U.S. patent application number 16/995520 was filed with the patent office on 2021-02-04 for stimulation devices and methods for treating dry eye.
The applicant listed for this patent is Oculeve, Inc.. Invention is credited to Manfred Franke, Mark Jeffrey Holdbrook, James Donald Loudin, John Wardle.
Application Number | 20210031040 16/995520 |
Document ID | / |
Family ID | 1000005152384 |
Filed Date | 2021-02-04 |
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United States Patent
Application |
20210031040 |
Kind Code |
A1 |
Franke; Manfred ; et
al. |
February 4, 2021 |
STIMULATION DEVICES AND METHODS FOR TREATING DRY EYE
Abstract
Described herein are devices and methods of use thereof for
treating dry eye, tired eye, or other forms of ocular discomfort
such as from contact lenses. The methods generally include applying
spatially and/or temporally patterned stimulation to one or more
anatomical structures located in an ocular or nasal region. The
electrical stimulation may elicit a reflex that activates the
lacrimal gland or may directly activate the lacrimal gland or
nerves innervating the lacrimal gland to produce tears. The devices
may be implantable or handheld, and may be configured to deliver
the spatially and/or temporally patterned stimulation patterns
described.
Inventors: |
Franke; Manfred; (Valencia,
CA) ; Loudin; James Donald; (Alhambra, CA) ;
Wardle; John; (San Clemente, CA) ; Holdbrook; Mark
Jeffrey; (Sunnyvale, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Oculeve, Inc. |
South San Francisco |
CA |
US |
|
|
Family ID: |
1000005152384 |
Appl. No.: |
16/995520 |
Filed: |
August 17, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16137464 |
Sep 20, 2018 |
10780273 |
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16995520 |
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15676910 |
Aug 14, 2017 |
10112048 |
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16137464 |
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14920860 |
Oct 22, 2015 |
9737712 |
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15676910 |
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62067416 |
Oct 22, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61N 1/0526 20130101;
A61N 1/36146 20130101; A61N 1/37205 20130101; A61N 1/3756 20130101;
A61N 1/0546 20130101; A61N 1/3758 20130101; A61N 1/36046 20130101;
A61N 1/3606 20130101; A61N 1/37247 20130101 |
International
Class: |
A61N 1/36 20060101
A61N001/36; A61N 1/05 20060101 A61N001/05; A61N 1/372 20060101
A61N001/372; A61N 1/375 20060101 A61N001/375 |
Claims
1.-20. (canceled)
21. A device for delivering an electrical stimulus to nasal mucosa
of a patient, comprising: a stimulator probe comprising a first
nasal insertion prong including a first electrode configured to
deliver current, the stimulator probe further comprising a second
electrode; a stimulator body comprising a power source and
configured to releasably couple the stimulator probe to the
stimulator body, the stimulator body being configured to be held by
the patient while delivering current from the first electrode, the
stimulator body comprising a return contact positioned to contact
tissue of the patient while the patient is holding the stimulator
body, the return contact configured to receive at least a portion
of the delivered current.
22. The device of claim 21, further comprising a user interface
configured to allow the patient to adjust an amount of current
delivered between the first electrode and the second electrode and
between the first electrode and the return contact.
23. The device of claim 22, wherein the user interface comprises
one or more operating mechanisms configured to adjust one or more
parameters of the delivered current.
24. The device of claim 21, wherein the current is configured to be
delivered between the first electrode and the return contact
through tissue of the patient.
25. The device of claim 21, wherein the current is configured to be
delivered between the first electrode and the second electrode
through tissue of the patient.
26. The device of claim 22, wherein the user interface is
positioned on the stimulator body.
27. The device of claim 21, wherein the first electrode and the
second electrode comprise a hydrogel.
28. The device of claim 21, wherein the stimulator probe is
disposable, and wherein the stimulator body is reusable.
29. The device of claim 21, wherein the first electrode and the
second electrode are spaced radially around a circumference of the
first nasal insertion prong.
30. The device of claim 21, wherein the first electrode and the
second electrode are spaced longitudinally along a length of the
first nasal insertion prong.
31. The device of claim 21, wherein the first nasal insertion prong
comprises an elongated extension configured to extend into a nasal
cavity.
32. The device of claim 21, wherein the first electrode is
positioned along a distal portion of the first nasal insertion
prong and the second electrode is positioned along a distal portion
of a second nasal insertion prong of the stimulator probe.
33. The device of claim 21, wherein the first electrode is
configured to contact the nasal mucosa and stimulate a nerve in the
nasal mucosa.
34. A method of increasing tear production in a patient,
comprising: delivering, from a first electrode of a handheld
stimulation device, current to nasal mucosa of a patient, the
handheld stimulation device comprising a stimulator probe
comprising the first electrode, the stimulator probe being
releasably coupled to a stimulator body of the handheld stimulation
device, the stimulator body being configured to be held by the
patient while delivering the current from the first electrode, the
stimulator body comprising a return contact positioned to contact
tissue of the patient while the patient is holding the stimulator
body; and receiving, at the return contact, at least a portion of
the delivered current.
35. The method of claim 34, wherein the first electrode, during the
delivery of the current, is in contact with nasal mucosa on a side
of a septum of the patient.
36. The method of claim 35, wherein the first electrode contacts
nasal mucosa such that delivering current from the first electrode
stimulates a nerve in the nasal mucosa.
37. The method of claim 36, wherein the nerve is an anterior
ethmoidal nerve.
38. The method of claim 34, wherein current is delivered
simultaneously from the first electrode to the return contact and
from the first electrode to a second electrode.
39. The method of claim 34, wherein current is delivered
sequentially from the first electrode to the return contact and
from the first electrode to a second electrode.
40. The method of claim 39, wherein the first electrode is
positioned along a distal portion of a first nasal insertion prong
and a second electrode is positioned along a distal portion of a
second nasal insertion prong of the stimulator probe.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation application of U.S.
patent application Ser. No. 16/137,464, filed Sep. 20, 2018, which
is a continuation of U.S. patent application Ser. No. 15/676,910,
filed Aug. 14, 2017, which issued as U.S. Pat. No. 10,112,048,
which is a divisional of U.S. patent application Ser. No.
14/920,860 filed Oct. 22, 2015, which issued as U.S. Pat. No.
9,737,712 on Aug. 22, 2017, which claims priority to U.S.
Provisional Patent Application No. 62/067,416, filed on Oct. 22,
2014, and titled "STIMULATION PATTERNS," each of which is hereby
incorporated by reference herein in its entirety.
FIELD
[0002] Described herein are devices and methods of use thereof for
treating dry eye or tiredness of the eye. The methods generally
include applying spatially and/or temporally patterned stimulation
to one or more anatomical structures located in an ocular or nasal
region. The electrical stimulation may elicit a reflex that
activates the lacrimal gland or may directly activate the lacrimal
gland or nerves innervating the lacrimal gland to produce
tears.
BACKGROUND
[0003] Dry Eye Disease ("DED") is a condition that affects millions
of people worldwide. More than 40 million people in North America
have some form of dry eye, and many millions more suffer worldwide.
DED results from the disruption of the natural tear film on the
surface of the eye, and can result in ocular discomfort, visual
disturbance, and a reduction in vision-related quality of life.
Activities of daily living such as driving, computer use,
housework, and reading have also been shown to be negatively
impacted by DED. Patients with severe cases of DED are at risk for
serious ocular health deficiencies such as corneal ulceration and
can experience a quality of life deficiency comparable to that of
moderate-severe angina.
[0004] DED is progressive in nature, and generally results from
insufficient tear coverage on the surface of the eye. This poor
tear coverage prevents healthy gas exchange and nutrient transport
for the ocular surface, promotes cellular desiccation, and creates
a poor refractive surface for vision. Poor tear coverage typically
results from: 1) insufficient aqueous tear production from the
lacrimal glands (e.g., secondary to post-menopausal hormonal
deficiency, autoimmune disease, LASIK surgery, etc.), and/or 2)
excessive evaporation of aqueous tear resulting from dysfunction of
the meibomian glands. In turn, low tear volume causes a
hyperosmolar environment that induces inflammation of the ocular
surface. This inflammatory response induces apoptosis of surface
cells, which in turn prevents proper distribution of the tear film
on the ocular surface so that any given tear volume is rendered
less effective. A vicious cycle is initiated where more
inflammation can ensue and cause further surface cell damage, etc.
Additionally, the neural control loop, which controls reflex tear
activation, is disrupted because the sensory neurons in the surface
of the eye are damaged. As a result, fewer tears are secreted and a
second vicious cycle develops that results in further progression
of the disease (fewer tears cause nerve cell loss, which results in
fewer tears, etc.).
[0005] There is a wide spectrum of treatments for DED, however,
these treatments do not provide adequate treatment of the
condition. Treatment options include: artificial tear substitutes,
ointments, gels, warm compresses, environmental modification,
topical cyclosporine, omega-3 fatty acid supplements, punctal
plugs, and moisture chamber goggles. Patients with severe disease
may further be treated with punctal cautery, systemic cholinergic
agonists, systemic anti-inflammatory agents, mucolytic agents,
autologous serum tears, PROSE scleral contact lenses, and
tarsorrhaphy. Despite these treatment options, DED continues to be
considered one of the most poorly treated diseases in
ophthalmology. Accordingly, it would be desirable to have a more
effective treatment for dry eye.
SUMMARY
[0006] Described here are methods for treating one or more
conditions (such as dry eye, tired eyes, reducing discomfort from
wearing contact lenses, etc.) by providing electrical stimulation
to an anatomical structure located in an ocular region or a nasal
region. Exemplary anatomical structures include nerves, muscles,
mucosal tissues, cutaneous sensory structures such as Parcian
corpuscles, Merkel cells, etc., within these regions. The
electrical stimulation, when delivered to certain targets as
described herein, is generally capable of initiating a reflex
circuit that activates the lacrimal gland to produce tears. The
reflex circuit may include stimulation of a nerve directly or a
cutaneous sensory cell that in turn activates a nerve which then
produces either sensory input to the brain, or motor input to a
nerve that activates a muscle near, e.g., the eye, which in turn
provides sensory input to the brain and initiation of the reflex to
activate the lacrimal gland. The electrical stimulation may
additionally or alternatively be capable, when delivered to other
certain targets as described herein, of directly driving efferent
fibers innervating the lacrimal gland to produce tears.
[0007] More specifically, methods of generating lacrimation (tear
production) by spatially controlling the delivery of electrical
stimuli and/or by modifying parameters of electrical waveforms to
generate afferent or efferent input are described. These methods
generally direct current flow through particular pathways and/or
modify the current pathways over time. The methods may also
optimize waveforms for a sensed paresthesia, e.g., a sensation of
tickle, twitch, and/or vibration in the eyelid and/or vicinity of
the eyelid, eyebrow, as well as the temporal and frontal area of
the head. Experimentation by the inventors has found that these
sensations are strongly associated with lacrimation.
[0008] Using the stimuli disclosed herein, it is believed that
sensory nerves are activated to send input to the brain to produce
lacrimation. Additionally or alternatively, the stimuli may
activate motor nerves that cause muscles in the vicinity of the
orbit, the nose, the mouth, and/or the frontal or temporal face to
vibrate in order to generate the sensation of tingle or twitch or
vibration as the effect, which initiates the reflex pathway and
thereby leads to lacrimation.
[0009] Implantable or hand-held devices may be employed when
applying the electrical stimulation. In some handheld variations,
the devices may comprise a stimulator body and a stimulator probe.
The stimulator probe may be releasably connected to the stimulator
body, and in some instances, the stimulator body is reusable and
the stimulator probe is disposable. In some variations, the device
further comprises a user interface. The user interface may comprise
one or more operating mechanisms to adjust one or more parameters
of the stimulus. Additionally or alternatively, the user interface
may comprise one or more feedback elements.
[0010] In handheld variations comprising a stimulator probe, the
stimulator probe may comprise one or more nasal insertion prongs,
and the stimulator body may comprise a control subsystem to control
a stimulus to be delivered to the patient via the stimulator probe.
In some of these variations, the stimulator probe comprises a
single nasal insertion prong, while in other variations the
stimulator probe comprises at least two nasal insertion prongs. The
stimulator probe may comprise at least one electrode, and may
comprise a plurality of electrodes. The electrode may comprise a
hydrogel, or in other variations, the electrode comprises one or
more of platinum, platinum-iridium, gold, or stainless steel. Some
variations of device may comprise return contacts not located on a
nasal insertion prong, such as return contacts on the stimulator
body or the stimulator probe.
[0011] The electrical stimulation applied to the anatomical
structures generally includes a plurality of waveform parameters
that define a waveform. Delivery of the electrical stimulus may
help to treat DED by inducing an increase in lacrimation, or
modifying the components of lacrimated tears, and may generate a
paresthesia sensed by a patient. These waveforms may be capable of
increasing tear output as well as patient comfort during and/or
after application of the stimulation. In some variations, the
stimulus is a biphasic pulse waveform, which may but need not be
symmetrical. The frequency of the biphasic pulse waveform may in
some variations be between 30 Hz and 80 Hz.
[0012] In other variations, the devices may include an implantable
microstimulator and an external controller. Exemplary implantable
devices that may be used to apply the electrical stimulation
described herein are disclosed in U.S. patent application Ser. No.
13/441,806, filed Apr. 6, 2012, and titled "Stimulation Devices and
Methods," which is hereby incorporated by reference in its
entirety. Exemplary hand-held devices, as well as additional
exemplary implantable devices, that may be used to apply the
electrical stimulation described herein are disclosed in U.S.
patent application Ser. No. 14/256,915, filed Apr. 18, 2014, and
titled "Nasal Stimulation Devices and Methods," which is hereby
incorporated by reference in its entirety.
[0013] In general, the methods disclosed herein include applying
electrical stimulation to an anatomical structure in an ocular
region or a nasal region to activate the lacrimal gland, where the
electrical stimulation is defined by a plurality of waveform
parameters, and increasing tear production using the electrical
stimulation. In some instances, the methods may comprise spatially
controlling the stimulus delivery to target particular anatomical
structure(s) and/or to modify the current pathways over time. The
method may further include confirming activation of the lacrimal
gland by evaluating a paresthesia sensed in the ocular region or
the nasal region.
[0014] The anatomical structure that is stimulated may be a nerve,
cutaneous sensory cells (Parcian corpuscles, Merkel cells etc.),
muscle, or tissue such as mucosa or sub-mucosa, in the ocular
region or nasal region. For example, the anatomical structure may
be the nasociliary nerve, the anterior or posterior ethmoid nerve,
or the infra-trochlear nerve. In some variations, the anatomical
structure is a muscle in the ocular region or the nasal region. In
some variations, the anatomical structure comprises a mucosal or
sub-mucosal surface in the ocular region or the nasal region. In
some instances, the anatomical structure may be cutaneous sensory
cells in the nasal or ocular glabrous skin, which naturally sense
mechanical input such as pressure, vibration, tingle, temperature,
or pain.
[0015] As further described herein, the flow of current for
stimulation may be spatially controlled. Current may be driven
between particular contacts and thus through particular pathways
through tissue, and may be driven via different pathways through
tissue over time to spatially pattern the stimulus. Current
steering and/or temporal patterning of waveform parameters may be
optimized for a particular patient to activate the lacrimal gland
to produce tears and elicit a paresthesia in that patient. Current
steering and/or temporal patterning, where at least one of the
waveform parameters is modulated over time, may also be determined
based on other factors such as clinical markers, including but not
limited to growth factor levels and/or osmolarity.
[0016] The plurality of waveform parameters that define the
stimulation waveforms may be selected from the group consisting of
on/off duration, frequency, pulse width, amplitude, and shape.
Other suitable waveform parameters may also be used. For example,
charge injection, which can be calculated by multiplying amplitude
and pulse width, may be used as a waveform parameter. In some
variations, the plurality of waveform parameters are selected from
the group consisting of on/off duration, frequency, pulse width,
amplitude, and shape. In some of these variations, the on/off
duration ranges from about 0.1 to 5.0 seconds on, and about 0.1 to
5.0 seconds off. In some of these variations, the on/off duration
is 1.0 second on, and 1.0 second off. In some of these variations,
the on/off duration is 5.0 seconds on, and 5.0 seconds off. In some
of these variations, the frequency ranges from about 10 to 200 Hz.
In some of these variations, the frequency ranges from about 30 to
150 Hz. In some of these variations, the frequency ranges from
about 50 to 80 Hz. In some variations, the frequency is 30 Hz. In
some variations, the frequency is 70 Hz. In some variations, the
amplitude ranges from about 0.1 to 10 mA. In some of these
variations, the maximum amplitude ranges from about 1 to 3 mA. In
some variations, the pulse width and amplitude generate a waveform
having a triangular, rectangular, or square shape. In some
variations, the electrical stimulation is continuously applied. In
other variations, the electrical stimulation has on and off
periods.
