U.S. patent application number 14/196990 was filed with the patent office on 2014-07-03 for systems, devices and methods for the treatment of neurological disorders and conditions.
This patent application is currently assigned to THE REGENTS OF THE UNIVERSITY OF CALIFORNIA. The applicant listed for this patent is THE REGENTS OF THE UNIVERSITY OF CALIFORNIA. Invention is credited to Ian A. Cook, Alejandro Covalin, Christopher M. DeGiorgio.
Application Number | 20140188200 14/196990 |
Document ID | / |
Family ID | 43857099 |
Filed Date | 2014-07-03 |
United States Patent
Application |
20140188200 |
Kind Code |
A1 |
DeGiorgio; Christopher M. ;
et al. |
July 3, 2014 |
SYSTEMS, DEVICES AND METHODS FOR THE TREATMENT OF NEUROLOGICAL
DISORDERS AND CONDITIONS
Abstract
The present disclosure relates to methods, devices, and systems
used for the treatment of and/or promoting recovery from various
neurological disorders and conditions, including epilepsy and other
seizure disorders and movement and other related disorders; for
promoting recovery from acute or chronic brain injury (e.g. stroke,
hypoxia/ischemia, head trauma, subarachnoid hemorrhage, and other
forms of brain injury, for awakening and/or promoting the recovery
of patients in various levels of coma, altered mental status or
vegetative state); or for promoting recovery from chronic daily
headache and migraine and related disorders via external
(cutaneous) stimulation of the sensory branches of the trigeminal
nerve in the face and forehead. More specifically, devices and
electrode assemblies configured for stimulation of the
supraorbital, supratrochlear, infraorbital, auriculotemporal,
zygomaticotemporal, zygomaticoorbital, zygomaticofacial, nasal and
infratrochlear nerves are disclosed.
Inventors: |
DeGiorgio; Christopher M.;
(Valencia, CA) ; Cook; Ian A.; (Los Angeles,
CA) ; Covalin; Alejandro; (Culver City, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
THE REGENTS OF THE UNIVERSITY OF CALIFORNIA |
Oakland |
CA |
US |
|
|
Assignee: |
THE REGENTS OF THE UNIVERSITY OF
CALIFORNIA
Oakland
CA
|
Family ID: |
43857099 |
Appl. No.: |
14/196990 |
Filed: |
March 4, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12898675 |
Oct 5, 2010 |
8688220 |
|
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14196990 |
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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: |
607/115 |
Current CPC
Class: |
A61N 1/36096 20130101;
A61N 1/36064 20130101; A61N 1/36082 20130101; A61N 1/36025
20130101; A61N 1/36067 20130101; A61N 1/36021 20130101; A61N 1/3616
20130101; A61N 1/0504 20130101; A61N 1/0456 20130101; A61N 1/0529
20130101; A61N 1/36175 20130101; A61N 1/0476 20130101; A61N 1/36171
20130101; A61N 1/0492 20130101; A61N 1/36075 20130101; A61N 1/0551
20130101 |
Class at
Publication: |
607/115 |
International
Class: |
A61N 1/04 20060101
A61N001/04 |
Claims
1. A system for trigeminal nerve stimulation for treatment of a
neurological disorder or condition, the system comprising: a pulse
generator; and a cutaneous electrode assembly in electrical
communication with the pulse generator, the assembly comprising: a
first electrode comprising at least one contact configured for
cutaneous placement over an ophthalmic nerve on one side of a
patient's forehead; a second electrode comprising at least one
contact configured for cutaneous placement over an ophthalmic nerve
on an opposing side of the patient's forehead; and an insulating
region surrounding each of the first and second electrodes.
2. The system of claim 1, further comprising a wire operably
connecting the pulse generator and the cutaneous electrode
assembly.
3. The system of claim 1, further comprising a regulating device
configured to regulate a maximum charge balanced output current
below approximately 30-50 mA.
