U.S. patent application number 16/291763 was filed with the patent office on 2019-09-05 for extracranial implantable devices, systems and methods for the treatment of neurological disorders.
This patent application is currently assigned to THE REGENTS OF THE UNIVERSITY OF CALIFORNIA. The applicant listed for this patent is NEUROSIGMA, INC., THE REGENTS OF THE UNIVERSITY OF CALIFORNIA. Invention is credited to Ian A. Cook, Christopher DeGiorgio, Leon Ekchian.
Application Number | 20190269922 16/291763 |
Document ID | / |
Family ID | 43857099 |
Filed Date | 2019-09-05 |
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United States Patent
Application |
20190269922 |
Kind Code |
A1 |
DeGiorgio; Christopher ; et
al. |
September 5, 2019 |
EXTRACRANIAL IMPLANTABLE DEVICES, SYSTEMS AND METHODS FOR THE
TREATMENT OF NEUROLOGICAL DISORDERS
Abstract
The present disclosure relates to methods, devices and systems
used for the treatment of neurological disorders via stimulation of
the superficial elements of the trigeminal nerve ("TNS"). More
specifically, minimally invasive methods of stimulation of the
superficial branches of the trigeminal nerve located extracranially
in the face, namely the supraorbital, supratrochlear,
infratrochlear, auriculotemporal, zygomaticotemporal,
zygomaticoorbital, zygomaticofacial, nasal, infraorbital, and
mentalis nerves (also referred to collectively as the superficial
trigeminal nerve) are disclosed herein. Systems and devices
configured for therapeutic stimulation of the branches of the
trigeminal nerves, such as the superficial trigeminal nerve, and
their methods of application are also described.
Inventors: |
DeGiorgio; Christopher;
(Valencia, CA) ; Cook; Ian A.; (Los Angeles,
CA) ; Ekchian; Leon; (Glendale, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
THE REGENTS OF THE UNIVERSITY OF CALIFORNIA
NEUROSIGMA, INC. |
Oakland
Los Angeles |
CA
CA |
US
US |
|
|
Assignee: |
THE REGENTS OF THE UNIVERSITY OF
CALIFORNIA
Oakland
CA
NEUROSIGMA, INC.
Los Angeles
CA
|
Family ID: |
43857099 |
Appl. No.: |
16/291763 |
Filed: |
March 4, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15144499 |
May 2, 2016 |
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16291763 |
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12898696 |
Oct 5, 2010 |
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15144499 |
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61248827 |
Oct 5, 2009 |
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61289829 |
Dec 23, 2009 |
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61305514 |
Feb 17, 2010 |
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61354641 |
Jun 14, 2010 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61N 1/0476 20130101;
A61N 1/3616 20130101; A61N 1/36096 20130101; A61N 1/36175 20130101;
A61N 1/36021 20130101; A61N 1/0492 20130101; A61N 1/0551 20130101;
A61N 1/36171 20130101; A61N 1/0529 20130101; A61N 1/0456 20130101;
A61N 1/36067 20130101; A61N 1/36025 20130101; A61N 1/36064
20130101; A61N 1/36075 20130101; A61N 1/0504 20130101; A61N 1/36082
20130101 |
International
Class: |
A61N 1/36 20060101
A61N001/36; A61N 1/04 20060101 A61N001/04; A61N 1/05 20060101
A61N001/05 |
Claims
1-20. (canceled)
21. A method for treating a neurological disorder or condition by
trigeminal nerve stimulation, comprising: implanting a subcutaneous
electrode assembly in a patient to place a first electrode contact
at one side of a supraorbital nerve on the patient's forehead and
to place a second electrode contact at an opposing side of the
supraorbital nerve on the patient's forehead; and applying
electrical signals to the subcutaneous electrode assembly so that
current that flows between the first electrode contact and the
second electrode contact at specified operational parameters
stimulates the supraorbital nerve to treat the neurological
disorder or condition, wherein the neurological disorder or
condition is epilepsy.
22. The method of claim 21, wherein the electrical signals are
applied to minimize current penetration into the patient's brain
such that a charge density at a surface of the patient's brain does
not exceed 20 .mu.C/cm.sup.2.
23. The method of claim 21, wherein the step of applying electrical
signals comprises applying electrical signals at a frequency
between approximately 20 and 300 Hz, at a current of 0.1 to 3 mA,
and at a pulse duration of less than or equal to 500 .mu.s.
24. The method of claim 21, wherein the step of applying electrical
signals comprises applying electrical signals at a frequency
between approximately 20 and 300 Hz, at a pulse duration between
approximately 50 and 500 .mu.s, at an output current density of not
greater than approximately 25 mA/cm.sup.2, and a charge density of
not greater than approximately 10 .mu.C/cm.sup.2 at the patient's
cerebral cortex.
25. The method of claim 21, wherein the implanting comprises
implanting the subcutaneous electrode assembly in the patient to
place a third electrode contact at one side of a supratrochlear
nerve on the patient's forehead and to place a fourth electrode
contact at an opposing side of the supratrochlear nerve on the
patient's forehead.
26. The method of claim 25, wherein the method further comprises
applying electrical signals to the subcutaneous electrode assembly
so that current that flows between the third electrode contact and
the fourth electrode contact at specified operational parameters
stimulates the supratrochlear nerve to treat the neurological
disorder or condition.
27. The method of claim 21, wherein the implanting comprises
implanting the subcutaneous electrode assembly in the patient to
place a fifth electrode contact at one side of an infraorbital
nerve and to place a sixth electrode contact at an opposing side of
the infraorbital nerve.
28. The method of claim 27, wherein the method further comprises
applying electrical signals to the subcutaneous electrode assembly
so that current that flows between the fifth electrode contact and
the sixth electrode contact at specified operational parameters
stimulates the infraorbital nerve to treat the neurological
disorder or condition.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation application of U.S.
application Ser. No. 15/144,499 filed on May 2, 2016, which itself
is a continuation application of U.S. application Ser. No.
12/898,696, entitled "Extracranial Implantable Devices, Systems and
Methods for the Treatment of Neurological Disorders," filed Oct. 5,
2010, which claims the benefit of U.S. Provisional Application No.
61/248,827, entitled "Devices and Methods for Treatment of
Psychiatric Disorders," filed Oct. 5, 2009, U.S. Provisional
Application No. 61/289,829, entitled "Extracranial Implantable
Devices, Systems and Methods for the Treatment of Neuropsychiatric
Disorders," filed Dec. 23, 2009, U.S. Provisional Application No.
61/305,514, entitled "Systems, Devices and Methods for the
Treatment of Neurological Disorders and Conditions," filed Feb. 17,
2010, and U.S. Provisional Application No. 61/354,641, entitled
"Extracranial Implantable Devices, Systems and Methods for the
Treatment of Neurological Disorders," filed Jun. 14, 2010, all of
which are incorporated herein by reference in their entirety.
[0002] This application is also related to U.S. application Ser.
No. 12/898,685, entitled "Extracranial Implantable Devices, Systems
and Methods for Treatment of Neuropsychiatric Disorders," filed
Oct. 5, 2010, now U.S. Pat. No. 8,958,880, issued Feb. 17, 2015,
U.S. application Ser. No. 12/898,675, entitled "Systems, Devices
and Methods for the Treatment of Neurological Disorders and
Conditions," filed Oct. 5, 2010, now U.S. Pat. No. 8,688,220,
issued Apr. 1, 2014, and U.S. application Ser. No. 12/898,686,
entitled "Devices, Systems and Methods for Treatment of
Neuropsychiatric Disorders," filed Oct. 5, 2010, now U.S. Pat. No.
8,380,315, issued Feb. 19, 2013, all of which are incorporated by
reference in their entirety.
FIELD
[0003] The present disclosure generally relates to neurostimulator
systems, devices, and methods of using the same and more
particularly relates to neurostimulator systems, devices and
methods including at least one implantable electrode for treating
neurological disorders by stimulating superficial, cutaneous
elements of cranial nerve(s).
BACKGROUND
[0004] Neurological disorders and conditions, such as seizure
disorders that are characterized by epileptic seizures, acute or
chronic brain injury, coma, chronic headache or migraine, and
movement and related disorders may be treated with medication. For
example, seizure disorders, frequently referred to as epilepsy, are
treated initially with anti-epileptic drugs. In some patients,
anti-epileptic drugs fail; for these patients, resective epilepsy
surgery or neurostimulation are therapeutic options.
Neurostimulation for epilepsy and seizure disorders may include
stimulation of the nervous system by vagus nerve stimulation (VNS),
which has been shown to be therapeutically useful and has been
approved by the U.S. Food and Drug Administration. In this method,
stimulating electrodes are surgically implanted on the vagus nerve
in the neck. In addition to complications related to anesthesia,
potential for infection, cost, and other adverse events with VNS,
many of the subjects who undergo VNS treatments do not achieve
relief from their seizures, and there is no reliable predictor of
good outcomes from the implanted VNS device.
[0005] Other approaches are the focus of on-going research. For
example, intracranial implantable approaches, such as deep brain
stimulation (DBS) of the anterior thalamus and responsive
neurostimulation (RNS) of the epileptic zone may be utilized. RNS
employs a device which monitors brain activity and delivers stimuli
to terminate seizure discharges. However, these methods are highly
surgically invasive because they involve placement of electrodes
within the brain, on the surface of the brain, or near sensitive
neuro-vascular structures. In addition, these treatments may also
have increased costs and side effects compared with other, less
invasive approaches. Despite this range of options, a substantial
percentage of patients do not recover from or get adequate relief
for the neurological disorder despite multiple trials of
pharmaceutical or surgical treatment.