[0017] A particular combination of current steering and/or spatial
or temporal patterning may be applied using a stimulator comprising
a plurality of combinations stored in memory. Selection of the
stored combinations may be random, predetermined, or controlled by
a user. In some instances, the stored combinations may be
patient-optimized waveforms.
[0018] Methods for treating dry eye in a patient in need thereof
are described herein. In one variation, the method may comprise
contacting nasal mucosa of the patient with an electrode, and
delivering current from the electrode through tissue of the patient
to a return contact, where the electrode is located on a nasal
insertion prong of a stimulator probe of a stimulator, and the
return contact is located on a stimulator body of the stimulator,
and the stimulator probe is reversibly attachable to the stimulator
body. The method may further comprise delivering current from the
electrode through tissue of the patient to a second electrode. The
second electrode may be located on the nasal insertion prong. In
some instances, the current is delivered simultaneously from the
electrode to the return contact and to the second electrode; in
others, the current is delivered sequentially from the electrode to
the return contact and to the second electrode. The electrode may
contact the nasal mucosa in the anterior nasal cavity, and in some
instances may contact the nasal mucosa at a location anterior to a
middle or inferior turbinate of the nasal cavity.
[0019] Also described here are methods for treating a patient
having dry eye using a stimulator comprising a stimulator body and
a stimulator probe, wherein the stimulator probe comprises a nasal
insertion prong comprising a first electrode and a second
electrode. The method may comprise inserting the nasal insertion
prong into a nostril of the patient, placing the first electrode
and the second electrode in contact with nasal mucosa on a first
side of a septum of the patient, placing a return contact in
contact with tissue of the patient, and delivering an electrical
stimulation waveform from the first electrode to the second
electrode, and from the first electrode to the return contact. The
first and second electrodes may be spaced longitudinally along the
length of the nasal insertion prong, or they may be spaced radially
around a circumference of the nasal insertion prong. In some
variations of the method, no electrodes are placed in contact with
nasal mucosa on a second side of the septum of the patient, and
delivering the electrical stimulation waveform results in bilateral
lacrimation.
[0020] Methods for increasing tear production in a patient are also
described here. The methods may comprise delivering an electrical
stimulus to tissue of a patient using a device comprising at least
three electrical contacts, wherein the electrical stimulus takes
one or more pathways between the at least three electrical contacts
during delivery, and wherein the one or more pathways of the
electrical stimulus change over time during delivery. The
electrical stimulus may take two pathways between the at least
three electrical contacts, such that a first amount of current
takes the first pathway and a second amount of current takes the
second pathway. In some instances, the ratio of the first amount to
the second amount changes over time during delivery. The ratio may
in some cases be changed by the patient using a user interface of
the device. The device may be implantable, or it may be handheld.
Some variations of the device have a single nasal insertion prong,
which may comprise one electrode, two electrodes, or more. Some
variations of the device comprise a stimulator body comprising an
electrical contact configured to deliver current or act as a return
contact.
[0021] In some variations the methods described herein comprise
applying patterned electrical stimulation to an anatomical
structure in an ocular region or a nasal region to activate the
lacrimal gland, and increasing tear production using the patterned
electrical stimulation, wherein the patterned electrical
stimulation comprises a biphasic waveform having cathodic and
anodic pulse pairs. In some variations, a subset of the pulse pairs
have a leading cathodic pulse and a subset of the pulse pairs have
a leading anodic pulse. In some variations, each pulse has a
duration and amplitude, wherein the ratio of duration to amplitude
for each pulse is variable over time. In some variations, the
biphasic waveform is charge balanced. In some of these variations,
the ratio of duration to amplitude for the cathodic pulse varies
over time according to a function having a phase of exponential
increase and a phase of exponential decrease. In some of these
variations, the ratio of duration to amplitude for the cathodic
pulse varies over time according to a sawtooth function. In some of
these variations, the ratio of duration to amplitude for the
cathodic pulse varies over time according to a sinusoidal
function.
[0022] In some variations the methods described herein comprise
implanting a stimulation device in an ocular region or a nasal
region of a subject to activate the lacrimal gland, applying
patterned electrical stimulation from the stimulation device, and
increasing tear production using the patterned electrical
stimulation, wherein tear production is bilateral. In some
variations, the tear production is approximately equal in both eyes
of the subject. Some variations of the methods described herein
comprise delivering a stimulus to an ocular region or a nasal
region of a subject to activate the lacrimal gland, wherein the
stimulus is an electrical waveform, and increasing tear production
using the patterned electrical stimulation, wherein tear production
is bilateral. In some variations, the stimulus is delivered
unilaterally.
[0023] The frequency, peak-to-peak amplitude, and pulse width of
the waveforms may be constant, but in some variations the
stimulator may be configured to vary the frequency, amplitude,
and/or pulse width of the waveform. This variation may occur
according to a pre-determined plan, or may be configured to occur
randomly within given parameters. For example, in some variations
the waveform may be configured such that the peak-to-peak amplitude
of the waveform varies over time (e.g., according to a sinusoidal
function having a beat frequency, a sawtoothed function, or an
exponential function); in some variations the waveform may be
configured such that the frequency of the waveform varies over time
(e.g., according to a sinusoidal function, a sawtoothed function,
or an exponential function); or in some variations the waveform may
be configured such that the pulse width of the waveform varies over
time (e.g., according to a sinusoidal function, a sawtoothed
function, or an exponential function). In some variations,
rectangular stimulation pulses of a variable fundamental frequency
are employed. In other variations, triangular stimulation pulses
may be used and modulated as described for rectangular stimulation
pulses.
[0024] In some variations, the methods described herein comprise a
method for inducing lacrimation. In some variations the method
comprises delivering an electrical stimulus to a patient having dry
eye, wherein the electrical stimulus is delivered from a handheld
stimulator, and wherein the electrical stimulus comprises a
waveform having a pulse width that varies during delivery. In some
variations the method comprises delivering an electrical stimulus
to a patient having dry eye using a handheld stimulator, wherein
the electrical stimulus can be one of a plurality of preset
waveforms comprising at least a first preset waveform and a second
preset waveform, and changing the electrical stimulus from the
first preset waveform to the second preset waveform while
delivering the electrical stimulus. The electrical stimulus may be
changed from the first preset waveform to the second preset
waveform by the patient.
[0025] In some variations, the methods described herein comprise
providing a device to a patient having dry eye, wherein the device
is configured to deliver a plurality of electrical waveforms to an
anatomical target in a patient, and instructing the patient to
select one or more of the plurality of waveforms based on an amount
of sensed paresthesia felt during delivery of the waveform. In some
of these variations, the anatomical target may be the nasal mucosa.
In some of these variations, the anatomical target may be the
anterior ethmoidal nerve. In others of these variations, the
anatomical target may be in an ocular region. In some of these
variations, at least one of the plurality of waveforms may have a
pulse width that varies over time. In some of these variations, the
pulse width may vary over time according to an exponential
function.
[0026] In some variations the methods described herein comprise
methods of reducing patient accommodation to electrical stimuli in
an ocular, orbital, or nasal region by using patterned
waveforms.
[0027] In some variations the methods described herein comprise
methods of preferentially activating different anatomical
structures, comprising implanting a stimulation device, delivering
a waveform having a biphasic pulse, and activating a different
anatomical structure by modifying the waveform. In some variations,
the waveform is modified by adjusting an amplitude of the biphasic
pulse. In some variations, the waveform is modified by adjusting
the order of a cathodic pulse and an anodic pulse of the biphasic
pulse.
[0028] Devices for delivering an electrical stimulus to nasal
mucosa of a patient are also described here. A device may comprise
a stimulator probe comprising a nasal insertion prong, wherein a
distal portion of the nasal insertion prong comprises first and
second electrodes. The first electrode may be configured to deliver
current. The device may also comprise a return contact located on
the stimulator probe at the base of the nasal insertion prong, and
may also comprise a user interface configured to allow the patient
to adjust an amount of current delivered between the first and
second electrodes and between the first electrode and the return
contact. The first electrode, second electrode, and/or return
contact may comprise a hydrogel. In some variations, the return
contact has an annular shape. The return contact may be configured
to contact tissue at or near a nostril.
[0029] A device for delivering an electrical stimulus to nasal
mucosa of a patient having dry eye may also comprise a first nasal
insertion prong, a second nasal insertion prong, and a user
interface. The first nasal insertion prong may be configured to be
inserted into a first nostril and may comprise a first electrode.
The second nasal insertion prong may be configured to be inserted
into a second nostril, and may comprise a second electrode. The
device may be configured to deliver a biphasic charge-balanced
pulsed waveform, where the user interface is configured to allow
the patient to adjust an amplitude:duration aspect ratio of the
waveform.
[0030] Systems for generating and applying the electrical
stimulation waveforms are further disclosed herein. The systems may
generally include one or more electrodes and a controller, wherein
the controller comprises a programmable memory configured to store
a plurality of patterned stimulation waveforms. The stimulation
waveforms may or may not be associated with a sensed paresthesia.
The controller may also be configured to execute a program that
cycles through a plurality of stimulus options. A user interface
may be included and configured in a manner that allows the patient
to select one or more of the stored plurality of stimuli.
[0031] In some variations, the stimulators are configured for
implantation in an ocular region or a nasal region. In some of
these variations, the stimulators are configured for placement on a
mucosal surface or within sub-mucosal tissue. The stimulators,
which may for example comprise one, two, three, or more active
electrodes, may also be configured for placement within a nasal
cavity or a sinus cavity. In other variations, the controller is
configured for placement external to the ocular region or the nasal
region. In some variations, the electrical stimulation is applied
by an electrode disposed within a nasal cavity or a sinus cavity.
In some variations, the patterned electrical stimulation is applied
by an electrode implanted near the lacrimal gland. In some of
variations, the systems are configured for activating cutaneous
sensors or nerve fibers innervating cutaneous sensors in the
mucosal surface or within sub-mucosal tissue. In some variations,
the systems are configured for activating cutaneous sensors or
nerve fibers innervating cutaneous sensors in tissue such as skin
and muscles of the ocular region, the forehead, or the temple area
of the head.
[0032] In some variations, the patterned electrical stimulation is
applied by a stimulator comprising a plurality of patterned
stimulation waveforms stored in memory. In some of these
variations, the applied patterned stimulation is randomly selected
from the plurality of stored patterned stimulation waveforms. In
some of these variations, the plurality of stored patterned
stimulation waveforms are patient-optimized waveforms. In some
variations, the applied patterned stimulation is stored in memory
as a patient-optimized waveform.
[0033] In some variations the systems described herein comprise one
or more stimulation electrodes and a controller, wherein the
controller comprises a programmable memory configured to store a
plurality of patterned stimulation waveforms associated with a
sensed paresthesia. In some variations, the one or more stimulation
electrodes are configured for implantation in an ocular region or a
nasal region. In some of these variations, the controller is
configured for placement external to the ocular region or the nasal
region. In some variations, the one or more stimulation electrodes
are configured for placement on a mucosal surface or within
sub-mucosal tissue. In some variations, the one or more stimulation
electrodes are configured for placement within a nasal cavity or a
sinus cavity.
[0034] In some variations, the programmable memory is capable of
storing up to 10 patterned stimulation waveforms. In some
variations the system further comprises a user interface for
selecting one or more of the stored plurality of patterned
waveforms. In some variations, the controller is configured to
execute a program that cycles through a plurality of waveform
parameter options.
[0035] In some variations, the devices described herein comprise a
handheld stimulator comprising a stimulator body comprising a user
interface, and a stimulator probe comprising a nasal insertion
prong comprising an electrode. The stimulator may be configured to
deliver a plurality of electrical waveforms, and the user interface
may be configured for selection of one of the plurality of
electrical waveforms. Each of the waveforms may have at least one
of a pulse shape, maximum amplitude, pulse width, or frequency that
is modulated over time. In some of these variations, each of the
waveforms has at least two of a pulse shape, maximum amplitude,
pulse width, or frequency that is modulated over time. In some
variations, each of the waveforms has a pulse shape that is
modulated over time. In some variations, the waveform comprises a
first period comprising a two-phase current-controlled waveform,
and a second period comprising a current-controlled phase followed
by a voltage-controlled phase.
BRIEF DESCRIPTION OF THE DRAWINGS
[0036] FIG. 1 illustrates a proposed pathway of action of sensory
output processed in various ganglia of the peripheral nervous
system and nuclei of the central nervous system.
[0037] FIGS. 2A-2C depict an exemplary implantable
microstimulator.
[0038] FIG. 3 depicts an exemplary external controller for an
implantable microstimulator.
[0039] FIGS. 4A-4C depict an exemplary handheld stimulator.
[0040] FIGS. 5A-5C show exemplary waveforms.
[0041] FIGS. 6A-6D illustrate exemplary amplitude variations over
time.
[0042] FIGS. 7A-7D illustrate exemplary pulse width variations over
time.
[0043] FIG. 8 shows an exemplary function defining pulse widths
increasing and decaying according to an exponential function.
[0044] FIG. 9 shows a flowchart illustrating a method used in
determining a patient-optimized waveform.
[0045] FIG. 10 illustrates exemplary shape modulation.
[0046] FIG. 11 illustrates exemplary pulse width modulation.
[0047] FIGS. 12A-12E illustrate exemplary modulations of amplitude
and frequency waveform parameters.
[0048] FIGS. 13A-13E depict exemplary waveforms showing multiple
parameters that are concurrently modulated over time.
[0049] FIG. 14A depicts paresthesia felt with stimulation applied
at 30 Hz (non-patterned).
[0050] FIG. 14B illustrates an exemplary moving paresthesia
obtained with waveform patterning. FIG. 14C illustrates another
exemplary moving paresthesia obtained with waveform patterning.
FIG. 14D depicts paresthesia felt by waveform patterning.
[0051] FIG. 15 is a bar-chart diagram comparing tearing results
from basal tearing (left, no stimulation) to 30 Hz non-patterned
waveform stimulation (middle) to patterned, patient-optimized
stimulation waveforms (right).
[0052] FIG. 16A shows bilateral Schirmer scores with no
stimulation, 30 Hz non-patterned stimulation, and patient-specific
patterned waveforms. FIG. 16B shows contralateral Schirmer scores
with no stimulation, 30 Hz non-patterned stimulation, and
patient-specific patterned waveforms.
[0053] FIGS. 17A-17B show bilateral responses to 30 Hz
non-patterned stimulation (17A) and patient-specific patterned
waveforms (17B).
[0054] FIG. 18 shows Schirmer scores for stimulation of left
frontal nerve areas in rabbits.
[0055] FIGS. 19A-19B illustrate distal portions of exemplary nasal
insertion prongs.
[0056] FIG. 20 shows a distal portion of an exemplary handheld
nasal stimulator having two nasal insertion prongs.
[0057] FIGS. 21A-21B depict perspective views of an exemplary
handheld nasal stimulator having a single nasal insertion
prong.
[0058] FIG. 22A shows a distal portion of an exemplary nasal
insertion prong. FIG. 22B shows a cross-sectional view of the nasal
insertion prong of FIG. 22A.
[0059] FIG. 23A shows a distal portion of an exemplary handheld
nasal stimulator having two nasal insertion prongs. FIG. 23B shows
a cut-away view of the handheld nasal stimulator of FIG. 23A.
[0060] FIG. 24 depicts a perspective view of an exemplary handheld
nasal stimulator having a single nasal insertion prong.
[0061] FIG. 25 illustrates a distal portion of an exemplary nasal
insertion prong.
[0062] FIG. 26 shows a perspective view of an exemplary handheld
nasal stimulator having a single nasal insertion prong.
[0063] FIGS. 27A-27C, 28A-28B, and 29A-29B are perspective views of
exemplary handheld nasal stimulators having return contacts.
[0064] FIGS. 29C-29E show schematic illustrations of configurations
of the handheld nasal stimulator of FIGS. 29A-29B.
[0065] FIG. 30A depicts an exemplary handheld stimulator comprising
two nasal insertion prongs. FIGS. 30B-30E depict variations of how
current may be driven between the electrodes of the stimulator of
FIG. 30A.
[0066] FIG. 31 depicts how current may be driven between electrodes
and a return contact of an exemplary handheld stimulator having a
single nasal insertion prong.
[0067] FIGS. 32A-32B illustrate how current may be driven between
electrodes of an exemplary handheld stimulator having two nasal
insertion prongs. FIG. 32C shows a schematic illustration of a
portion of the circuitry of the stimulator of FIGS. 32A-32B. FIG.
32D shows a schematic illustration of a portion of an alternative
configuration of circuitry for the stimulator of FIGS. 32A-32B.
[0068] FIG. 33 shows a cut-away view of the stimulator of FIGS.
23A-23B with depictions of how current may be directed between the
electrodes.
