at different pulse-widths (motor
threshold, 10 Hz) on the frequency of the bladder reflex
contraction. In FIGS. 14A and 14B, the responses are represented as
a percentage of control (% control), where the baseline response
before stimulation is defined as 100%.
[0123] FIG. 14A plots the time course of the mean responses of BRC
frequency without SNS or with SNS at PWs of 0.03 ms, 0.09 ms and
0.21 ms. Maximal inhibition appeared during stimulation. After
termination of the stimulus, bladder contractions returned to
control levels.
[0124] FIG. 14B summarizes stimulation PW effects on BRC in 10-min
periods before (pre-stim), during stim, and after SNS (post-stim).
Among tested PWs of 0.03 ms (n=8; T.sub.mot: 0.11.+-.0.02 mA or
3.27.+-.0.70 nC), 0.06 ms (n=11; 0.12.+-.0.02 mA or 6.+-.1.31 nC),
0.09 ms (n=10; 0.19.+-.0.03 mA or 16.88.+-.2.64 nC), 0.12 ms (n=9;
0.12.+-.0.03 mA or 14.9.+-.4.14 nC), and 0.21 ms (n=12;
0.16.+-.0.03 mA or 34.34.+-.5.90 nC), all produced statistically
significant inhibition on bladder contractions. Maximal inhibition
appeared during stimulation, while after termination of the
stimulus, bladder contractions returned to control levels in about
10 mins. SNS at 0.03 ms, 0.06 ms, 0.09 ms, 0.12 ms and 0.21 ms
decreased bladder contraction frequencies from 103.+-.3%,
100.+-.4%, 103.+-.4%, 107.+-.6% and 96.+-.4% of controls,
respectively, to 52.+-.16% (n=8, p=0.02, paired t test), 56.+-.15%
(n=11, p=0.02). 40.+-.19% (n=10, p=0.01), 64.+-.15% (n=9, p=0.03),
and 44.+-.18% (n=12, p=0.01), respectively. The amplitudes of
inhibitory effects (changes between pre stim and during stim) were
not different among PWs tested (p>0.05, one way ANOVA).
Inhibition of BRC at PW of 0.12 ms of SNS was sustained for 10 min
poststimulation (p=0.04, pre stim vs post stim, paired t test). The
amplitudes of changes between pre stim and post stim were not
different among PWs tested (p>0.05, one-way ANOVA).
[0125] In general, the results of the study showed that the
chronaxie of the T.sub.mot-PW curve was 0.04 ms, and that the
stimulation charges/energies (current.times.PW) associated with
shorter PWs of 0.02, 0.03, and 0.06 ms were significantly lower
than those with longer PW (e.g., >0.15 ms). SNS (T.sub.mot, 10
Hz) at selected PWs from 0.03 to 0.21 ms inhibited the frequency of
BRCs. Further, there were no significantly different attenuations
among tested PWs. SNS of PWs of 0.03, 0.06, and 0.09 ms decreased
bladder contraction frequency from 103.+-.3%, 100.+-.4%, and
103.+-.4% of controls, to 52.+-.16% (n=8, p=0.02, paired t-test),
56.+-.15% (n=11, p=0.02) and 40.+-.19% (n=10, p=0.01),
respectively.
[0126] The chronaxie of the L6 spinal nerve activation in the
anesthetized rat of about 0.04 ms is much shorter than 0.1-0.21 ms
typically used in previous preclinical and clinical studies. At
fixed 10 Hz, T.sub.mot intensity, shorter PWs SNS are equally
effective in attenuation of the frequency of bladder contractions
as the longer PWs. Shorter PW neuromodulation may be advantageous
due to potential decrease in battery-referred current consumption
which subsequently, enhances device longevity. It may also reduce
discomfort with short PW nerve stimulation due to higher nerve
fiber selectivity compared to the 0.21 ms pulse-width that is
widely used clinically.
[0127] For example, PW also affects the relative selectivity of
stimulation among different types of nerve fibers (diameter).
Shorter PWs will increase the differences in T.sub.mot from
different diameters of nerve fibers. The average recruited nerve
fiber diameter decreases (.about.20%) when the stimulus pulse-width
increases from 0.01 ms to 1 ms. The threshold difference between
large and small nerve fibers increases along with the increase in
the relative distance between the stimulating electrode and the
nerve fibers. Thus, preferential activation of large nerve fibers
over small fibers can be more pronounced with a shorter PW
stimulation especially when the electrode is placed farther from
the nerve roots.
[0128] The spinal nerve is composed of a wide range of fiber types,
including myelinated A.beta. and A.beta. fibers, as well as
unmyelinated C-fibers. Inhibitory effects of SNS on bladder
contractions may be stronger in rats pre-treated with capsaicin to
desensitize C-fibers, and demonstrated that an activation of large
fibers (without C-fibers) are associated with more effective
neuromodulation of the bladder micturition reflex. Therefore, short
PW SNS may increase fiber selectivity preferential to larger fibers
and may translate to a reduced discomfort with short PW nerve
stimulation.
[0129] Overall, the study identified the chronaxie (0.042 ms) of
SNS evoked motor response and demonstrated effective BRC inhibitory
effects between short and long PWs of SNS in a preclinical model.
Potential battery savings manifested by shorter pulse-width while
maintaining equivalent efficacy would provide more efficient
therapy delivery and increased longevity of the stimulator.
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