4. The system of claim 1, wherein 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.
5. The system of claim 1, wherein 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.
6. A method for treating a neurological disorder or condition by
trigeminal nerve stimulation, comprising: aligning a cutaneous
electrode assembly with the nasal midline of a patient, wherein the
cutaneous electrode assembly includes a first contact separated
from a second contact by an expected separation between the
ophthalmic nerves on the patient's forehead; applying the aligned
cutaneous electrode assembly on the patient's forehead such that
the first contact overlays a first one of the ophthalmic nerves and
the second contact overlays a remaining second one of the
ophthalmic nerves on the patient's forehead; and driving electrical
signals through the applied cutaneous electrode assembly to treat
the neurological disorder or condition.
7. The method of claim 6, wherein the step of driving electrical
signals comprises driving 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.
8. The method of claim 6, wherein the step of driving electrical
signals comprises driving 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.
9. The method of claim 6, wherein 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.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 12/898,675, filed Oct. 5, 2010, which in turn claims the
benefit of priority under 35 U.S.C. .sctn.119(e) to the following
applications: U.S. Application No. 61/248,827, entitled "Devices
and Methods for Treatment of Psychiatric Disorders," filed Oct. 5,
2009; U.S. Application No. 61/289,829, entitled "Extracranial
Implantable Devices, Systems and Methods for Treatment of
Neuropsychiatric Disorders," filed Dec. 23, 2009; U.S. Application
No. 61/305,514, entitled "Systems, Devices and Methods for
Treatment of Neurological Disorders and Conditions," filed Feb. 17,
2010; and U.S. Application No. 61/354,641, entitled "Extracranial
Implantable Devices, Systems and Methods for Treatment of
Neurological Disorders," filed Jun. 14, 2010, and each of the above
applications is hereby incorporated by reference as though fully
set forth herein.
[0002] This application is also related to the following copending
applications: U.S. application Ser. No. 12/898,685, entitled
"Extracranial Implantable Devices, Systems and Methods for
Treatment of Neuropsychiatric Disorders," filed on Oct. 5, 2010;
U.S. application Ser. No. 12/898,686, now U.S. Pat. No. 8,380,315,
entitled "Devices, Systems and Methods for Treatment of
Neuropsychiatric Disorders," filed on Oct. 10, 2010; U.S.
application Ser. No. 13/769,074 entitled "Devices, Systems and
Methods for Treatment of Neuropsychiatric Disorders", filed Feb.
15, 2013; U.S. application Ser. No. 12/898,696, entitled
"Extracranial Implantable Devices, Systems and Methods for
Treatment of Neurological Disorders," filed on Oct. 5, 2010, and
each of the above applications is hereby incorporated by reference
as though fully set forth herein.
TECHNICAL FIELD
[0003] The present disclosure generally relates to cutaneous
neurostimulator systems, devices and methods of using the same and
more particularly relates to cutaneous neurostimulator systems,
devices and methods for treating or promoting recovery from
neurological disorders or conditions, such as seizure disorders,
movement disorders, headache, acute or chronic brain injury,
altered mental status/coma, and other brain-related disorders and
conditions, by stimulating the superficial sensory branches of
cranial nerves.
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, movement
and related disorders, may be treated with medications and, in
certain cases, brain surgery. For example, currently available
treatment methods for epilepsy and other seizure related disorders
may include stimulation of the nervous system by vagus nerve
stimulation (VNS), which 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, implantable approaches, including deep brain stimulation
(DBS) of the anterior thalamus and intracranial stimulation of the
epileptic zone via a device which monitors brain activity and
delivers stimuli to terminate an impending seizure discharge, are
also being studied. However, these methods are invasive and may
have increased costs and side effects. Further, a substantial
percentage of patients do not recover from or get adequate relief
for the neurological condition or 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 a method of
treating neurological disorders and conditions and a system and
device configured to stimulate superficial (cutaneous) aspects of
the ophthalmic (supra-orbital), infra-orbital, and mentalis
branch(es) of the trigeminal nerve, specifically by providing a
method of treating neurological disorders and conditions using
cutaneous stimulation of the trigeminal nerve (TNS). In yet another
aspect of the present disclosure, a method of treating neurological
disorders and conditions using the disclosed electrode assembly is
provided.