DETAILED DESCRIPTION
[0069] Described herein are devices, systems, and methods for
treating one or more conditions (such as dry eye, tired eyes,
ocular discomfort from wearing contact lenses, etc.) by providing
electrical stimulation to an anatomical structure located in an
ocular region or a nasal region. Specifically, the methods
disclosed herein generally include applying electrical stimulation
to an anatomical structure in an ocular region or a nasal region to
activate the lacrimal gland, where the electrical stimulation is
defined by a plurality of waveform parameters. The electrical
stimulation may result in effects such as increased tear production
during or after delivery of the stimulus.
[0070] In general, the methods disclosed herein include
electrically stimulating nerves, muscles (thus indirectly nerves
via muscle spindles and golgi-tendon receptors providing sensory
information back to the central nervous system), and/or glands in
the orbit of the eye or the nasal mucosa and sub-mucosa. With that
approach, neural tissue may be activated in some manner. For
example, referring to FIG. 1, the inventors hypothesize that the
activation at an intra-nasal location 102 or at an ocular location
104 causes action potentials to run antidromically and
orthodromically from the activation point if the electrode is
activating the nerves directly, and orthodromically on afferent
nerves if glands and muscles are activated to cause sensory input
to the brain. Sensory input to the brain reaches the lacrimal
nucleus in the pons, after passing several ganglia on the way, as
shown by arrows 106, 108, 110, and 112. Here it is likely that
neural computation and data reduction happens in each of the
ganglia as well as in the nuclei in the pons before the information
is further relayed to areas of the sensory cortex in the cerebrum.
Accordingly, the activation of neural tissue, directly or
indirectly, may cause circuitry in the central nervous system
(e.g., brain, spinal cord, potentially the ganglia in the
peripheral nervous system) to respond to the input. Output from the
brainstem 118 may then send feedback, as shown by arrow 114, to the
lacrimal gland.
Exemplary Stimulators
[0071] The stimulation waveforms described herein may be delivered
via implanted or non-implanted (e.g., handheld) stimulators.
[0072] Exemplary Implantable Microstimulators
[0073] When the stimulation waveforms described herein are applied
using an implantable stimulator, the stimulator may comprise a
microstimulator comprising a housing and a corresponding and
complementary flexible extension connected to the housing, forming
a unitary microstimulator. An example is shown in FIGS. 2A-2C. As
shown there, the microstimulator 200 may comprise a housing 202 and
a flexible extension 204 connected to the housing 202. The housing
202 may be hermetically sealed, and may contain some or all of the
stimulation circuitry therein. The microstimulator 200 may comprise
any suitable stimulation circuits, such as those described in U.S.
patent application Ser. No. 13/441,806, which was previously
incorporated by reference in its entirety. The housing 202 may be
formed from one or more metals (e.g., titanium) or other
biocompatible materials.
[0074] The extension 204 may be formed from a flexible material
such as silicone, and may comprise a first electrode 206, a second
electrode 208, and a coil 210. While shown as having two
electrodes, implantable stimulators may have fewer (e.g., one) or
more (e.g., three, four, five, six, or more) electrodes. When the
implantable stimulator comprises a plurality of electrodes, the
current pathways through tissue may be controlled by delivering the
current to/from various electrodes, which may be varied over time.
In some variations, the extension 204 may be a molded component,
such as molded silicone. The extension may have a corresponding and
complementary shape to the housing, such that the extension and
housing together have a unitary shape, as shown in FIGS. 2A-2B. The
flexible extension 204 may conform to one or more portions of the
anatomy (e.g., the orbit or the lacrimal gland) when implanted in
tissue. FIG. 2B shows a side view of the microstimulator 200. As
shown there, the thickness of the extension 204 may be less than
that of the housing 202, and may increase to the thickness of
housing 202. Additionally, the width of the extension 204 is shown
in FIG. 2A as being greater than the width of the housing 202, and
may decrease to the thickness of the housing 202.
[0075] The electrodes 206 and 208 and coil 210 may be connected to
the microstimulator circuitry via one or more feedthroughs. For
example, FIG. 2C shows a perspective view of the housing 202 with
the extension 204 removed. As shown there, housing 202 may comprise
a plurality of feedthroughs 212 that extend through the housing
202. One or more elements (e.g., one of the electrodes 206 or 208
or the coil 210) may be electrically connected to the
hermetically-sealed stimulation circuitry by connection to the
feedthroughs 212. Additionally, some of the feedthroughs 212 may
comprise an insulating member 214 which may electrically isolate
the feedthrough 212 from the housing 202. This and other
implantable stimulators that may deliver the electrical stimuli
described herein are described in U.S. patent application Ser. No.
13/441,806, which was previously incorporated by reference in its
entirety; and in U.S. patent application Ser. No. 14/256,915, which
was previously incorporated by reference in its entirety.
[0076] When the stimulator is an implantable microstimulator, the
system may further comprise a controller, which may communicate
with the microstimulator to transmit and/or receive power,
information, or the like. For example, in variations in which a
stimulation system comprises a microstimulator having a passive
stimulation circuit (or a stimulation circuit that does not
otherwise include a battery or internal power supply), the
controller signal may power the stimulator via the output signal of
the controller. The controller may communicate with the
microstimulator wirelessly and/or via a wired connection. The
controller may be configured for implantation within the body, or
may be configured to remain external to the body. The controller
may be disposable, may be reusable, or may be partially reusable.
In some instances, the controller may be rechargeable.
[0077] FIG. 3 depicts an exemplary external controller. As shown
there, a stimulation system 300 includes a controller 302
comprising a hand-held device. The controller 302 may be brought
into the vicinity of an implanted microstimulator 306, and may
produce an output signal 308 received by the implanted
microstimulator 306. The implanted microstimulator may in turn
generate a stimulation signal 310 used to stimulate an anatomical
target, as described in more detail herein. This and other
controllers that may be used to deliver the electrical stimuli
described herein are described in U.S. patent application Ser. No.
13/441,806, which was previously incorporated by reference in its
entirety.
[0078] The length and width of the microstimulator may be selected
to permit placement of a portion of the microstimulator on,
partially within or about the lacrimal gland, or adjacent to a
desired tissue, such as the lacrimal gland or a nerve desired to be
stimulated, such as but not limited to the nasociliary nerve or
anterior ethmoidal nerve. Some of these implantation locations are
described in more detail in U.S. patent application Ser. No.
13/441,806, which was previously incorporated by reference in its
entirety; in U.S. patent application Ser. No. 14/256,915, which was
previously incorporated by reference in its entirety; and in U.S.
patent application Ser. No. 14/207,072, filed Mar. 12, 2014, and
titled "Implant Delivery Devices, Systems, and Methods," which is
hereby incorporated by reference in its entirety.
[0079] The microstimulator may be injectable into a patient using a
delivery system. The delivery system may comprise an insertion
device (such as conduit, a shaft to which the microstimulator is
removably attachable, or the like) and/or a dissection tool. In
some variations, the insertion device is a 12 or larger gauge
needle. In other variations, the insertion device comprises a
cannula. In some variations, the insertion device may comprise a
piston assembly, which in some variations may be spring-powered.
The microstimulator may be loaded into the insertion device, and
the insertion device may be inserted into an insertion pathway. In
some variations in which the microstimulator is implanted into an
ocular region, using an anatomical landmark at the corner of the
eye, a delivery device (e.g., a needle) may be positioned in
proximity to the lacrimal gland, and the microstimulator may be
deployed using the delivery device. Anatomical landmarks include,
but are not limited to, the lateral canthis, an eyelid margin, a
palpebral lobe of the lacrimal gland, the orbital rim, a bony
protuberance on the superior-lateral aspect of the orbit, the
vascular bed, or the like. In some variations, a microstimulator
may be implanted by lifting the eyelid, forming an insertion
pathway through the conjunctiva under the eyelid, and advancing the
microstimulator into the insertion pathway. The insertion pathway
may be formed using a dissection tool. In some variations, the
insertion pathway may be formed using a dissection element of an
insertion tool. In some variations, the insertion pathway may be
formed between the periosteum and the orbital bone. In other
variations, the insertion pathway may be formed between the
periosteum and the lacrimal gland. The microstimulator may have one
or more features to facilitate minimally invasive retrieval. U.S.
patent application Ser. No. 14/207,072, which was previously
incorporated by reference in its entirely, describes other
variations of insertion devices that may be used to implant
microstimulators described herein.
[0080] Exemplary Handheld Stimulators
[0081] The stimulator described here may also be handheld. The
handheld stimulators may comprise a stimulator body and a
stimulator probe. The stimulator probe may comprise at least one
nasal insertion prong configured to be inserted into a nostril of a
subject. The stimulator body may be configured to generate a
stimulus, which may be delivered to the subject via the nasal
insertion prong. The stimulator body may comprise a control
subsystem and a power source, which together may generate and
control the stimulus.
[0082] One variation of a handheld stimulator is shown in FIGS.
4A-4C. These figures show perspective, cut-away back, and cut-away
side views, respectively, of a handheld stimulator 400,
respectively. The stimulator 400 comprises a stimulator body 402
and a stimulator probe 404. The stimulator body 402 may comprise a
front housing 438, back housing 440, and proximal housing 442,
which may fit together to define a body cavity 454. The body cavity
454 may contain a control subsystem and a power source 452.
[0083] The stimulator body may comprise a user interface comprising
one or more operating mechanisms to adjust one or more parameters
of the stimulus, as described in more detail below. The operating
mechanisms may provide information to the control subsystem, which
may comprise a processor, memory, and/or stimulation subsystem. In
some variations, the operating mechanisms may comprise first and
second buttons, as illustrated for example in FIGS. 4A and 4C as
414 and 416. In some variations, pressing the first button may turn
on the stimulator and/or change the stimulus waveform, while
pressing the second button may turn off the stimulator and/or
change the stimulus waveform. Additionally or alternatively, the
user interface may comprise one or more feedback elements (e.g.,
based on light, sound, vibration, or the like). As shown in FIG.
4A, the user feedback elements may comprise light-based indicators,
shown there as indicators 418, which may provide information to the
user. It should be appreciated these features may be present in
each of the handheld stimulator devices comprises herein.
[0084] For each handheld stimulator described herein, in some
variations the stimulator body and stimulator probe may be
reversibly attachable. Some or all of the stimulator may be
disposable, and some or all of the stimulator may be reusable. For
example, in variations where the stimulator probe is releasably
connected to the stimulator body, the stimulator body may be
reusable, and the stimulator probe may be disposable and
periodically replaced. In some of these variations, the device
comprises a disabling mechanism that prevents stimulus delivery to
the subject when the stimulator probe is reconnected to the
stimulator body after being disconnected from the stimulator body.
Additionally or alternatively, the device may comprise a lockout
mechanism that prevents the stimulator probe from being reconnected
to the stimulator body after being disconnected from the stimulator
body. In some variations, the device further comprises a detachable
protective cap. The stimulators described herein may have
additional features as described in more detail in U.S. patent
application Ser. No. 14/256,915, which was previously incorporated
by reference in its entirety.
[0085] For each handheld stimulator described herein, the
stimulator probe may comprise at least one nasal insertion prong.
In the handheld stimulator variation shown in FIGS. 4A-4C, for
example, the stimulator probe 404 may comprise two nasal insertion
prongs 406 and 408. The nasal insertion prongs may be self-aligning
when inserted into the nostrils of the patient. The stimulator
probe 404 may further comprise ridges 420, which may allow the
patient to more easily grip the probe 404. The nasal insertion
prong may be configured to be at least partially inserted into the
nasal cavity of a patient. A nasal insertion prong may extend from
a base member of the stimulator probe and may comprise an elongate
portion having at its distal end a distal portion. The length of a
nasal insertion prongs is desirably long enough such that the
prongs can reach the desired stimulation location (e.g., the nasal
mucosa superior to the columella, such as near the interface
between the nasal bone and the upper lateral cartilage) in a range
of patients. A nasal insertion prong may comprise a flexible
material (e.g., a flexible polymer, such as a thermoplastic
elastomer (e.g., a thermoplastic elastomer alloy (e.g.,
Versaflex.TM.), thermoplastic polyurethane, or the like), silicone,
or the like) in order to allow the nasal insertion prong to
self-align to the desired stimulation location when inserted into a
user's nasal cavities and/or to be atraumatic to the nasal tissue
during regular use and insertion, and/or during a sudden movement
(e.g., a sneeze). This may also improve comfort for the user. In
some variations, the desired hardness of the material may be
between about 40 D and about 90 D, between about 50 D and about 80
D, between about 60 D and about 70 D, or about 65 D. In addition to
having material properties that may be atraumatic to nasal tissue,
it may be desirable for the distal tip of the nasal insertion prong
to have rounded edges to help minimize the risk of tissue damage
during advancement of the prong into the nose.
[0086] In some variations, the distal portion may have a diameter
(or greatest cross-sectional dimension) that is larger than the
diameter (or greatest cross-sectional dimension) of the elongate
portion of the prong proximal to the distal portion. This may allow
a portion of the distal portion (e.g., one or more electrodes,
described below) to be brought into contact with a subject's
tissue, while the elongate portion is not in contact with the
subject's tissue. For example, the diameter of the nasal insertion
prong at the distal portion may in some instances be between about
3 mm and about 7 mm, while the diameter of the elongate portion may
be between about 1 mm and about 6 mm proximal to the distal
portion. More specifically, in some variations the diameter of the
nasal insertion prong may be about 5 mm, and the diameter of the
elongate portion may be about 3 mm. The proximal portion of the
elongate portion may flare outward (i.e., have an increasing
diameter or greatest cross-sectional dimension) toward a base
member of the stimulator probe, which may in some variations act as
a stop to limit the distance that the nasal insertion prong may be
advanced into the nose of a user.
[0087] Each nasal insertion prong may comprise at least one
electrode. Each electrode may be connected to a lead, which may be
directly or indirectly connected to a control subsystem and power
source, such that an electrical stimulus may travel from the
control subsystem, through the leads, and through the electrodes,
as described in more detail in U.S. patent application Ser. No.
14/256,915, which was previously incorporated by reference in its
entirety.
[0088] An electrode may have any suitable design. For example, an
electrode may comprise an arc of a cylindrical surface, may be
ellipsoid, spherical, ovoid, or the like. An electrode may have any
suitable length, such as between about 1 mm and about 10 mm,
between about 3 mm and about 7 mm, about 5 mm, or more than about
10 mm. An electrode may be positioned on any suitable longitudinal
portion of a nasal insertion prong, and for nasal insertion prongs
comprising a plurality of electrodes, may be spaced along the nasal
insertion prong. The position of the electrode along the prong may
at least partially determine the placement of the electrode
relative to tissue when the stimulator probe is advanced into the
nose. In some variations, an electrode may be located at an
intermediate position along a prong. The electrode may be located
any suitable distance from the distal tip of the prong, such as
between about 0.1 mm and about 4 mm, about 4 mm and about 8 mm, or
more than 8 mm from the distal dip of the prong (e.g., 1 cm from
the distal tip). In some variations, an electrode may be located
about 2.5 mm from the distal tip of the prong. In some variations
in which an electrode is configured to deliver current, the
electrode may be located such that when inserted into the nasal
cavity, the electrode is capable of reaching the nasal mucosa or
other area desired to be stimulated. In some variations, the
distance from the base member of the stimulator probe to the
longitudinal center of an electrode configured to deliver current
(i.e., the farthest the center of the electrode could be inserted
into the nasal cavity) may be between about 25 mm and about 45 mm.
In other variations, the distance from the base member of the
stimulator probe to the longitudinal center of at least one
electrode may be between about 30 mm and about 40 mm. For example,
in some variations the distance from the base member of the
stimulator probe to the longitudinal center of at least one
electrode may be about 32.5 mm. However, it should be appreciated
that an electrode may be located at other positions, especially
when the electrode is configured to be a return electrode. An
electrode may also be connected to a distal end of a nasal
insertion prong. Generally, when an electrode is positioned at the
distal end of a prong, it may be desirable that the electrode have
no edges, or rounded edges, to help minimize the risk of tissue
damage during advancement of the electrode into the nose.
[0089] In some variations, the electrode comprises a hydrogel,
which is described in more detail in U.S. patent application Ser.
No. 14/630,471, filed Feb. 24, 2015, and titled "Polymer
Formulations for Nasolacrimal Stimulation," which is hereby
incorporated by reference in its entirety. However, it should be
appreciated that electrodes described herein may comprise other
conductive materials, such as metals (e.g., stainless steel,
titanium, tantalum, platinum or platinum-iridium, other alloys
thereof, or the like), conductive ceramics (e.g., titanium
nitride), liquids, gels, or the like. In some variations, the
electrode may comprise one or more materials configured to promote
electrical contact between electrodes of the stimulator probe and
tissue (i.e., all of an electrode or a portion of the electrode,
such as a covering). In some instances, the impedance provided by
tissue may be at least partially dependent on the presence or
absence of fluid-like materials (e.g., mucous) in the nasal cavity.
