U.S. patent application number 12/951852 was filed with the patent office on 2011-05-26 for optical stimulation therapy.
This patent application is currently assigned to Medtronic, Inc.. Invention is credited to Peng Cong, Timothy J. Denison, John G. Keimel, Gordon O. Munns, Christian S. Nielsen, John D. Norton, Kunal Paralikar, Wesley A. Santa.
Application Number | 20110125078 12/951852 |
Document ID | / |
Family ID | 44062605 |
Filed Date | 2011-05-26 |
United States Patent
Application |
20110125078 |
Kind Code |
A1 |
Denison; Timothy J. ; et
al. |
May 26, 2011 |
OPTICAL STIMULATION THERAPY
Abstract
A method for delivering optical stimulation comprises
transfecting a target tissue with a light-sensitive channel protein
sensitive to light in a wavelength range, delivering light in the
wavelength range to the target tissue via an optical stimulation
device, substantially simultaneously with delivering light to the
target tissue, sensing bioelectric signals, determining a patient
therapeutic state based on the bioelectric signals, and adjusting
the delivery of the light to the target tissue based on the sensed
patient therapeutic state.
Inventors: |
Denison; Timothy J.;
(Minneapolis, MN) ; Paralikar; Kunal;
(Minneapolis, MN) ; Munns; Gordon O.; (Stacy,
MN) ; Santa; Wesley A.; (Andover, MN) ; Cong;
Peng; (Plymouth, MN) ; Nielsen; Christian S.;
(River Falls, WI) ; Norton; John D.; (New
Brighton, MN) ; Keimel; John G.; (North Oaks,
MN) |
Assignee: |
Medtronic, Inc.
Minneapolis
MN
|
Family ID: |
44062605 |
Appl. No.: |
12/951852 |
Filed: |
November 22, 2010 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
61264550 |
Nov 25, 2009 |
|
|
|
61301836 |
Feb 5, 2010 |
|
|
|
Current U.S.
Class: |
604/20 ;
607/88 |
Current CPC
Class: |
A61N 1/365 20130101;
A61N 2005/063 20130101; A61N 2005/0651 20130101; A61B 2017/00084
20130101; A61N 5/0601 20130101; A61N 2005/0612 20130101; A61N 1/086
20170801; A61N 5/0622 20130101; A61B 2018/00839 20130101; A61N
5/062 20130101; A61N 2005/0626 20130101; A61M 5/14276 20130101 |
Class at
Publication: |
604/20 ;
607/88 |
International
Class: |
A61M 37/00 20060101
A61M037/00; A61N 5/06 20060101 A61N005/06 |
Claims
1. A method for delivering optical stimulation, the method
comprising: transfecting a target tissue with a light-sensitive
channel protein sensitive to light in a wavelength range;
delivering light in the wavelength range to the target tissue via
an optical stimulation device; substantially simultaneously with
delivering light to the target tissue, sensing bioelectric signals;
determining a patient therapeutic state based on the bioelectric
signals; and adjusting the delivery of the light to the target
tissue based on the sensed patient therapeutic state.
2. The method of claim 1, wherein adjusting the delivery of light
comprises adjusting the delivery of the light substantially
simultaneously with sensing the bioelectric signals and with
delivering light to the target tissue.
3. The method of claim 1, wherein sensing the bioelectric signals
comprises sensing at least one of a single cell action potential, a
local field potential proximate the target tissue, energy spectra
in the alpha band of brain activity, energy spectra in the beta
band or brain activity, energy spectra in the gamma band of brain
activity, electrocorticography signals, and electroencephalography
signals.
4. The method of claim 1, wherein delivering light to the target
tissue comprises delivering light through an optical light guide
optically coupled to the optical stimulation device.
5. The method of claim 1, wherein transfecting the target tissue
comprises delivering a therapeutic agent to the target tissue that
transfects the target tissue.
6. The method of claim 5, wherein the therapeutic agent is a gene
therapy agent.
7. The method of claim 1, wherein delivering light to the target
tissue comprises delivering the light according to an optical
stimulation program, and wherein adjusting the delivery of the
light to the target tissue based on the sensed patient therapeutic
state comprises adjusting the optical stimulation program.
8. The method of claim 7, wherein the program includes one or more
optical stimulation parameters, wherein adjusting the delivery of
light comprises adjusting at least one of the parameters, wherein
the optical stimulation parameters comprise at least one of a pulse
rate of the light, a pulse width of the light, an amplitude
intensity of the light, a duty cycle of the light, and a wavelength
of the light.
9. The method of claim 1, wherein transfecting the target tissue
comprises at least one of transfecting the target tissue with a
first light-sensitive channel protein sensitive to light having a
first wavelength range and transfecting the target tissue with a
second light-sensitive channel protein sensitive to light having a
second wavelength range.
10. The method of claim 9, wherein delivering light to the target
tissue comprises at least one of delivering light in the first
wavelength range to the target tissue and delivering light in the
second wavelength range to the target tissue.
11. A method for delivering optical stimulation, the method
comprising: transfecting a target tissue with a light-sensitive
channel protein sensitive to light in a wavelength range;
delivering light in the wavelength range to the target tissue via
an optical stimulation device; substantially simultaneously with
delivering light to the target tissue, sensing bioelectric signals
comprising at least one of a local field potential proximate the
target tissue; energy spectra in the alpha band of brain activity;
energy spectra in the beta band or brain activity; energy spectra
in the gamma band of brain activity; electrocorticography signals;
and electroencephalography signals; and adjusting the delivery of
light to the target tissue based on the sensed bioelectric
signals.
12. The method of claim 11, wherein adjusting the delivery of light
comprises adjusting the delivery of light substantially
simultaneously with sensing the bioelectric signals and with
delivering light to the target tissue.
13. The method of claim 11, wherein delivering light to the target
tissue comprises delivering light through an optical light guide
optically connected to the optical stimulation device.
14. The method of claim 11, wherein transfecting the target tissue
comprises delivering a therapeutic agent to the target tissue that
transfects the target tissue.
15. The method of claim 14, wherein the therapeutic agent is a gene
therapy agent.
16. The method of claim 11, wherein delivering light to the target
tissue comprises delivering the light according to an optical
stimulation program, the method further comprising adjusting the
optical stimulation program based on the bioelectric signals.
17. The method of claim 16, wherein the program includes one or
more optical stimulation parameters, wherein adjusting the delivery
of light comprises adjusting at least one of the parameters,
wherein the optical stimulation parameters comprise at least one of
a pulse rate of the light, a pulse width of the light, an amplitude
intensity of the light, a duty cycle of the light, and a wavelength
of the light.
18. The method of claim 11, wherein transfecting the target tissue
comprises at least one of transfecting the target tissue with a
first light-sensitive channel protein sensitive to light having a
first wavelength range and transfecting the target tissue with a
second light-sensitive channel protein sensitive to light having a
second wavelength range.
19. The method of claim 18, wherein delivering light to the target
tissue comprises at least one of delivering light in the first
wavelength range to the target tissue and delivering light in the
second wavelength range to the target tissue.
20. An implantable medical system comprising: a therapy delivery
module comprising a light source that generates light and a
controller that controls the output of the light source; an optical
light guide configured to deliver the light from the light source
to a target tissue; a lead with a sense electrode for sensing
bioelectric signals; and a sensing module configured to determine a
patient therapeutic state based on the sensed bioelectric signals
substantially simultaneously with the delivery of light from the
light source; wherein the controller is configured to adjust the
delivery of light to the target tissue based on the sensed patient
therapeutic state.
21. The implantable medical device of claim 20, wherein the optical
light guide comprises an optical fiber optically connected to the
light source.
22. The implantable medical device of claim 20, wherein the therapy
delivery module further comprises a fluid reservoir for a
therapeutic agent.
23. The implantable medical device of claim 22, further comprising
a pump for delivering the therapeutic agent to the target
tissue.
24. The implantable medical device of claim 22, wherein the
therapeutic agent is a gene therapy agent for transfecting the
target tissue with a light-sensitive channel protein sensitive to a
wavelength of light, wherein the light source is configured to
deliver light having the wavelength.
25. The implantable medical device of claim 20, further comprising
a pump comprising a fluid reservoir at a distal end of the optical
light guide, wherein the pump and the fluid reservoir are
implantable proximate the target tissue.
26. The implantable medical device of claim 25, wherein the pump is
an osmotic pump comprising the fluid reservoir and a compartment, a
semi-permeable membrane permitting ingress of fluid from a patient
into the compartment, and a displaceable barrier located between
the compartment and the fluid reservoir.
27. The implantable medical device of claim 20, the therapy module
further comprising a power management circuit configured to control
power delivered to the light source.
28. The implantable medical device of claim 20, wherein the
controller sets programmable stimulation parameters and delivers
light according to the programmable stimulation parameters.
29. The implantable medical device of claim 28, wherein the
controller is configured to adjust the parameters based on the
sensed patient therapeutic state.
30. The implantable medical device of claim 28, wherein the
parameters comprise at least one of a pulse rate of the light, a
pulse width of the light, an amplitude intensity of the light, a
duty cycle of the light, and a wavelength of the light.
31. An implantable medical device comprising: means for generating
light; means for controlling the output of the means for generating
light; means for directing the light from the means for generating
light to a target tissue; means for sensing bioelectric signals;
and means for sensing a patient therapeutic state based on the
sensed bioelectric signals substantially simultaneously with the
delivery of the light from the means for generating light; wherein
the means for controlling the output of the means for generating
light is configured to adjust the delivery of light to the target
tissue based on the sensed patient therapeutic state.
32. The implantable medical device of claim 31, further comprising
means for interpreting the bioelectric signals sensed by the means
for sensing bioelectric signals.
33. The implantable medical device of claim 31, wherein the means
for directing light to the target tissue comprises an optical light
guide.
34. The implantable medical device of claim 31, further comprising
means for storing a therapeutic agent.
35. The implantable medical device of claim 34, further comprising
means for delivering the therapeutic agent from the means for
storing the therapeutic agent to the target tissue.
36. The implantable medical device of claim 34, wherein the
therapeutic agent is a gene therapy agent for transfecting the
target tissue with a light-sensitive channel protein sensitive to a
wavelength of light, wherein the means for generating light is
configured to deliver light having the wavelength.
37. The implantable medical device of claim 31, further comprising
means for managing power delivered to the means for generating
light.
38. The implantable medical device of claim 31, wherein the means
for controlling the means for generating light sets programmable
stimulation parameters and delivers light according to the
programmable stimulation parameters.
39. The implantable medical device of claim 38, wherein the means
for controlling the means for generating light is configured to
adjust the parameters based on the sensed patient therapeutic
state.
40. The implantable medical device of claim 38, wherein the
parameters comprise at least one of a pulse rate of the light, a
pulse width of the light, an amplitude intensity of the light, a
duty cycle of the light, and a wavelength of the light.
Description
[0001] This application claims the benefit of U.S. Provisional
Application No. 61/264,550, filed Nov. 25, 2009 and of U.S.
Provisional Application No. 61/301,836, filed Feb. 5, 2010, both
assigned to the assignee of this application, the entire
disclosures of both of which are incorporated herein by
reference.
STATEMENT REGARDING SEQUENCE LISTING
[0002] The Sequence Listing in accordance with 37 C.F.R.
.sctn..sctn.1.821-1.824 associated with this application is
provided in text format in lieu of a paper copy, and is hereby
incorporated by reference into the specification in its entirety.
The name of the text file containing the Sequence Listing is
"SEQUENCELISTING.txt." The text file is 18 KB, was created on Feb.
5, 2010, and is being submitted electronically via EFS-Web.
TECHNICAL FIELD
[0003] The disclosure relates to optical stimulation therapy.
BACKGROUND
[0004] Electrical stimulation of neural tissue serves as the core
of many neurological therapies, and can provide relief for a
variety of disorders, improving the quality of life for many
patients. In some cases, electrical stimulation may be
characterized by a lack of specificity in the excitation of neural
tissue. In particular, it can be difficult to stimulate a specific,
localized neural population due to constraints on electrode
geometry and placement. For example, the area of stimulation may be
dictated by electrode size, which can be generally orders of
magnitude greater than the cellular targets of interest. In some
cases, this may lead to overexciting cellular networks and or
inefficient stimulation, and may result in stimulation of
non-target cells. In addition, inhibitory stimuli through the use
of electrical coupling generally may be accomplished only through a
electrical stimulation block that involves inefficient, high
frequency stimulation, thereby limiting the therapy modulation
strategy in some circumstances. The presence of electrodes in
tissue may also place limitations on electromagnetic exposure from
electromagnetic sources such as magnetic resonance imaging (MRI)
and electrosurgery devices. In addition, electrical stimulation can
undermine the ability to sense underlying electrical neural
activity simultaneously with delivery of electrical stimulation. In
particular, electrical stimulation currents flowing through the
tissue that are necessary to achieve a localized current density
high enough to depolarize the cell or axon can mask the
bioelectrical activity to be sensed.
SUMMARY
[0005] In general, the disclosure describes techniques for
delivering optical stimulation to neural tissue from an optical
stimulation device. The optical stimulation device, in some
examples, may deliver optical stimulation configured to support
optogenetic neuromodulation. For optogenetic neuromodulation,
cellular control and interfacing is achieved by activating
light-sensitive channel proteins, also referred to as opsins that
are embedded in desired neuronal populations. Opsins are expressed
on the neuronal membrane by lentiviral or retroviral-based delivery
of their genes, allowing for direct cellular targeting through
genetic mechanisms.
[0006] As examples, two microbial opsins, Channelrhodopsin-2
(cation channel activated by .about.450 nm light) and Halorhodopsin
(chloride pump activated by .about.580 nm light) may be suitable
for optogenetic stimulation, as they provide a mechanism to
modulate neural information flow by respectively exciting and
inhibiting action potentials in neural networks. Although these
opsins are described for purposes of illustration, an optical
stimulation device may be configured to deliver optical stimulation
for use with other suitable opsins. Accordingly, the description of
particular opsins should not be considered limiting of the
techniques broadly described in this disclosure.
[0007] In one aspect, the present disclosure is directed to a
method for delivering optical stimulation, the method comprising
transfecting a target tissue with a light-sensitive channel protein
sensitive to light in a wavelength range, delivering light in the
wavelength range to the target tissue via an optical stimulation
device, substantially simultaneously with delivering light to the
target tissue, sensing bioelectric signals, determining a patient
therapeutic state based on the bioelectric signals, and adjusting
the delivery of the light to the target tissue based on the sensed
patient therapeutic state.
[0008] In another aspect, the present disclosure is directed to a
method for delivering optical stimulation, the method comprising
transfecting a target tissue with a light-sensitive channel protein
sensitive to light in a wavelength range, delivering light in the
wavelength range to the target tissue via an optical stimulation
device, substantially simultaneously with delivering light to the
target tissue, sensing bioelectric signals comprising at least one
of: a local field potential proximate the target tissue, energy
spectra in the alpha band of brain activity, energy spectra in the
beta band or brain activity, energy spectra in the gamma band of
brain activity, electrocorticography signals, and
electroencephalography signals, and adjusting the delivery of light
to the target tissue based on the sensed bioelectric signals.
[0009] In another aspect, the present disclosure is directed to a
method for delivering optical stimulation, the method comprising
delivering light from an optical stimulation device to a target
tissue via an optical light guide, wherein the optical stimulation
device is remote from the target tissue, and sensing bioelectric
signals with a sense electrode, wherein the optical light guide and
the sense electrode each comprise a material that produces
substantially no induced current in an electromagnetic field.
[0010] In another aspect, the present disclosure is directed to an
implantable medical system comprising a therapy delivery module
comprising a light source that generates light and a controller
that controls the output of the light source, an optical light
guide configured to deliver the light from the light source to a
target tissue, a lead with a sense electrode for sensing
bioelectric signals, and a sensing module configured to determine a
patient therapeutic state based on the sensed bioelectric signals
substantially simultaneously with the delivery of light from the
light source, wherein the controller is configured to adjust the
delivery of light to the target tissue based on the sensed patient
therapeutic state.
[0011] In another aspect, the present disclosure is directed to an
implantable medical device comprising means for generating light,
means for controlling the output of the means for generating light,
means for directing the light from the means for generating light
to a target tissue, means for sensing bioelectric signals, and
means for sensing a patient therapeutic state based on the sensed
bioelectric signals substantially simultaneously with the delivery
of the light from the means for generating light, wherein the means
for controlling the output of the means for generating light is
configured to adjust the delivery of light to the target tissue
based on the sensed patient therapeutic state.
[0012] The details of one or more examples of the disclosure are
set forth in the accompanying drawings and the description below.
Other features, objects, and advantages will be apparent from the
description and drawings, and from the claims.
BRIEF DESCRIPTION OF DRAWINGS
[0013] FIG. 1 is a conceptual diagram illustrating an example
therapy system that includes an implantable stimulator coupled to
one or more optical fibers for optical stimulation and one or more
sense electrodes.
[0014] FIG. 2 is a conceptual diagram illustrating another example
therapy system that includes an implantable stimulator coupled to
one or more optical fibers.
[0015] FIG. 3 is a block diagram illustrating various example
components of an implantable optical stimulator.
[0016] FIG. 4 is a block diagram illustrating the example
components of another example implantable optical stimulator with a
sensing generator.
[0017] FIG. 5 is a conceptual diagram illustrating another example
therapy system that includes an implantable stimulator coupled to
one or more optical fibers for optical stimulation and one or more
catheters for delivery of a therapeutic agent.
[0018] FIG. 6 is a block diagram illustrating various example
components of the implantable stimulator and fluid delivery device
of FIG. 5.
[0019] FIG. 7 is a block diagram illustrating various example
components of an external programmer.
[0020] FIG. 8 is a conceptual diagram illustrating a comparison
between electrical stimulation and selective optogenetic modulation
of neuron cells.
[0021] FIG. 9 is a block diagram of an example system for
optogenetic neuromodulation of target neuron cells.
[0022] FIG. 10 is a schematic diagram of an example optical
stimulation circuit.
[0023] FIG. 11 is a schematic diagram of an example telemetry and
power management circuit.
[0024] FIG. 12 is a characterization of measurement results of the
example optogenetic neuromodulation system of FIG. 9.
[0025] FIG. 13 is a photograph and cross-sectional view of an
example compression feedthrough for passing an optical fiber
through an optical stimulator housing.
[0026] FIG. 14 is a conceptual diagram showing an example therapy
system that includes an implantable optical stimulator coupled to
an optical fiber through a window.
[0027] FIG. 15 is a conceptual diagram showing an osmotic pump used
for delivery of a therapeutic agent.
[0028] FIG. 16 is a flow diagram of an example method for
delivering optical stimulation.
[0029] FIG. 17 is a flow diagram of another example method for
delivering optical stimulation.
[0030] FIG. 18 is a flow diagram of another example method for
delivering optical stimulation.
[0031] FIG. 19 is a flow diagram of another example method for
delivering optical stimulation.
[0032] FIG. 20 is a flow diagram of another example method for
delivering optical stimulation.
DETAILED DESCRIPTION
[0033] The disclosure, in some examples, describes optical
stimulation techniques, such as optogenetic stimulation techniques.
The techniques may be capable of exciting or inhibiting neural
activity in target neuron populations. For optogenetic stimulation,
the target neurons may be selectively transfected with genes that
express opsins that are activated by light emitted into the target
tissue. The light may be selected to activate an opsin to initiate
neuronal spikes or to deactivate or inhibit an opsin to cease or
prevent neuronal spikes. The light may also be selected to activate
an opsin to suppress a neuronal spike. An optogenetic stimulation
system may be configured as an implantable medical device that can
deliver optical stimulation through implantable optical fibers or
other light-delivery apparatus to a target tissue, such as to
specific or highly specific neuron populations. The high degree of
specificity provided by the optical stimulation may limit or
prevent stimulation of non-target tissue, possibly reducing side
effects of stimulation.
[0034] As non-limiting examples, the optical stimulation may be
delivered to target tissue within the brain or spinal cord of a
human patient. However, the disclosure is not so limited. Rather,
optical stimulation may be delivered to any of a variety of target
tissue sites to support any of a variety or therapies. A few
examples include without limitation cardiac tissue to support
cardiac therapy such as pacing, cardioversion, defibrillation,
resynchronization, or other therapies, gastrointestinal tissue to
support gastrointestinal therapy such as therapy to address
obesity, motility disorders (e.g., gastroparesis), dyspepsia, or
other therapies, pelvic floor tissue (e.g., sacral or pudendal
nerve tissue) to support pelvic floor therapy such as pain therapy,
urinary or fecal incontinence therapy, sexual dysfunction, or other
therapies, or cranial tissue to support cranial nerve therapy such
as therapy to relieve occipital neuralgia, trigeminal neuralgia,
facial pain, migraine headaches, or the like.