SUMMARY
[0006] One aspect of the subject matter of the present disclosure
addresses the aforementioned needs by providing systems and devices
configured to stimulate cutaneous or superficial branches of the
trigeminal nerve, located in the face, including the following
nerves: the ophthalmic (supra-orbital), supratrochlear and
infratrochlear, auriculotemporal and zygomaticotemporal,
zygomaticofacial, zygomaticoorbital, infraorbital, nasal and
mentalis nerve(s) and methods of using the same to treat
neurological disorders. This disclosure also provides a method of
treating neurological disorders using trigeminal nerve stimulation
(TNS) with minimally invasive, implantable and easy-to-use devices
and systems.
[0007] In another aspect of the present disclosure, an implantable
subcutaneous electrode assembly configured for trigeminal nerve
stimulation is provided.
[0008] In yet another aspect of the present disclosure, a method of
treating neurological disorders using the disclosed implantable or
subcutaneous electrode assembly is provided.
[0009] Disclosed herein is a subcutaneous electrode assembly for
trigeminal nerve stimulation. In one embodiment, the subcutaneous
electrode assembly includes a first electrode comprising a first
pair of contacts configured for subcutaneous placement at a first
region of a patient's face; and a second electrode comprising a
second pair of contacts configured for subcutaneous placement at a
second region of a patient's face, wherein the first pair of
contacts and the second pair of contacts are configured to be
bilaterally implanted in proximity to, adjacent to or in contact
with at least one branch of the trigeminal nerve for treatment of a
neurological disorder by trigeminal nerve stimulation. The at least
one branch of the trigeminal nerve is selected from the group
consisting of: ophthalmic nerve, infraorbital nerve, mentalis
nerve, supratrochlear nerve, infratrochlear nerve,
zygomaticotemporal nerve, zygomaticofacial nerve, zygomaticoorbital
nerve, nasal nerve and auriculotemporal nerve.
[0010] Disclosed herein is a subcutaneous electrode assembly for
trigeminal nerve stimulation. In one embodiment, the subcutaneous
electrode assembly includes a first electrode comprising a first
plurality of contacts configured for subcutaneous placement at a
first region of a patient's face; and a second electrode comprising
a second plurality of contacts configured for subcutaneous
placement at a second region of a patient's face; wherein the first
plurality of contacts and the second plurality of contacts are
configured to be unilaterally implanted in proximity to, adjacent
to or in contact with at least two different branches of the
trigeminal nerve for treatment of a neurological disorder by
trigeminal nerve stimulation. The at least two different branches
of the trigeminal nerve are selected from the group consisting of:
ophthalmic nerve, infraorbital nerve, mentalis nerve,
supratrochlear nerve, infratrochlear nerve, zygomaticotemporal
nerve, zygomaticofacial nerve, nasal nerve, zygomaticoorbital
nerve, and auriculotemporal nerve.
[0011] Disclosed herein is a method for treating a neurological
disorder or condition by trigeminal nerve stimulation. In one
embodiment, the method includes implanting an electrode assembly in
a patient, the electrode assembly includes: a first electrode
comprising a first plurality of contacts configured for
subcutaneous placement at a first region of the patient's face; a
second electrode comprising a second plurality of contacts
configured for subcutaneous placement at a second region of the
patient's face; and wherein the first plurality of contacts and the
second plurality of contacts are configured to be implanted in
proximity to, adjacent to or in contact with at least one branch of
the trigeminal nerve; and applying electrical signals to the
electrode assembly at specified operational parameters to treat a
neurological disorder or condition. In one embodiment, the step of
applying electrical signals includes applying electrical signals at
a frequency between approximately 20 and 300 Hertz, at a current of
0.05 to 5 milliamperes (mA), at a pulse duration of less than or
equal to 500 microseconds. In one embodiment, the step of applying
electrical signals comprises applying electrical signals at a
frequency between approximately 20 and 300 Hertz, at a current of
0.05 to 2 milliamperes (mA) and at a pulse duration not exceeding
500 microseconds. In one embodiment, the neurological disorder or
condition is selected from the group consisting of: epilepsy and
other seizure related disorders, acute or chronic brain injury,
chronic daily headache and migraine and related disorders, and
movement disorders.
[0012] Disclosed herein is a system for trigeminal nerve
stimulation for treatment of a neurological disorder or condition.
In one embodiment, the system includes: a pulse generator; and a
subcutaneous electrode assembly including: a first electrode
comprising a first plurality of contacts configured for
subcutaneous placement at a first region of the patient's face; a
second electrode comprising a second plurality of contacts
configured for subcutaneous placement at a second region of the
patient's face; and wherein the first plurality of contacts and the
second plurality of contacts are configured to be implanted in
proximity to, adjacent to or in contact with at least one branch of
the trigeminal nerve. The system may further comprise a wire
operably connecting the pulse generator and the subcutaneous
electrode assembly. In some embodiments, the at least one branch of
the trigeminal nerve is selected from the group consisting of:
ophthalmic nerve, infraorbital nerve, mentalis nerve,
supratrochlear nerve, infratrochlear nerve, nasal nerve,
zygomaticotemporal nerve, zygomaticofacial nerve, zygomaticoorbital
nerve, and auriculotemporal nerve.
[0013] Disclosed herein is a subcutaneous electrode assembly for
trigeminal nerve stimulation. In one embodiment, the subcutaneous
electrode assembly includes: a first electrode comprising a first
single contact configured for subcutaneous placement at a first
region of a patient's face; and a second electrode comprising a
second single contact configured for subcutaneous placement at a
second region of a patient's face; wherein the first contact and
the second contact are configured to be implanted in proximity to,
adjacent to or in contact with at least one branch of the
trigeminal nerve for treatment of a neurological disorder by
trigeminal nerve stimulation. In some embodiments, the at least one
branch of the trigeminal nerve is selected from the group
consisting of: ophthalmic nerve, infraorbital nerve, mentalis
nerve, supratrochlear nerve, infratrochlear nerve,
zygomaticotemporal nerve, zygomaticofacial nerve, zygomaticoorbital
nerve, and auriculotemporal nerve.
[0014] Disclosed herein is a system for trigeminal nerve
stimulation for treatment of a neurological disorder or condition.
In one embodiment, the system includes: a pulse generator; and a
subcutaneous electrode assembly in electrical communication with
the pulse generator, the assembly comprising: a first electrode
comprising at least one contact configured for subcutaneous
placement at a first region of the patient's face, wherein the
first electrode is configured to be implanted in proximity to,
adjacent to or in contact with at least one branch of the
trigeminal nerve for treatment of a neurological disorder or
condition by trigeminal nerve stimulation, wherein the system is
configured for minimal current penetration into a brain of a
patient, and wherein the at least one branch of the trigeminal
nerve is selected from the group consisting of: ophthalmic nerve,
infraorbital nerve, mentalis nerve, supratrochlear nerve,
infratrochlear nerve, zygomaticotemporal nerve, zygomaticofacial
nerve, zygomaticoorbital nerve, nasal nerve, and auriculotemporal
nerve. In some embodiments, the assembly further comprises a second
electrode comprising at least one contact configured for
subcutaneous placement at a second region of the patient's face,
wherein the second electrode is configured to be implanted in
proximity to, adjacent to or in contact with at least one branch of
the trigeminal nerve, wherein the at least one branch of the
trigeminal nerve is selected from the group consisting of:
ophthalmic nerve, infraorbital nerve, mentalis nerve,
supratrochlear nerve, infratrochlear nerve, zygomaticotemporal
nerve, zygomaticofacial nerve, zygomaticoorbital nerve, nasal
nerve, and auriculotemporal nerve. In some embodiments, the first
electrode and the second electrode are configured for implantation
in proximity to, adjacent to or in contact with a same branch of
the trigeminal nerve. In some embodiments, the first electrode and
the second electrode are configured for implantation in proximity
to, adjacent to or in contact with a different branch of the
trigeminal nerve. In some embodiments, the system may further
include a wire operably connecting the pulse generator and the
subcutaneous electrode assembly. In some embodiments, the system
may further include a regulating device configured to regulate the
maximum charge balanced output current below approximately 30-50
mA. The neurological disorder or condition is selected from the
group consisting of: epilepsy, seizure related disorders, acute
brain injury, chronic brain injury, chronic daily headache,
migraine, disorders related to migraine and headache and movement
disorders. In some embodiments, the pulse generator is configured
to apply electrical signals at a frequency between approximately 20
and 300 Hertz, at a pulse duration between approximately 50 and 500
microseconds, at an output current density of not greater than
approximately 25 mA/cm.sup.2 and an output charge density of not
greater than approximately 10 microCoulomb/cm.sup.2 at the cerebral
cortex.