The material(s) may help to minimize the impact of subject tissue
impedance by providing a wet interface between the electrode and
tissue, which may act to normalize the impedance experienced by the
electrode. This may in turn normalize the output and sensation
experienced by the user.
[0090] The stimulators described herein may comprise at least one
lead configured to electrically connect the electrode(s) to the
stimulator body circuitry. A lead may extend at least partially
through a nasal insertion prong and may be formed from one or more
conductive materials (e.g., stainless steel, titanium, platinum or
platinum-iridium, other alloys thereof, or the like), conductive
ceramics (e.g., titanium nitride), and may be positioned such that
at least a portion of the lead contacts the electrode to provide a
conduction pathway between the lead and the electrode. In some
variations, a lead may comprise a spring, but it should be
appreciated that a lead may also comprise a conductive loop, a
post, or the like.
[0091] In the exemplary handheld stimulator 400 of FIGS. 4A-4C, the
probe 404 comprises a first electrode 410 on nasal insertion prong
406 and a second electrode 412 on nasal insertion prong 408. As
shown in the cut-away view of the stimulator 400 in FIG. 4B, the
electrodes 410 and 412 are connected to leads 430 and 432 located
within prongs 406 and 408, respectively. The leads 430 and 432 are
in turn connected to connectors 422 and 424, respectively.
Connectors 422 and 424 extend through lumens 408 and 410 in the
proximal housing 442, and may connect directly or indirectly to the
control subsystem and power source 452. As such, the electrical
stimulus may travel from the control subsystem through the
connectors 422 and 424, through the leads 430 and 432, and through
the electrodes 410 and 412.
[0092] While stimulator 400 is shown having two nasal insertion
prongs, each comprising a single electrode, in other variations
stimulators may comprise a single nasal insertion prong, and/or may
comprise a plurality of electrodes on a nasal insertion prong. In
some variations comprising a plurality of electrodes on a nasal
insertion prong, the electrodes may be spaced longitudinally along
the length of the nasal insertion prong, such that they are
configured to contact nasal tissue at differing depths within the
anterior nasal cavity when inserted into a nostril. FIG. 19A shows
an example of the distal end of such a nasal insertion prong 1900,
comprising a distal electrode 1902 and a proximal electrode 1904.
As shown there, each electrode comprises a hydrogel contacted by a
lead comprising a spring, but it should be appreciated that the
electrodes and leads may have other configurations, as described
herein. FIG. 20 shows a portion of an exemplary handheld stimulator
2000 comprising two nasal insertion prongs 2006 and 2008, which
each comprise two such electrodes: first electrodes 2010 and 2014
located more proximally on the prong, and second electrodes 2012
and 2016 located more distally on the prong.
[0093] While FIGS. 19A and 20 show the distal and proximal
electrodes as separated by a shorter distance than the length of
each electrode, it should be appreciated that the electrodes may be
longitudinally separated by any suitable distance. For example,
FIG. 19B shows an example of a distal end of a nasal insertion
prong 1950, comprising a distal electrode 1952 and proximal
electrode 1954 separated by a larger distance than the length of
each electrode. FIGS. 21A-21B show another exemplary stimulator
2100 comprising a stimulator body 2102 and a stimulator probe 2104
comprising a single nasal insertion prong 2106, where the nasal
insertion prong comprises two electrodes spaced longitudinally
along the prong. As shown in FIG. 21A, the nasal insertion prong
2106 may comprise a first electrode 2110 and a second electrode
2112, separated longitudinally along the nasal insertion prong by a
larger distance than the length of the electrodes. As shown there,
each electrode comprises a hydrogel contacted by a lead comprising
a spring, but it should be appreciated that the electrodes and
leads may have other configurations, as described herein.
[0094] In other variations, more than one electrode may be located
at the same longitudinal location along the length of the nasal
insertion prong. In these variations, the electrodes may be at
different locations around the circumference of a nasal insertion
prong, i.e., spaced radially around the nasal insertion prong, such
that they are configured to contact nasal tissue at different
locations at the same depth within the anterior nasal cavity when
the nasal insertion prong is inserted into a nostril. For example,
when placed into a nostril, an electrode may face toward the front
of the nose and another electrode may face toward the septum. In
some instances, each electrode may comprise a partial cylinder
(e.g., an arc of between about 10 degrees and 180 degrees). FIG.
22A shows an example of a distal end of such a nasal insertion
prong 2200, comprising a first electrode 2202 and a second
electrode 2204 separated by a vertical rib 2206. FIG. 22B shows a
cross-sectional view of the nasal insertion prong 2200. FIGS. 23A
and 23B show perspective and cut-away views, respectively, of a
handheld stimulator 2300 comprising two nasal insertion prongs 2306
and 2308 each having first and second electrodes separated by a
vertical rib. More specifically, each nasal insertion prong
comprises a pair of electrodes, 2310, 2312 and 2314, 2316,
respectively. Electrode pairs 2310, 2312 and 2314, 2316 are located
at the same longitudinal location along the length of the nasal
insertion prongs, spaced around the circumference. As another
example, FIG. 24 shows an exemplary stimulator 2400 comprising a
stimulator body 2402 and a stimulator probe 2404 comprising a
single nasal insertion prong 2406, where the nasal insertion prong
comprises first and second electrodes 2410 and 2412 spaced radially
around the circumference of the nasal insertion prong. Although
each electrode in FIGS. 22-24 is shown as comprising a hydrogel
contacted by a lead comprising a spring, it should be appreciated
that the electrodes and leads may have other configurations, as
described herein.
[0095] In yet other variations, the electrodes may be spaced both
longitudinally along the length of the nasal insertion prong and
radially around the circumference of the nasal insertion prong.
FIG. 25 shows an example of the distal end of such a nasal
insertion prong 2500, comprising three electrodes: a distal
electrode 2502 and first and second proximal electrodes 2504 and
2506 separated by a vertical rib 2508. As shown there, electrodes
2504 and 2506 have a common longitudinal location (i.e., are locate
horizontally adjacent to each other) and are located proximally
relative to electrode 2502. FIG. 26 shows an exemplary handheld
stimulator 2600 comprising a stimulator body 2602 and a stimulator
probe 2604 comprising a single nasal insertion prong 2606, where
the nasal insertion prong comprises electrodes spaced both
longitudinally along the length of the prong and radially around
the circumference of the prong. Electrode 2610 is located distally
to electrodes 2612 and 2614, which are spaced radially around the
nasal insertion prong 2606 and separated by a vertical rib 2616.
Although each electrode in FIGS. 25-26 is shown as comprising a
hydrogel contacted by a lead comprising a spring, it should be
appreciated that the electrodes and leads may have other
configurations, as described herein.
[0096] It should be appreciated that although the examples
described above comprise one, two, or three electrodes on the nasal
insertion prongs, nasal insertion prongs may have more (e.g., four,
five, six, or more) electrodes, which may be spaced longitudinally
along and/or radially around a nasal insertion prong in any
suitable arrangement. In some instances, each electrode may have a
separate lead, while in others, one or more electrodes may have
electrically connected leads (i.e., may be at the same
potential).
[0097] Additionally or alternatively, some variations of handheld
stimulators may comprise a return contact not located on a nasal
insertion prong, which may provide an alternative or additional
current pathway. For example, a handheld stimulator may comprise a
return contact located on the base member of a stimulator probe or
on a stimulator body. The return contact may be configured to be in
contact with various anatomical locations, such as but not limited
to a hand or an area of tissue near the opening of the nostril, the
columella, the philtrum, or the upper lip. Further, it should be
appreciate that in the configurations described herein, the return
contacts may instead be configured to deliver current.
[0098] For example, FIGS. 27A-27B show exemplary handheld nasal
stimulators each comprising a single prong and a return contact not
located on the nasal insertion prong. Shown there are handheld
nasal stimulators 2700 and 2740 each having return contacts 2702
and 2742 located on the stimulator bodies 2704 and 2744,
respectively. As such, the return contacts may be configured to be
in contact with the hand of a user, while the active electrodes
2706 and 2746, 2748 are configured to be in contact with the nasal
mucosa. FIG. 27C shows a nasal stimulator 2720 comprising two nasal
insertion prongs, each with an electrode, and comprising a return
contact 2722 located on a stimulator body 2724. As shown in FIGS.
27A-27C, handheld stimulators comprising return contacts located on
a stimulator body may have any suitable number of electrodes
located on a nasal insertion prong, such as one per prong (FIGS.
27A and 27C), two (FIG. 27B), three, four, five, six, or more
active electrodes.
[0099] The return contacts in FIGS. 27A-27C are shown as each
comprising a band around the stimulator bodies, but return contacts
configured to contact the hand of a user may have any suitable
shape. For example, a return contact may comprise a plurality of
intersecting bands to accommodate various ways in which a user
might hold the stimulator, or a plurality of bands or surfaces at
the same potential spaced around the stimulator body. It may be
desirable that the total surface area of the return contact be
great enough to reduce impedance to a point where current can be
driven through the return contact without exceeding a maximum
voltage. A return contact may comprise any suitable materials, such
as but not limited to one or more conductive materials, such as
metals (e.g., stainless steel, titanium, tantalum, platinum or
platinum-iridium, other alloys thereof, or the like), conductive
ceramics (e.g., titanium nitride), or hydrogels.
[0100] In other variations, a return contact may be located on the
base member of a stimulator probe, near the base of a nasal
insertion prong. For example, FIGS. 28A and 28B show nasal
stimulators 2800 and 2820 each having return contacts 2802 and 2822
located on the stimulator probes 2806 and 2826, respectively, near
the proximal end of the nasal insertion prongs 2804 and 2824. The
return contacts 2802 and 2822 are shown as having an annular shape
near the proximal end of the nasal insertion prongs, such that the
return contacts are configured to contact an area of tissue near
the opening of the nostril when the nasal insertion prong is
inserted into a nasal cavity. By having a return contact located
near the opening of the nostril, it may be possible to have current
flow through a desired portion of the septum while having only a
single nasal insertion prong (i.e., one or more electrodes on only
one side of the septum, as opposed to at least one electrode on
each side of the septum). It should be appreciated that in other
variations, the return contacts may have other suitable shapes,
such as a plurality of bands or contact points. As shown in FIGS.
28A-28B, handheld stimulators comprising return contacts located
near a base of a nasal insertion prong may have any suitable number
of electrodes located on the nasal insertion prong, such as one per
prong (FIG. 28A), two (FIG. 28B), three, four, five, six, or more
electrodes. It should be appreciated that although FIGS. 28A-28B
show a return contact located near the proximal end of a nasal
insertion prong of a stimulator comprising a single nasal insertion
prong, return contacts may also be positioned near the proximal end
of one or both nasal insertion prongs of a stimulator comprising
two nasal insertion prongs.
[0101] In yet other variations, a return contact may be located on
the base member of a stimulator probe, away from the proximal end
of a nasal insertion prong. For example, FIGS. 29A-29B show
handheld stimulators comprising a single nasal insertion prong
configured to be inserted into a first nostril, and a return
contact configured to contact an area of tissue near the opening of
a second nostril, against the skin and/or nasal mucosa. FIG. 29A
depicts a handheld stimulator 2900 comprising a single stimulator
probe 2908. The stimulator probe 2908 comprises a single nasal
insertion prong 2904 having a single electrode 2906. The base
member 2912 of the stimulator probe 2908 comprises a return contact
2910. The stimulator 2900 may be configured such that when the
nasal insertion prong 2904 is inserted into a first nostril, the
return contact 2910 is in contact with an area of tissue near the
opening of a second nostril. FIG. 29B shows a similar handheld
stimulator 2950 comprising a stimulator probe 2958 comprising a
single nasal insertion prong 2954 comprising two electrodes 2956
and 2962, and a base member 2952 comprising a return contact 2960
configured to contact an area of tissue near the opening of a
second nostril.
[0102] In the variation shown in FIG. 29B, the leads may have
various arrangements, such that each electrode or return contact
may be at a different potential, or two may be at the same
potential. For example, the leads connected to each of the
electrodes 2956, 2962, and the return contact 2960 may in some
variations be separate, as schematically illustrated in FIG. 29C.
In other variations, one of the two electrodes 2956, 2962 may have
a common lead with the return contact 2960, as schematically
illustrated in FIG. 29D, such that the electrode and the return
contact are at the same potential. In yet other variations, the two
electrodes 2956, 2962 may have a common lead, as shown in FIG. 29E.
A resistor may optionally be located between an electrode and the
return contact, or between the two electrodes, which may affect the
distribution of current delivery. For example, FIG. 29C shows a
resistor 2964 located between the electrode 2962 and the return
contact 2960. These various arrangements may affect the spatial
delivery of current, as described in more detail herein.
Spatial Control
[0103] The electrodes and return contacts described herein may
allow stimulus delivery by the stimulators to be spatially
controlled. That is, current steering may be achieved by driving
current particular pathways between the electrodes or return
contacts, and in some instances, the pathway(s) of current flow
through tissue may change over time to achieve spatial patterning.
The current being delivered by or to each electrode may in some
instances be individually controlled in order to achieve these
effects. For example, the same or different waveforms, or no
waveform, may be delivered by each of the electrodes at any given
time, and the stimulus delivery by each of the electrodes may vary
over time. Current steering may allow both the current pathways and
the quantity of current along each pathway to be controlled.
Current steering may enable particular areas of tissue to be
targeted by the stimuli, and spatial patterning may affect a
subject's perception of the stimulus and may reduce accommodation.
Spatial patterning may provide neural activation to varying tissue
over time (e.g., to varying sets of nerve branches, such as of the
anterior ethmoidal nerve within the nasal mucosa). In some
instances, for example, this could be interpreted as similar to a
physical movement of a system having a single fixed current
pathway, thereby reducing the need for a user to move the electrode
within the nose to activate varying sets of neural fibers.
[0104] In some variations, exemplary anatomical targets may include
nerves, muscles, mucosal or sub-mucosal tissues (e.g., nasal or
sinus mucosa or sub-mucosa), sensory cells in the glaborous and
hairy skin, glands, or other structures of a patient involved in
the process of lacrimation or glandular vasodilation that may be
electrically stimulated. For example, the anatomical structures may
include, but are not limited to, a lacrimal gland, one or more
meibomian glands, lacrimal ducts, cutaneous receptors
(mechanoreceptors, Meissner's corpuscles, neurotendinous spindles,
golgi tendon organs, Ruffini's corpuscles, Stretch Receptors,
Ruffini corpuscle end-organs, Pacinian corpuscle end-organs, hair
follicle receptors, free nerve endings, thermoreceptors, bulboid or
Krause corpuscles, nociceptors), parasympathetic nerves, fibers and
neurites, sympathetic nerves, fibers and neurites, rami lacrimales,
the lacrimal nerve, perivascular nerves of lacrimal artery and
branches thereof, nerve fibers innervating the meibomian glands,
myoepithelial cells of the lacrimal gland, acinar cells of the
lacrimal gland, or ductal cells of the lacrimal gland. In yet a
further variation, the anatomical structure is the infra-trochlear
nerve. In other variations, the anatomical structure is a cutaneous
receptor responsible for sensing changes in force or temperature
over time or a set of cutaneous receptors in an area of the skin
reporting changes in force applied to the skin directly or
indirectly by moving hair growing in the skin, or the nerves
innervating the cutaneous receptors reporting changes in force
applied to the skin or hair in the skin, or temperature changes in
the skin including the mucosa, the sub-mucosa in the nose, or the
conjunctiva in the eye.
[0105] In some instances, it may be desirable to deliver the
electrical stimuli described herein to one or more nerves that
innervate the lacrimal gland tissue. In others, it may be desirable
to deliver the electrical stimuli described herein to the nasal
mucosa. This may cause lacrimation by activating the nasolacrimal
reflex. In some instances, the targeted area may comprise tissue
innervated by the anterior ethmoidal branch of the nasociliary
nerve. In another variation, the anatomical structure is the
posterior ethmoid nerve. In some instances, the targeted area of
the nasal mucosa may be superior to the columella. It may in some
instances be near the inferior end of the nasal bone (i.e., near
the interface between the nasal bone and the upper lateral
cartilage). As such, the stimulus may be delivered between about 20
mm and about 35 mm into the nasal cavity of the patient, in some
cases via an electrode between about 25 mm and about 35 mm into the
nasal cavity of the patient. In other instances, the targeted area
may be the columella. It may be desirable that the stimulus be
delivered in the anterior portion of the nasal cavity, within the
nostrils and anterior to the turbinates, and in some instances, at
a location anterior to the middle turbinate, or at a location
anterior to the inferior turbinate. The stimulus may be delivered
at least partially through tissue of or near the septum, and it may
in some instances be desirable to direct stimulus such that a
portion is directed toward the front of the nose. This may allow
for selective activation of nerves in the front of the septum
(e.g., the ophthalmic branch of the trigeminal nerve) while
minimizing activation of nerves toward the rear of the nasal
septum, which may reduce negative side effects that may occur from
stimulation of nerves that innervate the teeth, and which may
reduce rhinorrhea. It may also in some instances be desirable to
direct the stimulus so as to reduce negative side effects that may
occur from stimulation of the olfactory area.