[0035] In one example, the optogenetic stimulation system may also
include a therapeutic agent delivery system, such as a pump, to
deliver a therapeutic agent capable of transfecting the target
neurons with the genes to express the opsins described above, such
as a liquid gene therapy agent including a lentiviral or retroviral
vector for transfecting the target neurons. The therapeutic agent
delivery system may provide regular, irregular, programmed, or
clinician-activated doses of the therapeutic agent to the target
neurons to ensure that the target neurons continue to express the
desired opsins. In another example, the optogenetic stimulation
system may also include sensing electrodes that sense electrical
signals within the patient, such as to provide a closed-feedback
loop for the control of the optical stimulation provided by the
optogenetic stimulation system.
[0036] The optogenetic system may be fully implantable in the
patient. In other examples, some portions of the optogenetic
stimulation system may be implantable in the patient, while other
components are configured to be external to the patient. For
example, one or more programmers may be external to the patient,
and communicate with an implanted stimulation device via wireless
telemetry. In other cases, a stimulation generator may be external
to the body, and be configured to deliver light, receive sensed
signals, and/or deliver fluid via percutaneously implanted optical
delivery elements (such as optical fibers), leads and/or conduits.
Optical fibers will be described for purposes of illustration, but
without limitation as the use of other types of optical delivery
elements. In some cases, optical fibers, electrical leads, or fluid
delivery conduits may be constructed as separate elements, or two
or more of such components combined with one another in a lead or
other elongated element.
[0037] FIG. 1 is a conceptual diagram illustrating an example
system 2 that may be used to deliver stimulation therapy to patient
6. Patient 6 ordinarily, but not necessarily, will be a human.
Generally, therapy system 2 includes an implantable stimulator 4
that delivers optical stimulation, such as light 15, to patient 6
via one or more implantable optical fibers 11. The terms "light" or
"optical light" as used herein refer to electromagnetic radiation
having a wavelength and intensity that has a physiologically
measurable effect and may include visible light, infrared light,
and ultraviolet light. In some examples, light that may be used to
provide the optical stimulation of system 2 may include visible
light having a wavelength of between about 380 nm and about 750 nm,
infrared light having a wavelength of between about 700 nm and
about 300 .mu.m, and ultraviolet light having a wavelength between
about 10 nm and about 400 nm. For example, a first optical fiber
11A may deliver visible light having a certain wavelength and
intensity, and a second optical fiber 11B may deliver visible light
having the same wavelength and intensity, or a different wavelength
at the same intensity, or the same wavelength and a different
intensity, or the second optical fiber 11B may deliver non-visible
light, such as infrared or ultraviolet light. The fibers 11A and
11B may be coupled to the same light source or different light
sources. In some cases, a single light source may be optically
multiplexed across the fibers 11A, 11B to deliver light via the
different fibers at different times. In some examples, the light
source may deliver light via both fibers 11A, 11B simultaneously.
The light delivered via one optical fiber 11A may be the same as
the light delivered via another optical fiber 11B, e.g., in terms
of characteristics or parameters such as wavelength, amplitude,
pulse width or pulse rate. Alternatively, the light delivered via
the optical fibers 11A, 11B may have different characteristics or
parameters.
[0038] The implantable optical fibers 11A, 11B may be deployed to a
target site as part of one or more bundles of optical fibers, such
as implantable optical fiber bundle 10, or separately. In some
cases, stereotactic or other positioning techniques may be used to
precisely position the optical fibers with respect to target tissue
sites. If only one optical fiber 11 is implanted, instead of
multiple fibers, then fiber bundle 10 and the single optical fiber
11 may be one and the same. The optical stimulation may be in the
form of optical light of a particular wavelength and may be
delivered as pulses, e.g., with a defined pulse width and pulse
rate. Various parameters of the pulses may be defined by a
stimulation program. The pulses may be delivered substantially
continuously for a relatively long period of time, such as several
seconds or more, or in pulse bursts, segments, or patterns, and may
be delivered alone or in combination with pulses defined by one or
more other stimulation programs. Although FIG. 1 shows a fully
implantable stimulator 4, techniques described in this disclosure
may be applied to external stimulators having optical fibers
deployed via percutaneously implantable leads. In addition, in some
examples, system 2 may include sense electrodes deployed within
patient 6, such as implantable sense electrodes 17 implanted on
leads 12A and 12B alongside optical fibers 11 and/or a sense
electrode located on a housing 14, i.e., "can" or "case," of the
implantable stimulator 4. Leads 12A, 12B may be implanted
side-by-side with optical fibers 11A, 11B, respectively, and
fastened or formed together. In other examples, leads and
associated sense electrodes may be formed in a common lead body
with one or more optical fibers, such as a conductor and one or
more electrodes placed on a lead sheath that covers an optical
fiber. In some examples, an electrical conductor and optical fiber
can run axially along the lead, while in another example an
electrical conductor may be wound in a coil that runs along the
lead while one or more optical fibers extend through the middle of
the coil. In other examples, implantable stimulator 4 may be
coupled to one or more leads which may or may not be bifurcated. In
such examples, the leads may be coupled to implantable stimulator 4
via a common lead extension or via separate lead extensions. The
sense electrodes may detect various types of bioelectric signals,
including local field potentials, energy spectra in different
bands, such as alpha, beta, or gamma bands of brain activity, and
electrical signals associated with electrocorticography (ECoG) or
electroencephalography (EEG). Other sensors may also be included
within or on housing 14 or external to housing 14 within patient,
including an accelerometer or other posture sensor and a pressure
sensor. In some examples, in addition to sensing bioelectric
signals or as an alternative, the sense electrodes could be
selectively used to deliver electrical stimulation, such that the
implantable stimulator may deliver optical stimulation and
electrical stimulation on, e.g., a selective basis. For example,
optical or electrical stimulation could be delivered at different
times or at the same time independently of one another or on a
coordinated basis.
[0039] In the example illustrated in FIG. 1, implantable stimulator
4 is implanted within a subcutaneous pocket in a clavicle region of
patient 6. Optical fibers 11 may be implanted using a stylet for
insertion stiffness while the optical fiber is being implanted in
the target tissue. For example, the stylet may allow a surgeon to
easily manipulate optical fiber 11 as it is guided from the
clavical region, though the neck, into cranium 18, and into brain
16 of patient. A stylet may also be used to guide optical fibers to
other target tissues and other treatments, such as peripheral nerve
stimulation (PNS), peripheral nerve field stimulation (PNFS), deep
brain stimulation (DBS), cortical stimulation (CS), pelvic floor
stimulation, gastric stimulation, and the like. The stylet may be
removable after insertion of optical fiber 11 so that the optical
fiber 11 is flexible after insertion such that the stylet does not
interfere with chronic treatment by the optical fiber. In one
example, optical fiber 11 or the lead carrying optical fiber 11 may
include a stylet lumen for receiving the stylet and for allow the
removal of the stylet.
[0040] Stimulator 4 generates programmable optical stimulation,
e.g., optical pulses with selected wavelengths and intensities, and
delivers the stimulation via one or more implantable optical fibers
11. In some cases, the wavelengths and intensities of the optical
pulses may be fixed, or limited to a narrow range. In other
examples, the wavelengths and intensities of the optical pulses may
be variable, i.e., tunable to produce a wider range of desired
wavelengths and intensities. In some cases, multiple sets of one or
more implantable optical fibers 11 may be provided. In the example
of FIG. 1, two optical fibers 11A and 11B (collectively referred to
as "optical fibers 11") are each carried as part of an optical
fiber bundle 10 until a distal end of bundle 10 is bifurcated into
separate optical fiber segments 11. Each optical fiber 11A, 11B may
be a single optical fiber. Alternatively, in some examples, each
optical fiber may include multiple fibers that together deliver
optical stimulation. Optical fibers 11A, 11B may provide optical
transmission between stimulator 4, which provides a light source
for the optical stimulation, and the area of treatment, shown as
the brain 16 of patient 6 in FIG. 1. Stimulator 4 provides optical
stimulation by generating optical light 15 with a desired
wavelength and intensity, as described in more detail below, and
directing the optical light 15 into optical fiber 11 at the
proximal end of the optical fiber. The optical light 15 is
transmitted along optical fiber 11 until it is emitted from a
distal end of optical fiber 12, as shown in FIG. 1.
[0041] Other means of light communication may be used in place of
an optical fiber, including a wave guide, a hollow tube, a liquid
filled tube, and a light pipe. In an alternative example, a light
source, such as a light emitting diode (LED), is implanted at the
target treatment site, e.g., at the distal end of a lead or on the
housing of a microstimulator device implanted proximate target
tissue, such that the light is emitted into the target tissue from
the LED, rather than via an optical fiber. In this case, a
conducting lead may be implanted to extend from an optical
stimulation controller to the LED to conduct electrical energy to
power the light source
[0042] Optical stimulation of the target tissue may be configured
to cause optogenetic modulation of a selected target population of
cells, such as, for example, a particular area of neurons within
the brain or spinal cord. The optogenetic modulation may activate
light-sensitive channel proteins, referred to herein as "opsins,"
that are expressed within the target population of cells. Opsin
expression may be triggered by a biological vector that introduces
the opsin to the target neurons. In one example, the biological
vector comprises a gene therapy agent, such as a lentivirus or
retrovirus that is designed to selectively transfect a particular
population of neurons to selectively deliver the genes to the
target neurons that will express for the desired opsins.
Optogenetic modulation may be particularly useful because the
genetic modification provided by biological vectors allow a
specific cell population to be targeted and transfected, without
modifying neighboring cell populations so that when the area is
exposed to stimulation light, only the selected and transfected
cell population is actually stimulated. Thus, biological vectors,
such as lentiviral-based or retroviral-based vectors, provide for
delivery of their genes, allowing for direct cellular targeting
through genetic mechanisms as opposed to reliance on electrode
positioning. This allows the "placement" of the therapeutic
stimulation to be performed by a highly selective biological vector
rather than relying on a surgeon who, no matter how skilled, cannot
place an electrode with the same precision. An example of this
advantage is shown in FIG. 8, which compares conventional
electrical stimulation of neurons, also referred to as galvanic
neuromodulation, and optogenetic neuromodulation in a rodent model
90. A cross section 92 of the rodent brain 94 shows an implanted
electrode 96 and an optical fiber 98 at a location where target
neurons have been transfected. As can be seen on the left portion
of FIG. 8, electrode 96 not only activates the target (transfected)
neurons 100, but also other nearby neurons (normal neurons) 102,
which are not desired to be activated. In contrast, genetic
transfection coupled with optical stimulation, as shown on the
right portion of FIG. 8, causes only the transfected target neurons
100 to be activated, while the non-transfected, non-target neurons
102 remain unactivated.
[0043] In one example, a first opsin may be used as an activating
or exciting opsin that, when exposed to a specific wavelength of
light or range of wavelengths, causes the target neuron membrane to
become permeable to cations into the neuron, which depolarizes the
neuron, also referred to as activating the neuron, and causes a
neural spike. A second opsin may be used as an inhibiting opsin
that, when exposed to a different wavelength of light or range of
wavelengths, acts to hyperpolarize the neuron, also referred to as
inhibiting or deactivating the neuron, to counteract the cation
permeability of the target neuron. An example of a first opsin is
channelrhodopsin-2 that is described in Berndt et al, "Bi-stable
neural state switches," Nature Neuroscience, vol. 12, pp. 229-34
(2008), U.S. Published Patent Application No. US 2007/0054319 to
Boyden et al., U.S. Published Patent Application No. US
2007/0053996 to Boyden et al., and U.S. Published Patent
Application No. US 2007/0261127 to Boyden et al., the disclosures
of which are incorporated herein by reference in their entireties,
which is activated to provide a cation-permeable channel that
activates the target neuron. For example, the cation-permeable
channel may activate the target neuron when exposed to light having
a wavelength between about 420 nm and about 500 nm, such as between
about 450 nm and about 495 nm, or in one example about 470 nm, and
with an intensity of between about 0.5 mW/mm.sup.2 and about 10
mW/mm.sup.2, such as between about 1 mW/mm.sup.2 and about 5
mW/mm.sup.2, and in one example about 2.4 mW/mm.sup.2. In one
example, a channelrhodopsin-2 opsin is activated by blue light
having a wavelength of between about 450 nm and about 495 nm, such
as between about 450 nm and about 470 nm. In one example, the
channelrhodopsin-2 opsin may only need to be exposed to this light
for a pulse of between about 1 ms and about 1 second, such as
between 5 ms and about 50 ms, and in one example about 10 ms. The
channelrhodopsin-2 opsin holds its activated state and slowly
deactivates with a probability window of several seconds. An
example channelrhodopsin-2 opsin may also be deactivated or
"switched off" by illumination of a second wavelength of light. In
one example, a modified channelrhodopsin-2 may be deactivated by
illumination with a green light having a wavelength of between
about 495 nm and about 570 nm, such as between about 510 nm and
about 550 nm, and in one example about 535 nm, with an intensity of
between about 0.5 mW/mm.sup.2 and about 10 mW/mm.sup.2, such as
between about 1 mW/mm.sup.2 and about 5 mW/mm.sup.2, and in one
example about 2.4 mW/mm.sup.2, and the channelrhodopsin-2 may be
exposed to a pulse of between about 20 ms and about 75 ms, such as
between about 40 ms and about 60 ms, and in one example about 50
ms. An example of a second opsin is a halorhodopsin described in
Han X. et al., "Multiple-Color Optical Activation, Silencing, and
Desynchronization of Neural Activity, with Single-Spike Temporal
Resolution," PLoS ONE, 2(3):e299,
http://www.plosone.org/article/info:doi/10.1371/journal.pone.0000299
(2007), the entire disclosure of which is incorporated herein by
reference. This second opsin may be activated to provide an anion
pump that inhibits or deactivates the target neuron. In one
example, the second opsin is activated, thus deactivating the
target neuron, when exposed to yellow light having a wavelength of
between about 550 nm and about 610 nm, such as between about 570 nm
and about 590 nm, and in one example about 580 nm, and with an
intensity of between about 0.5 mW/mm.sup.2 and about 25
mW/mm.sup.2, such as between about 10 and about 21 mW/mm.sup.2 in
one example or between about 1 mW/mm.sup.2 and about 5 mW/mm.sup.2
in another example. In one example, the halorhodopsin may only need
to be exposed to this light for between about 10 ms and about 1
second, such as between 20 ms and about 100 ms, and in one example
about 40 ms. Not only can halorhodopsin be used to inhibit the
firing of the target neurons, but it can also be used to deactivate
neurons that were previously activated by the activation of the
channelrhodopsin-2 described above. For example, if a 470 nm
wavelength light pulse of about 10 ms activates the
channelrhodopsin-2, which can remain actives for several seconds, a
535 nm wavelength light pulse may be emitted to deactivate the
channelrhodposin-2, and a 580 nm wavelength light pulse may be
emitted to activate the halorhodopsin and abruptly deactivate the
target neurons. In one example, both the first opsin that activates
the target neuron and the second opsin that inhibits the target
neuron may be activated simultaneously or substantially
simultaneously in order to modulate the threshold potential of the
target neuron, such as for the treatment of schizophrenia.
[0044] The devices and techniques described in this disclosure may
be used in conjunction with any of a variety of opsins or other
materials effective in supporting excitation, inhibition or other
desired effects on the target tissue. In one example, a first opsin
or set of opsins, also referred to as a light-activated cation
channel protein (or "LACC"), comprises the protein, or portions of
the protein Channelrhodopsin-2 (ChR2). ChR2 is a rhodopsin derived
from the unicellular green alga Chlamydomonas reinhardtii. The term
"rhodopsin" as used herein is a protein that comprises at least two
building blocks, an opsin protein, and a covalently bound cofactor,
usually retinal (retinaldehyde). The rhodopsin ChR2 is derived from
the opsin Channelopsin-2 (Chop2) (Nagel, et. al. Proc. Natl. Acad.
Sci. USA 100:13940, and references cited therein). The LACC protein
may incorporate retinal that is added to the system, or, depending
on the cell type that is used, background levels of retinal present
in the cell may produce the required retinal. The use of the term
"opsin" herein is intended to encompass either the opsin or the
rhodopsin form of the first opsin and the second opsin. Typically,
Chop2 and ChR2 can be interconverted by the addition or removal of
the cofactor. Thus, as used herein, a LACC protein comprises an
opsin with or without a co-factor. For example, as used herein,
where a nucleic acid codes for an opsin protein such as Chop2, it
codes for a light activated cation channel protein such as ChR2.
Additionally, as used herein, where a cell expresses an opsin
protein such as Chop2, it expresses a LACC protein.
[0045] The opsins may also cause the modulation of the flow of
anions such as chloride across a membrane when activated by light.
In one example, a second opsin or set of opsins, also referred to
as an anion pump, may comprise the protein, or portions of the
protein, halorhodopsin (NpHR). NpHR is a light-driven chloride pump
rhodopsin derived from the unicellular archaeon Natronomonas
pharaonis. Optically induced electrical and chemical changes due to
activation of the opsins by light are also contemplated.
[0046] In some examples, it may desirable to add cofactor (usually
in the nanomolar to micromolar range). In other examples, no
addition of retinal is required. In some examples, the medium may
provide the required cofactor. In one example, the opsin protein
covalently binds retinal. The term retinal, as used in comprises
all-trans retinal, 11-cis retinal, and other isomers of
retinal.
[0047] In some examples, the protein Bcdo can be expressed along
with ChR2. Bcdo converts the common dietary molecule beta carotene
into retinal (Yan et. al., Genomics 72 (2): 193 (2001)), thus
providing retinal to convert Chop2 to ChR2.
[0048] As used herein, the terms "ChR2," "Chop2," and "NpHR" mean
the full proteins or fragments thereof. In one example, the LACC
comprises the amino terminal 310 amino acids of Chop2 which is
referred to herein as Chop2-310. One example comprises the amino
terminal 310 amino acids of ChR2 which is referred to as ChR2-310.
The amino-terminal 310 amino acids of ChR2 show homology to the
7-transmembrane structure of many microbial-type rhodopsins, and
comprise a channel with a light-gated conductance. In an example, a
LACC protein comprises a 7-transmembrane protein. Preferably the
LACC protein is a 7-transmembrane protein that either has a binding
affinity for retinal, or has retinal bound to it.
[0049] In one example, the LACC is derived from a microbial-type
rhodopsin. In one example, the LACC of the present invention is
derived from a bacteriorhodopsin.
[0050] In one example, each opsin is a single-component protein
that is an opsin protein. As used herein, a single component
protein is a single covalently linked chain of amino acids.
Multiple component systems require communication between
non-covalently linked molecules, which can be much slower than
within-protein signaling via conformational changes. The opsin
allows the creation of light-gated membrane conductance with a
single protein component. While not being bound by theory, it is
believed that the retinal in ChR2, as a microbial type rhodopsin,
is strongly bound, allowing the retinal to re-isomerize to the
all-trans ground state in a dark reaction without the need for
other enzymes. This mechanism allows for fast recovery (closing of
the ionic channel) when the light is removed, and it obviates the
need for other enzyme components for re-generation of the all
trans-retinal and closing of the channel.
[0051] In one example, the light-activated cation-channel
Channelrhodopsin-2 (ChR2) is genetically introduced into a cellular
membrane.
[0052] The LACC protein may also comprise the protein sequence of
Chop2-310 [SEQ ID NO:1]. The anion pump protein may comprise the
protein sequence of NpHR [SEQ ID NO:4]. "Protein" in this sense
includes proteins, polypeptides, and peptides. Also included within
the opsin protein are amino acid variants of the naturally
occurring sequences, as determined herein. In one example, the
variants are greater than about 75% homologous to the protein
sequence of Chop2 or Chop2-310, such as greater than about 80%, for
example greater than about 85%, such as greater than about 90%. In
some examples, the homology will be as high as about 93 to about 95
or about 98%. In one example, the variants are greater than about
75% homologous to the protein sequence of NpHR, such as greater
than about 80%, for example greater than about 85%, such as greater
than 90%. In some examples, the homology will be as high as about
93 to about 95 or about 98%. Homology in this context means
sequence similarity or identity, with identity being preferred.