[0007] According to one aspect of the present invention, a method
for treating a neurological disorder or condition by trigeminal
nerve stimulation is provided. The method may include attaching an
electrode assembly to a patient. The electrode assembly may include
a first pair of contacts configured for placement on a first region
of the patient's face; a second pair of contacts configured for
placement on a second region of the patient's face; and an
insulating connection region connecting the first pair of contacts
and the second pair of contacts, wherein the first pair of contacts
and the second pair of contacts are configured to contact a portion
of the patient's face overlying at least one branch of the
trigeminal nerve. The method may further include applying
electrical signals to the electrode assembly at specified
operational parameters to treat a neurological disorder or
condition. In some embodiments, the operation of applying
electrical signals may include applying the 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/or an output
charge density of not greater than approximately 10
microCoulomb/cm.sup.2 at the cerebral cortex. In some embodiments,
the electrode assembly is attached to the patient so as to contact
the skin surface over at least one of an ophthalmic or a
supraorbital nerve. In some embodiments, the neurological disorder
or condition is epilepsy and other seizure related disorders. In
some embodiments, the neurological disorder or condition is acute
or chronic brain injury. In some embodiments, the neurological
disorder or condition is chronic daily headache and migraine and
related disorders. In some embodiments, the neurological disorder
is a movement disorder.
[0008] In another aspect of the present disclosure, an electrode
assembly may be configured for cutaneous trigeminal nerve
stimulation. In some embodiments, the electrode assembly may be a
component of a system or a kit. According to one aspect of the
present disclosure, a cutaneous electrode assembly for trigeminal
nerve stimulation is provided. The cutaneous electrode assembly may
include a first electrode having a first pair of contacts
configured for placement on a first region of a patient's face; a
second electrode having a second pair of contacts configured for
placement on a second region of a patient's face; and an insulating
connection region connecting the (electrodes) first pair of
contacts and the second pair of contacts, wherein the first pair of
contacts and the second pair of contacts are configured to contact
a portion of the patient's face overlying the cutaneous
distribution of at least one branch of the trigeminal nerve for
treatment of a neurological disorder or condition. The at least one
branch of the trigeminal nerve may be selected from the group
consisting of: superficial ophthalmic branch, infraorbital branch,
and mentalis branch. In some embodiments, the electrode assembly
may further include a retainer element configured to secure the
electrode assembly to a patient's forehead.
[0009] In another aspect of the present disclosure, a system for
trigeminal nerve stimulation for treatment of a neurological
disorder or condition is disclosed. In one embodiment, the system
includes a neurostimulator and a cutaneous electrode assembly
including: a first electrode having a first pair of contacts
configured for placement on a first region of the patient's face; a
second electrode having a second pair of contacts configured for
placement on a second region of the patient's face; and an
insulating connection region connecting the electrodes and the
first pair of contacts and the second pair of contacts, wherein the
first pair of contacts and the second pair of contacts are
configured to contact a portion of the patient's face overlying at
least one branch of the trigeminal nerve. The system may further
include a cable and/or lead wires operably or electrically
connecting the neurostimulator and the cutaneous electrode
assembly. In one embodiment, the at least one branch of the
trigeminal nerve is selected from the group consisting of:
superficial ophthalmic branch, infraorbital branch, and mentalis
branch. The system may further include a retainer element
configured to secure the electrode assembly to a patient's
forehead.
[0010] In another aspect, a system for trigeminal nerve stimulation
for treatment of a neurological disorder or condition is disclosed.
In one embodiment, the system includes: a pulse generator; and a
cutaneous electrode assembly in electrical communication with the
pulse generator. The electrode assembly may include: a first
electrode comprising at least one contact configured for cutaneous
placement at a first region of the patient's face, wherein the
first electrode is configured to contact a portion of the patient's
face overlying at least one branch of the trigeminal nerve, 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 cutaneous placement at a second region
of the patient's face, wherein the second electrode is configured
to contact a portion of the patient's face overlying 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 to contact a
portion of the patient's face overlying a same branch of the
trigeminal nerve. In some embodiments, the first electrode and the
second electrode are configured to contact a portion of the
patient's face overlying a different branch of the trigeminal
nerve. The system may further include a wire operably connecting
the pulse generator and the cutaneous electrode assembly. 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.