[0106] One way to achieve stimulation of one or more of these
target areas may be current steering. For example, current may be
directed to flow in a pathway such that it is concentrated in areas
where a target nerve (e.g., the anterior ethmoidal nerve) is
located (e.g., certain portions of the septum) while avoiding
stimulating areas that may cause discomfort or unnecessary
unpleasant sensations (e.g., portions of the trigeminal nerve that
innervate the teeth). By steering current in this way, preferential
activation of particular nerves may be achieved with waveforms that
might not otherwise be able to achieve preferential activation.
[0107] In handheld stimulation devices comprising one or more nasal
insertion prongs, for example, current steering may be used to
drive current between electrodes on the same prong and,
additionally or alternatively, in devices comprising two nasal
insertion prongs, between electrodes on different prongs. As
described herein, handheld stimulation devices may also comprise
one or more return contacts to provide additional possible current
pathways. Spatial control may allow both the current pathways and
the quantity of current along each pathway to be controlled, and
may allow these to be changed over time. By controlling the current
pathways, particular tissue areas can be targeted. In some
variations, current steering may be used to adjust the location of
stimulus delivery to a desired region of tissue without having to
move an implanted or temporarily inserted stimulator.
[0108] In some cases, the current steering may be accomplished by
having isolated circuits with separate current sources for each
pathway, wherein each is floating without a common ground. In other
cases, the current steering may be accomplished using a single
current source based on the impedance values of multiple pathways.
Current steering may also in some instances be carried out using a
multiplexor, which may be located inside a waveform generator. In
other instances it may be carried out using frequency selectivity,
for example, by different electrodes being connected to receiver
coils having different resonant frequencies, such that small
changes in controller frequencies may allow for selective delivery
of stimulus by the electrodes.
[0109] As one example of spatial control, FIG. 30A depicts an
illustrative stimulator 3000 comprising two nasal insertion prongs
3002 and 3004, each comprising two electrodes 3006, 3008 and 3010,
3012, respectively. Current steering may be used to drive current
via various pathways between the four electrodes, including between
the two nasal insertion prongs, between electrodes on the same
nasal insertion prong, or both, which may result in stimulation of
different anatomical targets.
[0110] FIGS. 30B-30E show variations of how current may be directed
between the electrodes. In some variations, the current may be
directed to flow from one or more electrodes on prong 3002 to one
or more electrodes on prong 3004. For example, in FIG. 30B, the
current is delivered by electrode 3006, while electrode 3008 does
not deliver any current. The current from electrode 3006 is steered
toward electrodes 3010 and 3012, which function as return
electrodes, such that a portion (e.g., 50%) of the current flows
from electrode 3006 to electrode 3010, and a portion (e.g., 50%) of
the current flows from electrode 3006 to 3012. In FIG. 30C, current
is also driven from one nasal insertion prong to the other, but in
this configuration, electrodes 3006 and 3008 both deliver current,
and electrodes 3010 and 3012 both act as return electrodes, such
that a portion (e.g., 50%) of the total current flows from
electrode 3006 to 3010, and a portion (e.g., 50%) of the total
current flows from electrode 3008 to electrode 3012. In FIG. 30D,
current is driven from one nasal insertion prong to the other, and
electrodes 3006 and 3008 both deliver current, and electrodes 3010
and 3012 both act as return electrodes. However, in contrast to the
example of FIG. 30C, a portion (e.g., 50%) of the total current
flows from electrode 3006 to 3012, and a portion (e.g., 50%) of the
total current flows from electrode 3008 to 3010. It should be
appreciated that the current need not be divided evenly between
pathways in these examples, and that more current may be directed
through one of the two pathways.
[0111] Whereas in the examples of FIGS. 30B-30D the current is
driven from an electrode on the first prong 3002 to an electrode on
the second prong 3004, in other variations, the current may be
directed between electrodes on the same prong. For example, in FIG.
30E, the current is delivered by electrode 3006, and electrode 3008
on the same prong and electrode 3010 on the other prong act as
return electrodes. That is, a portion (e.g., 80%) of the current
may travel from electrode 3006 on the first prong 3002 to electrode
3010 on the second prong 3004, while the remainder (e.g., 20%) may
travel from electrode 3006 to electrode 3008, both located on the
first prong 3002. In each arrangement illustrated in FIGS. 30B-30E,
the described current steering may be accomplished, for example, by
having isolated circuits with separate current sources for each
pathway, where each is floating without a common ground. Each
configuration of current steering in FIGS. 30B-30E may result in
different anatomical targets near and within the septum being
stimulated.
[0112] Current may also be steered between one or more electrodes
located on a nasal insertion prong and one or more return contacts.
Turning back to the handheld nasal stimulator of FIGS. 29A-29B,
each of the electrical configurations of FIGS. 29C-29E may result
in a different spatial configuration of current delivery, and thus
the anatomical target stimulated. For example, FIG. 29C shows a
resistor 2964 located between the electrode 2962 and the return
contact 2960. In this configuration, if electrode 2956 delivers
current, the presence of the resistor 2964 results in less current
being driven from the electrode 2956 to electrode 2962 and more
current being driven from the electrode 2956 to the return contact
2960, as compared to a configuration without the resistor 2964. As
a result, when the nasal insertion prong 2954 is inserted into a
nostril, such that the electrodes 2956 and 2962 are in contact with
the nasal mucosa, more current may be driven through the septum, as
compared to a configuration without the resistor 2964. In some
variations, the resistor may be variable. It may be controllable by
a use, such that the user can adjust the stimulation effect.
[0113] As another example, FIG. 31 illustrates current steering via
multiple pathways using a handheld stimulator 3150 comprising a
nasal insertion prong 3152 comprising first and second electrodes
3154 and 3156, as well as a return contact 3160 configured to be in
contact with a user's hand while the first and second electrodes
are in contact with a user's nasal mucosa. As illustrated, the
current may be steered such that a portion (e.g., 70%) travels from
electrode 3156 to electrode 3154 on the nasal insertion prong 3152,
illustrated by the arrow 3162, while a portion (e.g., 30%) travels
from electrode 3156 to the return contact 3160 on the stimulator
body 3158, illustrated by the arrow 3164. As a result, there may be
a higher current density, and thereby a higher voltage drop, across
the area of a target nerve (e.g., the anterior ethmoidal nerve),
while a lower current density would pass through other areas. It
should be appreciated that arrows 3162, 3164, and the other arrows
representing current pathways herein, are not intended to
illustrate the exact physical path of current through tissue, but
rather the origin and return of current with respect to the device.
The actual path of the current through the tissue as it travels
from the origin to the return will depend on the tissue shape and
properties.
[0114] The paths through which current is steered may be changed
over time to spatially pattern the stimulus delivery. That is, for
example, during a first time period the current may be driven via a
first set of pathway(s), and during a second time period the
current may be driven via a second set of pathway(s). This may
generate the sensation of a moving stimulus, which may reduce
patient accommodation to the stimulus. For example, the handheld
nasal stimulator 3000 may be configured to cycle, either in a
predetermined fashion, randomly, or under user control, through the
current steering patterns shown in FIGS. 30B-30E.
[0115] As another example, FIGS. 32A-32B show a stimulator 3200
comprising a first nasal insertion prong 3202 and a second nasal
insertion prong 3204. The first nasal insertion prong 3202
comprises a first electrode 3206 and a second electrode 3208, while
the second nasal insertion prong 3204 comprises a single electrode
3210. The stimulator 3200 may have a first configuration
(illustrated in FIG. 32A) in which current flows from electrode
3206 on the first nasal insertion prong 3202 to electrode 3210 on
the second nasal insertion prong 3204, and a second configuration
(illustrated in FIG. 32B) in which the current flows from electrode
3208 on the first nasal insertion prong 3202 to electrode 3210 on
the second nasal insertion prong 3204. In order to switch between
the first and second configurations, the stimulator 3200 may
comprise a switch 3222, schematically illustrated in FIG. 32C,
allowing selection of output 3224, which results in current
delivery from electrode 3206, or selection of output 3226, which
results in current delivery from electrode 3208. The variation
shown in FIG. 32C also shows two signal generators 3212 and 3214,
discussed in more detail below, but it should be appreciated the
stimulator may comprise fewer or more signal generators. For
example, FIG. 32D shows a schematic illustration of a portion of an
alternative configuration of circuitry for the stimulator
comprising a single signal generator 3252, the output from which
can be directed via selector switches 3258 and 3250 of multiplexor
3260 to first output 3254 or second output 3256. Output 3254 may go
to a first electrode (e.g., electrode 3206), and output 3256 may go
to a second electrode (e.g., electrode 3208).
[0116] By switching between current delivery to be from different
electrodes, the current pathway may be changed over time, which may
allow stimulation of different tissue areas over time. This may in
turn reduce accommodation and/or may allow particular anatomical
areas to be targeted. In some instances, it may be desirable to
temporarily target particular areas. For example, periodic partial
activation of CN-V2 may reduce the sensation of needing to sneeze
that may otherwise be perceived during stimulation of the anterior
ethmoidal nerve.
[0117] Similarly, FIG. 33 shows a cut-away view of the stimulator
2300 of FIGS. 23A-23B. As shown in FIG. 33, the stimulator 2300 can
be configured such that current may be steered via various
pathways. For example, current flowing from electrode 2312 on the
first nasal insertion prong may be driven to electrode 2316 on the
second nasal insertion prong via pathway 3202; to electrode 2314 on
the second nasal insertion prong via pathway 3206; or to electrode
2310 on the first nasal insertion prong via pathway 3204.
[0118] In some variations, the current may be steered sequentially
via the various pathways. This type of spatial patterning may be
achieved in stimulators comprising a single current source used to
drive two or more electrodes versus a common ground. This may be
implemented using, for example, a multiplexor. The current may also
be steered simultaneously via the various pathways. This type of
current steering may be achieved in stimulators comprising a
plurality of independent, or electrically floating, current
sources. In these variations, a multiplexor may also be used to
control which electrodes receive current from each source.
[0119] While the figures discussed above show the application of
current steering to a handheld nasal stimulator, it should be
appreciated that current steering may be applied with use of other
devices, such as implantable stimulators (e.g., stimulators
implanted in ocular or nasal regions) described herein. The ability
to target particular areas of tissue without moving the electrode
contact points may be particularly useful in the case of
implantable stimulators having a fixed position relative to
tissue.
[0120] When stimulators are configured for spatial patterning of
stimulus delivery, the spatial patterning may have any suitable
parameters. For example, current delivery may be switched between
two or more pathways at a predetermined frequency, such as about
every 0.5 seconds, 1 second, 2 seconds, 5 seconds, 10 seconds, or
longer. In other variations, a user may be able to switch between
two or more pathways using a user interface, such as a user
interface described herein. In yet other variations, the pathway
may be selected by a clinician for an individual patient. For
example, when the stimulator is an implantable stimulator, a
clinician may be able to select a pathway after implantation, so
that the stimulated tissue can be tailored after implantation
without having to adjust the implantation site.
Waveforms
[0121] The electrical stimulation waveforms delivered by the
stimulators described herein may be tailored for specific treatment
regimens and/or specific patients. In variations of stimulators
configured to deliver current via two or more pathways, different
waveforms may be delivered via each pathway, and the waveform
delivered via each pathway may be changed over time. Returning to
FIG. 32C, a stimulator may comprise a first signal generator 3212
configured to generate a first waveform, and a second signal
generator 3214 configured to generate a second waveform. A
multiplexer 3230 may have corresponding first and second select
lines 3218 and 3220. In combination with the switch 3222, described
above, the multiplexer 3230 may allow for the waveform from either
signal generator to be delivered to either electrode of the nasal
insertion prong 3202, or to the return 3228. While FIG. 32C shows
only two signal generators and two outputs, it should be
appreciated that a similar configuration may be used for any number
of signal generators and outputs. The waveform generated by each
signal generator may have any suitable parameters, and may be any
of the waveforms described in more detail herein.
[0122] As is described in more detail herein, when temporal
patterning of electrical stimulation waveforms is employed,
waveform parameters such as the shape, the frequency, the
amplitude, and the pulse width may be modulated. The frequency,
pulse-width, and/or amplitude of the waveform may be modulated
linearly, exponentially, as a sawtooth, a sinusoidal form, etc., or
they may be modulated randomly. The stimulation can also be
interrupted as part of the temporal patterning. That is, the
stimulation can be in an on/off condition, e.g., for durations of 1
second on/1 second off, 5 seconds on/5 seconds off, etc. Modulation
of the waveform shape (e.g., rectangular vs. triangular vs.
exponential) in a rhythmic or non-deterministic, non-rhythmic
fashion may also be used. Thus, numerous variations in temporal
waveform patterning can be achieved. It should be understood that
combinations of these parameter changes over time in a repetitive
manner may also be considered temporal patterning. In some
instances, random temporal patterning may be employed. Temporal
patterning may help to prevent patient habituation to the applied
stimulation (i.e., may help to prevent the patient response to the
stimulation decreasing during stimulation).
[0123] In some instances, it may be desirable to configure the
stimulation waveform to minimize side effects. In some instances,
it may be desirable to promote stimulation of larger-diameter
nerves (e.g., afferent fibers of the trigeminal nerve), which may
promote a therapeutic effect, while reducing the stimulation of
smaller nerves (e.g., a-delta fibers, c fibers, sympathetic and
parasympathetic fibers), which may result in pain, discomfort, or
mucus production. Generally, for smaller pulse-widths, the
activation threshold for larger-diameter nerves may be lower than
the activation threshold for the smaller nerve fibers. Conversely,
for larger pulse-widths, the activation threshold for
larger-diameter nerves may be higher than the activation threshold
for the smaller nerve fibers. Accordingly, in some instances, it
may be desirable to select a pulse width that preferably actuates
the larger-diameter nerves. In some variations, the pulse width may
be between 50 .mu.s and about 1200 .mu.s. As another example,
certain waveforms may minimize activation of the branches of the
trigeminal nerve (e.g., CN V2) that travel to the teeth. These may
include waveforms ranging from 30 .mu.s to 300 .mu.s in pulse
width, 10 Hz to 150 Hz in frequency, and 0.1 mA to 5 mA in
amplitude.
[0124] The stimulation may be delivered periodically at regular or
irregular intervals. Stimulation bursts may be delivered
periodically at regular or irregular intervals. The stimulation
amplitude, pulse width, or frequency may be modified during the
course of stimulation. For example, the stimulation amplitude may
be ramped from a low amplitude to a higher amplitude over a period
of time. In other variations, the stimulation amplitude may be
ramped from a high amplitude to a lower amplitude over a period of
time. The stimulation pulse width may also be ramped from a low
pulse width to a higher pulse width over a period of time. The
stimulation pulse width may be ramped from a high pulse width to a
lower pulse width over a period of time. The ramp period may be
between 1 second and 15 minutes. Alternatively, the ramp period may
be between 5 seconds and 30 seconds.
[0125] The temporally patterned stimulation waveforms described
herein may be used to increase the comfort of the patient and/or
may be used to improve the efficacy of the stimulation, and thus,
described below are waveform parameters that may be used alone or
in combination to increase comfort and/or efficacy.
[0126] It should be appreciated that the waveforms described here
may be delivered via a multi-polar, such as bipolar, tripolar,
quad-polar, or higher-polar configuration or a monopolar
configuration with distal return. The waveforms may be a
sinusoidal, quasi-sinusoidal, square-wave, sawtooth, ramped, or
triangular waveforms, truncated-versions thereof (e.g., where the
waveform plateaus when a certain amplitude is reached), or the
like, as described in more detail herein.
[0127] Shape
[0128] In some instances, the waveform shape or modulation thereof
may affect the comfort and/or efficacy of the stimulation. When the
stimulator (electrode device) is configured to create a pulse-based
electrical waveform, the pulses may be any suitable pulses (e.g., a
square pulse, a haversine pulse, or the like). The pulses delivered
by these waveforms may by biphasic, alternating monophasic, or
monophasic, or the like. When a pulse is biphasic, the pulse may
include a pair of single phase portions having opposite polarities
(e.g., a first phase and a charge-balancing phase having an
opposite polarity of the first phase). Each phase of the biphasic
pulse may be either voltage-controlled or current-controlled. In
some variations, both the first phase and the charge-balancing
phase of the biphasic pulse may be current-controlled. In other
variations, both the first phase and the charge-balancing phase of
the biphasic pulse may be voltage-controlled. In still other
variations, the first phase of the biphasic pulse may be
current-controlled, and the second phase of the biphasic pulse may
be voltage-controlled, or vice-versa. In some instances, a
combination of current-controlled bilateral stimulation and
voltage-controlled charge balancing may allow for unilateral
stimulation, and by modifying the waveform shape, may allow for
switching between areas of stimulation, e.g., between nostrils when
electrodes are located in each nostril, as described herein.