This homology will be determined using standard techniques known in
the art. The compositions of the opsins include the protein and
nucleic acid sequences provided herein including variants which are
more than about 50% homologous to the provided sequence, more than
about 55% homologous to the provided sequence, more than about 60%
homologous to the provided sequence, more than about 65% homologous
to the provided sequence, more than about 70% homologous to the
provided sequence, more than about 75% homologous to the provided
sequence, more than about 80% homologous to the provided sequence,
more than about 85% homologous to the provided sequence, more than
about 90% homologous to the provided sequence, or more than about
95% homologous to the provided sequence.
[0053] The LACC proteins may be shorter or longer than the protein
sequence of Chop2 or Chop2-310. Thus, in one example, included
within the definition of LACC proteins are portions or fragments of
the protein sequence of Chop2 or of Chop2-310. The anion pump
proteins may be shorter or longer than the protein sequence for
NpHR. Thus, in one example, included within the definition of anion
pump proteins are portions or fragments of the protein sequence of
NpHR. In addition, nucleic acids may be used to obtain additional
coding regions, and thus additional protein sequence, using
techniques known in the art.
[0054] In one example, the LACC proteins are derivative or variant
protein sequences, as compared to Chop2 or Chop2-310. In one
example, the anion pump proteins are derivative or variant protein
sequences as compared to NpHR. That is, the derivative LACC
proteins or derivative anion pump proteins may contain at least one
amino acid substitution, deletion or insertion, with amino acid
substitutions being particularly preferred. The amino acid
substitution, insertion or deletion may occur at any residue within
the LACC protein or the anion pump protein.
[0055] In one example, the LACC proteins are amino acid sequence
variants of the ChR2, Chop2, ChR2-310, Chop-310 or [SEQ ID NO:1].
In another example, the anion pump proteins are amino acid sequence
variants of NpHR. These variants fall into one or more of three
classes: substitutional, insertional or deletional variants. These
variants ordinarily are prepared by site specific mutagenesis of
nucleotides in the DNA encoding the LACC proteins or anion pump
proteins, using cassette or PCR mutagenesis or other techniques
well known in the art, to produce DNA encoding the variant, and
thereafter expressing the DNA in recombinant cell culture. Amino
acid sequence variants are characterized by the predetermined
nature of the variation, a feature that sets them apart from
naturally occurring allelic or interspecies variation of the LACC
proteins or anion pump proteins. The variants typically exhibit the
same qualitative biological activity as the naturally occurring
analogue, although variants can also be selected which have
modified characteristics.
[0056] While the site or region for introducing an amino acid
sequence variation is predetermined, the mutation per se need not
be predetermined. For example, in order to optimize the performance
of a mutation at a given site, random mutagenesis may be conducted
at the target codon or region and the expressed breast cancer
variants screened for the optimal combination of desired activity.
Techniques for making substitution mutations at predetermined sites
in DNA having a known sequence are well known, for example, M13
primer mutagenesis and PCR mutagenesis.
[0057] Amino acid substitutions are typically of single residues;
insertions usually will be on the order of from about 1 to 20 amino
acids, although considerably larger insertions may be tolerated.
Deletions range from about 1 to about 20 residues, although in some
cases deletions may be much larger.
[0058] Substitutions, deletions, insertions or any combination
thereof may be used to arrive at a final derivative. Generally
these changes are done on a few amino acids to minimize the
alteration of the molecule. However, larger changes may be
tolerated in certain circumstances. In some examples, small
alterations in the characteristics of the LACC proteins or anion
pump proteins are desired, substitutions are generally made in
accordance with Table 1:
TABLE-US-00001 Original Exemplerary Residue Substitution Ala Ser
Arg Lys Asn Gln, His Asp Glu Cys Ser Gln Asn Glu Asp Gly Pro His
Asn, Gln Ile, Leu, Val Leu Ile, Val Lys Arg, Gln, Glu Met Leu, Ile
Phe Met, Leu, Tyr Ser Thr Thr Ser Trp Tyr Tyr Trp, Phe Val Ile,
Leu
[0059] Substantial changes in function are made by selecting
substitutions that are less conservative than those shown in Table
1. For example, substitutions may be made which more significantly
affect the structure of the polypeptide backbone in the area of the
alteration, for example the alpha-helical or beta-sheet structure;
the charge or hydrophobicity of the molecule at the target site; or
the bulk of the side chain. The substitutions which in general are
expected to produce the greatest changes in the polypeptide's
properties are those in which (a) a hydrophilic residue, e.g. seryl
or threonyl is substituted for (or by) a hydrophobic residue, e.g.
leucyl, isoleucyl, phenylalanyl, valyl or alanyl; (b) a cysteine or
proline is substituted for (or by) any other residue; (c) a residue
having an electropositive side chain, e.g. lysyl, arginyl, or
histidyl, is substituted for (or by) an electronegative residue,
e.g. glutamyl or aspartyl; or (d) a residue having a bulky side
chain, e.g. phenylalanine, is substituted for (or by) one not
having a side chain, e.g. glycine.
[0060] The variants or derivatives of the LACC proteins typically
exhibit the same qualitative activity as the Chop2, ChR2, Chop-310,
or ChR2-310 protein, while variants or derivatives of the anion
pump proteins typically exhibit the same qualitative activity as
NpHR, although variants or derivatives also are selected to modify
the characteristics of the opsins as needed. Variants or
derivatives can show enhanced ion selectivity, stability, speed,
compatibility, and reduced toxicity. For example, the protein can
be modified such that it can be driven by a different wavelength of
light than the wavelength of around 460 nm of the wild type ChR2
protein. The protein can be modified, for example, such that it can
be driven at a higher wavelength such as about 480 nm, 490 nm, 500
nm, 510 nm, 520 nm, 530 nm, 540 nm, 550 nm, 560 nm, 570 nm, 580 nm,
or 590 nm. Similarly, the anion pump protein can be modified such
that it can be driven by a different wavelength of light than the
580 nm of the wild type NpHR.
[0061] The opsins may incorporate un-natural amino acids as well as
natural amino acids. The unnatural amino acids can be used to
enhance ion selectivity, stability, speed, compatibility, or to
lower toxicity.
[0062] In one example, the opsins may comprise a fusion protein
comprising a light-activated channel protein, such as a LACC
protein or anion pump protein described above. It is well known in
the art that fusion proteins can be made that will create a single
protein with the combined activities of several proteins. In one
example, the fusion proteins can be used to target Chop2, ChR2, or
NpHR to specific cells or regions within cells.
[0063] In one example, a fusion protein comprising a LACC protein
or anion pump protein is a fusion protein that targets sub-cellular
regions of the cell. The fusion proteins may target, for instance,
axons, dendrites, and synapses of neurons. In one example, a PDZ
(PSD-95, Dlg and ZO-1) domain is fused to ChR2 or Chop2 which
target dendrites. In another example, Axon initial segment (AIS)
domain is fused to ChR2 or Chop2 which target axons.
[0064] Other fusion proteins may be used, such as are proteins
combining an opsin and a fluorescent protein in order to allow for
monitoring of the localization of the opsin. Example fusion
proteins are those with red fluorescent protein (mCherry), yellow
fluorescent protein (YFP), enhanced yellow fluorescent protein
(EYFP), cyan fluorescent protein (CFP), green fluorescent protein
(GFP), and woodchuck hepatitis post-transcriptional regulatory
element (WPRE). These fusion proteins, such as a ChR2-mCherry
fusion protein or a NpHr-EYFP or NpHR-EYFP-WPRE fusion protein,
allow for the independent stimulation of ChR2 or NpHR and the
simultaneous monitoring of localization. The simultaneous
stimulation and monitoring of localization can be carried out in
many cell types including mammalian systems.
[0065] In one example, an opsin protein is provided that is
non-toxic in the cells in which it is expressed. In one example,
the opsin proteins do not perturb the basal electrical properties,
alter the dynamic electrical properties, or jeopardize the
prospects for cellular survival. In one example, the opsin proteins
do not alter the membrane resistance of the cells in the absence of
light. In one example, the opsin proteins do not lead to apoptosis
in the cells, nor lead to the generation of pyknotic nuclei. In one
example, in the absence of light, the presence of the opsin
proteins do not alter cell health or ongoing electrical activity,
at the level of subthreshold changes in voltage or in spike output,
either by shunting current through leaky channels or by altering
the voltage dependence of existing neuronal input-output
relationships. In one example, the presence of opsin protein
creates no significant long-term plastic or homeostatic alterations
in the electrical properties of neurons expressing the protein.
[0066] It would be understood by a person of skill in the art that
the opsin proteins can be coded for by various nucleic acids. Each
amino acid in the protein is represented by one or more sets of 3
nucleic acids (codons). Since many amino acids are represented by
more than one codon, there is not a unique nucleic acid sequence
that codes for a given protein. It is well understood by persons of
skill in the art how to make a nucleic acid that can code for the
opsin proteins by knowing the amino acid sequence of the protein. A
nucleic acid sequence that codes for a polypeptide or protein is
the "gene" of that polypeptide or protein. A gene can be RNA, DNA,
or other nucleic acid than will code for the polypeptide or
protein. An example nucleic acid sequence for coding for a LACC
comprises SEQ ID NO:2. An example nucleic acid sequence for coding
for an anion pump protein comprises SEQ ID NO:5.
[0067] It is known by persons of skill in the art that the codon
systems in different organisms can be slightly different, and that
therefore where the expression of a given protein from a given
organism is desired, the nucleic acid sequence can be modified for
expression within that organism.
[0068] In one example, the nucleic acid sequence codes for an opsin
protein that is optimized for expression with a mammalian cell. A
preferred embodiment comprises a nucleic acid sequence optimized
for expression in a human cell. In one example, a nucleic acid
sequence that codes for a light-activated cation protein that is
optimized for expression with a human cell comprises SEQ ID NO:3.
In one example, a nucleic acid sequence that codes for an anion
pump protein that is optimized for expression with a mammalian cell
comprises SEQ ID NO:5.
[0069] In one example, reagents are provided for genetically
targeted expression of the opsin proteins including ChR2 and NpHR.
Genetic targeting may be used to deliver opsin proteins to specific
cell types, to specific cell subtypes, to specific spatial regions
within an organism, and to sub-cellular regions within a cell.
Genetic targeting also relates to the control of the amount of
opsin protein expressed, and the timing of the expression.
[0070] In one example, a reagent for genetically targeted
expression of the opsin protein comprises a vector which contains
the gene for the opsin protein. As used herein, the term "vector"
refers to a nucleic acid molecule capable of transporting between
different genetic environments another nucleic acid to which it has
been operatively linked. The term "vector" also refers to a virus
or organism that is capable of transporting the nucleic acid
molecule. One example vector is an episome, such as a nucleic acid
molecule capable of extra-chromosomal replication. Example vectors
are those capable of autonomous replication and/or expression of
nucleic acids to which they are linked. Vectors capable of
directing the expression of genes to which they are operatively
linked are referred to herein as "expression vectors". Other
example vectors are viruses such as lentiviruses, retroviruses,
adenoviruses and phages. In some examples, vectors may genetically
insert opsin proteins into both dividing and non-dividing cells.
Example vectors can genetically insert opsin proteins in-vivo or
in-vitro.
[0071] Those vectors that include a prokaryotic replicon may also
include a prokaryotic promoter capable of directing the expression
(transcription and translation) of the opsin protein in a bacterial
host cell, such as E. coli. A promoter is an expression control
element formed by a DNA sequence that permits binding of RNA
polymerase and transcription to occur. Promoter sequences
compatible with bacterial hosts are typically provided in plasmid
vectors containing convenience restriction sites for insertion of a
DNA segment of the present invention. Examples of such vector
plasmids are pUC8, pUC9, pBR322, and pBR329 available from BioRad
Laboratories, (Richmond, Calif.) and pPL and pKK223 available from
Pharmacia, (Piscataway, N.J.).
[0072] Expression vectors compatible with eukaryotic cells, may
also be used. Eukaryotic cell expression vectors are well known in
the art and are available from several commercial sources. Such
vectors may be provided containing convenient restriction sites for
insertion of the desired DNA homologue. Examples of such vectors
are pKSV-10 (Pharmacia), pBPV-1/PML2d (International
Biotechnologies, Inc.), and pTDT1 (ATCC, No. 31255).
[0073] One example of an expression vector is a lentivirus
comprising the gene for ChR2 or Chop2 and an EF1-alpha promoter.
This lentivirus vector may be used to create stable cell lines. The
term "cell line" as used herein is an established cell culture that
will continue to proliferate given the appropriate medium.
[0074] In one example, an expression vector is a lentivirus
comprising the gene for the opsin and a cell specific promoter.
Examples of cell specific promoters are promoters for somatostatin,
parvalbumin, GABA.alpha.6, L7, and calbindin. Other example cell
specific promoters are promoters for kinases such as PKC, PKA, and
CaMKII; promoters for other ligand receptors such as NMDAR1,
NMDAR2B, GluR2; promoters for ion channels including calcium
channels, potassium channels, chloride channels, and sodium
channels; and promoters for other markers that label classical
mature and dividing cell types, such as calretinin, nestin, and
beta3-tubulin.
[0075] Another example is a lentivirus containing tetracycline
elements that allow control of the gene expression levels of ChR2
or NpHR, simply by altering levels of exogenous drugs such as
doxycycline. This method, or other methods that place ChR2 or NpHR
under the control of a drug-dependent promoter, will enable control
of the dosage of ChR2 NpHR in cells, allowing a given amount of
light to have different effects on electrical activation, substance
release, or cellular development.
[0076] Nucleic acid sequences comprising the gene for opsin
proteins and promoters for genetically targeted expression of the
proteins may also be provided. The genetically targeted expression
of the opsin proteins can be facilitated by the selection of
promoters. The term "promoter" as used herein is nucleic acid
sequence that enables a specific gene to be transcribed. The
promoter may reside near a region of DNA to be transcribed. The
promoter is usually recognized by an RNA polymerase, which, under
the control of the promoter, creates RNA, which is then converted
into the protein for which it codes. By use of the appropriate
promoter, the level of expression of opsin protein can be
controlled. Cells use promoters to control where, when, and how
much of a specific protein is expressed. Therefore, by selecting a
promoter that is selectively expressed predominantly within one
type of cell, one subtype of cells, a given spatial region within
an organism, or sub-cellular region within a cell, the expression
of an opsin protein can be controlled accordingly. The use of
promoters also allows the control of the amount of LACC expressed,
and the timing of the expression. The promoters can be prokaryotic
or eukaryotic promoters.
[0077] In one example, a nucleic acid sequence comprises the gene
for an opsin protein and a general purpose promoter. A general
purpose promoter allows expression of the opsin protein in a wide
variety of cell types. One example of a general purpose promoter is
the EF1-alpha promoter. The EF-1 alpha gene encodes for elongation
factor-1 alpha which is one of the most abundant proteins in
eukaryotic cells and is expressed in almost all kinds of mammalian
cells. The promoter of this "housekeeping" gene can lead to
persistent expression of the transgene in vivo. Another example
promoter is the CMV (cytomegalovirus) promoter, which can drive
gene expression at very high levels. Still other example
general-purpose promoters include those for CaMKII and synapsin I
(Dittgen et. al, PNAS 101:18206-11 (2004)).
[0078] In one example, a nucleic acid sequence comprising the gene
for an opsin protein and a cell specific promoter is provided.
Examples of cell specific promoters are promoters for somatostatin,
parvalbumin, GABA.alpha.6, L7, and calbindin. Other example cell
specific promoters are promoters for kinases such as PKC, PKA, and
CaMKII; promoters for other ligand receptors such as NMDAR1,
NMDAR2B, GluR2; promoters for ion channels including calcium
channels, potassium channels, chloride channels, and sodium
channels; and promoters for other markers that label classical
mature and dividing cell types, such as calretinin, nestin, and
beta3-tubulin. In one example, the nucleic acid comprises a
bacterial artificial chromosome (BAC).
[0079] In one example, a promoter is an inducible promoter. For
instance, the promoter may be inducible by a trans-acting factor
which responds to an exogenously administered drug. The promoters
may be, but are not limited to tetracycline-on or tetracycline-off,
or tamoxifen-inducible Cre-ER.
[0080] In another example, a first opsin or set of opsins may be
designed to activate a first population of cells upon exposure to a
first wavelength of light or range of wavelengths, while a second
opsin or set of opsins may be designed to inhibit a second
population of cells upon exposure to the same wavelength or range
of wavelengths of light, allowing for even more targeted control of
the overall bioelectrical response of the target tissue or
tissues.
[0081] Optical fibers 11 may be made from a plastic or glass, and
as such may provide advantages over the leads and electrodes use
for conventional electrical stimulation. First, because optical
fibers 11 are not electrically conducting, they do not provide a
galvanic path for induced currents at the tissue interface so there
is no risk of tissue capture or excessive heating that can occur
due to modalities such as magnetic resonance imaging (MRI) or
electromagnetic interference (EMI). Moreover, the elimination of
conductors from the tissue interface helps to mitigate MRI
interference that is seen with typical electrical stimulation
electrodes, allowing for continued high-resolution imaging
post-implant. Second, because there is not a relatively large
electrical current flowing through the target tissue, as is the
case with electrical stimulation, optical stimulation does not mask
or block the relatively smaller bioelectric activity that is
electrically sensed at the same time optical stimulation is
delivered. Thus, optical stimulation allows for simultaneous
electrical sensing of the resulting reaction by the target tissue,
allowing system 2 to provide for closed-loop feedback and control
of the optical stimulation.
[0082] The architecture of an example implantable optogenetic
neuromodulation system 110 is shown in FIG. 9. System 110 may
comprise a hermetically-sealed chronic optical delivery system.
System 110 may include an optical fiber 11 for light delivery, a
fiber feedthrough 112, shown in FIG. 13, that couples optical fiber
11 to a light source 63 optically connected, or "pigtailed" to
optical fiber 11, and provides a hermetic barrier between
stimulator 114 and the tissue, an optical stimulation circuit 116
for driving light source 63, a microcontroller 118, also referred
to as a processor, to manage system 110, a power source, such as a
rechargeable battery 122, and an RF-power conditioning module 120
for bidirectional data communication and, if desired, recharging of
the rechargeable battery 122. In one example, system 110 may
include a temperature sensor 124 for use in implementing a
closed-loop system to manage power flow in implant 114.
[0083] Examples of light source 63 that may be used in system 110
include one or more light-emitting diodes LEDs and one or more
lasers. In one example, light source 63 may include one light
source for activation of the target tissue, such as a light source
to activate a channelrhodopsin-2 opsin, and another light source to
inhibit the target tissue, such as a light source to activate a
halorhodopsin opsin. Light source 63 may also include a light
source to stop the activation of the target tissue, but not
necessarily to inhibit the target tissue, such as a light source
that deactivates or "switches off" the channelrhodopsin-2 opsin. In
one example, light source 63 may comprise a standard commercially
available LED tuned to a blue light wavelength of between about 459
nm and about 469 nm with an output power of between about 3.5 mW
and about 5.5 mW for the activation of channelrhodopsin-2, a
standard commercially available LED tuned to a green light
wavelength of between about 515 nm and about 540 nm with an output
power of between about 0.02 mW and about 1.5 mW for the
deactivation of channelrhodopsin-2, and a standard commercially
available LED tuned to a yellow light wavelength of about 558 nm
with a power output of between about 0.02 mW and about 0.025 mW for
activation of the halorhodopsin. In another example, light source
63 is one or more lasers that provide the optical stimulation to
the target tissue. In one example, light source 63 may comprise a
blue laser for the activation of channelrhodopsin-2, such as a
standard commercially available semiconductor laser having a
wavelength of about 470 nm with an output power of about 7.24 mW
and a yellow laser for the activation of halorhodopsin, such as a
standard commercially available semiconductor laser having a
wavelength of about 532 nm with an output power of about 12 mW. If
a battery power source is used, choice of the appropriate battery
will depend on voltage, power and capacity/longevity needs that
will depend on light source, circuitry and telemetry choices.
[0084] The system 110 may also include a charge pump 126 to convert
the voltage of battery 122 to a voltage level appropriate to drive
light source 63, and, in some examples, to convert the battery
voltage to other voltage levels appropriate for other functions.