[0015] Disclosed herein is a subcutaneous electrode assembly for
trigeminal nerve stimulation for treatment of a neurological
disorder or condition. In some embodiments, the assembly includes:
a first electrode comprising at least one contact configured for
subcutaneous placement at a first region of the patient's face,
wherein the first electrode is configured to be implanted in
proximity to, adjacent to or in contact with at least one branch of
the trigeminal nerve for treatment of a neurological disorder or
condition by trigeminal nerve stimulation, wherein the assembly is
configured for minimal current penetration into a brain of a
patient, and wherein the at least one branch of the trigeminal
nerve is selected from the group consisting of: ophthalmic nerve,
infraorbital nerve, mentalis nerve, supratrochlear nerve,
infratrochlear nerve, zygomaticotemporal nerve, zygomaticofacial
nerve, zygomaticoorbital nerve, nasal nerve, and auriculotemporal
nerve. In some embodiments, the assembly may further include a
second electrode comprising at least one contact configured for
subcutaneous placement at a second region of the patient's face,
wherein the second electrode is configured to be implanted in
proximity to, adjacent to or in contact with at least one branch of
the trigeminal nerve, wherein the at least one branch of the
trigeminal nerve is selected from the group consisting of:
ophthalmic nerve, infraorbital nerve, mentalis nerve,
supratrochlear nerve, infratrochlear nerve, zygomaticotemporal
nerve, zygomaticofacial nerve, zygomaticoorbital nerve, nasal
nerve, and auriculotemporal nerve. In some embodiments, the first
electrode and the second electrode are configured for implantation
in proximity to, adjacent to or in contact with a same branch of
the trigeminal nerve. In some embodiments, the first electrode and
the second electrode are configured for implantation in proximity
to, adjacent to or in contact with a different branch of the
trigeminal nerve. The neurological disorder or condition is
selected from the group consisting of: epilepsy, seizure related
disorders, acute brain injury, chronic brain injury, chronic daily
headache, migraine, disorders related to migraine and headache, and
movement disorders
[0016] Disclosed herein is a method for treating a neurological
disorder or condition by trigeminal nerve stimulation. In one
embodiment, the method includes implanting an electrode assembly in
a patient, the subcutaneous electrode assembly comprising: a first
electrode comprising at least one contact configured for
subcutaneous placement at a first region of the patient's face,
wherein the first electrode is configured to be implanted in
proximity to, adjacent to or in contact with at least one branch of
the trigeminal nerve for treatment of a neurological disorder or
condition by trigeminal nerve stimulation, wherein the assembly is
configured for minimal current penetration into a brain of a
patient, and wherein the at least one branch of the trigeminal
nerve is selected from the group consisting of: ophthalmic nerve,
infraorbital nerve, mentalis nerve, supratrochlear nerve,
infratrochlear nerve, zygomaticotemporal nerve, zygomaticofacial
nerve, zygomaticoorbital nerve, nasal nerve, and auriculotemporal
nerve; and applying electrical signals to the electrode assembly at
specified operational parameters to treat a neurological disorder
or condition. In some embodiments, the method further includes an
assembly comprising a second electrode comprising at least one
contact configured for subcutaneous placement at a second region of
the patient's face, wherein the second electrode is configured to
be implanted in proximity to, adjacent to or in contact with at
least one branch of the trigeminal nerve, wherein the at least one
branch of the trigeminal nerve is selected from the group
consisting of: ophthalmic nerve, infraorbital nerve, mentalis
nerve, supratrochlear nerve, infratrochlear nerve,
zygomaticotemporal nerve, zygomaticofacial nerve, zygomaticoorbital
nerve, nasal nerve, and auriculotemporal nerve. In some
embodiments, the step of applying electrical signals comprises
applying electrical signals at a frequency between approximately 20
and 300 Hertz, at a current of 0.05 to 5 milliamperes (mA) and at a
pulse duration of less than or equal to 500 microseconds. In some
embodiments, the step of applying electrical signals comprises
applying electrical signals at a frequency between approximately 20
and 300 Hertz, at a pulse duration between approximately 50 and 500
microseconds, at an output current density of not greater than
approximately 25 mA/cm.sup.2 and a charge density of not greater
than approximately 10 microCoulomb/cm.sup.2 at the cerebral cortex.
The neurological disorder or condition is selected from the group
consisting of: epilepsy, seizure related disorders, acute brain
injury, chronic brain injury, chronic daily headache, migraine,
disorders related to migraine and headache and movement
disorders.
[0017] Disclosed herein is a kit for trigeminal nerve stimulation
for treatment of a neurological disorder or condition. In some
embodiments, the kit includes a subcutaneous electrode assembly as
disclosed herein; and instructions for implanting the electrode
assembly in a patient for treatment of a neurological disorder or
condition. In some embodiments the kit may further include: a pulse
generator; and instructions for applying electrical signals to the
electrode assembly for treatment of a neurological disorder or
condition.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] The present disclosure, both as to its organization and
manner of operation, may be understood by reference to the
following description, taken in connection with the accompanying
drawings, in which:
[0019] FIGS. 1A and 1B illustrate the location of several branches
(nerves) of the trigeminal nerve and the location of the major
foramina for the superficial branches of the trigeminal nerve;
[0020] FIG. 2A shows a subject wearing an embodiment of a system
for trigeminal nerve stimulation including a subcutaneous electrode
assembly provided according to aspects of the present
disclosure;
[0021] FIG. 2B is the subcutaneous electrode assembly of FIG. 2A,
wherein a multicontact electrode is shown;
[0022] FIG. 3 depicts another embodiment of a subcutaneous
electrode assembly configured for stimulation of a plurality of
nerve branches which may be used with the system of FIG. 2A;
[0023] FIG. 4 depicts another embodiment of a subcutaneous
electrode assembly configured for stimulation of the
auriculotemporal or zygomaticofacial nerve branches which may be
used with the system of FIG. 2A;
[0024] FIG. 5 illustrates the results from a pilot study of
external trigeminal nerve stimulation ("TNS"); and
[0025] FIG. 6 summarizes one embodiment of current, charge, current
density and charge density parameters for a subject exposed to
transcutaneous stimulation of the supraorbital nerve.
DETAILED DESCRIPTION
[0026] The present disclosure relates to methods, devices and
systems used for the treatment of neurological disorders via
stimulation of the superficial elements of the trigeminal nerve
("TNS"). More specifically, minimally invasive methods of
stimulation of the superficial branches of the trigeminal nerve
located extracranially in the face, namely the supraorbital,
supratrochlear, infratrochlear, auriculotemporal,
zygomaticotemporal, zygomaticoorbital, zygomaticofacial,
infraorbital, and mentalis nerves (also referred to collectively as
the superficial trigeminal nerve) are disclosed herein. Systems and
devices configured for therapeutic stimulation of the branches of
the trigeminal nerves, such as the superficial trigeminal nerve,
and their methods of application are also described. The cutaneous
branches of the trigeminal nerve in the face provide an opportunity
for a minimally invasive method of stimulating structures of the
brain and the brainstem including, but not limited to, the
trigeminal nerve nuclei and tracts, locus coeruleus, nucleus
tractus solitarius, ventral posterior and ventral medial thalamus,
the cerebral cortex, and other structures which may play a role in
the disorders listed above.
[0027] The systems, devices and methods disclosed herein provide a
less invasive form of neurostimulation to treat a variety of
neurological disorders including, but not limited to, seizures,
headache, migraine and related disorders, movement disorders, coma,
and brain injury. More specifically, an implantable or subcutaneous
electrode assembly and a system comprising the same configured for
trigeminal nerve stimulation are disclosed herein. As described in
more detail below, electrodes are not placed within the brain or
near critical structures like the vagus nerve, carotid artery, or
jugular vein. The electrodes are also not directly or physically
attached or anchored to the nerve (e.g. by suturing), which
requires intracranial invasion and may cause a spinal fluid leak,
infection, nerve damage and/or severe pain. Instead, subcutaneous
electrodes (or an electrode assembly) are placed at or near a
region of a patient's face or cranium that is in proximity to,
adjacent to, in contact with, or distal to the trigeminal nerve (or
the relevant branch(es) thereof) by attaching to subcutaneous or
connective tissues above the periosteum or pericranium (a membrane
that lines the outer surface of the skull) and below the epidermis
(the outermost layer of skin). The nerve is stimulated at
operational parameters within a defined range to minimize current
penetration into the brain and further determined by factors such
as patient history, disorder to be treated, or individual
sensitivity to the stimulation. The electrode assembly placement as
described herein does not require intracranial invasion (i.e.
implantation below the skull) thereby reducing the risks of a
spinal fluid leak and infection. In some embodiments, the electrode
assembly may be placed or otherwise configured to stimulate the
smaller branches of the trigeminal nerve. That is, the assembly is
placed further away from the brain and the main branch of the
nerve. Surprisingly, placement of the assembly further away from
the brain and the main branch of the nerve is believed to be as
efficacious as direct attachment to the main branch of the nerve
and may provide increased safety for the patient.
[0028] In some clinical situations, brain stimulation has been
found to be of sufficient clinical use to have been approved by the
US Food and Drug Administration, for example, electroconvulsive
therapy (ECT) and repetitive transcranial magnetic stimulation
(rTMS) for psychiatric conditions. Some brain stimulation methods
aim to generate currents in large volumes of the cortex and treat
the brain as a bulk conductor, for example, ECT at the whole-lobe
level and rTMS at the large regional level (i.e. dorsolateral
prefrontal cortex). Additionally, deep brain stimulation is
generally predicated on stimulation of small but regional volumes
that lead to discharges in a very large number of cells. The
systems, devices and methods of the present disclosure send
minimal, if any, current into the brain; instead, signals are sent
into the brain in order to modulate the activity of relevant
neuroanatomical structures. Without wishing to be bound by any
particular theory, the electrical pulses generate signals in the
cutaneous branches of the trigeminal nerve and the electric fields
are generally confined to the skin tissue and there is minimal, if
any, leakage into the brain. These electrical pulses trigger a
cascade of change in neuronal signaling events that involve very
limited and precise recruitment of specific networks of neurons.