[0129] In some variations in which the waveform comprises a
biphasic pulse, it may be desirable to configure the biphasic pulse
to be charge-balanced, so that the net charge delivered by the
biphasic pulse is approximately zero. In some variations, a
biphasic pulse may be symmetric, such that the first phase and the
charge-balancing phase have the same pulse width and amplitude.
Having a symmetric biphasic pulse may allow the same type of
stimulus to be delivered, e.g., to each nasal cavity. The pulses of
a first phase may stimulate a first side of the nose (while
providing a charge-balancing phase to a second side of the nose),
while the pulses of the opposite phase may stimulate the second
side of the nose (while providing a charge-balancing phase to the
first side of the nose).
[0130] In other variations in which the waveform comprises a
biphasic pulse, a biphasic pulse may be asymmetric, where the
amplitude and/or pulse width of the first pulse may differ from
that of the charge-balancing phase. Even if the biphasic pulse is
asymmetric, the biphasic pulse may be charge-balanced. For example,
the cathodic pulse may have lower amplitude but longer duration
than the anodic pulse, or the cathodic pulse may have higher
amplitude but shorter duration than the anodic pulse. In both
instances, the charge injection (amplitude times duration) may be
equal for each pulse, such that the net charge delivered by the
biphasic pulse is approximately zero.
[0131] The shape of the waveform may be changed to preferentially
activate the tissue near an electrode. For example, FIGS. 5A-5C
illustrate exemplary waveforms configured to preferentially
activate tissue near one of two electrodes, and where the
preferential activation may move from near one electrode to the
other over time. In variations in which the stimulator is a
handheld stimulator configured to have an electrode in each
nostril, for example, this preferential activation may allow for
preferential activation of tissue in one of the two nostrils, which
may change over time. For example, FIG. 5A shows a variation of a
biphasic charge-balanced waveform 518 in which the aspect ratios
(amplitude:duration) of the pulses changes over time. Shown there
is a waveform that has a first pattern wherein a leading cathodic
pulse has a greater amplitude and shorter duration in comparison to
the following anodic pulse. This pattern is found in the time
periods indicated by 510 and 514. The waveform has a second pattern
where the leading cathodic pulse has a lesser amplitude and longer
duration in comparison to the following anodic pulse. This pattern
is found in the time periods indicated by 512 and 516. It should be
appreciated that each time period may have any suitable duration
and thus comprise any suitable number of pulses. As one example,
each time period may last for about 1 second. In other examples,
each time period may last for less than 1 second, about 1 to about
5 seconds, about 5 to about 10 seconds, about 10 to about 20
seconds, or longer.
[0132] In some variations the waveform may transition between two
aspect ratios in an abrupt fashion. In other variations the
transition may be gradual, where the aspect ratio of the cathodic
pulse may increase over time and then decrease over time, while the
aspect ratio of the anodic pulse may decrease over time and then
increase over time. FIG. 5B shows an example of a waveform 520 that
gradually transitions between aspect ratios. These increases and
decreases may have any suitable form, such as linear increases and
decreases or sinusoidal increases and decreases. In other
variations, the transition may have a sawtooth shape, in which the
aspect ratio of the cathodic pulse increases gradually over time
while the aspect ratio of the anodic pulse decreases gradually over
time, and then the aspect ratio of the cathodic pulse decreases
abruptly while the aspect ratio of the anodic pulse increases
abruptly.
[0133] In some variations, the polarity is switched back and forth
between a pattern in which the cathodic pulse is first and a
pattern in which the anodic pulse is first. For example, FIG. 5C
shows an illustrative version of such a stimulation waveform 522.
As shown there, the time periods indicated by 502 and 506 may have
a cathodic pulse and then an anodic pulse, while the time periods
indicated by 504 and 508 may have an anodic pulse and then a
cathodic pulse. It should be appreciated that each time period may
have any suitable duration. As one example, each time period may
last for about 1 second. In other examples, each time period may
last for less than 1 second, about 1-5 seconds, about 5-10 seconds,
about 10-20 seconds, or longer. In some variations, each time
period may last for a single pair of pulses, such that the
stimulation waveform comprises a repeating pattern of two anodic
pulses and two cathodic pulses.
[0134] Although the patterns having variable amplitude:duration
aspect ratios may have uniform charge injection, they may
preferentially activate the tissue near one of the two electrodes.
That is, when the leading cathodic pulse has a greater amplitude
and shorter duration than the anodic pulse, the waveform may
preferentially activate tissue near a cathodic electrode; when the
leading cathodic pulse has a lesser amplitude and longer duration
than the anodic pulse, the waveform may preferentially activate
tissue near an anodic electrode. Changing aspect ratios and
switching polarities as described herein may increase the
lacrimation response and/or change tear composition resulting from
stimulation. This may be because switching polarities leads to
non-linear addition of the stimuli as perceived by the central
nervous system, as well as because switching polarities may reduce
a patient's accommodation to the stimuli. Additionally, some
stimulators described herein may be configured such that a user may
be able to change the aspect ratios of a biphasic waveform in order
to change the location or extent of preferential activation, such
as by using a user interface. For some patients, adjusting the
aspect ratio may result in a perception of a more symmetrical
waveform and/or result in a more symmetrically bilateral treatment
effect. In some instances, it may be desirable to have an
asymmetrical bilateral treatment effect, or a unilateral treatment
effect, for example in a patient having more severe dry eye in one
eye than the other. In these instances, a patient may use a user
interface to adjust the aspect ratio to achieve the desired
asymmetrical effect.
[0135] Frequency
[0136] In order to treat dry eye or otherwise produce a tearing
response by stimulating tissue, the stimulators described herein
may be configured to generate one of more waveforms at frequencies
suitable for stimulating targeted tissue (e.g., a nerve). The
frequency may affect the comfort and/or efficacy of the
stimulation. Generally, the frequency is preferably between about
0.1 Hz and about 200 Hz. In some of these variations, the frequency
is preferably between about 10 Hz and about 200 Hz. In some of
these variations, the frequency is preferably between about 30 Hz
and about 150 Hz. In others of these variations, the frequency is
preferably between about 50 Hz and about 80 Hz. In others of these
variations, the frequency is preferably between about 30 Hz and
about 60 Hz. In some variations, the frequency may be about 1.5 Hz,
about 10.25 Hz, about 70 Hz, about 150 Hz, about 25 Hz, about 27.5
Hz, about 30 Hz, about 32.5 Hz, about 35 Hz, about 37.5 Hz, about
40 Hz, about 42.5 Hz, about 45 Hz, about 47.5 Hz, about 50 Hz,
about 52.5 Hz, about 55 Hz, about 57.5 Hz, about 60 Hz, about 62.5
Hz, or about 65 Hz. In some variations, high frequencies, such as
those between about 145 Hz and about 155 Hz may be too high for
each pulse to stimulate/activate the target tissues. As a result,
the stimulation may be interpreted by the patient to have an
element of randomness, which in turn may help to reduce patient
habituation. The frequencies described herein may be suitable for
stimulating the targeted tissue to initiate a reflex circuit that
activates the lacrimal gland to produce tears, and/or suitable for
directly driving efferent fibers innervating the lacrimal gland. In
some instances, the frequency may be chosen for preferential
activation of certain anatomical targets, as described herein.
[0137] Amplitude
[0138] In order to treat dry eye or otherwise produce a tearing
response by stimulating tissue, the stimulators described herein
may be configured to deliver a current suitable for stimulating
targeted tissue (e.g., a nerve). The maximum amplitude or
modulation thereof may affect the comfort and/or efficacy of the
stimulation. When the stimulus comprises a biphasic pulse and the
first phase of the biphasic pulse is current-controlled, the first
phase may preferably have an amplitude between about 1.0 mA and
about 10 mA. Amplitudes within these ranges may be high enough to
stimulate targeted tissue, but sufficiently low as to avoid any
significant heating of tissue, ablation of tissue, or the like. In
some variations the amplitude may be between about 1.0 mA and about
5.0 mA. In other variations, the first phase may have an amplitude
of about 0.1 mA, about 0.2 mA, about 0.3 mA, about 0.4 mA, about
0.5 mA, about 0.6 mA, about 0.7 mA, about 0.8 mA, about 0.9 mA, or
about 1.0 mA. In some variations, the amplitude may be variable.
For example, the amplitude may vary between about 1.3 mA and about
1.5 mA, about 2.2 mA and about 2.5 mA, about 3.2 mA and about 3.7
mA, about 4.3 mA and about 5.0 mA. When the first phase of a
biphasic pulse is voltage-controlled, the first phase may
preferably have an amplitude between about 10 mV and about 100
V.
[0139] When a stimulator is configured to deliver a pulse-based
waveform, in some variations, the amplitude of the pulses may be
constant over time. In other variations, the amplitude of the
pulses may vary over time. This may reduce patient accommodation.
In some variations, the amplitude of pulses may increase (linearly,
exponentially, etc.) from a minimum value to a maximum value, drop
to the minimum value, and repeat as necessary. In some variations,
the amplitude of the pulses may vary according to a sinusoidal
profile. In another variation, as illustrated in FIG. 6A, the
amplitude may periodically increase from a baseline amplitude (A)
to a higher amplitude (B) for a single pulse. In yet another
variation, as illustrated in FIGS. 6B-6C, the amplitude of the
pulses may follow a periodically increasing and decreasing pattern
between two lower amplitudes (A, B), and periodically increase to a
higher amplitude (C) for a single pulse (FIG. 6B) or for a
plurality of pulses (e.g., two pulses) (FIG. 6C). In yet another
variation, as illustrated in FIG. 6D, a higher amplitude pulse (or
pulses) may be preceded by a brief pause (i.e., no current
delivery). Each of these types of amplitude modulation may be
implemented alone or in combination with any other type of
amplitude modulation, and may reduce patient accommodation.
[0140] In some variations in which the amplitude varies over time,
the amplitude may vary at a frequency suitable for reducing patient
accommodation or increasing patient comfort such as between about
0.1 Hz and about 5 Hz, between about 1 Hz and about 5 Hz, between
about 1 Hz and 2 Hz, between about 2 Hz and 3 Hz, between about 3
Hz and 4 Hz, or about 4 Hz and about 5 Hz. In some variation, the
amplitude may vary at a frequency of about 1.0 Hz, about 1.1 Hz,
about 1.2 Hz, about 1.3 Hz, about 1.4 Hz, about 1.5 Hz, about 1.6
Hz, about 1.7 Hz, about 1.8 Hz, about 1.9 Hz, about 2.0 Hz, about
2.1 Hz, about 2.2 Hz, about 2.3 Hz, about 2.4 Hz, about 2.5 Hz,
about 2.6 Hz, about 2.7 Hz, about 2.8 Hz, about 2.9 Hz, about 3.0
Hz, about 3.1 Hz, about 3.2 Hz, about 3.3 Hz about 3.4 Hz, about
3.5 Hz, about 3.6 Hz, about 3.7 Hz, about 3.8 Hz, about 3.9 Hz, or
about 4.0 Hz. In other variations, the stimulation waveform may be
a modulated high frequency signal (e.g., sinusoidal), which may be
modulated at a beat frequency of the ranges described above. In
such variations, the carrier frequency may be between about 100 Hz
and about 100 kHz.
[0141] Pulse Width
[0142] In order to treat dry eye or otherwise produce a tearing
response by stimulating tissue, the stimulators described herein
may be configured to deliver a waveform in which the first phase
may preferably have a pulse width between about 1 .mu.s and about
10 ms. In some of these variations, the pulse width may be between
about 10 .mu.s and about 100 .mu.s. In other variations, the pulse
width may be between about 100 .mu.s and about 1 ms. In yet other
variations, the pulse width may be between about 0 .mu.s and about
300 .mu.s. In yet other variations, the pulse width may be between
about 0 .mu.s and 500 .mu.s. As described above, it may be
desirable to select a pulse width that preferably actuates
larger-diameter nerves. In some variations, the pulse width may be
between 50 .mu.s and about 1200 .mu.s. As another example, pulse
widths of 30 .mu.s to 300 .mu.s may minimize activation of the
branches of the trigeminal nerve (e.g., CN V2) that travel to the
teeth.
[0143] In some variations, the pulse width may be constant over
time. In other variations, the pulse width may vary over time.
Pulse width modulation over time may increase the efficacy and/or
comfort of the stimulation. In some variations, the pulse width may
increase (linearly, exponentially, etc.) from a minimum value to a
maximum value, drop to the minimum value, and repeat as necessary.
In some variations, the pulse width may vary according to a
sinusoidal profile. In another variation, as illustrated in FIG.
7A, the pulse width may periodically increase from a baseline pulse
width (A) to a longer pulse width (B) for a single pulse. In yet
another variation, as illustrated in FIGS. 7B-7C, the pulse width
may follow a periodically increasing and decreasing pattern between
two shorter pulse widths (A, B), and periodically lengthen to a
longer pulse width (C) for a single pulse (FIG. 7B) or for a
plurality of pulses (e.g., two pulses) (FIG. 7C). In yet another
variation, as illustrated in FIG. 7D, a longer pulse width pulse
(or pulses) may be preceded by a brief pause (i.e., no current
delivery). Each of these types of pulse width modulation may be
implemented alone or in combination with any other type of pulse
width modulation. In any form of pulse width modulation, the pulse
width may vary at any suitable frequency. In some variations the
pulse width may vary at about 0.1 Hz, about 0.2 Hz, about 0.3 Hz,
about 0.4 Hz, about 0.5 Hz, about 0.6 Hz, about 0.7 Hz, about 0.8
Hz, about 0.9 Hz, about 1 Hz, about 1.1 Hz, about 1.2 Hz, about 1.3
Hz, about 1.4 Hz, or about 1.5 Hz. In some variations, modulation
of the pulse width at a rate between about 0.5 Hz and 1 Hz may be
desirable to increase patient comfort during stimulation.
[0144] In some variations, the increase and decrease of pulse width
may be defined by a function implemented by the stimulator. For
example, the pulse width may be defined by a function such that the
pulse width varies exponentially. In one variation, the function
defining pulse width may comprise two phases--a first phase during
which the pulse width of the leading pulse increases over time, and
a second phase during which the pulse width of the leading pulse
decreases over time. During the first phase, the pulse width of the
leading pulse approaches the maximum pulse width according to an
exponential function, where at time t, PW{t} is defined by the
equation
PW { t } = ( PW max - PW min ) ( 1 - e - ( t .tau. ) )
##EQU00001##
where PW.sub.max is the maximum allowed pulse width, PW.sub.min is
the minimum allowed pulse width, and .tau. is a time constant.
[0145] Once a predetermined amount of time has elapsed (a multiple
of time constant .tau.), the pulse width modulation may enter the
second phase. During the second phase, the pulse width of the
leading pulse exponentially decays from its maximum value to a
minimum value following the exponential equation
PW { t } = ( PW max - PW min ) ( e - ( t .tau. ) ) .
##EQU00002##
[0146] After a predetermined amount of time has elapsed (a multiple
of time constant T), the pulse width modulation may re-enter the
first phase, and the cycle may repeat. The pulse width of the
secondary (charge balancing) pulse is increased and decreased
accordingly to retain charge full balancing. PWmax, PWmin, and
.tau. may have any suitable values to achieve the pulse widths
described herein, but in one example the waveform may have a PWmax
of 300 .mu.s, PWmin of 0 .mu.s, and .tau. of 1/5 .mu.s. In other
variations, for example, PWmax, may be about 100 .mu.s, about 200
.mu.s, about 300 .mu.s, about 400 .mu.s, or about 500 .mu.s; PWmin
may be about 0 .mu.s, about 10 .mu.s, about 50 .mu.s, or about 100
.mu.s; and T may be about 1/3 .mu.s, about 1/4 .mu.s, about 1/5
.mu.s, or about 1/6 .mu.s. An exemplary function defining
exponentially increasing and decaying pulse widths is shown in FIG.
8.
[0147] On/Off Periods
[0148] In some instances, the waveforms described herein may be
delivered in a continuous fashion, while in other instances, the
waveforms may be delivered in a non-continuous fashion having on
periods and off periods, which may reduce patient accommodation.
Exemplary on/off durations include without limitation, 1 second
on/1 second off, 1 second on/2 seconds off, 2 seconds on/1 seconds
off, 5 seconds on/5 seconds off, 0.2 seconds on/0.8 seconds off,
less than 1 second on/less than 10 seconds off.