The charge pump 126 may be tuned from 2.times. to 5.times. to
accommodate power source voltage variation, such as battery voltage
variation for a battery power source in the case of a primary
battery or a rechargeable battery. In other words, charge pump 126
may be configured to provide different conversion ratios depending
on the voltage level of the battery 122 over time as the battery
discharges. Charge pump 126 may be a capacitive charge pump or an
inductive charge pump, depending on the energy requirements of
light source 63. For example, if light source 63 has a large power
requirement, such as with a laser light source described in more
detail below, than an inductive charge pump may be used because it
is better at delivering higher power. Conversely, if light source
63 has low power requirements, such as with some low power
light-emitting diodes (LEDs), then a capacitive charge pump may be
used because it does not require the use of a bulky induction coil.
In the example of FIG. 9, system 110 includes a rechargeable
battery source 122 to power light source 63, which may be an
LED-based light source, or possibly a higher voltage laser device.
The battery source 122 may be recharged, e.g., by transcutaneous
inductive transfer of energy from an external recharge device to a
recharge circuit for the battery source.
[0085] The circuit functionality of the system 110 may be
partitioned into an optical stimulator circuit 116, shown in FIG.
10, a telemetry and power management circuit 120, shown in FIG. 11,
and a microcontroller 118. In one example, optical stimulator
circuit 116 and power management circuit 120 are fabricated as
integrated circuits (ICs) in a 0.8 .mu.m HV CMOS process.
[0086] Turning to FIG. 13, an example of a feedthrough 112 that may
be used to provide a hermetic seal at the junction between optical
fiber 11 and stimulator 4 is the optical feedthrough assembly
disclosed in U.S. Pat. No. 7,349,618, entitled "Optical Feedthrough
Assembly For Use In Implantable Medical Device," assigned to the
assignee of this application, the entire disclosure of which is
incorporated herein by reference.
[0087] In another example, shown in FIG. 14, instead of a fiber
feedthrough, an optical stimulation device 160 may comprise a
window 162 formed in housing 164 of implantable stimulator 160,
such as by hermetically sealing window 162 in stimulator housing
164. Hermetically-sealed window 162 may be optically connected to
an optical light guide, such as optical fiber 11. Window 162 may
also be optically connected to the output of a light source, such
as an LED 166, within housing 164. The optical connection 168
between window 162 and LED 166 is shown schematically in FIG. 14.
In one example, the optical connection between window 162 and
optical fiber 11 is achieved through an optical index matching gel
170 applied to window 162. Index matching gel 170 ensures that the
light produced by LED 166 maintains the desired wavelength, e.g. an
excitation wavelength or inhibition wavelength corresponding to the
light-sensitive channel protein at the target tissue, as described
above. In this example, there is no need to have a feedthrough.
Rather, the light from the light source 166 is delivered through
window 162 to a proximal end 172 of the optically-connected optical
fiber 11, such as through the index matching gel 170. This approach
may provide more flexibility in terms of coupling the light source
stimulation site because the window can be selected and configured
to form part of the focusing optics for the light transmitted into
the optical fiber. Further examples of an optical window are
provided in the co-pending application entitled "Optical
Stimulation Therapy," having the Attorney Docket No.
"1023-918US01/P0035812.02," filed on the same date as the present
application, as well as in U.S. Pat. No. 5,902,326 and PCT
Publication No. WO2008/061135, all of which are assigned to the
assignee of this application, the entire disclosures of which are
incorporated herein by reference.
[0088] As discussed above with respect to FIG. 1, system 2 may also
include one or more sense electrodes 17 carried on one or more
implantable leads 12A, 12B to permit implantable stimulator 4 to
sense electrical signals from patient 6. Implantable leads 12A, 12B
may be carried on optical fiber bundle 10 and on each individual
optical fiber 11. In this way, optical fiber bundle 10 and optical
fibers 11 act as leads for carrying sense electrodes 17. In another
example, one or more optical fibers 11 and one or more conducting
leads 12 may be carried together as a unitary lead that contains
both the one or more optical fibers 11 and the conducting lead 12.
In one example, a unitary lead may contain both an optical fiber
and a conducting lead, wherein sense electrodes are placed on a
lead sheath that covers the optical fiber. In this example, the
electrical conductors could be axial, running along the length of
the lead with the optical fiber extending alongside the electrical
conductor, or with the optical fiber being wound in a coil around
the one or more electrical conductors, or with the electrical
conductor being embedded within the optical fiber. In another
example, the one or more electrical conductors may be wound in a
coil, with the optical fiber extending inside the center of the
coil, or with the optical fiber wound in a generally coaxial coil.
In another example, rather than optical fibers, system 2 may
include a lead that carries one or more electrical conductors that
provide power to one or more light sources, such as an LED or a
laser, located at the distal end of the lead. The lead may also
carry one or more sense electrodes that are coupled to one or more
of the electrical conductors carried by the lead. The conductors
coupled to a light source or to a sense electrode may be arranged
in any of the configurations described above with respect to
electrical conductors or optical fibers above.
[0089] FIG. 1 further depicts a housing electrode 13 that may be
used in conjunction with or in place of sense electrodes 17. In
some cases, housing 14 may include multiple housing electrodes.
Housing electrode 13 may be formed integrally with an outer surface
of hermetically-sealed housing 14 of implantable stimulator 4, also
referred to in this disclosure as implantable medical device (IMD)
4, or otherwise coupled to housing 14. Housing electrode 13 may be
used to form unipolar electrode combinations with one or more
electrodes carried on leads 12A, 12B to sense bioelectric
potentials. Alternatively, electrodes carried on leads 12A, 12B may
be used in bipolar or multipolar combinations to sense bioelectric
potentials. To sense bioelectric potentials in proximity to the
tissue illuminated by the optical stimulation, at least one of the
electrodes in a given electrode combination should be positioned
near the distal end of an optical fiber 11A, 11B.
[0090] A proximal end of fiber bundle 10 may be both optically and
mechanically coupled to header 8 on implantable stimulator 4 either
directly or indirectly via an optical extension. Alternatively,
fiber bundle 10 may be optically and mechanically coupled to a
window as described above. Optical fibers 11 permit passage of
light energy along the body of optical fibers 11 to connect the
distal ends of fibers 11 to a light source in implantable
stimulator 4. Fiber bundle 10 traverses from the implant site of
implantable stimulator 4 along the neck of patient 6 to cranium 18
of patient 6 to access brain 16. Optical fibers 11A and 11B may be
implanted within the right and left hemispheres, respectively, in
order to deliver optical stimulation to one or more regions of
brain 16, which may be selected based on the patient condition or
disorder. Alternatively, a single optical fiber 11 may be implanted
at a specific treatment point within brain 16, or multiple optical
fibers 11A, 11B may each be directed at the specific treatment
target site, wherein the treatment target site may be selected
based on the patient condition or disorder.
[0091] In the example of FIG. 1, implantable stimulator 4 may
deliver, for example, deep brain stimulation (DBS) or cortical
stimulation (CS) therapy to patient 6 via the optical fibers 11 to
treat any of a variety of neurological disorders or diseases.
Example neurological disorders may include depression, dementia,
obsessive-compulsive disorder and movement disorders, such as
Parkinson's disease, spasticity, epilepsy, and dystonia. DBS also
may be useful for treating other patient conditions, such as
migraines and obesity. However, the disclosure is not limited to
the configuration of fiber bundle 10 or optical fibers 11 shown in
FIG. 1, or to the delivery of DBS or CS therapy.
[0092] Optical fibers 11 and lead segments 12A, 12B, if used, may
be implanted within a desired location of brain 16 through
respective holes in cranium 18. Optical fibers 11 may be placed at
any location within brain 16 such that the emitted light 15 is
capable of providing optical stimulation to targeted tissue during
treatment. Example locations for optical fibers 11 within brain 16
may include the pedunculopontine nucleus (PPN), thalamus, basal
ganglia structures (e.g., globus pallidus, substantia nigra,
subthalmic nucleus), zona inserta, fiber tracts, lenticular
fasciculus (and branches thereof), ansa lenticularis, and/or the
Field of Forel (thalamic fasciculus). In the case of migraines,
optical fibers 11 may be implanted to provide stimulation to the
visual cortex of brain 16 in order to reduce or eliminate migraine
headaches afflicting patient 6. However, the target therapy
delivery site may depend upon the patient condition or disorder
being treated.
[0093] The sense electrodes 17 of lead segments 12A, 12B are shown
as ring electrodes. Ring electrodes are commonly used in DBS
applications because they are simple to program and are capable of
sensing an electrical field to any tissue proximate to lead
segments 12A, 12B. In other implementations, sense electrodes 17 of
lead segments 12A, 12B may have different configurations. For
example, the electrodes of lead segments 12A, 12B may have a
complex electrode array geometry that is capable of sensing
bioelectric potentials in a directional or localized manner.
[0094] Therapy system 2 also may include a clinician programmer 20
and/or a patient programmer 22. Clinician programmer 20 may be a
handheld computing device that permits a clinician to program
stimulation therapy for patient 6 via a user interface, e.g., using
input keys and a display. For example, using clinician programmer
20, the clinician may specify stimulation parameters, i.e., create
programs, for use in delivery of stimulation therapy. Clinician
programmer 20 may support telemetry (e.g., radio frequency (RF)
telemetry) with implantable stimulator 4 to download programs and,
optionally, upload operational or physiological data stored by
implantable stimulator 4. In this manner, the clinician may
periodically interrogate implantable stimulator 4 to evaluate
efficacy and, if necessary, modify the programs or create new
programs. In some examples, clinician programmer 20 transmits
programs to patient programmer 22 in addition to or instead of
implantable stimulator 4.
[0095] Like clinician programmer 20, patient programmer 22 may be a
handheld computing device. Patient programmer 22 may also include a
display and input keys to allow patient 6 to interact with patient
programmer 22 and implantable stimulator 4. In this manner, patient
programmer 22 provides patient 6 with a user interface for control
of the stimulation therapy delivered by implantable stimulator 4.
For example, patient 6 may use patient programmer 22 to start, stop
or adjust optical stimulation therapy. In particular, patient
programmer 22 may permit patient 6 to adjust stimulation parameters
of a program such as duration of treatment, optical intensity or
amplitude, pulse width, pulse frequency, burst length, and burst
rate. Patient 6 may also select a program, e.g., from among a
plurality of stored programs, as the present program to control
delivery of stimulation by implantable stimulator 4.
[0096] In some examples, implantable stimulator 4 delivers
stimulation according to a group of programs at a given time. Each
program of such a program group may include respective values for
each of a plurality of therapy parameters, such as respective
values for each of optical intensity or amplitude, pulse width,
pulse shape, pulse rate, burst frequency, burst rate, burst width,
and optical fiber configuration (e.g., the combination of optical
fibers used and with what light intensity and wavelengths).
Implantable stimulator 4 may interleave pulses or other signals
according to the different programs of a program group, e.g., cycle
through the programs, to simultaneously treat different symptoms or
different body regions, or provide a combined therapeutic effect.
In such examples, clinician programmer 20 may be used to create
programs, and assemble the programs into program groups. Patient
programmer 22 may be used to adjust stimulation parameters of one
or more programs of a program group, and select a program group,
e.g., from among a plurality of stored program groups, as the
current program group to control delivery of stimulation by
implantable stimulator 4.
[0097] Implantable stimulator 4, clinician programmer 20, and
patient programmer 22 may communicate via cables or a wireless
communication, as shown in FIG. 1. Clinician programmer 20 and
patient programmer 22 may, for example, communicate via wireless
communication with implantable stimulator 4 using RF telemetry
techniques known in the art. Clinician programmer 20 and patient
programmer 22 also may communicate with each other using any of a
variety of local wireless communication techniques, such as RF
communication according to the 802.11 or Bluetooth specification
sets, infrared communication, e.g., according to the IrDA standard,
or other standard or proprietary telemetry protocols. Each of
clinician programmer 20 and patient programmer 22 may include a
transceiver to permit bi-directional communication with implantable
stimulator 4.
[0098] FIG. 2 is a conceptual diagram illustrating system 30 that
delivers stimulation therapy to spinal cord 38 of patient 36, also
known as spinal cord stimulation (SCS). Other stimulation systems
may be configured to deliver electrical stimulation to
gastrointestinal organs, pelvic nerves or muscle, peripheral
nerves, or other stimulation sites. In the example of FIG. 2,
system 30 delivers optical stimulation therapy from implantable
stimulator 34 to spinal cord 38 via one or more optical fibers 32A
and 32B (collectively "optical fibers 32"). System 30 and, more
particularly, implantable stimulator 34 may operate in a manner
similar to implantable stimulator 4 (FIG. 1). That is, in one
example, implantable stimulator 34 delivers controlled optical
stimulation pulses or waveforms to patient 36 via one or more
regulated stimulation optical fibers 32.
[0099] In the example of FIG. 2, the distal ends of optical fibers
32 are placed adjacent to the target tissue of spinal cord 38 such
that light is emitted from the distal ends into the target tissue.
The proximal ends of optical fibers 32 may be both optically and
mechanically coupled to implantable stimulator 34 either directly
or indirectly via a fiber extension and header. Alternatively, in
some examples, optical fibers 32 may be implanted and coupled to an
external stimulator, e.g., through a percutaneous port.
[0100] Stimulator 34 may be implanted in patient 36 at a location
minimally noticeable to the patient. For SCS, stimulator 34 may be
located in the lower abdomen, lower back, buttock or other location
to secure the stimulator. Optical fibers 32 are tunneled from
stimulator 34 through tissue to reach the target tissue adjacent to
spinal cord 38 for optical stimulation delivery. Light is directed
through optical fibers 32 so that the light is emitted from the
distal ends of leads 32 in order to provide optical stimulation
pulses from each optical fiber 32 to the target tissue. The
stimulation pulses may be delivered using various optical fiber
arrangements such as the use of a single optical fiber 32 to
stimulate the target tissue or multiple optical fibers 32 arranged
in a particular pattern around the target tissue. In one example,
optical fibers 32 run along the spinal cord and shine light
generally perpendicular to the axis of the spinal column. In one
example, optical fibers 32 are anchored within or along the spinal
column, such as with stereotactic techniques, to precisely position
optical fibers 32 to provide the desired directionality of light
emitted from optical fibers 32 and to prevent migration of optical
fibers 32 after implantation. Anchoring of optical fibers 32 may
prevent migration of optical fibers 32 during use and may also
allow optical fibers 32 to be subjected to controlled bends to
prevent light leakage from the optical fibers 32. In another
example, optical fibers 32 allow for sharp angles within the small
dimensions of the target tissue, such as in brain 16 or spinal cord
38. In another example, optical fibers are not used, but rather the
light source is implanted at the target tissue at the end of an
electrode, such as implanting a wire that extends from the
stimulator 34 to the target tissue to power an LED to expose the
target tissue to light. In another example, an LED is carried on
the housing of a device that is implanted proximate the target
tissue to expose the target tissue to light, while the device, such
as a microstimulator device, may be connected to an implantable
stimulator that is connected to the device by a wire. In still
another example, an LED within the device housing may deliver light
through a window in the device to target tissue proximate the
window.
[0101] Implantable stimulator 34 delivers stimulation to spinal
cord 38 to reduce the amount of pain perceived by patient 36. As
mentioned above, however, the stimulator may be used with a variety
of different therapies, such as peripheral nerve stimulation (PNS),
peripheral nerve field stimulation (PNFS), deep brain stimulation
(DBS), cortical stimulation (CS), pelvic floor stimulation, gastric
stimulation, and the like. The stimulation delivered by implantable
stimulator 34 may take the form of optical stimulation pulses or
bursts, and may be characterized by controlled light intensity, as
well as programmed pulse widths and pulse rates in the case of
stimulation current pulses or controlled burst widths, burst
frequencies, and burst rates for optical stimulation bursts.
Stimulation may be delivered via selected combinations of optical
fibers emitting light at multiple locations along the target tissue
or at multiple target tissues. Stimulation of spinal cord 38 may,
for example, prevent pain signals from traveling through the spinal
cord and to the brain of the patient. Patient 36 perceives the
interruption of pain signals as a reduction in pain and, therefore,
efficacious therapy.
[0102] With reference to FIG. 2, a user, such as a clinician or
patient 36, may interact with a user interface of external
programmer 40 to program stimulator 34. Programming of stimulator
34 may refer generally to the generation and transfer of commands,
programs, or other information to control the operation of the
stimulator. For example, programmer 40 may transmit programs,
parameter adjustments, program selections, group selections, or
other information to control the operation of stimulator 34, e.g.,
by wireless telemetry. In accordance with this disclosure,
programmer 40 may transmit to the stimulator 34 information
regarding the patient and regarding therapy the patient received
during previous sessions including, for example, images that show
placement of optical fibers 32.
[0103] In some cases, external programmer 40 may be characterized
as a physician or clinician programmer, such as clinician
programmer 20 (FIG. 1), if it is primarily intended for use by a
physician or clinician. In other cases, external programmer 40 may
be characterized as a patient programmer, such as patient
programmer 22 (FIG. 1), if it is primarily intended for use by a
patient. In general, a physician or clinician programmer may
support selection and generation of programs by a clinician for use
by stimulator 34, whereas a patient programmer may support
adjustment and selection of such programs by a patient during
ordinary use.
[0104] Whether programmer 40 is configured for clinician or patient
use, programmer 40 may communicate to implantable stimulator 34 or
any other computing device via wireless communication. Programmer
40, for example, may communicate via wireless communication with
implantable stimulator 34 using radio frequency (RF) telemetry
techniques known in the art. Programmer 40 may also communicate
with another programmer or computing device via a wired or wireless
connection using any of a variety of local wireless communication
techniques, such as RF communication according to the 802.11 or
Bluetooth specification sets, infrared communication according to
the IRDA specification set, or other standard or proprietary
telemetry protocols. Programmer 40 may also communicate with
another programming or computing device via exchange of removable
media, such as magnetic or optical disks, or memory cards or
sticks. Further, programmer 40 may communicate with implantable
stimulator 34 and other programming devices via remote telemetry
techniques known in the art, communicating via a local area network
(LAN), wide area network (WAN), public switched telephone network
(PSTN), or cellular telephone network, for example.
[0105] Programming of stimulator 34 may also include graphically
defining a desired stimulation field(s) within zones in one or more
target tissues adjacent to the distal ends of one or more optical
fibers 32, and generating, via a programmer, the optical
stimulation required to create the stimulation field. Programming
of stimulator 34 may also include translating one or more user
input stimulation zones into a set of optical fibers 32 for
delivering optical stimulation therapy to a patient, and a set of
parameters such as pulse amplitudes, pulse widths, and pulse
frequency associated with such optical fibers 32. Programming may
further include manipulating the shape and position of the zone,
including behaviors of the zone while moving and when colliding
with other zones or system interlocks. As the stimulation zone is
sized, moved, or shaped, the programmer may automatically compute
updated optical fiber selections and parameters for delivery of
stimulation indicated by the stimulation zone.
[0106] FIG. 3 is a block diagram illustrating various components of
an example implantable stimulator 34. Although the components shown
in FIG. 3 are described in reference to implantable stimulator 34,
the components may also be included within implantable stimulator 4
shown in FIG. 1 and used within system 2. In the example of FIG. 3,
implantable stimulator 34 includes processor 50, memory 52, power
source 54, telemetry module 56, antenna 57, and an optical
stimulation generator 60 including a light source 63. Implantable
stimulator 34 is also shown in FIG. 3 coupled to one or more
implantable optical fibers 48A-D (collectively "optical fibers
48"). Implantable stimulator 34 may be a multi-channel device in
the sense that it may be configured to include multiple optical
paths (e.g., multiple light sources and optical fibers) that may
deliver different optical stimulation waveforms, some of which may
have different wavelengths. Although four optical fibers are shown
in FIG. 3, more or less optical fibers may be used in different
implementations, such as one, two, five or more optical fibers and
associated light sources may be provided. The optical fibers may be
detachable from a housing associated with implantable stimulator
34, or be fixed to such a housing.