The neuroanatomic pathways allow targeted modulation of activity in
areas involved in depression (locus coeruleus, anterior cingulate,
insular cortex). Thus, the systems, devices and methods as
disclosed herein utilize the brain's existing infrastructure to
transmit signals to the targets of interest. In the context of this
disclosure minimal current penetration means (1) a charge density
of approximately 0 .mu.C/cm.sup.2 at the cerebral cortex, or (2)
calculated, measured, or modeled charge densities below the
following thresholds at the cerebral cortex: (a) at currents,
charge densities, or charge per phase not likely to cause
activation of pyramidal neurons and axons; and (b) to prevent brain
injury, a charge density of less than 10 .mu.C/cm.sup.2 in one
embodiment, and, in other embodiments, a charge density of less
than 0.001 to 0.1 .mu.C/cm.sup.2, and at combinations of charge
density and charge per phase not known to cause brain injury. In
some embodiments, a lower charge density may be used when the
central nervous system of an individual patient is sufficiently
sensitive to lower levels of stimulation that the lower level will
still permit clinical benefit to accrue.
[0029] The following description is provided to enable any person
skilled in the art to make and use the subject matter of this
disclosure, and it sets forth the best modes contemplated by the
inventors of carrying out the various aspects of the disclosure.
Various modifications, however, will remain readily apparent to
those skilled in the art, since the principles of the disclosed
subject matter have been defined herein specifically to describe:
(1) methods of treating neurological disorders by trigeminal nerve
stimulation, (2) a system and an implantable electrode assembly
configured for trigeminal nerve stimulation; and (3) methods of
treating neurological disorders using such system and electrode
assembly.
[0030] For a discussion related to the trigeminal nerve, reference
is first made to FIGS. 1A-1B, which illustrate the location of
several branches of the trigeminal nerve and the location of the
major foramina for the superficial branches of the trigeminal
nerve. The trigeminal nerve is the largest of the 12 paired cranial
nerves, and has extensive connections with the brainstem and other
brain structures. The trigeminal nerve (frequently identified as
the fifth cranial nerve, cranial nerve V, or CN V) has three major
divisions, the cutaneous branches of which are all bilateral and
highly accessible. The supraorbital nerve, or ophthalmic nerve, is
frequently referred to as the V1 division and this division also
includes the supratrochlear nerve and the infratrochlear nerve. The
infraorbital branch or maxillary nerve is commonly referred to as
the V2 division and this division also includes the
zygomaticofacial nerve and the infraorbital nerve. The mentalis
branch of the mandibular nerve is referred to as the V3 division
and this division also includes the auriculotemporal nerve. The
supraorbital nerve supplies sensory information about the forehead,
the upper eyelid, the anterior part of the nose, and the eye. The
infraorbital branch supplies sensory information about the lower
eyelid, cheek, and upper lip. The mentalis branch supplies sensory
information about the skin of the lower face (e.g. jaw and tongue)
and lips. These branches exit the skull through three foramina, as
shown in FIGS. 1A-B. The supraorbital nerve or ophthalmic nerve
exits at foramen 1, approximately 2.1-2.6 cm from the nasal midline
(in adults), and is located immediately above the orbital ridge
that is located below the eyebrow. The infraorbital branch or
maxillary nerve exits at foramen 2, approximately 2.4-3.0 cm from
the nasal midline (in adults) and the mentalis nerve exits at
foramen 3, approximately 2.0-2.3 cm from the nasal midline (in
adults). The nasal nerve is a division of the ophthalmic nerve.
Other sensory branches, including the zygomaticofacial,
zygomaticoorbital, zygomaticotemporal, and auriculotemporal, arise
from other foramina.
[0031] Fibers from the three major branches join together to form
the trigeminal ganglion. From there, fibers ascend into the
brainstem at the level of the pons, to synapse with the main
sensory nucleus of the pons and the spinal nucleus and tract of CN
V. Pain fibers descend in the spinal nucleus and tract of V, and
then ascend to the ventral posterior medial nucleus (VPM) of the
thalamus, and then project to the cerebral cortex. Light touch
sensory fibers are large myelinated fibers, which ascend to the
ventral posterior lateral (VPL) nucleus of the thalamus, and also
project to the cerebral cortex.
[0032] The trigeminal nuclei have projections to other cranial
nerve structures, including the nucleus tractus solitarius (NTS),
and the locus coeruleus, among others. The NTS receives afferents
from the vagus nerve and trigeminal nerve. NTS integrates input
from multiple sources, and projects to structures in the brainstem
and forebrain, including the locus coeruleus. The locus coeruleus
is a paired nuclear structure in the dorsal pons, and is located
just beneath the floor of the fourth ventricle. The locus coeruleus
has extensive axonal projections to a large number of brainstem,
sub-cortical and cortical structures, and is an important part of
the reticular activating system. The locus coeruleus is a core part
of the brainstem noradrenergic pathway, and produces the
neurotransmitter norepinephrine. Norepinephrine may play a role in
attention, alertness, blood pressure and heart rate regulation,
anxiety, and mood.
[0033] While not wishing to be bound by any particular theory, in
certain embodiments, the connections between the trigeminal nerve,
locus coeruleus, nucleus and tractus solitarius, thalamus, and
cerebral cortex, may be relevant to a potential role of the
trigeminal nerve in numerous neurological disorders, including coma
and brain injury, seizure disorders, headache, migraine, and
movement disorders, as may be apparent to one skilled in the art.
Thus, subcutaneous stimulation of the trigeminal nerve at custom
tailored settings and parameters could be effective in the
treatment of multiple neurological disorders.
[0034] Neurological Disorders
[0035] Coma and Vegetative State. Subcutaneous neurostimulation may
improve consciousness in persons in coma and vegetative state.
Without wishing to be bound by a particular theory, the brainstem
reticular activating system (including locus coeruleus) and
thalamus may play a role in alerting, awakening, and activating
higher cortical structures. Stimulation of these and other brain
structures, to which the trigeminal nerve and nuclei project, could
assist in promoting awakening in coma, as well as recovery of
cognition and motor function after various forms of brain injury.
Given the projections of the trigeminal nerve to key brainstem,
thalamic, and cortical structures involved in wakefulness and
consciousness, the trigeminal nerve represents one method to
activate these key structures.
[0036] Headache and Migraine. Without wishing to be bound by a
particular theory, headache and migraine involve pathways linked to
the trigeminal nerve. Activation of specific trigeminal structures
and pathways may play a role in headache. (Nature Medicine 2002;
8:136-142). Afferent trigeminal nerve fibers from vascular
structures in the pia covering the cerebral cortex are activated,
and activate or sensitize the trigeminal ganglion and the caudal
trigeminal nuclei, which in turn activate the superior salvitory
nucleus and the sphenopalatine ganglia. (Nature Medicine 2002;
8:136-142). Projections from these structures to vessels in the
dura mater (the outer protective lining of the brain) lead to the
release of vasoactive peptides, protein extravasation, and
activation of nitric acid pathways, all of which result in
dilatation of dural vessels, which may lead to headache. This is
frequently referred to as the trigeminal-vascular reflex, and may
be a mechanism in the genesis of migraine. (Nature Medicine 2002;
8:136-142). Without wishing to be bound by a particular theory,
surgically lesioning or blocking the trigeminal nerve may inhibit
this response, leading to a reduction in the cascade of events
involved with migraine and other headache syndromes. As disclosed
herein, acute or chronic electrical stimulation of the trigeminal
nerve via its cutaneous or superficial braches in the face, at
frequencies which inhibit the circuit described above, is one
method to modulate this trigeminal-vascular reflex response, and
reduce or inhibit headaches or migraines in which the trigeminal
nuclei and nerves play a role.
[0037] Movement Disorders. Movement disorders are characterized by
involuntary movements of the body, and include, but are not limited
to, tremors, twitches, and spasms, involuntary increases in tone of
muscles, such as dystonias, and complex movements, such as
dyskinesias and choreas. Without wishing to be bound by any
particular theory, we hypothesize that TNS may modulate activity in
key structures involved in movement disorders, including but not
limited to the thalamus, basal ganglia, brain stem, and cerebral
cortex, and may inhibit, by afferent stimulation, abnormal neuronal
activity in motor systems which give rise to these involuntary
phenomena.