[0149] Exemplary Waveforms
[0150] It should be appreciated any of the above waveform
parameters and variations in parameters may be combined to generate
a temporally patterned waveform as described herein, and these
waveforms may be delivered by any of the stimulators described
herein. For example, in variations where the waveform comprises a
biphasic pulse, the biphasic pulse may have any suitable
frequencies, pulse widths, and amplitudes. The stimulation
amplitude, pulse width, and frequency may be the same from pulse to
pulse, or may vary over time, as described in more detail herein.
Combinations of these parameters may increase the efficacy and/or
comfort of stimulation, and in some cases, the efficacy and/or
comfort may differ by individual patient, as described in more
detail herein. Exemplary waveform parameters categorized by device
type are listed below in Table 1.
TABLE-US-00001 TABLE 1 Exemplary Waveform Parameters Waveform
Parameters Device Stimulation Frequency Pulse Amplitude Type Target
On/Off (Hz) Width (PW) (mA) Ocular Orbital nerves Constant on 30
Fixed from 0.1 to 10 Stimulator (afferent & 1 sec on/ 30 50
.mu.s to 1200 .mu.s (implantable) efferent) 1 sec off 5 sec on/ 30
5 sec off 1 sec on/ 70 1 sec off 1 sec on/ 155 1 sec off Constant
on Modulated from 30 to 70 in triangular fashion Constant on 30
Triangular modulated from 50 .mu.s to max PW at 0.5 Hz Constant on
30 Triangular modulated from 50 .mu.s to max PW at 1 Hz Constant on
70 Triangular modulated from 50 .mu.s to max PW at 0.5 Hz Nasal
Internal and Constant on 30 0 .mu.s to 300 .mu.s 0.1 to 10
Stimulator external nasal Constant on 50 (handheld or nerves
Constant on 80 implantable) (e.g., anterior Constant on 150
ethmoidal nerve) 1 sec on/ 30 1 sec off 1 sec on/ 50 1 sec off 1
sec on/ 80 1 sec off Constant on 30 1 sec on/ 70 1 sec off
[0151] In variations in which a waveform is an alternating
monophasic pulsed waveform, each pulse delivered by the stimulator
may have a single phase, and successive pulses may have alternating
polarities. Generally, the alternating monophasic pulses are
delivered in pairs at a given frequency (such as one or more of the
frequencies listed above, such as between 30 Hz and 80 Hz), and may
have an inter-pulse interval between the first and second pulse of
the pair (e.g., about 100 .mu.s, between 50 .mu.s and 150 .mu.s or
the like). Each pulse may be current-controlled or
voltage-controlled, and consecutive pulses need not be both
current-controlled or both voltage-controlled. In some variations
where the pulse waveform is charged-balanced, the waveform may
comprise a passive charge-balancing phase after delivery of a pair
of monophasic pulses, which may allow the waveform to compensate
for charge differences between the pulses.
[0152] When a stimulator configured to deliver an electrical
stimulation waveform is positioned to place an electrode on either
side of the nasal septum, alternating monophasic pulses may promote
bilateral stimulation of nasal tissue. The pulses of a first phase
may stimulate a first side of the nose (while providing a
charge-balancing phase to a second side of the nose), while the
pulses of the opposite phase may stimulate the second side of the
nose (while providing a charge-balancing phase to the first side of
the nose), since nerves may respond differently to anodic and
cathodic pulses. The inter-pulse interval may give time for the
stimulation provided by a first phase pulse to activate/polarize
the target nerves prior to being reversed by an opposite phase
pulse.
[0153] Stimuli comprising the waveforms described herein may be
delivered to these anatomical targets using stimulators such as
those described herein according to treatment regimens described in
U.S. patent application Ser. No. 13/441,806, which was previously
incorporated by reference in its entirety, and in U.S. patent
application Ser. No. 14/256,915, which was previously incorporated
by reference in its entirety.
[0154] Patient-Optimized Waveforms
[0155] Experimentation by the inventors has found that in some
instances, lacrimation caused by stimulation may be increased by
identification of one or more patient-optimized waveforms for a
particular patient, where the patient-optimized waveforms may
comprise combinations of the waveform parameters described herein.
As such, a method for identification of patient-optimized waveforms
is desirable. Experimentation by the inventors has also found that
sensed paresthesia is strongly associated with lacrimation, and
thus patient perceptions of paresthesia may be used in
identification of patient-optimized waveforms. An exemplary method
for obtaining patient-optimized waveforms in a patient having a
microstimulator implanted in an ocular region is illustrated in
FIG. 9. It may be desirable to perform this method for each
individual to increase the effectiveness of stimulation (e.g., to
increase tearing). The stimulation waveform(s) and/or current
steering may also be configured to optimize certain clinical
indicators of effectiveness, including but not limited to growth
factor levels and/or osmolarity.
[0156] As shown there, a waveform may be assessed to determine if
it is a patient-optimized waveform by delivering an electrical
stimulus comprising the waveform to the patient using a stimulator
described herein. The method may comprise first delivering a
waveform at the lowest amplitude and/or pulse width and asking the
patient for feedback on the sensation as the amplitude and/or pulse
width is increased. The method may then comprise assessing whether
the patient feels any sensation during delivery of the electrical
stimulus. If not, a different waveform may be selected (e.g.,
having a different combination of parameters, such as frequency,
amplitude, pulse width, on/off period, or the temporal modulation
of these parameters). The method may further comprise ensuring that
the patient is not experiencing discomfort. If the patient is
experiencing discomfort, the method may be restarted with a new
waveform, or the amplitude and/or the pulse width may be reduced to
alleviate discomfort. Similarly, the method may comprise ensuring
that the sensation during application of the waveform is
comfortable to the patient. The amplitude and/or pulse width may be
adjusted to achieve patient comfort. Comfort may be assessed with
the patient's eyes both open and closed.
[0157] A waveform may be designated as a patient-optimized waveform
if the patient perceives the waveform as the most comfortable
and/or effective waveform felt that day; and/or if the patient
feels his/her eyes getting wet; and/or if the patient perceives
paresthesia--more particularly, if both a tickle and a vibration
are perceived as moving in the eyelid. If the patient perceives a
tickle in the eyelid but no vibration, the amplitude and/or pulse
width may be adjusted to achieve increased perception of tickle
and/or vibration. If the patient perceives a vibration but not
tickle, the amplitude and/or pulse width may be adjusted to achieve
an increased sensation of movement of the vibration (e.g., between
the eyelid and eyebrow). It may also be desirable that a patient
feels a sensation (e.g., tickle or vibration) after delivery of the
stimulus ends. In each case of an identified patient-optimized
waveform, a lower amplitude and/or pulse width may be tested to
determine whether the same sensation can be achieved using a lower
amplitude and/or pulse width. In variations of stimulators
configured to allow for spatial control of current pathways,
patient-optimization may also comprise testing different current
pathways or combinations of current pathways.
[0158] While the method in FIG. 9 is described with respect to a
patient having an implantable stimulator located in an ocular
region, it should be appreciated that a similar method may be used
to identify one or more patient-optimized waveforms for an
implantable stimulator in another region (e.g., a nasal region) or
for a handheld stimulator. Once a patient-optimized waveform or
waveforms are identified, a stimulator may be configured to deliver
the waveform(s). In some variations, an external device may be used
to configure the stimulator to deliver the identified waveform(s).
In variations in which the system comprises a controller for use
with an implantable stimulator having a passive stimulation
circuit, a controller configured to generate an output signal that
results in the identified stimulation waveform(s) may be used.
Devices Having a Plurality of Waveforms
[0159] Some variations of the stimulators described herein may be
configured with a plurality of waveforms, such that a clinician
and/or patient may select a desired waveform from the plurality of
available waveforms. For example, the stimulator may include a
plurality of stimulation waveforms saved on a chip. For example, 2,
3, 4, 5, 6, 7, 8, 9, 10, or more than 10 stimulation waveforms may
be saved on a chip. In one variation, two to ten stimulation
waveforms are saved on a chip. In other variations, two to eight
stimulation waveforms, or three to five stimulation waveforms may
be saved on the device chip. In some variations, a preferred set of
waveforms to be saved on a stimulator may be preselected by a
clinician based on initial testing of a variety of stimulation
waveforms for a particular patient, such as via the method
described above. It may be useful for the saved stimulation
waveforms to be those that elicit strong paresthesia in the
patient, because experimentation by the inventors has found that
sensed paresthesia is more strongly associated with lacrimation, as
described herein. In other variations, a stimulator may be
preconfigured with a plurality of stimulation waveforms not unique
to an individual patient.
[0160] In some variations, for every stimulation provided during
the day, a different waveform may be randomly selected from the
saved plurality of waveforms. By randomly selecting a different
waveform each time, the risk of patient developing tolerance to any
particular stimulation pattern may be lowered. In another
implementation, a multiplexor might be used to provide different
combinations of internally saved waveforms to form a
"quasi-non-repetitive" waveform when combining pieces from
different repetitive waveforms. By multiplexing different waveforms
to one combined waveform, habituation to the waveform can
potentially be limited further. For stimulators having a plurality
of possible current pathways, the same or different waveforms may
be delivered via each pathway.
[0161] In some variations, a patient may be able to selectively
choose between the plurality of stimulation waveforms saved on the
stimulator, for example, using a user interface such as a user
interface as described herein. In variations having such a user
interface, the user interface may comprise one or more operating
mechanisms, which may allow the user (i.e., the patient) to control
the stimulation waveform. For example, the user interface may
comprise one or more structures, such as but not limited to a
button, slider, lever, touch pad, knob, or deformable/squeezable
portion of the housing, which may allow the user to change the
stimulation waveform.
[0162] The different waveforms may be configured such that a
patient may perceive them as spanning a range of intensities. In
variations in which the stimulator is configured to deliver
waveforms with different shapes, a patient may be able to change
the tissue that is preferentially stimulated by the waveform as
described herein by selecting a waveform having a different shape
(e.g., switching from a waveform having a cathodic pulse first to a
waveform having an anodic pulse first). In some variations, when a
patient turns on the stimulator for a second or subsequent
treatment period, the stimulator may initially turn on to a
waveform selected previously by the patient (e.g., the waveform
used during the previous treatment session, the most commonly used
waveform during a plurality of treatment sessions, etc.).
[0163] For example, in the instance where a handheld nasal
stimulator is employed, after the user has placed a portion of the
stimulator in contact with the nasal tissue, the user may increase
the perceived intensity of the stimulus by changing between the
plurality of stimulation waveforms. It may be desirable for the
patient to increase the intensity of the stimulus until the
stimulus causes preferred paresthesia (e.g., tingling, tickling,
prickling) without causing discomfort. As such, the patient may be
able to self-determine the proper stimulation intensity and
self-adjust the stimulus to a waveform effective to achieve the
desired result (e.g., tear production). It may be desirable for the
user to increase the intensity of the stimulus slowly in order to
minimize discomfort. Some patients might prefer their sensation
level to change over the course of time. They might want to start
with a strong sensation, followed by a weak sensation. They might
prefer to start with a weak sensation (e.g., light tickle) followed
by a stronger temporary sensation (e.g., light discomfort for a
very short time). Some patients may be able to reduce a sensation
of needing to sneeze during stimulation if strong and weak
sensations are varied.
[0164] In one particular example, a stimulator described herein may
be configured to deliver a plurality of different waveforms each
having a combination of one or more of shape modulation, maximum
amplitude modulation, pulse width modulation, and frequency
modulation, as described herein.
[0165] One or more of the waveforms may have a pulse shape that is
modulated over time. In a variation illustrated in FIG. 10, the
pulse shape may be cycled between four periods. The first period
may comprise a two-phase current-controlled waveform with
symmetrical phases. The second period may comprise a
current-controlled first phase, followed by a voltage-controlled
second phase. This may help to preferentially stimulate a location
closer to one electrode. The first phase may have a current sourced
by a first electrode and sunk by a second electrode, while the
second phase may have a current sourced by the second electrode and
sunk by the first electrode. The third period may comprise a
two-phase current-controlled waveform with symmetrical phases
(i.e., the third period may be the same as the first period). The
fourth period may comprise a current-controlled first phase,
followed by a voltage-controlled second phase. The first phase may
have a current sourced by the second electrode and sunk by the
first electrode, while the second phase may have a current sourced
by the first electrode and sunk by the second electrode. In each
period, the pulses may be charged-balanced. The pulse shape may be
modulated at any suitable frequency, such as about 0.1 Hz.
[0166] One or more of the waveforms may have a pulse width that is
modulated over time. In one variation, the pulse width of the
current-controlled phases may be modulated from 0 .mu.s to 300
.mu.s. The modulation may follow an exponential function that
describes the increase and decrease of the pulse width over time,
as illustrated in FIG. 11 and as described in more detail with
respect to FIG. 8.
[0167] One or more of the waveforms may have a maximum amplitude
that is modulated over time. The amplitude modulation of the
current-controlled phases may approximate a triangular shape, a
rectangular shape, or any other suitable shape. Exemplary amplitude
modulations at various frequencies are illustrated in FIGS.
12A-12E, which show amplitude modulations having a rectangular
shape (FIG. 12B) and amplitude modulations that approximate
triangular shapes (12C-12E). The maximum amplitude may be modulated
at any suitable frequency, such as between about 0.5 Hz and about 3
Hz. It should be appreciated that in some other variations, the
maximum amplitude may be constant, as shown in FIG. 12A.
[0168] FIGS. 13A-13E depict exemplary waveforms 1310, 1320, 1330,
1340, and 1350, respectively, wherein one or more of these
parameters are modulated over time, where each type of modulation
is independent from and concurrent with the other types of
modulation. Boxes 1302, 1304, and 1306 on FIG. 13E highlight
modulation of shape, pulse width, and maximum amplitude,
respectively. In some variations (e.g., those of FIGS. 13B-13E) all
three of shape, pulse width, and maximum amplitude are modulated
over time, but it should be appreciated that in other variations of
the waveform (e.g., that of FIG. 13A), only one or two of these
parameters may be modulated over time.
[0169] The five waveforms of FIGS. 13A-13E may be available on the
stimulator (e.g., stimulator 400 described above with respect to
FIGS. 4A-4C, or microstimulator 200 described above with respect to
FIGS. 2A-2C), and the stimulator may be configured such that the
patient can use a user interface (e.g., an interface comprising two
buttons) to select between the five different waveforms. In some
variations of the device, when the device is used for a treatment
period, turned off, and turned back on for an additional treatment
period, the device may automatically turn on to the last
stimulation setting used.
[0170] Setting 1, illustrated in FIG. 13A, may have a stimulation
frequency of 30 Hz; a minimum stimulation current amplitude of 0.7
mA, a maximum stimulation current amplitude of 0.7 mA, and thus no
variation in maximum stimulation current amplitude (as shown in
FIG. 12A); a minimum pulse width of 0 .mu.s; a maximum pulse width
of 300 .mu.s; a pulse width modulation frequency of 1 Hz (rising
and falling according to an exponential function, as shown in FIG.
11); a minimum charge injection per phase (at 0 .mu.s pulse width)
of 0 .mu.C; a maximum charge injection per phase (at 0.7 mA and 300
.mu.s) of 0.21 .mu.C; and a pulse shape that is modulated as
described above with respect to FIG. 10.
[0171] Setting 2, illustrated in FIG. 13B, may have a stimulation
frequency of 37.5 Hz; a minimum stimulation current amplitude of
1.33 mA, a maximum stimulation current amplitude of 1.5 mA, a
variation in maximum stimulation current amplitude of 0.17 mA, and
an amplitude modulation frequency of 2.1 Hz (as shown in FIG. 12B);
a minimum pulse width of 0 .mu.s; a maximum pulse width of 300
.mu.s; a pulse width modulation frequency of 1 Hz (rising and
falling according to an exponential function, as shown in FIG. 11);
a minimum charge injection per phase (at 0 .mu.s pulse width) of 0
.mu.C; a maximum charge injection per phase (at 1.5 mA and 300
.mu.s) of 0.45 .mu.C; and a pulse shape that is modulated as
described above with respect to FIG. 10.
[0172] Setting 3, illustrated in FIG. 13C, may have a stimulation
frequency of 45 Hz; a minimum stimulation current amplitude of 2.17
mA, a maximum stimulation current amplitude of 2.5 mA, a variation
in maximum stimulation current amplitude of 0.33 mA, and an
amplitude modulation frequency of 2.6 Hz (as shown in FIG. 12C); a
minimum pulse width of 0 .mu.s; a maximum pulse width of 300 .mu.s;
a pulse width modulation frequency of 1 Hz (rising and falling
according to an exponential function, as shown in FIG. 11); a
minimum charge injection per phase (at 0 .mu.s pulse width) of 0
.mu.C; a maximum charge injection per phase (at 2.5 mA and 300
.mu.s) of 0.75 .mu.C; and a pulse shape that is modulated as
described above with respect to FIG. 10.