[0011] In another aspect, a cutaneous electrode assembly for
trigeminal nerve stimulation for treatment of a neurological
disorder or condition is disclosed. In one embodiment, the assembly
includes: a first electrode comprising at least one contact
configured for cutaneous placement at a first region of the
patient's face, wherein the first electrode is configured to
contact a portion of the patient's face overlying at least one
branch of the trigeminal nerve, 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 cutaneous placement
at a second region of the patient's face, wherein the second
electrode is configured to contact a portion of the patient's face
overlying 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 one embodiments,
the first electrode and the second electrode are configured to
contact a portion of the patient's face overlying a same branch of
the trigeminal nerve. In one embodiment, the first electrode and
the second electrode are configured to contact a portion of the
patient's face overlying 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.
[0012] In another aspect, a method for treating a neurological
disorder or condition by trigeminal nerve stimulation is disclosed.
In one embodiment, the method comprises: contacting a first region
of a patient's face with a cutaneous electrode assembly, the
cutaneous electrode assembly comprising: a first electrode
comprising at least one contact configured for cutaneous placement
at a first region of the patient's face, wherein the first
electrode is configured to contact a portion of the patient's face
overlying at least one branch of the trigeminal nerve, 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 one embodiment, the assembly further comprises a
second electrode comprising at least one contact configured for
cutaneous placement at a second region of the patient's face,
wherein the second electrode is configured to contact a portion of
the patient's face overlying 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 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 5
milliamperes (mA) and 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 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. 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.
[0013] In another aspect, a kit for trigeminal nerve stimulation
for treatment of a neurological disorder or condition is disclosed.
The kit may include the cutaneous electrode assembly as described
herein and instructions for placement of the electrode assembly on
a patient for treatment of a neurological disorder or condition.
The kit may further include a neurostimulator and instructions for
applying electrical signals to the electrode assembly for treatment
of a neurological disorder or condition.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] 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:
[0015] FIGS. 1A-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;
[0016] FIG. 2 shows an example of a subject wearing one embodiment
of a cutaneous electrode assembly according to a method of
neurological disorder and condition treatment by TNS provided
according to aspects of the present disclosure;
[0017] FIG. 3A is an enlarged view of the cutaneous electrode
assembly of FIG. 2;
[0018] FIG. 3B illustrates representative dimensions of the
cutaneous electrode assembly of FIG. 3A;
[0019] FIGS. 4A-4C depict various embodiments of the cutaneous
electrode assembly of FIG. 2;
[0020] FIG. 5 illustrates the results from a pilot study of
external trigeminal nerve stimulation ("TNS"); and
[0021] FIG. 6 summarizes one embodiment of current, charge, current
density and charge density parameters for a subject exposed to
cutaneous stimulation of the supraorbital nerve.
DETAILED DESCRIPTION
[0022] The present disclosure relates to methods, devices, and
systems used for the treatment of and/or promoting recovery from
various neurological disorders and conditions, including epilepsy
and other seizure disorders and movement and other related
disorders; for promoting recovery from acute or chronic brain
injury (e.g. stroke, hypoxia/ischemia, head trauma, subarachnoid
hemorrhage, and other forms of brain injury, for awakening and/or
promoting the recovery of patients in various levels of coma,
altered mental status or vegetative state); or for promoting
recovery from chronic daily headache and migraine and related
disorders via external (cutaneous) stimulation of the sensory
branches of the trigeminal nerve in the face and forehead. More
specifically, devices and electrode assemblies configured for
stimulation of the sensory components of the ophthalmic nerve and
its branches, the infraorbital nerve and its branches, and the
mentalis nerves or its branches, and including the supraorbital,
supratrochlear, infraorbital, auriculotemporal, zygomaticotemporal,
zygomaticoorbital, zygomaticofacial, nasal and infratrochlear
nerves. Methods for the treatment of seizure disorders, such as
epilepsy, and other neurological disorders and conditions by eTNS
(external trigeminal nerve stimulation) are also provided. The
methods, systems and devices described herein may be noninvasive or
minimally invasive.