[0038] Tardive and other Dyskinesias. Many medications which act on
the dopaminergic neurons in the brain have a liability for inducing
involuntary movements. This has been reported for treatment of
Parkinson's disease with levodopa, for the use of neuroleptic
medications in psychosis, bipolar disorder, and other conditions
(Damier, Curr Opin Neurol 22:394-399, 2009), and for dopaminergic
medications used to address gastrointestinal symptoms (Rao and
Camilleri, Ailment Pharmacol Ther 31:11-19. 2010). Other
individuals may suffer from dyskinesia on a genetic-related basis
(Coubes et al., Lancet 355:2220-1, 2000). These dyskinesia
syndromes consist of involuntary movements that usually start
oro-facially, with the muscles of the tongue, lips, mouth or face,
but can increase in severity and come to involve other parts of
body. The exact mechanisms by which these dyskinesias arise is not
clear, but surgical treatment approaches have implicated the
thalamus and the globus pallidum as locations where deep brain
stimulation can lead to improvement (Kupsch et al., J Neurol 250
Suppl 1:147-152 2003). While not wishing to be bound by any
particular theory, the connections between the trigeminal nerve,
nucleus and tractus solitarius, and thalamus may provide a
mechanism by which trigeminal nerve stimulation can ameliorate
symptoms of dyskinesia by activating these key structures.
[0039] Seizure Disorders. Without wishing to be bound by any
particular theory, trigeminal nerve stimulation may modulate
activity in the locus coeruleus, brainstem, thalamus, and cerebral
cortex, and may activate inhibitory mechanisms and pathways which
affect neuronal excitability. Trigeminal nerve stimulation may also
inhibit excitatory mechanisms and pathways, resulting in inhibition
of epileptic discharges and their spread in cortex, and subcortical
structures. These processes may have a direct or indirect effect on
activity in the epileptic focus itself.
[0040] Accordingly, stimulation of the superficial or cutaneous
branches of the trigeminal nerve as disclosed herein provide a
minimally invasive neuromodulation option. Further, stimulation
parameters can be tailored for the individual condition, such that
the brainstem, thalamic, or cortical structures involved in the
individual condition can be activated or inhibited depending on the
pathophysiology of the condition being treated.
[0041] For a discussion of certain embodiments of methods, systems
and devices using implantable electrodes according to aspects of
the present disclosure, reference is now made to FIGS. 2A-4 which
show various embodiments of the systems and devices that may be
used for the subcutaneous stimulation of the superficial branches
of the trigeminal nerve and methods of using the same.
[0042] According to one aspect of the present disclosure, a method
of treating neurological disorders using trigeminal nerve
stimulation ("TNS") is provided. In some embodiments, the method of
treating these disorders by stimulating superficial branches of the
trigeminal nerve comprises implanting electrodes adjacent to, in
proximity to, in contact with, or distal to at least one of the
three paired foramina or superficial branches of the trigeminal
nerves in the face (FIGS. 1A-1B), and stimulating the electrodes
using a pulse generator for a period of time at specified
operational parameters. The electrode assembly placement does not
require intracranial invasion (i.e. implantation below the skull)
because the electrode assembly is attached or otherwise anchored to
subcutaneous or connective tissues located above the periosteum or
pericranium and below the epidermis in order to place the electrode
assembly in proximity to, adjacent to, in contact with or distal to
the target nerve branch. In some embodiments, the electrode
assembly may be configured to stimulate the smaller branches of the
trigeminal nerve. Surprisingly, placement of the assembly further
away from the brain and the main branch of the nerve is believed to
be as efficacious as direct attachment or other contact with the
main branch of the nerve and may provide increased safety for the
patient.
[0043] In one embodiment, the implanted electrodes are positioned
adjacent to the foramina of the supraorbital or ophthalmic nerves
(FIGS. 1A-1B, Foramen 1) since unilateral stimulation or bilateral
stimulation of the trigeminal nerve is achievable by placing single
or separate electrodes on the right and/or left sides. In one
embodiment, the electrode assembly is configured for unilateral
stimulation. In one embodiment, the electrode assembly is
configured for bilateral stimulation. In some embodiments,
bilateral stimulation may offer similar or better efficacy than
unilateral stimulation because the function of different brain
structures may not be the same on right and left (e.g. verbal
expression is most commonly localized to speech centers in the left
hemisphere, and injury there produces catastrophic loss of the
ability to speak, while damage to the corresponding region on the
right does not produce this profound loss of function, but may
alter subtle functions). There may also be synergistic effects that
arise with bilateral stimulation.
[0044] In some embodiments, a patient may be implanted with two
separate electrodes in the soft tissues of the forehead, with each
electrode near the foramen or branches of the ophthalmic nerve. In
alternative embodiments, the implanted/implantable electrode(s) can
also be positioned adjacent to, in proximity to, or in contact with
the infraorbital foramen (infraorbital nerves) (FIGS. 1A-1B,
Foramen 2) or the mentalis foramen (mentalis nerves) (FIGS. 1A-1B,
Foramen 3). In other embodiments, electrodes may be placed adjacent
to, in proximity to, or in contact with the supratrochlear nerve,
infratrochlear nerve, zygomaticotemporal, zygomaticofacial,
zygomaticoorbital, nasal, and/or auriculotemporal nerves and their
respective foramina. Unilateral stimulation or bilateral
stimulation of the trigeminal nerve is achievable by placing single
or separate electrodes on the right and/or left sides of the face
to unilaterally apply stimulation near one superficial foramen of
the trigeminal nerves. In still other embodiments, the electrodes
may be implanted over a plurality of superficial foramina in the
face to simultaneously or asynchronously stimulate different
trigeminal nerves. In other embodiments, the stimulation may take
place in the cutaneous territories of branches of the trigeminal
nerves, without attachment to the nerves.
[0045] As can be understood from FIGS. 2A-2B, and with reference to
FIGS. 3-4, in one embodiment, a system 10 for the treatment of
neurological disorders and conditions via subcutaneous TNS includes
an implantable or subcutaneous electrode assembly 20, a pulse
generator 30 and electrical cable or wire 40 which may be placed
under the skin.
[0046] The pulse generator may be any of a variety of appropriate
stimulating, signal generating devices. In some embodiments, the
pulse generator 30 may include electronic circuitry for receiving
data and/or power from outside the body by inductive,
radio-frequency (RF), or other electromagnetic coupling. In some
embodiments, electronic circuitry includes an inductive coil for
receiving and transmitting RF data and/or power, an integrated
circuit (IC) chip for decoding and storing stimulation parameters
and generating stimulation pulses, and additional discrete
electronic components required to complete the electronic circuit
functions, e.g. capacitor(s), resistor(s), transistor(s), coil(s),
and the like.
[0047] In other embodiments, pulse generator 30 may include a
programmable memory for storing a set(s) of data, stimulation, and
control parameters. Among other things, memory may allow
stimulation and control parameters to be adjusted to settings that
are safe and efficacious with minimal discomfort for each
individual. Specific parameters may provide therapeutic advantages
for various neurological disorders. For instance, some patients may
respond favorably to intermittent stimulation, while others may
require continuous stimulation to treat their symptoms.
[0048] In some embodiments, the implantable pulse generator 30 may
include a power source and/or power storage device. Possible
options for providing power to the system include but are not
limited to: an external power source coupled to pulse generator 30,
e.g., via an RF link, a self-contained power source utilizing any
suitable means of generation or storage of energy (e.g., a primary
battery, a replenishable or rechargeable battery such as a lithium
ion battery, an electrolytic capacitor, a super-capacitor, a
kinetic generator, or the like), and if the self-contained power
source is replenishable or rechargeable, means of replenishing or
recharging the power source (e.g., an RF link, an optical link, a
thermal link, an inductive link, or other energy-coupling
link).
[0049] In some embodiments, pulse generator 30 operates
independently. In other embodiments, pulse generator 30 operates in
coordination with other implanted device(s) or other device(s)
external to the patient's body. For example, a pulse generator may
communicate with other implanted pulse generators or
neurostimulators, other implanted devices, and/or devices external
to a patient's body via, e.g., an RF link, an ultrasonic link, a
thermal link, an optical link, or the like. Specifically, a pulse
generator may communicate with an external remote control (e.g.,
patient and/or physician programmer) that is capable of sending
commands and/or data to a pulse generator and that may also be
capable of receiving commands and/or data from a pulse
generator.
[0050] In some embodiments, the system may include a regulation
device. The regulation device is configured to be attached to the
pulse generator 15 and is configured to govern the maximum charge
balanced output current below approximately 30-50 mA to minimize
current penetration to the brain and increase patient tolerance.
The regulation device may be internally programmed to range from
0.25-5.0, 0-10, 0, 15 (all in mA), depending on the surface area,
placement, and orientation of the electrode, and whether the
electrode is stimulating near or adjacent to the skull, or away
from the skull, (e.g. mentalis nerve), where current ranges may be
higher or lower. Current TENS units stimulate with maximum output
currents of up to 100 mA, which result in currents which may
penetrate the skull and which may not be well tolerated.
[0051] In one embodiment, the electrical cable or wire 40 is
configured to provide a physical and electrical link between the
pulse generator 30 and the electrode assembly 20. In other
embodiments, the pulse generator 30 and the electrode assembly 20
communicate wirelessly (i.e. the wire 40 is not used). The system
10 and/or the electrode assembly 20 may be part of a kit. In some
embodiments, the kit may also include instructions for treatment of
a neurological disorder or condition according to a method
disclosed herein.
[0052] In one embodiment, as shown in FIG. 2A, the electrode
assembly 20 shown in the illustrated embodiment is also referred to
as a bilateral supraorbital electrode. The electrode assembly 20 is
connectable to an implanted/implantable pulse generator by
electrical cables 40. Alternatively, the electrodes may be
connectable to an external pulse generator wirelessly, with
transfer of energy across the skin by inductive coupling between a
coil implanted in the patient and a coil in the external pulse
generator (not shown).