[0173] Setting 4, illustrated in FIG. 13D, may have a stimulation
frequency of 52.5 Hz; a minimum stimulation current amplitude of
3.2 mA, a maximum stimulation current amplitude of 3.7 mA, a
variation in maximum stimulation current amplitude of 0.5 mA, and
an amplitude modulation frequency of 2.8 Hz (as shown in FIG. 12D);
a minimum pulse width of 0 .mu.s; a maximum pulse width of 300
.mu.s; a pulse width modulation frequency of 1 Hz (rising and
falling according to an exponential function, as shown in FIG. 11);
a minimum charge injection per phase (at 0 .mu.s pulse width) of 0
.mu.C; a maximum charge injection per phase (at 3.7 mA and 300
.mu.s) of 1.11 .mu.C; and a pulse shape that is modulated as
described above with respect to FIG. 10.
[0174] Setting 5, illustrated in FIG. 13E, may have a stimulation
frequency of 60 Hz; a minimum stimulation current amplitude of 4.3
mA, a maximum stimulation current amplitude of 5.0 mA, a variation
in maximum stimulation current amplitude of 0.67 mA, and an
amplitude modulation frequency of 2.5 Hz (as shown in FIG. 12E); a
minimum pulse width of 0 .mu.s; a maximum pulse width of 300 .mu.s;
a pulse width modulation frequency of 1 Hz (rising and falling
according to an exponential function, as shown in FIG. 11); a
minimum charge injection per phase (at 0 .mu.s pulse width) of 0
.mu.C; a maximum charge injection per phase (at 5.0 mA and 300
.mu.s) of 1.5 .mu.C; and a pulse shape that is modulated as
described above with respect to FIG. 10.
[0175] Through waveforms having these parameter combinations, a
large parameter space may be provided on a single device with a
simple user interface and a limited number of settings. This may
increase the ability of a single device having a limited number of
preset waveforms to deliver a waveform that is as effective or
nearly as effective for an individual patient as a waveform in
which parameters are individually tuned for each patient.
EXAMPLES
[0176] The following examples further illustrate the electrical
stimulation patterns and their effects as disclosed herein, and
should not be construed in any way as limiting their scope.
Example 1: Stimulation Using a Lacrimal Implant
[0177] Patients having microstimulators implanted in an ocular
region were tested with 30 Hz non-patterned stimulation (control)
and with on/off patterns (1 second on/1 second off, 2 seconds on/2
seconds off, and 5 seconds on/5 seconds off) at different
frequencies (30 Hz, 70 Hz, and 155 Hz). The implanted
microstimulators had the features shown in FIGS. 2A-2C and
described herein.
[0178] Patient perception of the stimulus differed between the 30
Hz non-patterned waveform control and temporally patterned
waveforms. Specifically, whereas 3 patients receiving the 30 Hz
non-patterned waveform felt that their perception of the waveform
faded over the stimulation period, when receiving temporally
patterned waveforms, no patients reported perception of the
waveform fading over the stimulation period. When the stimulus was
a 30 Hz, 1 second on/off waveform ("Pattern 1"), 3 patients
perceived the waveform as continuous, while 15 perceived the
waveform as intermittent. When the stimulus was a 30 Hz, 5 second
on/off waveform ("Pattern 2"), all patients perceived the waveform
as intermittent. When the stimulus was a 70 Hz, 1 second on/off
waveform ("Pattern 3"), 2 patients perceived the waveform as
continuous, and 10 perceived the waveform as intermittent. Patients
reported that they perceived Pattern 3 as "stronger," "faster," and
"sharper" than the other waveforms. When the stimulus was a 155 Hz,
1 second on/off waveform ("Pattern 4"), whether patients perceived
the waveform as continuous or intermittent was amplitude-dependent,
and qualitative perceptions ranged, including reports of the
waveform as "weaker," "strong," or a "pinch."
[0179] Moreover, patients reported a change in the quality and/or
location of paresthesia. FIG. 14A depicts the area 1402 of
paresthesia felt with stimulation using the 30 Hz non-patterned
waveform. With the temporally patterned waveforms, patients felt
movement of the paresthesia (in the form of vibration and/or
tickle), as shown in FIG. 14B (the vibration and/or the tingle
moved along their eyelid in the directions of the arrows 1404).
Some patients felt continuously present vibration in one area 1408
and continuously present or partially appearing and reappearing
sensation or tickle in other areas 1406, as shown in FIG. 14C.
Other patients experienced an increase in affected area with
paresthesia with temporally patterned waveforms, shown in FIG. 14D
as area 1410 extending along one or both of the eyebrows and/or
along or in the nose.
[0180] Patient perceptions after cessation of stimulation also
differed between the 30 Hz non-patterned waveform and the
temporally patterned waveforms. Whereas patients did not perceive
paresthesia after cessation of the control, patients reported
perceiving paresthesia in the form of a tingling sensation after
cessation of Patterns 1, 3, and 4.
[0181] Schirmer scores increased with temporally patterned
waveforms as compared to the 30 Hz non-patterned waveform control.
With Pattern 1, one third of patients had Schirmer scores that
increased by 50%. With Pattern 3, three quarters of patients had
Schirmer scores that increased by 50-100%. With Pattern 4, three
eighths of patients had Schirmer scores that increased by 100% or
more.
[0182] Some of the temporally patterned waveforms also provided
additional advantages. For example, Pattern 1 used less power than
the control while also reducing patient accommodation; and Pattern
4 allowed for both nerve stimulation and block.
Example 2: Stimulation Using a Lacrimal Implant (2)
[0183] In patients having a microstimulator implanted in an ocular
region, use of temporally patterned waveforms generated an increase
in lacrimation as measured by Schirmer's test in comparison to
basal tearing (control 1=no electric stimulation) and in comparison
to stimulation at 30 Hz (non-patterned) (control 2). The implanted
microstimulators had the features shown in FIGS. 2A-2C and
described herein. The data is provided below in Table 2, and a
bar-chart diagram comparing averaged tearing results from basal
tearing (left, no stimulation) to 30 Hz non-patterned waveform
stimulation (middle) to temporally patterned, patient-optimized
stimulation waveforms (right) is shown in FIG. 15. Based on the
data in Table 2, the averaged value for basal tearing was 4.71 mm,
the averaged value was 4.96 mm for non-patterned stimulation at 30
Hz, and the average value was 8.29 mm when temporally patterned
stimulation was used. Overall, the increase in average Schirmer
score using non-patterned stimulation at 30 Hz was about 5% as
compared to basal tearing, and the increase in average Schirmer
score using temporally patterned waveforms was about 76% as
compared to basal tearing. Thus, patient-optimized pattered
waveforms were able to increase tearing by a much greater amount
(in this case, over 70 percentage points) than a 30 Hz
non-patterned waveform.
TABLE-US-00002 TABLE 2 Schirmer Scores from 12 Patients. 30 Hz
Non-Patterned Basal Schirmer Schirmer Patterned Schirmer Implanted
Score (mm) Score (mm) Score (mm) Side L R Ave L R Ave L R Ave
Patterned Waveform R 8 5 6.5 3 4 3.5 8 5 6.5 30 Hz amplitude
modulated by about 30% L 3 8 5.5 3 5 4 5 8 6.5 70 Hz amplitude
modulated by about 30% L 3 2 2.5 3 5 4 3 8 5.5 70 Hz 1 sec on, 1
sec off L 2 3 2.5 5 5 5 5 3 4 70 Hz amplitude modulated by about
30% L 12 18 15 10 9 9.5 13 19 16 30 Hz amplitude modulated by 100%
L 4 3 3.5 6 6 6 7 7 7 70 Hz amplitude modulated by about 30% R 2 3
2.5 3 3 3 8 7 7.5 30 Hz 1 sec on, 1 sec off L 5 7 6 5 5 5 8 8 8 70
Hz 1 sec on, 1 sec off L 2 2 2 2 1 1.5 5 5 5 70 Hz amplitude
modulated by about 30% R 4 2 3 12 6 9 18 12 15 30 Hz 5 sec on, 5
sec off L 4 2 3 7 2 4.5 7 7 7 30 Hz 1 sec on, 1 sec off L 4 5 4.5 5
4 4.5 7 16 11.5 frequency-modulated 30 Hz to 70 Hz randomized
[0184] The temporally patterned waveforms were also capable of
generating paresthesia in patients in whom paresthesia was not felt
during stimulation or who only experienced short-lived paresthesia
(e.g., less than 30 seconds, often only less than 10 seconds, of
paresthesia felt even though stimulation was supplied
continuously). The newly acquired or re-acquired paresthesia was
further accompanied by increases in lacrimation and improved
patient satisfaction.
[0185] Patients often reported the feeling of vibration during
stimulation and tingle during stimulation pauses (for example,
during off portions of waveforms having a 1 second on/1 second off
pattern), and in certain cases for seconds or minutes after the
stimulation had stopped after application. There were several
reports of patients feeling that the vibration or the tingle moved
physically along their eyelid and eyebrow, in two cases even in
their nasal area (outside and/or inside the nose). Patient
reception was generally very positive.
Example 3: Stimulation Using a Lacrimal Implant (3)
[0186] Nineteen patients had microstimulators implanted in an
ocular region. (Twelve of these patients are the same patients as
in Example 2.) For each patient, a patient-optimized temporally
patterned waveform was determined by modulating waveform frequency,
pulse width, and on/off periods while gathering patient feedback in
order to maximize the reported paresthesia in the area of the
orbit, as described above.
[0187] Each waveform was provided using the same
controller/energizer for each patient. The waveforms tested for
each patient included: [0188] 30 Hz [0189] 30 Hz, 1 second on, 1
second off [0190] 30 Hz, 5 seconds on, 5 seconds off [0191] 70 Hz,
1 second on, 1 second off [0192] 30 Hz, pulse-width modulated from
100% to 0% and back to 100% in 1 sec [0193] 30 Hz, pulse-width
modulated from 100% to 70% and back to 100% in 1 sec [0194] 70 Hz,
pulse-width modulated from 100% to 70% and back to 100% in 1 sec
[0195] frequency modulated from 30 Hz to 70 Hz in an approximately
linear fashion by steps of 5 Hz (i.e., for the increasing portion
of the frequency modulation, 30 Hz, 35 Hz, 40 Hz, 50 Hz, 55 Hz, 60
Hz, 65 Hz, 70 Hz), modulated up and down in 1 sec (from 70 to 30
and back to 70 in one second) [0196] frequency modulated from 30 Hz
to 70 Hz in a random fashion, with frequencies 5 Hz apart (30 Hz,
35 Hz, 40 Hz, 45 Hz, 55 Hz, 60 Hz, 65 Hz, 70 Hz)
[0197] Patients were asked a series of questions for each waveform,
including: [0198] whether the waveform was causing discomfort;
[0199] how they would compare the sensation from the waveform to
other waveforms, including 30 Hz non-patterned waveform, and any
other waveforms previously tested on the same day; [0200] whether
they had the sensation of their eyes getting wet; [0201] whether
they felt a combination of a tickle and vibration; [0202] whether
the sensation (tickle and/or vibration) felt as though it was
moving (this suggests less likelihood of accommodation); and [0203]
the location of the sensation.
[0204] It was desirable that the patient feel sensation in the
upper eyelid, since this was considered likely to correspond with
activating the lacrimal and the frontal nerves in the orbit. The
closer the sensation was to the eye itself and the larger the area
of paresthesia, the more optimal a waveform was rated.
Additionally, waveforms that were perceived as a mixture of tickle
and vibration sensations in locations that corresponded with the
sensory pathways of the ophthalmic branch of the trigeminal nerve
(CN V1) were desirable. These locations included not only the
eyelid, but also the eyebrow, the temple area of the forehead, the
nose (especially the inside of the nose), and certain areas of the
forehead.
[0205] For each patient, three Schirmer scores were recorded: a
basal Schirmer score without any stimulation ("basal Schirmer"), an
acute Schirmer score during application of a 30 Hz non-patterned
waveform ("30 Hz Schirmer"), and an acute Schirmer score during
application of the patient-optimized patterned waveform for each
patient ("patterned Schirmer").
[0206] Average bilateral 30 Hz Schirmer scores and average
bilateral patterned Schirmer scores were both higher than average
bilateral basal Schirmer scores. Average bilateral patterned
Schirmer scores were higher than average bilateral 30 Hz Schirmer
scores. Specific data for average bilateral Schirmer scores are
shown in FIG. 16A. As shown there, the 15 patients with severe DED
(defined as having basal Schirmer scores <10 mm) averaged a 22%
increase over basal Schirmer scores for 30 Hz Schirmer scores and a
78% increase over basal Schirmer scores for patterned Schirmer
scores.
[0207] More patients showed increased bilateral Schirmer scores
when stimulated using the patient-optimized temporally patterned
waveform than the 30 Hz non-patterned waveform. As shown in FIGS.
17A-17B, amongst the 15 patients with severe DED, the number of
non-responders decreased from 47% (as shown in FIG. 17A) using the
30 Hz waveform to 20% (as shown in FIG. 17B) using the
patient-optimized temporally patterned waveform.
[0208] The comparison of ipsilateral (i.e., the eye on the same
side as ocular implant), contralateral (i.e., the eye opposite the
ocular implant), and bilateral (i.e., the average of both eyes)
Schirmer scores indicated that stimulation from a single ocular
implant resulted in bilateral tear production, but the effect was
more pronounced for patient-optimized temporally patterned waveform
stimulation. Ipsilateral 30 Hz Schirmer scores were found to be
higher than bilateral 30 Hz Schirmer scores, indicating that 30 Hz
stimulation resulted in more tear production in the ipsilateral eye
than the contralateral eye; and conversely, contralateral 30 Hz
Schirmer scores were found to be lower than bilateral 30 Hz
Schirmer scores, indicating that 30 Hz stimulation resulted in less
tear production in the contralateral eye than the ipsilateral
eye.
[0209] In contrast, both ipsilateral and contralateral patterned
Schirmer scores were found to be similar to bilateral patterned
Schirmer scores. This suggested that temporally patterned
stimulation better stimulated tear production in the contralateral
eye than the 30 Hz stimulation, such that the patient-optimized
temporally patterned waveform was equally effective in stimulating
tear production in both the ipsilateral and contralateral eyes. It
was hypothesized that this was a result of the reflexive drive
(activated by stimulating the lacrimal and frontal nerves) adding
to the direct drive (lacrimal nerve only). FIG. 16B shows
contralateral Schirmer scores for the 15 patients with severe DED.
As shown there, the patients averaged a 9% increase over basal
Schirmer scores for 30 Hz Schirmer scores and an 82% increase over
basal Schirmer scores for patterned Schirmer scores.
[0210] By switching frequencies, either linearly or randomly,
patients experienced a mixture of vibration and tickle. By changing
to the higher frequency of 70 Hz at 1 second on/1 second off,
modulating the frequency (30 to 70 Hz in 5 Hz increments), and/or
changing the pulse width, specific patients reported the sense of
tickle in addition to vibration, tickle alone or the impression of
a moving vibration, often in the combination with a moving
sensation of tickle. It was also found that stimulation with a
patient-optimized temporally patterned waveform allowed patients to
find the location for holding the energizers/controllers in order
to couple to the implant more quickly and repeatedly.
Example 4: Electrical Stimulation of the Nasal Mucosa
[0211] A patterned waveform was delivered to the nasal mucosa of
subjects using a device as described with respect to FIGS. 4A-4C.
The temporally patterned waveforms delivered included the waveforms
shown in FIGS. 13A-13E and described herein, as well as waveforms
at 30 Hz, 70 Hz, and 155 Hz with on/off periods of 1 second on/off
and 5 seconds on/off. Tear output at the same level as
non-patterned stimulation was able to be achieved while reducing
subject tendency to sneeze. Subjects also reported the feeling of a
nasal massage that was in most cases seen as improved sensory
impression. Subjects furthermore were able to use increased
stimulation amplitudes during nasal stimulation leading to
increased tearing without discomfort, as the maximal amplitude of
charge used to stimulate was only applied for a short time. Subject
reception was generally very positive.
Example 5: Frontal Nerve Stimulation (Rabbit)
[0212] A rabbit was implanted with fine wire electrodes into its
left frontal nerve area, and stimulation was applied at 30 Hz with
amplitudes between 0.1 mA and 5.0 mA. Stimulation and baseline
measurements were repeated 3 times each. As shown in Table 3 below
and FIG. 18, while increased lacrimation was observed with the 30
Hz (non-patterned) waveform, the increase in lacrimation was more
pronounced using a temporally patterned stimulation with on and off
periods of 10 seconds each, as measured by Schirmer scores taken
during stimulus delivery.
TABLE-US-00003 TABLE 3 Patterned Baseline Waveform 30 Hz ST ST ST
AVG DEV AVG DEV AVG DEV No Stim Right 5.5 0.7 7.8 0.4 5.3 3.2 Eye
Stim Eye Left 5.0 1.4 16.5 2.8 9.0 2.8 Eye
* * * * *