[0023] The methods, devices and systems described herein may also
enhance neurological function, alertness, attention, and cognitive
function after various forms of brain injury, e.g., stroke, head
injury, hypoxic/ischemic brain injury, and/or other forms of acute
and chronic brain injury and/or with respect to movement and other
related disorders. The use of a cutaneous device as described
herein may allow for rapid intervention soon after brain injury
thereby possibly enhancing neurological recovery by stimulating the
cutaneous branches of the trigeminal nerve. The unique anatomy of
the trigeminal nerve, and its direct and indirect projections to
key areas of the brainstem, thalamus and cortex involved with
sensory processing, attention, and autonomic function, may allow
the use of external stimulation for a variety of neurological
conditions in which stimulation may be desirable.
[0024] 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 epilepsy and other neurological conditions and
disorders (e.g. 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
uC/cm2 at the cerebral cortex, or (2) calculated, measured, or
modeled charge densities below the following thresholds: (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/cm2 in one
embodiment, and, in other embodiments, a charge density of less
than 0.001 to 0.1 .mu.C/cm2, 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.
[0025] 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) systems and electrode assemblies configured for cutaneous
trigeminal nerve stimulation; and (2) methods of treating
neurological disorders and conditions, including epilepsy and other
seizure disorders, by superficial trigeminal nerve stimulation
using the electrode assembly.
[0026] 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 cranial nerve and has
extensive connections with the brainstem and other brain
structures. The trigeminal nerve has three major sensory branches
over the face, all of which are bilateral, and highly accessible.
The supraorbital nerve, or ophthalmic nerve, is frequently referred
to as the V1 division. The infraorbital branch, or the maxillary
nerve, is commonly referred to as the V2 division. The superficial
branch, or the mandibular nerve (also known as the mentalis
branch), is referred to as the V3 division. The supraorbital nerve
supplies sensory information about pain, temperature, and light
touch to the skin of the forehead, the upper eyelid, the anterior
part of the nose, and the eye. The infraorbital branch supplies
sensory information about pain, temperature, and light touch
sensation to the lower eyelid, cheek, and upper lip. The mentalis
branch supplies similar sensory modalities to the jaw, tongue, and
lower lip.
[0027] As can be understood from FIGS. 1A and 1B, these branches
exit the skull through three foramina. The supraorbital nerve or
ophthalmic nerve exits at foramen 1 (the supraorbital foramen or
notch), 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 nasal nerve is a division of the
ophthalmic nerve. The infraorbital branch or maxillary nerve exits
at foramen 2 (the infraorbital foramen), approximately 2.4-3.0 cm
from the nasal midline (in adults) and the mentalis nerve exits at
foramen 3 (the mentalis foramen) approximately 2.0-2.3 cm from the
nasal midline (in adults). Other sensory branches, including the
zygomaticofacial, zygomaticoorbital, zygomaticotemporal, and
auriculotemporal, arise from other foramina
[0028] 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, the mesencephalic nucleus of V, and the spinal
nucleus and tract of 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. Afferent sensory fibers project from the trigeminal
nuclei to the thalamus and the cerebral cortex.
[0029] The trigeminal nucleus has projections to the nucleus
tractus solitarius (NTS), the locus ceruleus, the cerebral cortex,
and the vagus nerve. 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 ceruleus.
[0030] The locus ceruleus 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 broad number of brainstem, sub-cortical and cortical structures,
and is an important part of the reticular activating system. The
locus ceruleus is a core part of the brainstem noradrenergic
pathway, and produces the neurotransmitter norepinephrine.
Norepinephrine plays a key role in attention, alertness, blood
pressure and heart rate regulation, anxiety and mood.
[0031] 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, cutaneous stimulation of the trigeminal nerve at custom
tailored settings and parameters within a predefined range could be
effective in the treatment of multiple neurological disorders.
Neurological Disorders
[0032] Coma and Vegetative State.
[0033] 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.
[0034] Headache and Migraine.
[0035] 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.
[0036] Movement Disorders.
[0037] 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.
[0039] 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 orofacially, 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.
[0040] Seizure Disorders.
[0041] 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
[0042] Accordingly, stimulation of the superficial or cutaneous
branches of the trigeminal nerve as disclosed herein provides an
avenue for non-invasive neuromodulation. 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.