[0053] As shown in FIG. 2B, in one embodiment, the implantable or
subcutaneous electrode assembly 20 may include a set of
multicontact electrodes 20a, 20b configured for the bilateral
simultaneous and asynchronous stimulation of the ophthalmic nerves.
The multicontact electrodes 20a, 20b of the electrode assembly 20
comprise an electrode including a first pair of contacts 112a, 112b
for implantation at a first region of the patient's face, such as
the patient's right forehead or the right side of the patient's
face, and an electrode including a second pair of contacts 112c,
112d for implantation at a second region of the patient's face,
such as in the patient's left forehead or the left side of the
patient's face. In other embodiments, the first and second region
of the patient's face may be on the same side of the face but each
region may correspond to a different nerve branch, foramina or etc.
For example, the first region may correspond to the supraorbital
nerve and the second region may correspond to the infraorbital
nerve. The electrode assembly 20 may also include an insulated
region 116 or a plurality of insulated regions 116 configured to
separate the individual electrode contacts. The first pair of
contacts comprises a first upper contact 112a and a first lower
contact 112b, while the second pair of contacts comprises a second
upper contact 112c and a second lower contact 112d. The electrode
assembly 20 comprises four electrodes that deliver the stimulation
pulses to the nerves bilaterally. While the electrode assembly 20
is shown in FIG. 2B with only pairs of electrical contacts (112a/b,
112c/d), in other embodiments, there may be a greater or lesser
number of contacts on each of the electrodes 20a and 20b.
[0054] In some embodiments, as shown in FIG. 3, the electrode
assembly 20 may comprise a multicontact electrode 20c with a
plurality of contacts 112 and a plurality of insulated regions 116.
The electrode assembly of FIG. 3 is configured to unilaterally
stimulate both the supraorbital nerve and the infraorbital nerve.
In other embodiments, the electrode assembly may comprise a
plurality of multicontact electrodes which may include a plurality
of contacts and a plurality of insulated regions. In various
embodiments, the geometry or layout of the electrode assembly may
be a linear electrode with a single contact or a series or
plurality of conductive contacts and insulating spaces, or a
flatter, "ribbon" or "strip" electrode, also with the possibility
of one or more conductive area(s) and insulated area(s) on the
surface(s). Those of skill in the art will recognize that other
related geometries are also contemplated to be within the scope of
the present disclosure.
[0055] FIG. 4 depicts still another embodiment of an electrode
assembly 20 that may be used in the system 200. In some
embodiments, as shown in FIG. 4, the electrode assembly 20 may
comprise a multicontact electrode 20d with a plurality of contacts
112 and a plurality of insulated regions 116. The electrode
assembly of FIG. 4 is configured to unilaterally stimulate at least
one of the auriculotemporal nerve or the zygomaticofacial nerve. In
other embodiments, the electrode assembly 20d may be configured to
stimulate both the auriculotemporal nerve and the zygomaticofacial
nerve. As can be understood from FIG. 4, in one embodiment, the
electrode assembly may be implanted unilaterally. The electrode
assembly is configured to be placed at, near or over a superficial
foramina in the face and simultaneously or asynchronously stimulate
one or more different trigeminal nerves (e.g. the auriculotemporal
nerve and/or the zygomaticofacial nerve). In other embodiments, the
electrode assembly may be implanted bilaterally to stimulate the
target nerve on both sides of a patient's face.
[0056] Those skilled in the art will appreciate that various
adaptations and modifications of the above-described embodiments of
the electrode assembly 20 are within the scope and spirit of the
present disclosure. For example, one embodiment of the present
device comprises a unilateral electrode assembly configured for the
unilateral stimulation of ophthalmic nerves (see FIG. 3). In other
embodiments, the implantable electrode assembly may be configured
for the stimulation of the infraorbital nerves or the mentalis
nerves. In other embodiments, an electrode assembly may be
configured for the simultaneous or asynchronous stimulation of a
plurality of elements of the trigeminal nerves, either unilaterally
or bilaterally. In other embodiments, both external, transcutaneous
electrodes and implanted subcutaneous electrodes are used to
simultaneously or asynchronously stimulate one or more branches of
the trigeminal nerves. One example of the external, transcutaneous
electrode assemblies are described in U.S. patent application Ser.
No. 12/898,675, entitled "Systems, Devices and Methods for the
Treatment of Neurological Disorders and Conditions," now U.S. Pat.
No. 8,688,220, referenced herein above.
[0057] For ease of the reader, the remaining discussion is made
with respect to FIG. 2B. However, it is understood that the
disclosure also applies to embodiments which include a single
multicontact electrode with a plurality of contacts, a single
contact electrode, and embodiments which include a plurality of
multicontact electrodes with a plurality of contacts and
embodiments configured for unilateral or bilateral stimulation and
other embodiments within the spirit and scope of the present
disclosure.
[0058] As can be understood from FIG. 2B, the electrode assembly 20
is configured to stimulate both the right and left ophthalmic
nerves either simultaneously or asynchronously. The placement of
the first implanted electrode contact pair 112a, 112b and the
second electrode contact pair 112c, 112d on opposite sides of the
nasal midline assures that stimulation current moves
orthodromically or in the direction of the afferent ophthalmic or
supraorbital nerve. Furthermore, this configuration of the
electrode assembly 20 allows the electrode contact points 112a/112b
and 112c/112d to be stimulated independently and/or unilaterally,
as the response to stimulus may be localized and thus varied from
one side of the midline to the other side. Depending on the
location of the pulse generator, in some embodiments, the
electrodes and/or their connectors (e.g. the wires 40) are longer
than 150 mm where the supraorbital, infraorbital and/or the
mentalis branch is the desired target. For other branches, a
shorter electrode/connector length may be desired depending on the
placement of the pulse generator.
[0059] For stimulations where electrical pulses of a single
polarity are generated, the upper electrode contact points 112a,
112c and lower contact points 112b, 112d have fixed polarities. For
stimulations where electrical pulses of alternating polarities are
generated, the upper contact points 112a, 112c and lower contact
points 112b, 112d have alternating polarities.
[0060] Each of the contacts 112a, 112b, 112c, and 112d .mu.s
configured to deliver an electrical pulse with minimal risk of
scalp tissue injury due to excess charge accumulation, and with
minimal potential for current penetration beyond the inner surface
of the skull bone. The distance between the first implanted
electrode pair 112a, 112b and the second electrode pair 112c, 112d
.mu.s configured to stimulate the ophthalmic nerves while
minimizing any current delivery to the surface of the brain. The
electrode size and the inter-electrode distance of electrode
placement may vary for children and adults, males and females,
depending upon the dimensions of an individual person's
anatomy.
[0061] Electrode assembly 20, and in particular the contact points
112a, 112b, 112c, 112d, may be made of a noble or refractory metal
or compound, such as titanium, titanium nitride, platinum, iridium,
tantalum, niobium, rhenium, palladium, gold, nichrome, stainless
steel, or alloys of any of these, in order to avoid corrosion or
electrolysis which could damage the surrounding tissues and the
device. Other compounds for implantable electrodes will be apparent
to one skilled in the art.
[0062] In various embodiments, the distance between contacts 112a
and 112b and the distance between contacts 112c and 112d can be in
a range greater than, equal to, and/or less than one or more of 0.1
cm, 0.5 cm, 1 cm, 2 cm, 3 cm, 4 cm, 5 cm, 6 cm, 7 cm, 8 cm, 9 cm,
or 10 cm. Those of skill in the art will recognize that one or more
of the above distances can be used as a border of a range of
distances.
[0063] In some embodiments, sensing electrodes may be included in
the electrode assembly to monitor physiological parameters, such as
electroencephalographic data, and permit a feedback system that can
adaptively adjust the stimulation parameters to optimize
therapeutic benefit and safety. In some embodiments, the sensing
electrode is one of the stimulating electrodes and is used for
sensing during the `off` part of the duty cycle. In some
embodiments, the sensing electrode is an additional electrode and
is dedicated to sensing only.
[0064] As shown in FIG. 2B, the electrode assembly may comprise two
implanted electrodes 20a, 20b which are placed adjacent to the
supraorbital foramina of a patient 5, which is located over the
orbital ridge approximately 2.1 to 2.6 cm lateral to the nasal
midline. The superior ends 13a, 13b of the electrodes 20a, 20b
.mu.ndicate the place at which the electrodes 20a, 20b connect to
leads (not shown) for conveying the electrical stimuli from the
pulse generator (not shown). The pulse generator itself may be
placed in a variety of locations under the skin, such as
pectorally, on the back, in the tissues of the neck, or under the
scalp, and the leads placed under the skin of the patient to
connect them. In other embodiments, the pulse generator may be
located externally, such as attached to the patient's clothing.
[0065] In some embodiments, such as the embodiment shown in FIGS.
2A-2B, the neurostimulation is provided using an electrical pulse
generator at the following exemplary settings: frequency between
approximately 20-150 Hz, current between approximately 0.05-20 mA,
pulse duration of between approximately 50-250 microseconds, a duty
cycle of 10% to 50%, for at least one hour per day. For optimal
patient comfort and low power consumption, stimulation parameters
at the lower end of these ranges may be preferred. In other
embodiments, different values of the operational parameters may be
used as described in more detail below. In alternative embodiments,
a single implanted electrode may be used.