[0107] In other examples, different optical fiber configurations of
three optical fibers, four optical fibers, or more per target
tissue may be provided. In addition, multiple optical fibers may be
provided to a single target tissue site in the form of one or more
optical fiber bundles that may be the same or different from fiber
bundle to fiber bundle. In another example, a set of one or more
optical fibers or fiber bundles may be provided to a first target
tissue site while a second set of one or more optical fibers or
fiber bundles may be provided to a second target tissue site. For
example, a set of one or more optical fibers or fiber bundles may
be directed to the subthalmic nucleus while another set of one or
more optical fibers or fiber bundles may be directed to the
pedunculopontine nucleus such that the combined use of the two sets
of optical fibers may provide closed-loop deep brain stimulation to
treat movement disorders such as Parkinson's disease, spasticity,
epilepsy, and dystonia. In some cases, bioelectric signals may be
sensed by the implanted device to detect onset of seizure, movement
disorder symptoms, or other conditions, and trigger stimulation to
alleviate such symptoms. As an additional example, the optogenetic
stimulation may be applied to support a cell-targeted treatment for
schizophrenia. In another example, two or more sets of optical
fibers or optical fiber bundles may be placed at various epileptic
foci and used for distributed treatment of the epileptic foci. In
some examples, one or more optical fibers or fiber bundles may be
selectively turned on or off in order to manage power.
[0108] Memory 52 may store instructions for execution by processor
50, optical stimulation therapy data, sensor data, and/or other
information regarding therapy for patient 6. Processor 50 may
control optical stimulation generator 60 to deliver stimulation
according to a selected one or more of a plurality of programs or
program groups stored in memory 52. Memory 52 may include any
electronic data storage media, such as random access memory (RAM),
read-only memory (ROM), electronically-erasable programmable ROM
(EEPROM), flash memory, or the like. Memory 52 may store program
instructions that, when executed by processor 50, cause the
processor to perform various functions ascribed to processor 50 and
implantable stimulator 4 in this disclosure.
[0109] In accordance with the techniques described in this
disclosure, information stored on the memory 52 may include
information regarding therapy that the patient 6 had previously
received. Storing such information may be useful for subsequent
treatments such that, for example, a clinician may retrieve the
stored information to determine the therapy applied to the patient
during his/her last visit, in accordance with this disclosure.
[0110] Processor 50 may include one or more microprocessors,
digital signal processors (DSPs), application-specific integrated
circuits (ASICs), field-programmable gate arrays (FPGAs), or other
digital logic circuitry. Processor 50 controls operation of
implantable stimulator 34, e.g., controls stimulation generator 60
to deliver stimulation therapy according to a selected program or
group of programs retrieved from memory 52. For example, processor
50 may control stimulation generator 60 to deliver optical signals,
e.g., as stimulation pulses, with intensities, wavelengths, pulse
widths (if applicable), and rates specified by one or more
stimulation programs. Processor 50 may also control optical
stimulation generator 60 to selectively deliver the stimulation via
subsets of optical fibers 48, also referred to as optical fiber
combinations, and with stimulation specified by one or more
programs. Different optical fibers may be directed to different
target tissue sites.
[0111] Upon selection of a particular program group, processor 50
may control optical stimulation generator 60 to deliver optical
stimulation according to the programs in the groups, e.g.,
simultaneously or on a time-interleaved basis. A group may include
a single program or multiple programs. As mentioned previously,
each program may specify a set of stimulation parameters, such as
amplitude, pulse width and pulse rate, if applicable. In addition,
each program may specify a particular optical fiber combination for
delivery of optical stimulation. The optical fiber combination may
specify particular optical fibers in a single array or multiple
arrays.
[0112] Optical stimulation generator 60 is optically coupled to
optical fibers 48A-48D. Optical stimulation generator 60 may
include stimulation generation circuitry to generate stimulation
pulses and circuitry for switching stimulation across different
optical fiber combinations, e.g., in response to control by
processor 50. Optical stimulation generator 60 produces an optical
stimulation signal in accordance with a program based on control
signals from processor 50. Optical stimulation generator 60 may
also include one or more light sources 63, such as one or more
lasers or one or more light-emitting diodes (LEDs) that produce
optical light within stimulator 34 that is then transmitted along
optical fibers 48 to provide optical stimulation treatment to a
target tissue. Alternatively, light source 63 may be separate from
optical stimulation generator 60 such that optical stimulation
generator 60 provides the signal that powers light source 63.
[0113] As described above, stimulator 34 delivers optical
stimulation to the target neurons to activate one or more opsins
that have been expressed in the target neurons. In one example, as
described above, a first opsin is activated by a first wavelength
of light so that the target neurons become permeable to cations to
initiate neuronal spikes and fire the target neuron and a second
opsin is activated by a second wavelength of light to deactivate or
inhibit the target neurons. In this example, stimulator 34 may
provide for a useful chronic device enabling continuous therapy by
providing light at both the first wavelength and the second
wavelength on an alternating or selective basis in order to provide
for both selective activation and inhibition of the target neurons.
For example, if channelrhodopsin-2 is used as the activation opsin
and halorhodopsin is used as the inhibition opsin, then optical
stimulation generator 60, and particularly light source 63, may be
configured to provide a first wavelength of between about 420 nm
and about 475 nm, such as about 450 nm, to activate the
channelrhodopsin-2 and activate the target neurons and a second
wavelength of between about 510 nm and about 580 nm, such as about
535 nm, to activate the halorhodopsin and inhibit the target
neurons. In another example, optical stimulation generator 60 may
be configured to mimic more classical stimulation paradigms, such
as by activating the standard, wild-type, channelrhodopsin-2
channel that acts as a light-activated transconductor, wherein the
standard channelrhodopsin-2 channel may be activated by brief
pulses of light with a wavelength of about 450 nm with an intensity
of between about 8 mW/mm.sup.2 and about 12 mW/mm.sup.2 and a duty
cycle of about 1% and a pulse frequency of between about 100 Hz and
about 120 Hz, such as a 100 .mu.s pulse every 10 ms. In addition,
because light scatters in tissue and the required voxel size for
therapy may not be well established, optical stimulation generator
60 may be designed to be scaleable with the ability to incorporate
multiple stimulation circuits and outputs to increase the volume of
activation by using multiple pathways. In another example, one or
more lenses may be used to focus or dissipate the light, as desired
to provide more intense or scattered optical stimulation in the
target tissue. In one example, a lens may be created at a distal
end of an optical fiber by modifying or distorting the distal end
to form a lens that may focus or dissipate light once it reaches
the distal end.
[0114] Optical stimulation generator 60 may provide for the two
wavelengths of stimulation light by having two light sources, one
for each wavelength, such as a LED dedicated to each wavelength of
light that feed into optical fibers 48 to deliver each wavelength
of light to the target neurons depending on which LED is activated
by optical stimulation generator 60 as controlled by processor 50.
Alternatively, a single light source 63 that is capable of emitting
both wavelengths may be used, such as a tunable LED or other
tunable light source, wherein a particular wavelength is selected
based on a treatment program run by processor 50 that causes
optical stimulation generator 60 to control light source 63 to emit
the selected wavelength, such as by tuning the tunable LED or other
tunable light source to the selected wavelength.
[0115] Optical stimulation generator 60 may also control, under the
direction of processor 50, several other parameters with respect to
the optical stimulation of the target tissue, such as the intensity
of light emitted to stimulate the target tissue, the number of
pulses of light to be emitted, the pulse width, the frequency of
pulses, and the pattern of pulses, including burst patterns wherein
optical stimulation generator 60 may control burst width, burst
frequency, the number of pulses per burst, and the number of
bursts. In one example, optical stimulation generator 60 is capable
of delivering light with an intensity of between about 1
mW/mm.sup.2 and about 5 mW/mm.sup.2. When light pulses are used as
part of a stimulation program, optical stimulation generator 60
may, for example, produce pulses with a pulse width of between
about 100 .mu.s and about 15 ms, such as pulses with a pulse width
of about 10 ms, and with a pulse frequency of between about 0.1 Hz
and about 1 kHz, such as a frequency of about 0.2 Hz. In one
example, optical stimulation generator 60 may drive optical
stimulation with programmable modulation patterns that mimic
existing patterns used in electrical stimulation for deep brain
stimulation (DBS), and also allow for novel patterns that leverage
the capabilities of the inhibitory optical transducer in the cell
membranes.
[0116] In one example, shown in FIG. 10, optical stimulation
generator 60 includes a stimulation engine circuit 116. In one
example, optical stimulation engine 116 may include the capability
to titrate pulse frequency and pulse width controlled via an
external telemetry command and may provide programmable optical
pulse trains to excite the transduction molecules. In one example,
a constant current of 100nA may be used to drive a reference
current generator 121, which may consist of an R-2R-based
digital-to-analog converter (DAC) 122 to generate an 8-bit
reference current 124 with a maximum value of 5 .mu.A. In this
example, the reference current 124 is then amplified in a current
output stage 126 with a gain set by the ratio of R.sub.O and
R.sub.Ref, which may be between 10 and 100, such as 40. With 512
current output stages 128, the optical stimulation circuit 116 can
drive two optical outputs 130A, 130B for activation and inhibition
with separate sources, each delivering a maximum current of 51.2 mA
with 10 bit accuracy. In the example shown in FIG. 10, optical
outputs 130A and 130B are shown as LEDs 132A and 132B, one for the
activation wavelength and one for the inhibition wavelength of the
opsins of the target neurons. The power requirements for optical
components such as a LED or laser light source are generally larger
than is required for conventional electrical stimulation. Moreover,
the power required for optical components may be larger than that
which can typically be provided by an implantable power source,
such as a battery. Therefore, in one example, optical stimulation
generator 60 includes a power management system within stimulation
engine circuit 116 to allow power source 54 to provide power
conditioning to boost the power provided by power source 54 to a
level sufficient to power optical stimulation. Power management may
be provided by the use of low overhead drivers to keep power
dissipation low, and by an ability to modulate light intensity and
its patterns as needed. In one example, a sense-resistor-based
architecture may be used for current output stage 128 to eliminate
the need to keep any output transistors 134 in saturation, reducing
voltage headroom requirements to improve efficiency. A
switched-capacitor 136 feedback may be used in current output stage
128 for low power consumption. The example optical stimulation
circuit 116 shown in FIG. 10 may allow the stimulation pulse rate
to be tuned from about 0.15 Hz to about 1 kHz and may allow tuning
of the pulse width from about 100 .mu.s to about 12 ms. Thus,
optical stimulation generator 60 may be configurable, e.g., based
on signals from processor 50, to store a desired voltage for
delivery of optical stimulation light at an intensity specified by
a program, and optical stimulation generator 60 may be configurable
to deliver stimulation pulses with controlled pulse widths and
pulse frequencies based on signals from processor 50.
[0117] Referring again to FIG. 3, telemetry module 56 may include a
radio frequency (RF) transceiver to permit bi-directional
communication between implantable stimulator 34 and each of
clinician programmer 20 and patient programmer 22. Telemetry module
56 may include an antenna 57 that may take on a variety of forms.
For example, antenna 57 may be formed by a conductive coil or wire
embedded in a housing associated with medical device 4.
Alternatively, antenna 57 may be mounted on a circuit board
carrying other components of implantable stimulator 34 or take the
form of a circuit trace on the circuit board. In this way,
telemetry module 56 may permit communication with clinician
programmer 20 and patient programmer 22 in FIG. 1 or external
programmer 40 in FIG. 2, to receive, for example, new programs or
program groups, or adjustments to programs or program groups.
Telemetry module 56 may also permit communication with clinician
programmer 20 to receive, for example, an image captured by the
programmer of the lead placement along with information regarding
the captured image and the therapy received by the patient during
previous sessions, in accordance with this disclosure. Telemetry
module 56 may also communicate information regarding previous
therapy sessions that have been stored in memory 52, to an external
programmer during a subsequent therapy session; the information
regarding a previous therapy session may have been imported by a
programmer used in the previous session.
[0118] Power source 54 may be a non-rechargeable primary cell
battery or a rechargeable battery and may be coupled to power
circuitry. However, the disclosure is not limited to examples in
which the power source is a battery. In another example, power
source 54 may comprise a supercapacitor. In some examples, power
source 54 may be rechargeable via induction or ultrasonic energy
transmission, and include an appropriate circuit for recovering
transcutaneously received energy. For example, power source 54 may
be coupled to a secondary coil and a rectifier circuit for
inductive energy transfer. In additional examples, power source 54
may include a small rechargeable circuit and a power generation
circuit to produce the operating power. Recharging may be
accomplished through proximal inductive interaction between an
external charger and an inductive charging coil within stimulator
4. In some examples, power requirements may be small enough to
allow stimulator 4 to utilize patient motion at least in part and
implement a kinetic energy-scavenging device to trickle charge a
rechargeable battery. A voltage regulator may generate one or more
regulated voltages using the battery power.
[0119] In one example, telemetry and power management may be
controlled through a circuit 120, shown schematically in FIG. 11.
Telemetry and power management circuit 120 provides for a
bidirectional telemetry and RF-charging system. In one example, the
telemetry carrier frequency is 175 kHz to align with a common ISM
band and uses OOK at 4.4 kbps to stay within regulatory limits. A
telemetry decoder 142 may use a chopper amplifier circuit, such as
the chopper amplifier circuit described in Denison et al., "A 2
.mu.W 100 nV/rtHz Chopper-Stabilized Instrumentation Amplifier for
Chronic Measurement of Neural Field Potentials," IEEE Journal of
Solid-State Circuits, vol. 43, pp. 2934-45 (2007), or as described
in commonly assigned U.S. Patent Application Publication No.
2008/0269841, to Grevious et al., entitled "Chopper Mixer Telemetry
Circuit," or as described in commonly assigned U.S. Patent
Application Publication No. 2008/01800278, to Denison, entitled
"Chopper-stabilized Instrumentation Amplifier for Wireless
Telemetry," the entire disclosure of each of which is incorporated
herein by reference, which may be configured as a combined down
mixer-amplifier. An uplink 146 may be an H-bridge driver. One or
more telemetry capacitors 148 may provide a tuning range of 50-130
kHz.
[0120] The system may include a temperature sensor, such as
temperature sensor 124 shown in FIG. 9, to monitor the temperature
at stimulator 34 or proximate to stimulator 34 during optical
stimulation and recharge. Temperature sensor 124 may be used to
adjust light delivery to the target tissue based on the temperature
sensed by temperature sensor 124. For example, temperature sensor
124 may be used to ensure that the peak temperature is constrained
to under a 2.degree. C. increase over nominal body temperature per
FDA guidelines, which can be a concern for driving less efficient
opsin channels. In one example, if temperature sensor 124
determines a rise in temperature above a permitted temperature,
such as more than about a 2.degree. C. increase over nominal body
temperature, power management circuit 120 will modulate power in
the device to avoid overheating of tissue and send an alert to
processor 50. In another example, processor 50 may cease optical
stimulation and, in some examples, switch to electrical stimulation
to mitigate the risk of overheating. In another example, adjusting
the delivery of light from light source 63 may comprise one or more
of: adjusting a pulse rate, a pulse width, an amplitude intensity,
or a duty cycle of light delivered from light source 63. Light
source 63 is controlled by microcontroller 118, which may receive
signals from temperature sensor 124, and optical stimulation engine
116. Thus, it will be understood that any of the embodiments that
provide optical stimulation may also deliver electrical
stimulation. Further examples of sensing the temperature at or
proximate the optical stimulation device are provided in the
co-pending application entitled "Optical Stimulation Therapy,"
having the Attorney Docket No. "1023-918US01/P0035812.02," filed on
the same date as the present application, which is assigned to the
same assignee as the present application, the entire disclosure of
which is incorporated herein by reference.
[0121] FIG. 4 is a block diagram illustrating various components of
another example implantable stimulator 34. Like the implantable
stimulator 34 shown in FIG. 3, the example of FIG. 4 includes an
optical stimulation generator 60, a processor 50, memory 52, a
telemetry module 56, and a power source 54 which have the same
general configurations as described above for the example of FIG.
3. The example stimulator 34 of FIG. 4 also includes sensing
circuitry 65 electrically coupled to one or more leads 49A, 49B
(collectively referred to as "leads 49") that each carry one or
more sense electrodes, such as sense electrodes 17 shown in FIG. 1.
Sensing circuitry 65 receives electrical signals from the sense
electrodes along leads 49 to provide for sensing of bioelectric
activity within the patient before, during, and after optical
stimulation controlled by optical stimulation generator 60.
[0122] FIG. 7 is a functional block diagram illustrating various
components of an external programmer 40 for an implantable
stimulator 14. Although the components shown in FIG. 4 are
described in reference to external programmer 40, the components
may also be included within clinician programmer 20 or patient
programmer 22 shown in FIG. 1. As shown in FIG. 7, external
programmer 40 includes processor 53, memory 55, telemetry module
67, user interface 59, and power source 61. In general, processor
53 controls user interface 59, stores and retrieves data to and
from memory 55, and controls transmission of data with implantable
stimulator 34 through telemetry module 67. Processor 53 may take
the form of one or more microprocessors, controllers, DSPs, ASICS,
FPGAs, or equivalent discrete or integrated logic circuitry. The
functions attributed to processor 53 herein may be embodied as
software, firmware, hardware or any combination thereof.
[0123] Memory 55 may store instructions that cause processor 53 to
provide various aspects of the functionality ascribed to external
programmer 40 herein. Memory 55 may include any fixed or removable
magnetic, optical, or electrical media, such as RAM, ROM, CD-ROM,
magnetic disks, EEPROM, or the like. Memory 55 may also include a
removable memory portion that may be used to provide memory updates
or increases in memory capacities. A removable memory may also
allow patient data to be easily transferred to another computing
device, or to be removed before programmer 40 is used to program
therapy for another patient. Memory 55 may also store information
that controls operation of implantable stimulator 4, such as
therapy delivery values.
[0124] A clinician or patient 36 interacts with user interface 59
in order to, for example, manually select, change or modify
programs, adjust optical amplitude, pulse width, pulse rate, and
other stimulation parameters, provide efficacy feedback, or view
stimulation data. User interface 59 may include a screen and one or
more input buttons that allow external programmer 40 to receive
input from a user. The screen may be a liquid crystal display
(LCD), plasma display, dot matrix display, or touch screen. The
input buttons may include a touch pad, increase and decrease
buttons, emergency shut off button, and other input media needed to
control the stimulation therapy.
[0125] Telemetry module 67 allows the transfer of data to and from
stimulator 34. Telemetry module 67 may communicate automatically
with stimulator 34 at a scheduled time or when the telemetry module
detects the proximity of the stimulator. Alternatively, telemetry
module 67 may communicate with stimulator 34 when signaled by a
user through user interface 59. To support RF communication,
telemetry module 67 may include appropriate electronic components,
such as amplifiers, filters, mixers, encoders, decoders, and the
like.
[0126] Programmer 40 may communicate wirelessly with implantable
stimulator 34 using, for example, RF communication or proximal
inductive interaction. This wireless communication is possible
through the use of telemetry module 67 which may be coupled to an
internal antenna or an external antenna. Telemetry module 67 may be
similar to telemetry module 57 of implantable stimulator 34.
[0127] Programmer 40 may also be configured to communicate with
another computing device via wireless communication techniques, or
direct communication through a wired, e.g., network, connection.
Examples of local wireless communication techniques that may be
employed to facilitate communication between programmer 24 and
another computing device include RF communication based on the
802.11 or Bluetooth specification sets, infrared communication,
e.g., based on the IrDA standard.
[0128] Power source 61 delivers operating power to the components
of programmer 40. Power source 61 may be a rechargeable battery,
such as a lithium ion or nickel metal hydride battery. Other
rechargeable or conventional batteries may also be used. In some
cases, external programmer 40 may be used when coupled to an
alternating current (AC) outlet, i.e., AC line power, either
directly or via an AC/DC adapter. Power source 61 may include
circuitry to monitor power remaining within a battery. In this
manner, user interface 59 may provide a current battery level
indicator or low battery level indicator when the battery needs to
be replaced or recharged. In some cases, power source 61 may be
capable of estimating the remaining time of operation using the
current battery.
[0129] In other examples, rather than being a handheld computing
device or a dedicated computing device, programmer 40 may be a
larger workstation or a separate application within another
multi-function device. For example, the multi-function device may
be a cellular phone, personal computer, laptop, workstation
computer, or personal digital assistant that can be configured with
an application to simulate programmer 40. Alternatively, a notebook
computer, tablet computer, or other personal computer may enter an
application to become programmer 40 with a wireless adapter
connected to the personal computer for communicating with
stimulator 34.
[0130] A conceptual diagram illustrating another example therapy
system 70 is shown in FIG. 5. Like systems 2 and 30 described
above, therapy system 70 is used to deliver optical stimulation
therapy to patient 6. Therapy system 70 includes an implantable
medical device (IMD) 72 that delivers optical stimulation to
patient 6 via one or more implantable optical fibers 11. The
optical stimulation provided by IMD 72 is essentially the same as
described above for simulator 4 in FIG. 1 and stimulator 34 in FIG.