[0043] For a discussion of certain embodiments of methods, systems
and devices using cutaneous electrodes according to aspects of the
present disclosure, reference is made to FIGS. 2-4C. FIGS. 2-4C
illustrate various embodiments of a cutaneous electrode assembly
and system according to aspects of the present disclosure.
[0044] One sample embodiment of the present disclosure takes the
form of a method of treating epilepsy and related seizure disorders
and other neurological disorders and conditions as described herein
using trigeminal nerve stimulation ("TNS"). Broadly speaking, the
method of treatment includes positioning external electrodes over
or near at least one of the foramina or branches of the trigeminal
nerve (FIG. 1A-1B), and stimulating the electrodes using a
stimulator or pulse generator for a fixed time at specified
operational parameters. In one embodiment, the external electrodes
are positioned over the foramina of the supraorbital or ophthalmic
nerves (FIG. 1A, Foramen 1) since unilateral or bilateral
stimulation of the trigeminal nerve is achievable by placing single
or separate electrodes on the right and/or left sides of a
patient's face (e.g. by placing an electrode assembly, such as two
separate electrodes, a single paired electrode or two pairs of
electrodes, over the forehead or other region of the patient's
face). In one embodiment, the electrode assembly is configured for
unilateral stimulation. In one embodiment, the electrode assembly
is stimulated 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. FIG. 2 shows an example of a
patient 5 wearing an electrode assembly 10 on the forehead,
corresponding to the foramina of the ophthalmic nerves. In
alternative embodiments, the electrode assembly 10 can be
positioned over the foramina of the maxillary nerves (FIG. 1A,
Foramen 2) or the mandibular nerves (FIG. 1B, Foramen 3). In yet
other embodiments, the stimulation can be unilaterally applied to
one foramen of the trigeminal nerves. In other embodiments, the
method of treating epilepsy and related seizure disorders and other
neurological disorders and conditions as described herein comprises
positioning external electrodes over a plurality of foramina and
simultaneously stimulating different trigeminal nerves. In other
embodiments, electrodes may be positioned at a region of the
patient's face (on the right and/or left side) corresponding with
the supratrochlear nerve, infratrochlear nerve, zygomaticotemporal,
zygomaticofacial, zygomaticoorbital, nasal and/or auriculotemporal
nerves and/or their respective foramina.
[0045] In one embodiment, as can be understood from FIGS. 2-4C, a
system 100 for treatment of neurological disorders and conditions
via TNS includes an electrode assembly 10, a neurostimulator or
pulse generator 15 and electrical cable or wire 20. The electrode
assembly 10 may be configured for the bilateral simultaneous and
asynchronous stimulation of the ophthalmic nerves. In other
embodiments, the electrode assembly may be configured for
unilateral or bilateral stimulation of one or more branches of the
trigeminal nerve as disclosed elsewhere herein. The neurostimulator
or pulse generator may be any type of appropriate stimulating,
signal-generating device. In the illustrated embodiment, the
stimulator 15 is portable and attached to the belt of the patient
5. However, either a portable or non-portable stimulator can be
used. In one embodiment, the electrical cable or wire 20 is
configured to provide a physical and electrical link between the
stimulator 15 and the electrode assembly 10 via lead wires. In
other embodiments, the stimulator 15 and the electrode assembly 10
communicate wirelessly (i.e. the wire 20 and lead wires are not
used). The system 100 and/or the electrode assembly 10 may be a
part of a kit. In some embodiments, the kit may also include
instructions for placement of the electrode assembly and/or the
system. In some embodiments, the kit may also include instructions
for treatment of a neurological disorder or condition according to
a method disclosed herein.
[0046] The cutaneous electrode assembly 10 shown in the illustrated
embodiment is also referred to as a bilateral supraorbital
electrode. As shown in FIGS. 3A and 3B, the electrode assembly 10
includes a first pair of electrodes (also referred to as contacts)
12a, 12b for placement on a first region of the patient's face, and
a second pair of electrodes (also referred to as contacts) 14a, 14b
for placement on a second region of the patient's face. In some
embodiments, the first region is the right side of the patient's
face and the second region is the left side of the patient's face.