[0066] As can be understood from FIG. 3, in one embodiment, the
electrode assembly may be implanted unilaterally. The electrode
assembly may also be configured to stimulate more than one nerve.
For example, as shown in FIG. 3, the electrode assembly is
configured to be placed at, near or over a plurality of superficial
foramina in the face and simultaneously or asynchronously stimulate
different trigeminal nerves (e.g. the supraorbital nerve and the
infraorbital nerve).
[0067] As can be best understood from FIGS. 2A-2B, in one
embodiment, the electrode assembly 20 is implanted in the soft
tissues of the forehead of the patient 5. The electrode assembly 20
is then connected to an implanted pulse generator 30 via the
implanted electrical cables 40, which are placed under or in the
patient's skin. In the illustrated embodiment, the stimulation via
the pulse generator 30 is via electrical cables 40. In alternative
embodiments, the electrical stimulation can be performed
wirelessly, with an external, non-implanted pulse generator, which
uses inductive coupling to deliver energy to the implanted
electrode assembly 20. In other embodiments, the electrode assembly
may be connected to an external pulse generator via wires or
wirelessly.
[0068] The stimulation is carried out at the operational parameters
as described herein. In some embodiments, the values of the
operational parameters are within a range that produces minimal
current penetration into the brain and may further be selected such
that a patient will experience a stimulation sensation, such as
mild tingling over the forehead, scalp, or teeth, without causing
the patient significant discomfort or pain. These values may vary
according to the treatment of interest.
[0069] According to one aspect of the present disclosure, there is
provided a method of treatment of neurological disorders using the
electrode assembly 20, as described above. In one embodiment, the
method of treating neurological disorders comprises implanting the
electrode assembly 20 subcutaneously (e.g. in the forehead of a
patient), connecting the electrode assembly 20 to an implanted
pulse generator 30, and stimulating the electrode assembly 20 at
defined values of the operational parameters. In one embodiment,
the bilateral supraorbital electrode 20 illustrated in FIGS. 2A-2B
is stimulated at a stimulus frequency between about 20 and about
300 Hz, at a pulse-duration between 50 microseconds (.mu.sec) to
250 .mu.sec, at an output current of less than 10 mA at the
cerebral cortex for at least one-half to one hour per day. In some
cases, stimulation can be provided for less than one-half hour per
day or may be provided for up to 24 hours per day.
[0070] Accepted standards of safe stimulation may be incorporated
for chronic stimulation. Parameters may be selected or calculated
to deliver no stimulation or negligible stimulation to the surface
of the brain. The currently accepted safe parameters for chronic
stimulation are less than a charge per phase of <20
.mu.C/cm.sup.2/phase at the surface of the brain (Exp Neurol 1983;
79:397-41). In general, for any region of the surface of the brain,
the cumulative charge per phase resulting from all the electrode
contacts should not exceed this threshold. It is recognized that
these guidelines are subject to change, and that parameters should
be selected which deliver no current or negligible current to the
surface of the brain, while still being sufficient to stimulate the
nerves disclosed herein.
[0071] According to one aspect of the present disclosure, the
method of treating neurological disorders by TNS comprises
selecting optimal values for the operational parameters for the
stimulation of each individual patient. In one embodiment, the
values of the operational parameters are selected such that a
patient will experience a stimulation sensation, such as a mild
tingling over the forehead, scalp, or face, without being in
discomfort or in pain. In some embodiments, lower currents (e.g.
0.05-5 mA) and careful electrode placement may be selected to avoid
recruitment of nerves supplying pain sensation to the teeth. In
some embodiments, lower currents (e.g. 0.05-5 mA) may also be
selected to avoid penetration of the current into the skull and
brain, especially in supraorbital locations.
[0072] In one embodiment, the method of selecting operational
parameters comprises evaluating variables such as the pulse
duration, the electrode current, the duty cycle and the stimulation
frequency; the parameters are selected to ensure that the total
charge, the charge density, and charge per phase are well within
accepted safety limits for the scalp or facial tissue, nerve and
brain while preventing or minimizing current penetration beneath
the bone tissue of the skull. Additionally, in some embodiments,
selection of the electrical stimulation parameters, electrode
design, and inter-electrode distance is made such that the
electrical stimulation zone includes the superficial elements of
the trigeminal nerves (approximately 3-4 mm deep), while preventing
or minimizing current penetration beneath the bone tissue of the
skull.
[0073] In various embodiments, the stimulation parameters delivered
by the implanted pulse generator may be determined (programmed) at
the time the device is surgically implanted. In other embodiments,
these parameters may be modified, controlled, or otherwise
programmed by an external device. This external programming element
communicates with the implanted components wirelessly. This may
take place, for example, by radiofrequency signals, by inductive
coupling, or other means apparent to one skilled in the art.
[0074] In various embodiments, the stimulation is delivered at a
specific pulse width or range of pulse widths. The stimulation can
be set to deliver pulse widths in the range greater than, equal to,
and/or less than one or more of 50 .mu.s, 60 .mu.s, 70 .mu.s, 80
.mu.s, 90 .mu.s, 100 .mu.s, 125 .mu.s, 150 .mu.s, 175 .mu.s, 200
.mu.s, 225 .mu.s, 250 .mu.s, up to 500 .mu.s. Those of skill in the
art will recognized that one or more of the above times can be used
as a border of a range of pulse widths.
[0075] In some embodiments, the stimulation amplitude is delivered
as a voltage or current controlled stimulation. In other
embodiments it can be delivered as a capacitive discharge. In
various embodiments, the current amplitude can be in any range
within a lower limit of about 300 .mu.A and an upper limit of about
30 mA-35 mA, depending on the surface area of the electrodes,
inter-electrode distance, the branch(es) stimulated, and the
modeling data as described above. In some embodiments, the current
used will range from 0.1 mA to 10 mA. In other embodiments, the
current used will range from 0.1-3 mA. In various embodiments, the
amplitude can be in a range greater than, equal to, and/or less
than one or more of 50 .mu.A, 75 .mu.A, 100 .mu.A, 125 .mu.A, 150
.mu.A, 175 .mu.A, 200 .mu.A, 225 .mu.A, 250 .mu.A, 275 .mu.A, 300
.mu.A, 325 .mu.A, 350 .mu.A, 375 .mu.A, 400 .mu.A, 425 .mu.A, 450
.mu.A, 475 .mu.A, 500 .mu.A, 525 .mu.A, 550 .mu.A, 575 .mu.A, 600
.mu.A, 625 .mu.A, 650 .mu.A, 675 .mu.A, 700 .mu.A, 725 .mu.A, 850
.mu.A, 875 .mu.A, 900 .mu.A, 925 .mu.A, 950 .mu.A, 975 .mu.A, 1 mA,
2 mA, 3 mA, 4 mA, 5 mA, 6 mA, 7 mA, 8 mA, 9 mA, 10 mA, 20 mA. Those
of skill in the art will recognize that one or more of the above
amplitudes can be used as a border of a range of amplitudes. The
current may be delivered constantly or intermittently.
[0076] In some embodiments, treatment at a given current amplitude
is delivered so as to minimize or eliminate any spread of current
to the cerebral cortex, while ensuring that accepted limits of
charge density and charge per phase at the brain surface (e.g.,
generally <20 .mu.C/cm.sup.2/phase, Exp Neurol 1983; 79:397-411)
are adhered to, for the safety of the patient. Without wishing to
be bound by any particular theory, it is believed that with the use
of multicontact electrodes as described herein, even lower charge
densities may be employed because more fibers within the nerves may
be engaged in the neurostimulation process.
[0077] In various embodiments, the stimulation can be delivered at
one or more frequencies, or within a range of frequencies. The
stimulation can be set to be delivered at frequencies less than,
equal to, and/or greater than one or more of 50 Hz, 45 Hz, 40 Hz,
35 Hz, 30 Hz, 25 Hz, 20 Hz, 15 Hz, or 10 Hz. In various
embodiments, the stimulation can be set to be delivered at
frequencies greater than, equal to, and/or less than, one or more
of 20 Hz, 30 Hz, 40 Hz, 50 Hz, 60 Hz, 70 Hz, 80 Hz, 90 Hz, 100 Hz,
125 Hz, 150 Hz, up to 300 Hz. Those of skill in the art will
recognize that one or more of the above frequencies can be used as
a border of a range of frequencies.
[0078] In various embodiments, the stimulation is delivered at a
specific duty cycle or range of duty cycles. The stimulation can be
set to be delivered at a duty cycle in the range greater than,
equal to, and/or less than one or more of 5%, 10%, 15%, 20%, 25%,
30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,
95%, or 100%. In some embodiments, to ensure preservation of the
nerve, a duty cycle of 10% to 50% may be preferable. In some
embodiments, duty cycles up to 100% may be useful in particular
circumstances. Those of skill in the art will recognize that one or
more of the above percentages can be used as a border of a range of
duty cycles.
[0079] In some embodiments, an external device may be used to
identify the location of the branch or branches of the trigeminal
nerve that will be targeted in an individual patient for
stimulation by the implanted electrode assembly disclosed herein.