2. IMD 72 also may provide the ability to deliver a therapeutic
agent 73 to a target site within patient 6. An example therapeutic
agent that IMD 72 may be configured to deliver is a gene therapy
agent that provides targeted delivery of a light-sensitive ion
channel protein, also referred to as an "opsin," to specific target
cells, such as neurons within brain 16 or the spinal cord of
patient 6, such as by contacting the target cells with a vector,
such as a lentivirus or a retrovirus, comprising a nucleic acid
sequence that codes for the opsin so that the target cells express
the opsin.
[0131] In the example of FIG. 5, the therapeutic agent is a
therapeutic fluid, which IMD 72 delivers to patient 6 through one
or more catheters 74 coupled to IMD 72 that are implanted so that a
distal end of catheter 74 is located proximate to the target cells.
Stereotactic techniques or other positioning techniques may be used
to precisely position fluid delivery catheters and/or optical
fibers with respect to target tissue sites and to maintain the
precise positioning throughout use. In some examples, after
positioning, one or more fluid delivery catheters and/or optical
fibers may be held precisely in place using fixation techniques or
mechanisms such as those similar to the Medtronic StimLoc.TM. burr
hole cover, manufactured by Medtronic, Inc., of Minneapolis, Minn.
In some examples, the optical stimulation generator, i.e.,
including a light source, controller, power source, and telemetry
circuitry, could be formed as a microstimulator that is
structurally mounted on or integrated with a burr hole cover, such
as a StimLoc.TM. burr hole cover. In this case, the optical fiber
would run only from the skull to deep brain structures, instead of
running from an implant pocket, such as an implant pocket near the
clavicle. For this example, in some cases, the microstimulator
device can be anchored to the skull using one or more bone
morphogenetic proteins (BMPs), which is a material used in spine
and biologics procedures to fuse cervical or spinal discs.
[0132] In one example, one or more catheters 74 are provided to
deliver the therapeutic agent 73 at or near the same location
within the target tissue that is exposed to light 15 so that the
therapeutic agent will promote expression of opsin by the target
tissue at the same point where the target tissue will be exposed to
optical stimulation. Catheters 74 could be side by side with
optical fibers 11, as shown in FIG. 5, or the optical fibers and
fluid delivery conduits may be combined into a common unitary lead,
such as within separate lumens within the unitary lead with a fluid
conduit in side-by-side arrangement with an optical fiber or in a
coaxial arrangement with the optical fiber being within the fluid
conduit or vice versa. In one example (not shown), the optical
fiber that delivers light stimulation to the target tissue may be a
fiber with a hollow core so that light is passed through the outer
fiber portion while the therapeutic agent is passed through the
hollow core. In this case, the fiber may have an annular
cross-section. In yet another example, a conduit may be provided
that delivers the therapeutic agent to the target tissue while the
optical fiber is threaded through the conduit such that the
therapeutic agent is delivered in the annular region between the
outer diameter of the optical fiber and the inner wall of the lead
body.
[0133] Catheter 74 can comprise a unitary catheter or a plurality
of catheter segments connected together to form an overall catheter
length. An external programmer, such as clinician programmer 20 or
patient programmer 22 or the external programmer 40 shown in FIG.
7, is configured to wirelessly communicate with IMD 72 as needed,
such as to provide or retrieve therapy information or control
aspects of therapy delivery (e.g., modify the therapy parameters
such as rate or timing of delivery, turn IMD 72 on or off, and so
forth) from IMD 72 to patient 6.
[0134] IMD 72 may be implanted within a subcutaneous pocket
relatively close to the therapy delivery site. For example, in the
example shown in FIG. 5, IMD 72 is implanted within a clavicle
region of patient 6 so that IMD 72 may deliver the therapeutic
agent to brain 16 of patient 6. In other examples, IMD 72 may be
implanted within other suitable sites within patient 6, which may
depend, for example, on the target site within patient 6 for the
delivery of the therapeutic agent, such as within the abdomen for
delivery of the therapeutic agent to the spinal cord of patient. In
still other examples, IMD 72 may be external to patient 6 with a
percutaneous catheter connected between IMD 72 and the target
delivery site within patient 6.
[0135] Catheter 74 may be coupled to IMD 72 either directly or with
the aid of a catheter extension (not shown in FIG. 5). In the
example shown in FIG. 5, catheter 74 traverses from the implant
site of IMD 72 to one or more target sites. Catheter 74 is
positioned such that one or more fluid delivery outlets (not shown
in FIG. 5) of catheter 74 are proximate to the target sites within
patient 6. In the example of FIG. 5, IMD 72 delivers a therapeutic
agent through catheter 74 to target sites within brain 16. IMD 72
may be configured for intrathecal delivery into the intrathecal
space, as well as epidural delivery into the epidural space, both
of which surround the spinal cord. The epidural space (also known
as "extradural space" or "peridural space") is the space within the
spinal canal (formed by the surrounding vertebrae) lying outside
the dura mater, which encloses the arachnoid mater, subarachnoid
space, the cerebrospinal fluid, and spinal cord. The intrathecal
space is within the subarachnoid space, which is further inward
past the epidural space and dura mater and through the theca.
[0136] Although the target site shown in FIG. 5 is within brain 16
of patient 6, other applications of therapy system 70 include
alternative target delivery sites. The target delivery site in
other applications of therapy system 70 can be located within
patient 6 proximate to, e.g., sacral nerves (e.g., the S2, S3, or
S4 sacral nerves), the spinal cord, or any other suitable nerve,
organ, muscle or muscle group in patient 6, which may be selected
based on, for example, a patient condition. In one such
application, therapy system 70 may be used to deliver a therapeutic
agent to tissue proximate to a pudendal nerve, a perineal nerve or
other areas of the nervous system, in which cases, catheter 74
would be implanted and substantially fixed proximate to the
respective nerve. As another example delivery site, catheter 74 may
be positioned to deliver a therapeutic agent to a deep brain site
or within the heart (e.g., intraventricular delivery of the agent)
or blood vessels. Delivery of a therapeutic agent within brain 16
may help manage any number of disorders or diseases including,
e.g., chronic pain, diabetes, depression or other mood disorders,
dementia, obsessive-compulsive disorder, migraines, obesity, and
movement disorders, such as Parkinson's disease, spasticity, and
epilepsy. In one example, the target site to which therapeutic
agent is delivered via catheter 74 is proximate to the site that is
stimulated by light 15 from optical fibers 11 so that the
therapeutic agent 73 will modify the target cells that are desired
to be stimulated by light 15. In one example, described in more
detail below, the therapeutic agent is a gene therapy fluid that
modifies neurons within brain 16 to form opsins that are sensitive
to the wavelength of light that is emitted by optical fibers
11.
[0137] In one example, IMD 72 can deliver one or more therapeutic
agents to patient 6 according to one or more dosing programs that
set forth different therapy parameters, such as a therapy schedule
specifying programmed doses, dose rates for the programmed doses,
and specific times to deliver the programmed doses. The dosing
programs may be a part of a program group for therapy, where the
group includes a plurality of dosing programs and/or therapy
schedules. In some examples, IMD 72 may be configured to deliver a
therapeutic agent to patient 6 according to different therapy
schedules on a selective basis. IMD 72 may include a memory to
store one or more therapy programs, instructions defining the
extent to which patient 6 may adjust therapy parameters, switch
between dosing programs, or undertake other therapy adjustments.
Patient 6 or a clinician may select and/or generate additional
dosing programs for use by IMD 72 via an external programmer at any
time during therapy or as designated by the clinician.
[0138] In some examples, a single catheter 74 or multiple catheters
74 may be coupled to IMD 72 to target the same or different tissue
or nerve sites within patient 6. Thus, although two catheters 74
are shown in FIG. 5, in other examples, system 70 may include a
single catheter, or more than two catheters, or the single or
multiple catheters 74 may define multiple lumens for delivering
different therapeutic agents to patient 6 or for delivering a
therapeutic agent to different tissue sites within patient 6.
Accordingly, in some examples, IMD 72 may include a plurality of
reservoirs for storing more than one type of therapeutic agent. In
some examples, IMD 72 may include a single long tube that contains
the therapeutic agent in place of a reservoir. However, for ease of
description, an IMD 72 including a single reservoir is primarily
discussed in this disclosure with reference to the example of FIG.
5.
[0139] The external programmer that is used to program IMD 72, such
as programmer 40 shown in FIG. 7, is an external computing device
that is configured to communicate with IMD 72 by wireless
telemetry. For example, the programmer may be a clinician
programmer that the clinician uses to communicate with IMD 72 and
program therapy delivered by IMD 72. Alternatively, the programmer
may be a patient programmer that allows patient 6 to view and
modify therapy parameters associated with therapy programs. In one
example the external programmer to program IMD 72 is the same
external programmer 40 that is used to program stimulator 2 shown
in FIG. 1 or to program stimulator 34 shown in FIG. 2, 3, or 4. The
clinician programmer may include additional or alternative
programming features than the patient programmer. For example, more
complex or sensitive tasks may only be allowed by the clinician
programmer to prevent patient 6 from making undesired or unsafe
changes to the operation of IMD 72. In one example, programmer 40
to control the delivery of the therapeutic agent through catheter
74 is included as part of clinician programmer 20 or patient
programmer 22 described with respect to FIG. 1 so that the
programmer 20, 22, 40 provides control over the delivery of optical
stimulation therapy and the therapeutic agent.
[0140] When programmer 40 is configured for use by the clinician,
programmer 40 may be used to transmit initial programming
information to IMD 72. This initial information may include
hardware information for system 70 such as the type of catheter 74,
the position of catheter 74 within patient 6, the type and amount,
e.g., by volume of therapeutic agent(s) delivered by IMD 72,
frequency of introduction of therapeutic agent(s), a refill
interval for the therapeutic agent(s), a baseline orientation of at
least a portion of IMD 72 relative to a reference point, therapy
parameters of therapy programs stored within IMD 72 or within
programmer 40, and any other information the clinician desires to
program into IMD 72.
[0141] The clinician uses programmer 40 to program IMD 72 with one
or more therapy programs that define the therapy delivered by IMD
72. During a programming session, the clinician may determine one
or more dosing programs that may provide effective therapy to
patient 6, such as the frequency for the introduction of a gene
therapy agent to a target tissue within patient 6. Patient 6 may
provide feedback to the clinician as to efficacy of a program being
evaluated or desired modifications to the program. Once the
clinician has identified one or more programs that may be
beneficial to patient 6, the patient may continue the evaluation
process and determine which dosing program or therapy schedule best
alleviates the condition of the patient or otherwise provides
efficacious therapy to the patient.
[0142] The dosing program information may set forth therapy
parameters, such as different predetermined dosages of the
therapeutic agent (e.g., a dose amount), the rate of delivery of
the therapeutic agent (e.g., rate of delivery of the fluid), the
maximum acceptable dose, a time interval between successive
supplemental doses, a maximum dose that may be delivered over a
given time interval, and so forth. IMD 72 may include a feature
that prevents dosing the therapeutic agent in a manner inconsistent
with the dosing program. Programmer 40 may assist the clinician in
the creation/identification of dosing programs by providing a
methodical system of identifying potentially beneficial therapy
parameters. In one example, the dosing program may be coordinated
with the optical stimulation provided by stimulator 34. For
example, a dose of the therapeutic agent may be delivered, followed
by a period of inactivity to allow the therapeutic agent to
transfect the cells at the target site, such as for a few hours or
a few days depending on the known time needed for the therapeutic
agent to transfect the neurons, followed by an optical stimulation
program, such as a program of light pulses having a particular
pulse width, pulse frequency, and light wavelength and intensity.
The optical stimulation may be followed up by a second dose of
therapeutic agent. In another example, the dosing program may
include one or more boluses of therapeutic agent delivered at
selected times or intervals.
[0143] In some cases, programmer 40 may also be configured for use
by patient 6. When configured as the patient programmer, programmer
40 may have limited functionality in order to prevent patient 6
from altering critical functions or applications that may be
detrimental to patient 6. In this manner, programmer 40 may only
allow patient 6 to adjust certain therapy parameters or set an
available range for a particular therapy parameter. Programmer 40
may also provide an indication to patient 6 when therapy is being
delivered or when IMD 72 needs to be refilled or when the power
source within programmer 40 or IMD 72 need to be replaced or
recharged.
[0144] Whether programmer 40 is configured for clinician or patient
use, programmer 40 may communicate to IMD 72 or any other computing
device via wireless communication. Programmer 40, for example, may
communicate via wireless communication with IMD 72 using radio
frequency (RF) telemetry techniques. Programmer 40 may also
communicate with another programmer or computing device via a wired
or wireless connection using any of a variety of communication
techniques including, e.g., RF communication according to the
802.11 or Bluetooth specification sets, infrared (IR) communication
according to the IRDA specification set, or other standard or
proprietary telemetry protocols. Programmer 40 may also communicate
with another programming or computing device via exchange of
removable media, such as magnetic or optical disks, or memory cards
or sticks including, e.g., non-volatile memory. Further, programmer
40 may communicate with IMD 72 and another programmer via, e.g., a
local area network (LAN), wide area network (WAN), public switched
telephone network (PSTN), or cellular telephone network, or any
other terrestrial or satellite network appropriate for use with
programmer 40 and IMD 72.
[0145] FIG. 6 is a functional block diagram illustrating components
of an example of IMD 72, which includes a processor 50, memory 52,
telemetry module 56, fluid delivery pump 76, reservoir 78, refill
port 80, internal tubing 82, catheter access port 84, and power
source 54. Processor 50, memory 52, telemetry module 56, and power
source 54 may be the same components as those described above with
respect to FIG. 3. Processor 50 is communicatively connected to
memory 52, telemetry module 56, and fluid delivery pump 76. Fluid
delivery pump 76 is in fluid communication with reservoir 78 and
catheter access port 84 via internal tubing 82. Reservoir 78 is
connected to refill port 80. Catheter access port 84 is connected
to internal tubing 82 and catheter 74. IMD 72 also includes power
source 54, which is configured to deliver operating power to
various components of the IMD.
[0146] During operation of IMD 72, processor 50 controls fluid
delivery pump 76 with the aid of instructions associated with
program information that is stored in memory 52 to deliver a
therapeutic agent to patient 6 via catheter 74. Instructions
executed by processor 50 may, for example, define dosing programs
and/or therapy schedules that specify the amount of a therapeutic
agent that is delivered to a target tissue site within patient 6
from reservoir 78 via catheter 74. The instructions may further
specify the time at which the therapeutic agent will be delivered
and the time interval over which the agent will be delivered. The
amount of the agent and the time over which the agent will be
delivered are a function of, or alternatively determine, the dosage
rate at which the fluid is delivered. The therapy programs may also
include other therapy parameters, such as the frequency of dose
delivery, the type of therapeutic agent delivered if IMD 72 is
configured to deliver more than one type of therapeutic agent, and
so forth. Components described as processors within IMD 72,
external programmer 40, or any other device described in this
disclosure may each comprise one or more processors, such as one or
more microprocessors, digital signal processors (DSPs), application
specific integrated circuits (ASICs), field programmable gate
arrays (FPGAs), programmable logic circuitry, or the like, either
alone or in any suitable combination.
[0147] Upon instruction from processor 50, fluid delivery pump 76
draws fluid from reservoir 78 and pumps the fluid through internal
tubing 82 to catheter 74 through which the fluid is delivered to
patient 6 to effect one or more of the treatments described above.
Internal tubing 82 is a segment of tubing or a series of cavities
within IMD 72 that run from reservoir 78, around or through fluid
delivery pump 76 to catheter access port 84. Fluid delivery pump 76
can be any mechanism that delivers a therapeutic agent in some
metered or other desired flow dosage to the therapy site within
patient 6 from reservoir 78 via implanted catheter 74.
[0148] In one example, fluid delivery pump 76 can be a squeeze pump
that squeezes internal tubing 82 in a controlled manner, e.g., such
as a peristaltic pump, to progressively move fluid from reservoir
78 to the distal end of catheter 74 and then into patient 6
according to parameters specified by a set of program information
stored on memory 52 and executed by processor 50. Fluid delivery
pump 76 can also be an axial pump, a centrifugal pump, a pusher
plate, a piston-driven pump, or other means for moving fluid
through internal tubing 82 and catheter 74. In one particular
example, fluid delivery pump 76 can be an electromechanical pump
that delivers fluid by the application of pressure generated by a
piston that moves in the presence of a varying magnetic field and
that is configured to draw fluid from reservoir 78 and pump the
fluid through internal tubing 82 and catheter 74 to patient 6.
[0149] Periodically, fluid may need to be supplied percutaneously
to reservoir 78 because all of a therapeutic agent has been or will
be delivered to patient 6, or because a clinician wishes to replace
an existing agent with a different agent or similar agent with
different concentrations of therapeutic ingredients. Refill port 80
can therefore comprise a self-sealing membrane to prevent loss of
therapeutic agent delivered to reservoir 78 via refill port 80. For
example, after a percutaneous delivery system, e.g., a hypodermic
needle, penetrates the membrane of refill port 80, the membrane may
seal shut when the needle is removed from refill port 80.
[0150] In another example, shown in FIG. 15, a small pump 180 and
fluid reservoir 182 may be located proximate a distal end 184 of a
delivery device, such as an optical fiber 11, rather than within
IMD 72, as shown schematically in FIG. 15. In one example, optical
fiber 11 and pump 180 are implantable proximate the target tissue
so that light 15 emitted from optical fiber 11 is substantially
aligned with the target tissue adjacent to an output tube 196 of
pump 180. This alignment allows light 15 to be directed to the same
target tissue that is being transfected by the therapeutic agent.
Pump 180 may be carried on another delivery device, such as a
catheter or lead. In one example, pump 180 comprises a small fluid
reservoir 182 containing the therapeutic agent (e.g., transfecting
agent) that is to be delivered to the target tissue. Pump 180 may
be an osmotic pump that utilizes the principles of osmosis to force
fluid from reservoir 182.
[0151] Osmosis is the transfer of a solvent, e.g., water, across a
barrier, generally from an area of lesser solute concentration to
an area of greater solute concentration. In one example, osmotic
pump 180 may be adapted to cause fluid to flow from the patient's
surrounding tissue into a small compartment 188 through a
semi-permeable membrane 190. This ingress of fluid into compartment
188, in turn, displaces a barrier 192 located between compartment
188 and the adjacent reservoir 182 containing the therapeutic
agent. Displacement of barrier 192 forces the therapeutic agent
from reservoir 182 into the patient's body at a controlled rate,
for example through an opening 194 in reservoir 182 and/or through
a delivery outlet tube 196. Delivery may occur after reservoir 182
is immersed in the body fluid. The rate of delivery may be
controlled, for example, by selection of dimensions of compartment
188 and fluid reservoir 182, the flexibility and dimension of
displaceable barrier 192, the size of opening 194 from fluid
reservoir 182, the construction of permeable membrane 190, and/or
the environment within compartment 188 into which the body fluid
flows. Descriptions of osmotic pumps may be found in commonly
assigned U.S. Patent Application Publication Nos. 2009/0281528 and
2008/0102119 entitled "Osmotic Pump Apparatus and Associated
Methods," both of which are incorporated herein by reference in
their entirety.
[0152] In some cases, use of osmotic pump 180 and associated
reservoir 182 located at distal end 184 of a delivery device such
as optical fiber 11 may have advantages over pumps and reservoirs
located within IMD 72. For instance, the volume of tissue
transfected by the therapeutic agent may be small. Likewise, the
volume of tissue receiving an adequate amount of light 15 may also
be small. By implanting a pump that is attached to the distal end
184 of the delivery device, such as optical fiber 11, allows for
the alignment of these two small volumes such that the desired
target tissue is transfected by the therapeutic agent and is
exposed to an adequate amount of light 15, e.g. in order to
activate the transfected target tissue.
[0153] Referring again to FIG. 5, at various times during the
operation of IMD 72 to treat patient 6, communication to and from
IMD 72 may be necessary to, e.g., change therapy programs, adjust
parameters within one or more programs, configure or adjust a
particular bolus, send or receive an estimated length of catheter
74, or to otherwise download information to or from IMD 72.