The external device may be used for mapping and targeting the
desired branch or branches of the trigeminal nerve and for
identifying the individual stimulation parameters that are optimal
for efficacy and safety. In one embodiment, the device may include
a plurality of external (transcutaneous) TNS electrodes. The
practitioner approximates the location of the target branch and
affixes the electrodes to the patient's skin above the target
location. Stimulation may be applied and the actual location or
preferred (optimal) stimulation location of the target branch or
branches may be determined. Stimulation parameters may also be
established. Once the location and/or stimulation parameters have
been established via the external device, that data may be used to
help guide the placement of the implanted electrodes for an
individual patient and to establish the customized stimulation
parameters for that patient.
[0080] In addition, the use of external electrodes for stimulation
of the trigeminal nerve may identify individuals who are likely to
derive therapeutic benefit from this minimally invasive system in
addition to the optimal specific locations and parameters of
stimulation based on person-to-person variability. Various
neurodiagnostic, imaging, or cutaneous nerve mapping methods may be
able to delineate differences in individual anatomy to optimize
stimulation for efficacy and/or safety. Furthermore, the use of
this minimally invasive system may allow screening and
identification of those individuals who are likely to derive
benefit from other implantable systems, such as deep brain
stimulation. This can be conceptualized as linking the three
approaches as stage I (external TNS of the trigeminal nerve), stage
II (implanted TNS of the superficial trigeminal nerve), and stage
III (deep brain stimulation), such that stage I can screen for
stage II, and stage II for stage III. By monitoring a patient for
evidence of useful therapeutic effect, such as by reduction in the
severity of symptoms, the results of treatment at one stage may be
used to judge the likely effect of treatment with a more invasive
treatment from a higher stage.
[0081] A method of evaluating the use of trigeminal nerve
stimulation for treatment of a neurological disorder in a patient
is disclosed herein. The method may include applying a
transcutaneous system for stimulation of the trigeminal nerve to
the patient and monitoring the patient for at least one of evidence
of a useful therapeutic response or evidence of tolerability of TNS
treatment, providing a subcutaneous electrode assembly or system as
disclosed herein, and implanting the subcutaneous electrode
assembly or system as disclosed herein in the patient for treatment
of a neurological disorder.
[0082] A method of evaluating the use of deep brain stimulation for
treatment of a neurological disorder in a patient is disclosed
herein. The method may include applying a transcutaneous system for
stimulation of the trigeminal nerve to the patient and monitoring
the patient for at least one of evidence of a useful therapeutic
response or evidence of tolerability of TNS treatment thereby
generating external measurement criteria, providing a subcutaneous
electrode assembly or system as disclosed herein, implanting the
subcutaneous electrode assembly or system as disclosed herein in
the patient for treatment of a neurological disorder, monitoring
the patient for at least one of a useful therapeutic response or
tolerability of the implanted device, thereby generating
extracranial measurement criteria, and analyzing the external
measurement criteria and extracranial measurement criteria to
determine whether the patient will benefit from deep brain
stimulation.
[0083] The following examples are presented to set forth more
clearly the subject matter of this disclosure without imposing any
limits on the scope thereof and to illustrate the clinical benefits
of trigeminal nerve stimulation. In Example 1, patients with
epilepsy were treated by TNS with external transcutaneous
electrodes. In the second example, a patient was treated using
transcutaneous electrodes for bilateral supraorbital
stimulation.
Example 1
[0084] FIG. 5 illustrates the results from a pilot study of
external trigeminal nerve stimulation. Research subjects with
epilepsy who met inclusion and exclusion criteria for a pilot
feasibility study of external trigeminal nerve stimulation were
enrolled in this study. Subjects initially participated in a
1-month baseline period where seizures were counted, followed by
active stimulation of the infraorbital or ophthalmic branch of the
trigeminal nerve. Inclusion criteria were: subjects with poorly
controlled epilepsy; ages 18-65 years; at least three
complex-partial or generalized tonic-clonic seizures per month; no
serious or progressive medical or psychiatric conditions; and
exposure to at least 2 antiepileptic drugs (AED's). Subjects with a
vagus nerve stimulator were excluded from the study. All subjects
received unblinded TNS augmentation (adjunctive) treatment for at
least 8-12 hours each day. Assessments were made at study intake
and at monthly periodic visits for three months following the
one-month baseline. These initial assessments were then followed-up
with visits to a neurologist skilled in epilepsy for three to six
month intervals for up to three years or as approved by the local
Institutional Research Committee.
[0085] Subjects underwent stimulation using an electrical
stimulator, such as the EMS Model 7500 commercially available from
TENS Products, Inc. (Grand Lake, Colo.) at a frequency of 120
Hertz, a current less than 20 mA, pulse duration of 250 .mu.pec,
and a duty cycle at 15 to 30 seconds on and 15 to 30 seconds off,
for a minimum of 8 hours per day.
[0086] FIG. 5 illustrates the clinical results from this pilot
study showing the effectiveness of external trigeminal nerve
stimulation. Five of twelve subjects experienced greater than 50%
reduction in adjusted mean daily seizure rate at 6 and 12 months of
treatment. Mean reduction at 3 months was 66% and was 59% at 12
months. (DeGiorgio et al., Neurology 2009; 72:936-938). Overall,
the data from the table of FIG. 5 show that the trigeminal nerve
stimulation using the described operational parameter values was
effective in reducing seizures and was well tolerated by the
subjects tested. No serious adverse events were reported.
Importantly, the therapeutic effect of the device was observed in
several standard measures, indicating the broad-reaching benefits
of this treatment on a variety of outcome measures.
Example 2
[0087] FIG. 6 summarizes current, charge, current density and
charge density in a subject exposed to transcutaneous stimulation
of the supraorbital nerve. FIG. 6 illustrates representative
parameters for bilateral supraorbital stimulation recorded in a
subject using an EMS 7500 stimulator, 120 HZ, 150-250 .mu.sec, Tyco
superior silver electrodes 1.25'', one inch from the midline above
the eyebrows. Data recorded with Fluke Oscilloscope, 50 mV/div,
resistor=10.1.OMEGA.. In general, these findings show that as the
pulse width increased, the maximum tolerable current decreased.
[0088] Transcutaneous electrical stimulation of the supraorbital
branch of the trigeminal nerve with round 1.25-inch TENS patch
electrodes results in current densities and charge density/phase
that are well within the limits of safety. In general, the maximum
current comfortably tolerated by TNS patients studied previously is
approximately 25 mA's, and patients typically are stimulated at an
amplitude setting well below 25 mA's (6-10 mA's).
[0089] The 1.25-inch TENS electrodes are circular electrodes with a
radius of 1.59 cm. The surface area can be calculated as
A=.pi..sup.2=[.pi.].times.[1.59 cm].sup.2=7.92 cm.sup.2. Using
these electrodes, typical stimulation current ranges from 6-10 mA
at pulse durations of 150-250 .mu.sec.
[0090] Current Density: In a typical subject, stimulation currents
of 6-10 mA result in current densities ranging from 0.76 to 1.3
mA/cm.sup.2. McCreery et al have established a maximum safe current
density of 25 mA/cm at the stimulating electrode for transcranial
electrical stimulation. Assuming even higher currents of up to 25
mA with electrodes of surface area 7.92 cm.sup.2, current densities
may range to a maximum of 3.16 mA/cm.sup.2. From 0.76 mA/cm.sup.2
to 3.16 mA/cm.sup.2, TNS delivers a current density 8-33 times less
than the maximum safe allowable current density. Charge Density
(Charge density/phase): Yuen et al. have identified a safe limit
for charge density/phase delivered at the cerebral cortex of 40
.mu.C/cm.sup.2 [Yuen et al., 1981] and more recently McCreery et
al. (McCreery et al., 1990) have identified 10 .mu.C/cm.sup.2 as
the safe limit. Assuming 10 mA at 250 .mu.sec, the charge
density/phase is [0.010 A].times.[250 .mu.sec]/7.92=0.32
.mu.C/cm.sup.2 at the stimulating electrode. Assuming even higher
levels of stimulation, 25 mA at 250 .mu.sec, the maximum charge
density per phase is 0.79 .mu.C/cm.sup.2. At these levels, the
charge density is generally 12 to 120 fold less at the stimulating
electrode than the maximum allowed at the cerebral cortex. Since
the cortex is a minimum of 10-13 mm from the stimulating
electrodes, and given the interposed layers of skin, fat, bone,
dura, and CSF, the actual charge densities will be significantly
lower. This is of importance in avoiding the undesired passage of
current directly through brain tissue as a bulk conductor.
[0091] As shown in FIG. 6, stimulation intensity responses in a
subject with electrodes of surface area 7.92 cm2, at pulse
durations between 150-250 .mu.sec, results in current densities at
the scalp well below currently recommended current densities for
transcranial stimulation, which are 25 mA/cm.sup.2, and charge
densities at the scalp significantly lower than safe charge
densities at the cerebral cortex (0.15-0.18 .mu.C/cm.sup.2).
[0092] Those skilled in the art will appreciate that various
adaptations and modifications of the above described preferred
embodiments may be configured without departing from the scope and
spirit of this disclosure. Stimulation of the target nerve may be
accomplished by application of energy in many forms, such as
magnetic or ultrasonic. Therefore, it is to be understood that the
subject matter of this disclosure may be practiced other than as
specifically described herein.
* * * * *