Processor 50 therefore controls telemetry module 56 to wirelessly
communicate between IMD 72 and other devices including, e.g.
programmer 40. Telemetry module 56 in IMD 72, as well as telemetry
modules in other devices described in this disclosure, such as
programmer 40, can be configured to use RF communication techniques
to wirelessly send and receive information to and from other
devices respectively. In addition, telemetry module 56 may
communicate with programmer 40 via proximal inductive interaction
between IMD 72 and the external programmer. Telemetry module 56 may
send information to external programmer 40 on a continuous basis,
at periodic intervals, or upon request from the programmer.
[0154] Power source 54 delivers operating power to various
components of IMD 72. Power source 54 may include a small
rechargeable or non-rechargeable battery and a power generation
circuit to produce the operating power. In the case of a
rechargeable battery, recharging may be accomplished through
proximal inductive interaction between an external charger and an
inductive charging coil within IMD 72. In some examples, power
requirements may be small enough to allow IMD 72 to utilize patient
motion and implement a kinetic energy-scavenging device to trickle
charge a rechargeable battery. In other examples, traditional
batteries may be used for a limited period of time. As another
alternative, an external inductive power supply could
transcutaneously power IMD 72 as needed or desired. Measurement
results for an example optogenetic stimulator system are summarized
in FIG. 12. The system was configured to produce a benchmark pulse
train of 10 ms current pulse with an amplitude of 50 mA and a 5s
period, which after passing through the optical link between the
light source and target tissue results in an optical power density
of 5.3 mW/mm.sup.2 at the tissue interface. This power density is
adequate for optical activation or deactivation, such as to
activate a channelrhodopsin-2 for neuron activation and
halorhodopsin for neuron deactivation. FIG. 12 also shows that RF
powering provides 50 mA recharging current at a distance of 25 mm
insuring a fast recharging capability for higher power designs
relying on other opsin channels. Its efficiency is 7% at 25 mm,
which is comparable to other inductively-powered neural
systems.
[0155] The benchmarked system power, currently limited by the
conversion efficiency of the LED devices, is approximately 400
.mu.W assuming successful opsin transfection into chronic neural
circuits and equivalent neuromodulation. This power level is
comparable to current deep brain stimulation systems, while
providing the advantages of genetically-targeted stimulation,
MRI/EMI compatibility and enhanced modulation capabilities.
[0156] An optogenetic modulation system such as system 2 of FIG. 1
provides for closed-loop feedback of the optical stimulation being
generated by stimulator 4. For example, a stimulation program may
be initiated by processor 50 that causes optical stimulation
generator 60 to activate a light source 63, such as an LED or
laser, which exposes a target tissue, such as a neuron population
within brain 16 of patient 6, to light 15. As described above,
because optical stimulation of light 15 does not generate a large
electrical amplitude within the target tissue, bioelectrical
activity within the target tissue may be monitored and recorded by
sense electrodes, such as the implanted sense electrodes 17 on
leads 12A and 12B, or a housing sense electrode 13. Moreover,
unlike with electronic stimulation wherein sensing substantially
simultaneously with the delivery of an electrical stimulation pulse
is impossible because of the masking effect of the large
stimulation amplitude compared to the bioelectric activity of
interest, the sensing of bioelectric activity that is provided by
sense electrodes 13 and/or 17 can be performed continuously before,
during, and after optical stimulation of the target tissue. The
ability to perform substantially simultaneous sensing also allows
for the elimination of circuitry that attempts to compensate for or
remove the artifacts resulting from electrical stimulation,
allowing for an implantable stimulator with a smaller size that
uses less power than electrical stimulators. This simultaneous
sensing allows processor 50 or an external programmer, such as
clinician programmer 20 or patient programmer 22, to not only
record the effect of the performed optical stimulation, but also to
provide a feedback loop that allows for adjustments to the
treatment parameters of subsequent optical stimulations. In one
example, the sense electrodes 13, 17 are used along with processor
50 to provide closed loop feedback based on sensed bioelectrical
signals, such as single cell action potentials, local field
potentials, energy spectra in different bands, such as alpha, beta,
or gamma bands of brain activity, electrical signals associated
with electrocorticography (ECoG) or electroencephalography
(EEG).
[0157] In one example, local field potentials (LFPs) may be used to
sense neuronal activity in the brain continuously and substantially
simultaneously with the delivery of optical stimulation. Low
frequency power fluctuations of neuronal LFPs within discrete
frequency bands can provide useful biomarkers for discriminating
normal physiological brain activity from pathological states. LFPs
may provide a measurement of the average or composite field
behavior of many cells surrounding an electrode. Because LFPs
represent the ensemble activity of thousands to millions of cells
in an in vivo neural population, their recording may avoid chronic
issues like tissue encapsulation and micromotion encountered in
single-unit recording. LFP biomarkers are ubiquitous and span a
broad frequency spectrum, from approximately 1 Hz oscillations in
deep sleep to greater than approximately 500 Hz "fast ripples" in
the hippocampus, and show a wide Q variation. As an example, high
gamma band power fluctuations in the motor cortex may signal motion
intent. Example techniques for monitoring selective frequency bands
of physiological signals, including LFPs, are described in commonly
assigned U.S. Patent Application Publication No. 2009/0082691 to
Denison, entitled "Frequency Selective Monitoring of Physiological
Signals," the entire disclosure of which is incorporated herein by
reference.
[0158] Sensors may also be used to sense other biological
parameters within the target tissue, such as inertial signals from
an accelerometer, and pressure from a pressure sensor. After
sensing a particular signal, processor 50 will run an algorithm and
modulate the light provided to the target tissue appropriately. For
example, sense electrodes 13, 17 may show that a particular optical
stimulation program did not provide sufficient activation or
inhibition of activity within the target tissue, i.e., the optical
stimulation may not have activated the target neurons such that a
neuronal spike was not created. Processor 50 may be programmed to
recognize the result of the optical stimulation and to determine a
subsequent course of action, such as to maintain the same treatment
program because the present treatment was sufficient or to modify
the treatment program because the present treatment was either
insufficient or overly sufficient. For example, if processor 50
determines that the present treatment provided insufficient
stimulation of the target tissue, such as the desired neural
activation was not achieved in brain 16 of patient, processor 50
may instruct optical stimulation generator 60 to either repeat the
same treatment program or to modify the treatment program, such as
by providing more pulses, pulses with a different wavelength,
pulses with a shorter or longer pulse width, or pulses with a
higher or lower intensity, pulses delivered in longer or shorter
bursts or at higher or lower burst frequencies. If the repeated or
modified optical stimulation treatment is still insufficient, then
processor 50 may be programmed to determine that the target tissue
is no longer responsive to light 15 because the desired opsins are
no longer being expressed and to instruct fluid delivery pump 76 to
deliver additional therapeutic agent, such as a gene therapy agent,
to promote expression of the opsins of interest in the target
tissue. Either immediately thereafter or after some
programmably-selected delay, processor 50 may then instruct optical
stimulation generator 60 to provide another round of optical
stimulation to determine if the therapeutic agent was effective in
promoting optical stimulation of the target tissue. In another
example, sense electrodes are used to detect electrical signals or
other parameters within the target tissue in order to predict
certain outcomes such that processor 50 may direct optical
stimulation to encourage, inhibit, abort, or prevent the outcome.
For example, sense electrodes may be used to detect the start of a
seizure and processor 50 may respond by initiating optical
stimulation to attempt to abort the seizure, or sense electrodes
may be used to predict an oncoming seizure so that optical
stimulation may be used to prevent the seizure. The sense
electrodes may also be used to determine if the optical stimulation
has inhibited or aborted the seizure, such as by monitoring the
beta band of brain activity to determine if the patient is in a
therapeutically beneficial state compared to before the optical
stimulation. If the optical stimulation has aborted the seizure,
processor 50 may instruct that optical stimulation be ceased. If
the optical stimulation was unable to inhibit or cease the seizure,
processor 50 may alter the treatment program, such as by increasing
light intensity, changing pulse parameters (such as pulse width,
pulse rate), changing pulse type (i.e. regular pulses versus pulse
bursts), changing the optical fibers used in the optical
stimulation, such as by using a different set of optical fibers or
a different number of optical fibers. In another example, sense
electrodes may be used to measure beta bands of brain activity to
modulate optical stimulation for movement disorder therapy. In
another example, a posture sensor such as an accelerometer may be
used for posture responsive stimulation associated with spinal cord
stimulation.
[0159] In another example, optical stimulation may be controlled
based on a determination of whether a patient is in a movement
state based on a brain signal of the patient. The brain signal may
include a bioelectrical signal, such as an electroencephalogram
(EEG) signal, an electrocorticogram (ECoG) signal, a signal
generated from measured local field potentials (LFPs) within one or
more regions of a patient's brain and/or action potentials from
single cells within the patient's brain. In some examples, the
brain signal may be detected within a dorsal-lateral prefrontal
(DLPF) cortex of the patient's brain. The movement state includes
the state in which the patient is generating thoughts of movement
(i.e., is intending to move), initiating movement, attempting to
initiate movement or is actually undergoing movement. In order to
determine whether the bioelectrical signal indicates the patient is
in a movement state or a rest state, the bioelectrical signal may
be analyzed for comparison of a voltage or amplitude value with a
stored value, temporal or frequency correlation with a template
signal, a particular power level within a particular frequency band
of the bioelectrical signal, or combinations thereof. In one
example, a processor of a bioelectrical sensing device may monitor
the power level of the mu rhythm within an alpha frequency band
(e.g., about 5 Hertz (Hz) to about 10 Hz) of an EEG signal. If the
power level of the mu rhythm falls below a particular threshold,
which may be determined during a trial period, the EEG signal may
indicate the patient is in a movement state. Other biomarkers in
other spectral bands may be used, such as spectral power,
amplitude, or other characteristics of signals in the alpha, beta,
gamma, or high gamma bands. The sensing device may then control a
therapy device to deliver optical stimulation to the patient to
mitigate the effects of a movement disorder. For example, the
sensing device may generate a control signal that is transmitted to
the therapy device and causes the therapy device to initiate
optical stimulation delivery or adjust one or more parameters of
the optical stimulation. In some examples, the therapy systems and
methods also include deactivating the delivery of therapy or
changing therapy parameters upon determining the patient is in the
rest state (i.e., as stopped moving) or has successfully initiated
movement, depending upon the type of movement disorder symptom the
therapy system is implemented to address. In addition, in some
examples, a first determination that the patient is in a movement
stated based on brain signals may be confirmed by a second
determination that is based on another source that is independent
of the brain signals, such as a motion sensor. Examples of the
types of signals that may be sensed and how they may be interpreted
are disclosed in the commonly-assigned U.S. patent application Ser.
No. 12/237,799, which is entitled, "Therapy Control Based On A
Patient Movement State," and was filed on Sep. 25, 2008, the
disclosure of which is incorporated herein by reference in its
entirety.
[0160] As discussed above, because optical fibers 11 are not
electrically conducting, they do not provide a galvanic path for
induced currents at the tissue interface so there is little to no
risk of tissue capture or excessive heating that can occur due to
gradient B fields or radio frequency (RF) fields, such as the
fields associated with modalities such as magnetic resonance
imaging (MRI) or electromagnetic interference (EMI). Moreover, the
elimination of conductors from the tissue interface helps to
mitigate MRI interference that is seen with typical electrical
stimulation electrodes, allowing for continued high-resolution
imaging post-implant. To retain these benefits provided by optical
therapy delivery while also incorporating sensing capabilities into
the system, in one example the structures that are proximate the
target tissue, such as the sense electrodes, leads, fluid delivery
structures, and optical fibers 11, are made from materials that
produce substantially no induced current in an electromagnetic
field, and in one example the structures proximate the target
tissue produce substantially no heating in gradient B fields or RF
fields. For example, the sense electrodes and any leads carrying
them may exhibit a very high resistivity and overall impedance so
that they may be used to detect the types of signals discussed
above, including LFPs, action potentials, and other biological
signals. In some examples, such sensors have a high overall
impedance (e.g., the cumulative impedance of the entire structure
of sensor 154) of between about 100 Kiloohms and about 1 Megaohm.
Examples of materials that may be used include a conductive polymer
or a carbon fiber.
[0161] In one example, shown in FIG. 5, a high-impedance sensor 154
may be carried by an optical light guide, such as optical fiber 11,
wherein sensor 154 is distributed along the length of optical fiber
11. Sensing is performed between high-impedance sensor 154
distributed along optical fiber 11 and a sensor on the housing of
an implantable stimulator, such as housing sensor 13 on housing 14,
wherein sensor 154 and housing sensor 13 are in a uni-polar mode.
In example, sensor 154 may be formed of a material that produces
substantially no induced current in an electromagnetic field, such
as the fields created by MRI or EMI. In one example, sensor 154 has
an overall impedance of between about 100 Kiloohms and about 1
Megaohm. In one example, sense electrode 154 does not comprise any
material that will produce significant induced current and/or
heating when exposed to an electromagnetic field, such as gradient
B fields or RF fields, for example the fields created by MRI or
EMI. Examples of materials that may be used for sensor 154 include
a carbon fiber or a conductive polymer.
[0162] In one example, a sensor electrode 154 made from a
conductive polymer or a carbon fiber is extruded over optical fiber
11 along the length of optical fiber 11, and a sheath (not shown),
such as a polyether urethane sheath, is deposited over and
surrounding the conductive polymer sensor 154. In one example,
elongated sensor electrode 154 is formed of a conductive polymer or
a carbon fiber, and a sheath is deposited over sensor 154, followed
by extruding an optical fiber around the sheathed sensor 154. A
high-impedance material is used because a current loop may be
formed between sensor(s) 154, housing electrode 13, internal
circuitry within housing 13, and any intervening tissue. If a lower
inductance material were used in the present of a magnetic field
such as the fields resulting from MRI or EMI, undesirable tissue
capture or excessive heating may occur. In one example, the
materials of each component, e.g., optical fiber 11, sensor 154,
and the sheath, comprises a material that produce substantially no
induced current and/or heating in an electromagnetic field, such as
gradient B fields or RF fields. In one example, all structures that
are proximate the target tissue, such as optical fiber 11, sensor
154, and the sheath, do not comprise any material that will produce
significant induced current and/or heating when exposed to an
electromagnetic field, such as gradient B fields or RF fields, for
example the fields created by MRI or EMI.
[0163] The use of materials for optical fiber 11 and sensor 154
having a very high impedance that produce substantially no induced
current and/or heating in an electromagnetic field is advantageous
in a neurostimulation system such as those described herein. The
lack of an induced current results in little to no risk of tissue
capture or excessive heating, even from components that would
traditionally do so, such as sense electrodes and the leads
thereto. This, in turn allows MRI and other imaging technologies
that may create electromagnetic fields, to be used substantially
simultaneously with optical stimulation such that imaging and
analysis of the patients tissue may be taken and performed at the
time of stimulation. Moreover, the use of materials that do not
produce induced current in an electromagnetic field from the tissue
interface, such as the materials of optical fibers 11 and sensor
154, helps to mitigate MRI interference that is seen with typical
electrical stimulation electrodes and sense electrodes, allowing
for continued high-resolution imaging post-implant while still
permitting for substantially simultaneous sensing during normal,
day-to-day use of the optical stimulator. Further examples of sense
electrodes and/or leads comprising a material having a very low
conductivity that produces substantially no induced current in an
electromagnetic field are provided in the co-pending application
entitled "Optical Stimulation Therapy," having the Attorney Docket
No. "1023-918US01/P0035812.02," filed on the same date as the
present application, which is assigned to the same assignee as the
present application, the entire disclosure of which is incorporated
herein by reference.
[0164] In another example, housing electrode 13 is not used and
need not be present, and sensing is performed between two sensors
electrodes 156A, 156B which may be carried on the same optical
fiber 11 (optical fiber 11B in FIG. 5), wherein sensing occurs in a
bi-polar mode between sensors 156A and 156B. In one example,
sensors 156A and 156B are positioned to extend along opposite
diametrically opposed sides of optical fiber 11. Any current loop
that might exists in such an arrangement would be created between
the conductors of sensors 156A and 156B and the sensing circuitry
65 in housing 14 (FIG. 4). Sensing circuitry 65 may include a high
impedance differential filter having an impedance on the order of
about 1 Megaohm, and a differential amplifier that may filter out
the common-mode signal from the two bi-polar sensed signals from
sensors 156A, 156B. The high-impedance circuitry of sensing circuit
65 along with the small area between sensing conductors 156A and
156B due to their close positioning (only being spaced apart by
optical fiber 11) results in very low magnetic flux that is less
likely to induce large voltages. In some examples, sensors 156A,
156B have a high overall impedance (e.g., the cumulative impedance
of the entire structure of each sensor 156A and 156B) of between
about 100 Kiloohms and about 1 Megaohm. In one example, sensors
156A, 156B are made from a conductive polymer or a carbon fiber. In
one example, in order to have enough physical spacing between the
sense conductors 156A, 156B so that a sufficient differential
signal may be detected, one of sensors 156A, 156B may extend
further than the other, e.g., so that the distal ends of sensors
156A, 156B are spaced apart. For example, in FIG. 5, sensor 156A is
shown as extending nearly to the distal end of optical fiber 11B,
while sensor 156B terminates more proximal to the distal end of
optical fiber 11B than sensor 156A.
[0165] Although optogenetic modulation systems have been described
with respect to modification and stimulation of neuron populations,
such as brain or spinal cord neurons, the present invention is not
so limited. Optogenetic modulation systems in accordance with the
present invention may be used for treatment of other target
tissues, such as, for example, cardiac tissue, gastrointestinal
tissue, and pelvic floor tissue. In one example, an optogenetic
modulation system may be used for treatment of atrial fibrillation
by providing ventricular rate control though modification of the
atrio-ventricular (AV) node so that conduction to the ventricles
during AF is slowed to within a desired physiological range.
[0166] In one example, stimulation of the AV node may include
transfection of the AV node with a light-sensitive ion channel,
such as a Kv1.3 potassium channel, a G-protein (Gi) channel, a leak
channel with correct voltage and time dependence, and IKr or IKs
channels, and implanting a stimulator similar to stimulator 4 or
stimulator 34 described above that delivers light to the
transfected AV node tissue. One or more sense electrodes may also
be used to detect AF and enable optical stimulation of the AV node.
In one example, a lead is placed in the right atrium appendage to
detect AF while one or more optical fibers are positioned in the AV
node to deliver light to the transfected tissue.
[0167] In another example, an optogenetic modulation system may
provide for the suppression of AF triggers, such as triggers that
originate in the pulmonary veins (PV) or the large vein ostia in
the right atrium. AF triggers have been suppressed by using
ablation to electrically isolate the trigger sites from the rest of
the atrium. However, a disadvantage of ablation is that it
irreversibly destroys tissue and may be associated with diminish
atrial kick and compromised hemodynamics. Light-sensitive ion
channels may be introduced to the PV ostia which, when triggered by
optical stimulation, may depolarize the tissue to the extent that
electrical activity from the focal triggers cannot travel to the
rest of the atrium to trigger AF. In one example, the
light-sensitive ion channel to suppress AF triggers may be a leak
channel, such as a rhodopsin, that will provide for depolarization
of the cell. In another example, atrial cells around the PV ostia
may be transfected with a light-sensitive ion channel that could be
optically stimulated with a generally circular light source or
array of optical fibers when rapid triggered activity is detected
in order to prevent initiation and/or sustenance of AF. In another
example, optical stimulation may be provided in pulses with an
appropriate duty cycle so that membrane potential is not
hyperpolarized to stimulation levels.
[0168] In another example, an optogenetic modulation system may be
used to suppress sympathetic activity associated with hypertension.
In one example, light-sensitive ion channels that suppress this
parasympathetic activity, such as leak channels or inwardly
rectifying potassium channels, may be introduced to renal nerve
cell bodies or sympathetic neurons in the lumbar region. Optical
stimulation of these cells anchors the cell membranes to their
resting potential and suppress the sympathetic activity. The
optical stimulation may be performed on a substantially continuous
basis or upon detection of elevated blood pressure, such as through
the use of an implanted blood pressure sensor, for example a
pressure sensor implanted in the RV outflow tract.
[0169] In yet another example, an optogenetic modulation system may
be used to suppress errant biological pacemaker activity.
Biological pacemakers have the potential to replace electronic
pacemakers, however, the path to generating an effective biological
pacemaker, including errant activity from the biological pacemaker
that can cause undesired rapid firing of the biological pacemaker.
A light-sensitive leak channel or IK1 channel, such as those
encoded by Kir2.1 subunits, could be delivered at the same time as
the biological pacemaker channels. Optical stimulation may be
performed to activate the leak channels or IK1 channels and
depolarize or hyperpolarize the cells so that rapid spontaneous
activity by the biological pacemaker is either brought within the
physiological range or stopped altogether. In another example, leak
channels or IK1 channels may be introduced to the tissue
encompassing the biological pacemaker so that upon optical
stimulation the encompassing tissue can prevent rapid electrical
activity of the biological pacemaker from propagating to the rest
of the atria and ventricles.
[0170] In another example, optogenetic modulation system may be
used to terminate or suppress ventricular tachycardia (VT). Prior
methods that attempt to stop VT include anti-tachycardia pacing,
such as with an implantable cardioverter-defibrillator, or with a
shock across the heart. During VT, electrical activity in the
atrium travels in a circuitous path, and is often rapid. This
electrical activity can compromise ventricular hemodynamics and be
fatal. In one example, light-sensitive channels may be introduced
to a line of tissue upon detection of VT. Once optically
stimulated, the VT circuit can be shifted to this functional line
of tissue, which would be associated with a change in the
morphology of the VT on a far-field electrocardiogram. Other means
of monitoring whether the VT circuit has shifted may include
measuring the electrical potential using a monophasic action
potential (MAP) electrode located proximate the functional line of
tissue. Once it is confirmed that the VT circuit has shifted to the
functional line of tissue, the optical stimulation is ceased to
deactivate the light-sensitive channels, thus making the myocardium
excitable and terminating the VT. This optical treatment of VT
would be painless, as compared to the generally painful electric
shock necessary to terminate most VT.
[0171] FIG. 16 is a flow diagram of an example method 200 for
delivering optical stimulation. The example method 200 comprises
delivering light to a target tissue via an optical stimulation
device (202), such as from a light source of stimulators 4, 34, or
72 described above. During delivery of the light, a temperature at
optical stimulation device 4, 34, 72 or proximate optical
stimulation device 4, 34, 72 is sensed (204), and delivery of the
light to the target tissue is adjusted based on the sensed
temperature (206). Adjusting delivery of the light to the target
tissue (206) may comprise reducing the power supplied to the light
source, such as if the sensed temperature exceeds a threshold
temperature, or adjusting at least one of a pulse rate of the
light, a pulse width of the light, an amplitude intensity of the
light, and a duty cycle of the light delivered by the light source.
Adjusting delivery of the light (206) may also include ceasing
delivery of the light, and if light delivery is ceased, optionally
delivering electrical stimulation in place of the light
stimulation.
[0172] FIG. 17 is a flow diagram of an example method 210 for
delivering optical stimulation. The example method 210 comprises
delivering light from an optical stimulation device, such as
simulator 4, 34, or 72, to a target tissue via an optical light
guide, such as an optical fiber 11, wherein the optical stimulation
device is remote from the target tissue (212). The method 210 also
comprises sensing bioelectric signals with a sense electrode (214),
such as sense electrodes 17, wherein optical light guide 11 and
sense electrode 17 each comprise a material that produces
substantially no induced current in an electromagnetic field, such
as, for example, an electromagnetic field produced by a magnetic
resonance imaging (MRI) device. In one example, the material of the
sense electrodes and/or the optical fiber comprise at least one of
a conductive polymer or a carbon fiber. In one example method, the
sense electrode is on a lead, such as lead 12A, or 12B, and the
lead is made from a material that produces substantially no induced
current in an electromagnetic field.
[0173] FIG. 18 is a flow diagram of an example method 220 for
delivering optical stimulation. The example method 220 comprises
delivering light from a light source of an optical stimulation
device, such as LED 166 within stimulator 160 (FIG. 14), to a
window 162 of optical stimulation device 160 (222), delivering the
light from window 162 to an optical light guide, such as an optical
fiber 11, optically connected to window 162 (224), and delivering
the light to a target tissue via optical light guide 11 (226).
Optical light guide 11 may be optically connected to window 162 via
an optical index matching gel 170. Window 162 may be hermetically
sealed within housing 164 of optical stimulation device 160. The
example method may also include transfecting the target tissue with
a light-sensitive channel protein sensitive to light in a
wavelength range, wherein delivering light from light source 166
comprises delivering the light in the wavelength range, wherein
delivering light from window 162 to optical light guide 11
comprises delivering the light in the wavelength range, and wherein
delivering the light to the target tissue comprises delivering the
light in the wavelength range.
[0174] FIG. 19 is a flow diagram of an example method 230 for
delivering optical stimulation. The example method 230 comprises
transfecting a target tissue with a light-sensitive channel protein
sensitive to light in a wavelength range (232) and delivering light
in the wavelength range to the target tissue via an optical
stimulation device (234). The example method 230 also comprises
sensing bioelectric signals substantially simultaneously and
continuously with delivering light to the target tissue (236),
determining a patient therapeutic state based on the bioelectric
signals (238), and adjusting delivery of the light to the target
tissue based on the sensed patient therapeutic state (240).
[0175] Determining patient therapeutic state (238) may include
determining whether the bioelectric signals indicate normal
physiological activity of the target tissue, such as normal neural
activity, or undesired activity, such as a pathological state. For
example, the method may be used to provide closed-loop deep brain
stimulation to treat movement disorders such as Parkinson's
disease, spasticity, epilepsy, and dystonia. In some cases, the
sensed bioelectric signals may result in a determination that the
patient's therapeutic state indicates the onset of seizure,
movement disorder symptoms, or other conditions. Upon such a
determination, the method may trigger initiation or adjustment of
optical stimulation to alleviate such symptoms. As an additional
example, the method may be applied to support a cell-targeted
treatment for schizophrenia, or for treatment of epilepsy via
sensing and optical stimulation at various epileptic foci that
provide distributed treatment of the epileptic foci.
[0176] FIG. 20 is a flow diagram of another example method 250 for
delivering optical stimulation. Like method 230 of FIG. 19, the
example method 250 comprises transfecting a target tissue with a
light-sensitive channel protein sensitive to light in a wavelength
range (252) and delivering light in the wavelength range to the
target tissue via an optical stimulation device (254). The example
method 250 of FIG. 20 also comprises sensing bioelectric signals
substantially simultaneously with delivering light to the target
tissue (256), wherein the bioelectric signals comprises at least
one of a local field potential proximate the target tissue, energy
spectra in the alpha band of brain activity (.alpha. band), energy
spectra in the beta band of brain activity (.beta. band), energy
spectra in the gamma band of brain activity (.gamma. band),
electrocorticography (ECoG) signals, and electroencephalography
(EEG) signals. The example method 250 further comprises adjusting
the delivery of light to the target tissue based on the sensed
bioelectric signals (258).
[0177] Transfecting the target tissue (232, 252) and delivering
light to the target tissue (234, 254) may be performed by a common
implantable medical device, such as stimulator 4, 34, or 72. For
example, stimulator 72 (FIGS. 5 and 6) comprises a reservoir 78 and
fluid delivery pump 76 for the delivery of a therapeutic agent
capable of transfecting the target tissue, and an optical
stimulation generator 60, which may include a light source 63 (FIG.
3). A controller, such as processor 50, may control the output of
light source 63 and may also direct the adjusting of light delivery
(240, 258) based on the sensed bioelectric signals and/or patient
therapeutic state.
[0178] Transfecting the target tissue (232, 252) may comprise
delivering a therapeutic agent, such as a gene therapy agent, to
the target tissue that transfects the target tissue, such as via a
pump 76 from a reservoir 78 in optical stimulator 72 (FIG. 6) or
using an osmotic pump 180 at a distal end 184 of a delivery device
such as the optical fiber 11 (FIG. 15). Transfecting the target
tissue (232, 252) may also comprise transfecting the target tissue
with a first light-sensitive channel protein sensitive to light
having a first wavelength range, for example an activating or
exciting channel protein such as Channelrhodopsin-2 (described
above), and transfecting the target tissue with a second
light-sensitive channel protein sensitive to light having a second
wavelength range, for example an inhibiting channel protein such as
halorhodopsin (described above). If both the target tissue is
transfected with both the first light-sensitive channel protein and
the second light-sensitive channel protein, then delivering light
to the target tissue (234, 254) comprises at least one of
delivering light to the target tissue in the first wavelength range
and delivering light to the target tissue in the second wavelength
range.
[0179] Delivering light to the target tissue (234, 254) may
comprise delivering light through an optical light guide, such as
an optical fiber 11, optically coupled to the optical stimulation
device, which may deliver the light from light source 63 to the
target tissue. Delivering light to the target tissue (234, 254) may
comprise delivering the light according to an optical stimulation
program, such as a program configured for a particular patient
condition or therapy. The optical stimulation program may include
one or more optical stimulation parameters, such as a pulse rate of
the light, a pulse width of the light, an amplitude intensity of
the light, a duty cycle of the light, and a wavelength of the
light. If an optical stimulation program is used, adjusting the
delivery of the light to the target tissue (240, 258) may comprise
adjusting the optical stimulation program, such as by adjusting at
least one of the parameters (e.g., adjusting the pulse rate of the
light, pulse width of the light, amplitude intensity of the light,
duty cycle of the light, or wavelength of the light). Adjusting the
delivery of light (240, 258) may also comprise adjusting the light
substantially simultaneously with sensing the bioelectric signals
(236, 256) and with delivering light to the target tissue (234,
254).
[0180] Sensing bioelectric signals (236, 256) may be provided by
one or more sense electrodes on one or more leads, such as sense
electrodes 17 on leads 12A, 12B (FIG. 1). A sensing module, such as
sensing circuitry 65 controlled by processor 50, may be provided.
In one example, sensing circuitry 65 is configured to sense and/or
interpret bioelectric signals from sense electrodes 17
substantially simultaneously with the delivery of light from light
source 63. In one example, processor 50 may be configured to
determine a patient therapeutic state based on the bioelectric
signals sensed by sense electrodes 17 and sensing circuitry 65.
[0181] Various examples have been described. These and other
examples are within the scope of the following claims.
Sequence CWU 1
1
51310PRTChlamydomonas reinhardtii 1Met Asp Tyr Gly Gly Ala Leu Ser
Ala Val Gly Arg Glu Leu Leu Phe1 5 10 15Val Thr Asn Pro Val Val Val
Asn Gly Ser Val Leu Val Pro Glu Asp 20 25 30Gln Cys Tyr Cys Ala Gly
Trp Ile Glu Ser Arg Gly Thr Asn Gly Ala 35 40 45Gln Thr Ala Ser Asn
Val Leu Gln Trp Leu Ala Ala Gly Phe Ser Ile 50 55 60Leu Leu Leu Met
Phe Tyr Ala Tyr Gln Thr Trp Lys Ser Thr Cys Gly65 70 75 80Trp Glu
Glu Ile Tyr Val Cys Ala Ile Glu Met Val Lys Val Ile Leu 85 90 95Glu
Phe Phe Phe Glu Phe Lys Asn Pro Ser Met Leu Tyr Leu Ala Thr 100 105
110Gly His Arg Val Gln Trp Leu Arg Tyr Ala Glu Trp Leu Leu Thr Cys
115 120 125Pro Val Ile Leu Ile His Leu Ser Asn Leu Thr Gly Leu Ser
Asn Asp 130 135 140Tyr Ser Arg Arg Thr Met Gly Leu Leu Val Ser Asp
Ile Gly Thr Ile145 150 155 160Val Trp Gly Ala Thr Ser Ala Met Ala
Thr Gly Tyr Val Lys Val Ile 165 170 175Phe Phe Cys Leu Gly Leu Cys
Tyr Gly Ala Asn Thr Phe Phe His Ala 180 185 190Ala Lys Ala Tyr Ile
Glu Gly Tyr His Thr Val Pro Lys Gly Arg Cys 195 200 205Arg Gln Val
Val Thr Gly Met Ala Trp Leu Phe Phe Val Ser Trp Gly 210 215 220Met
Phe Pro Ile Leu Phe Ile Leu Gly Pro Glu Gly Phe Gly Val Leu225 230
235 240Ser Val Tyr Gly Ser Thr Val Gly His Thr Ile Ile Asp Leu Met
Ser 245 250 255Lys Asn Cys Trp Gly Leu Leu Gly His Tyr Leu Arg Val
Leu Ile His 260 265 270Glu His Ile Leu Ile His Gly Asp Ile Arg Lys
Thr Thr Lys Leu Asn 275 280 285Ile Gly Gly Thr Glu Ile Glu Val Glu
Thr Leu Val Glu Asp Glu Ala 290 295 300Glu Ala Gly Ala Val Pro305
3102930DNAChlamydomonas reinhardtii 2atggattatg gaggcgccct
gagtgccgtt gggcgcgagc tgctatttgt aacgaaccca 60gtagtcgtca atggctctgt
acttgtgcct gaggaccagt gttactgcgc gggctggatt 120gagtcgcgtg
gcacaaacgg tgcccaaacg gcgtcgaacg tgctgcaatg gcttgctgct
180ggcttctcca tcctactgct tatgttttac gcctaccaaa catggaagtc
aacctgcggc 240tgggaggaga tctatgtgtg cgctatcgag atggtcaagg
tgattctcga gttcttcttc 300gagtttaaga acccgtccat gctgtatcta
gccacaggcc accgcgtcca gtggttgcgt 360tacgccgagt ggcttctcac
ctgcccggtc attctcattc acctgtcaaa cctgacgggc 420ttgtccaacg
actacagcag gcgcaccatg ggtctgcttg tgtctgatat tggcacaatt
480gtgtggggcg ccacttccgc catggccacc ggatacgtca aggtcatctt
cttctgcctg 540ggtctgtgtt atggtgctaa cacgttcttt cacgctgcca
aggcctacat cgagggttac 600cacaccgtgc cgaagggccg gtgtcgccag
gtggtgactg gcatggcttg gctcttcttc 660gtatcatggg gtatgttccc
catcctgttc atcctcggcc ccgagggctt cggcgtcctg 720agcgtgtacg
gctccaccgt cggccacacc atcattgacc tgatgtcgaa gaactgctgg
780ggtctgctcg gccactacct gcgcgtgctg atccacgagc atatcctcat
ccacggcgac 840attcgcaaga ccaccaaatt gaacattggt ggcactgaga
ttgaggtcga gacgctggtg 900gaggacgagg ccgaggctgg cgcggtaccc
9303930DNAChlamydomonas reinhardtii 3atggactatg gcggcgcttt
gtctgccgtc ggacgcgaac ttttgttcgt tactaatcct 60gtggtggtga acgggtccgt
cctggtccct gaggatcaat gttactgtgc cggatggatt 120gaatctcgcg
gcacgaacgg cgctcagacc gcgtcaaatg tcctgcagtg gcttgcagca
180ggattcagca ttttgctgct gatgttctat gcctaccaaa cctggaaatc
tacatgcggc 240tgggaggaga tctatgtgtg cgccattgaa atggttaagg
tgattctcga gttctttttt 300gagtttaaga atccctctat gctctacctt
gccacaggac accgggtgca gtggctgcgc 360tatgcagagt ggctgctcac
ttgtcctgtc atccttatcc acctgagcaa cctcaccggc 420ctgagcaacg
actacagcag gagaaccatg ggactccttg tctcagacat cgggactatc
480gtgtgggggg ctaccagcgc catggcaacc ggctatgtta aagtcatctt
cttttgtctt 540ggattgtgct atggcgcgaa cacatttttt cacgccgcca
aagcatatat cgagggttat 600catactgtgc caaagggtcg gtgccgccag
gtcgtgaccg gcatggcatg gctgtttttc 660gtgagctggg gtatgttccc
aattctcttc attttggggc ccgaaggttt tggcgtcctg 720agcgtctatg
gctccaccgt aggtcacacg attattgatc tgatgagtaa aaattgttgg
780gggttgttgg gacactacct gcgcgtcctg atccacgagc acatattgat
tcacggagat 840atccgcaaaa ccaccaaact gaacatcggc ggaacggaga
tcgaggtcga gactctcgtc 900gaagacgaag ccgaggccgg agccgtgcca
9304308PRTNatronomonas pharaonis 4Met Arg Gly Thr Pro Leu Leu Leu
Val Val Ser Leu Phe Ser Leu Leu1 5 10 15Gln Asp Thr Glu Thr Leu Pro
Pro Val Thr Glu Ser Ala Val Ala Leu 20 25 30Gln Ala Glu Val Thr Gln
Arg Glu Leu Phe Glu Phe Val Leu Asn Asp 35 40 45Pro Leu Leu Ala Ser
Ser Leu Tyr Ile Asn Ile Ala Leu Ala Gly Leu 50 55 60Ser Ile Leu Leu
Phe Val Phe Met Thr Arg Gly Leu Asp Asp Pro Arg65 70 75 80Ala Lys
Leu Ile Ala Val Ser Thr Ile Leu Val Pro Val Val Ser Ile 85 90 95Ala
Ser Tyr Thr Gly Leu Ala Ser Gly Leu Thr Ile Ser Val Leu Glu 100 105
110Met Pro Ala Gly His Phe Ala Glu Gly Ser Ser Val Met Leu Gly Gly
115 120 125Glu Glu Val Asp Gly Val Val Thr Met Trp Gly Arg Tyr Leu
Thr Trp 130 135 140Ala Leu Ser Thr Pro Met Ile Leu Leu Ala Leu Gly
Leu Leu Ala Gly145 150 155 160Ser Asn Ala Thr Lys Leu Phe Thr Ala
Ile Thr Phe Asp Ile Ala Met 165 170 175Cys Val Thr Gly Leu Ala Ala
Ala Leu Thr Thr Ser Ser His Leu Met 180 185 190Arg Trp Phe Trp Tyr
Ala Ile Ser Cys Ala Cys Phe Leu Val Val Leu 195 200 205Tyr Ile Leu
Leu Val Glu Trp Ala Gln Asp Ala Lys Ala Ala Gly Thr 210 215 220Ala
Asp Met Phe Asn Thr Leu Lys Leu Leu Thr Val Val Met Trp Leu225 230
235 240Gly Tyr Pro Ile Val Trp Ala Leu Gly Val Glu Gly Ile Ala Val
Leu 245 250 255Pro Val Gly Val Thr Ser Trp Gly Tyr Ser Phe Leu Asp
Ile Val Ala 260 265 270Lys Tyr Ile Phe Ala Phe Leu Leu Leu Asn Tyr
Leu Thr Ser Asn Glu 275 280 285Ser Val Val Ser Gly Ser Ile Leu Asp
Val Pro Ser Ala Ser Gly Thr 290 295 300Pro Ala Asp
Asp3055924DNANatronomonas pharaonis 5atgaggggta cgcccctgct
cctcgtcgtc tctctgttct ctctgcttca ggacacagag 60accctgcctc ccgtgaccga
gagtgccgtg gcccttcaag ccgaggttac ccaaagggag 120ttgttcgagt
tcgtgctgaa cgaccctttg cttgcaagca gtctctatat caacatcgca
180cttgcaggac tgagtatact gctgttcgtt tttatgaccc gaggactcga
tgatccacgg 240gcaaaactta ttgctgtgtc aaccatcctt gtgcctgtcg
tcagcattgc ctcctacact 300ggattggcga gcggcctgac aatttccgtt
cttgaaatgc cagcgggcca ttttgcagaa 360ggcagctcag tgatgctggg
aggagaagag gtagatggtg tagtcaccat gtggggacgg 420tatctcacct
gggcactttc cacgcccatg attctcctcg ctctgggtct cctggccgga
480agcaatgcta caaagctctt cacagctatc actttcgata tcgctatgtg
cgtgactggc 540cttgccgcgg ccctgactac ctcctcccac ctcatgagat
ggttctggta cgctatcagt 600tgtgcatgct ttctggtggt cttgtatatc
ctgctggtgg agtgggcaca ggacgccaaa 660gccgcgggaa ccgctgacat
gttcaatacc ctgaagctgt tgacagtagt gatgtggctg 720gggtatccaa
ttgtgtgggc tcttggagtc gagggtatcg cggtgttgcc cgttggggtg
780acgagctggg gatattcttt cctggatatc gtggcaaagt acattttcgc
attcttgctc 840ctgaactatc tgacgtcaaa cgaatctgtc gtgtccggca
gcattttgga tgttccatct 900gcttctggga ccccggctga tgat 924
* * * * *
References