The first pair of contacts comprises a first upper contact 12a and
a first lower contact 12b, while the second pair of contacts
comprises a second upper contact 14a and a second lower contact
14b. An insulative connection region 16 connects the first and
second contact pairs to each other. The electrode assembly 10
comprises an inner contact surface 18 that comes into contact with
a patient's skin at four contact areas, each corresponding to one
of the four contacts 12a, 12b, 14a, 14b. The inner contact surface
18 comprising the four contact areas may also include a buffered
gel-like adhesive that provides good electrical conductivity with
minimum skin irritation, an example of such gel includes the
commercially available hydrogels from AmGel Technologies (AmGel
Technologies, Fallbrook, Calif. USA).
[0047] Optionally, the electrode assembly 10 comprises a retainer
element 24 configured to secure the electrode assembly to a
patient's forehead. In one embodiment, the retainer element 24 can
be an elastic band or strap. In alternative embodiments, the
electrode assembly 10 can be secured in place by a hat, band, or a
cap, which may also serve to conceal the electrode assembly from
view or an appropriate adhesive.
[0048] In some embodiments, the system 100 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 mA, 0-10 mA, 0-15 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, (mentalis), where current ranges may be higher or
lower. Current TENS units stimulate with maximum output currents of
up to 100 mA's, which result in currents which may penetrate the
skull and which may not be well tolerated.
[0049] The electrode assembly 10 as shown in FIGS. 3A and 3B is
configured to stimulate both the right and left ophthalmic nerves
either simultaneously or asynchronously. The insulative connection
region 16 serves to assist a patient in lining up the electrode
assembly 10 with the midline of the nose to ensure proper placement
of the electrode assembly 10 over both ophthalmic nerves, which lie
on the average about 2.1 to 2.6 cm from the nasal midline of an
adult patient. Thus, the electrode assembly can be placed
accurately (e.g. by the patient) without knowledge of the location
of the ophthalmic nerve or key landmarks relative to the nerve,
thereby reducing the possibility of inadequate stimulation due to
errors in positioning of the electrodes. FIGS. 4A-4C illustrate
other embodiments of the electrode assembly 10, which
configurations may be used to stimulate the right and/or left
ophthalmic nerve and/or other branches of the trigeminal nerve as
disclosed herein, such as the zygomaticofacial and/or the
auriculotemporal nerves. It can be appreciated that a single
electrode or multiple electrodes may be used. The bilateral
supraorbital electrode is configured for bilateral supraorbital
stimulation. It is scalable based on the location of use,
stimulation parameters, and input from computer modeling so as to
negate or minimize or render safe current penetration into the
brain. As skin irritation may occur, a similar configuration could
be applied unilaterally, so as to provide relief to one side of the
forehead, to promote skin tolerability and to reduce the risk of
irritation. Other configurations of size and inter electrode
distance can be conceived for different branches of the trigeminal
nerve, including but not limited to those as shown in FIGS.
4A-4C.
[0050] The placement of the first contact pair 12a, 12b and the
second contact pair 14a, 14b 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 10 allows
the contact pairs 12a,12b and 14a,14b 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. That is, the presently disclosed electrode assembly
permits individual adjustment of current for the first and second
regions or right and left sides, as applicable, thereby reducing
asymmetric stimulation and/or perceived asymmetric stimulation.
[0051] For stimulations wherein electrical pulses of a single
polarity are generated, the upper contacts 12a, 14a and lower
contacts 12b, 14b may have fixed polarities. For stimulations
wherein electrical pulses of alternating polarities are generated,
the upper contacts 12a, 14a and lower contacts 12b, 14b may have
alternating polarities. Also, the inferior electrode typically
serves as the cathode for the leading phase of the stimulating
pulse. In the case of a monophasic stimulation, the inferior
electrode generally becomes the cathode.
[0052] FIG. 3B illustrates the dimensions of one embodiment of the
cutaneous or supraorbital electrode assembly of FIG. 2 to show the
relative relationship of the electrodes from the midline and from
each other. The size of the electrodes and the inter-electrode
distance are sized to facilitate current delivery to the skin and
nerve, while reducing and/or minimizing current density beyond the
inner table ((dense layer) of the skull (inner skull bone). As
explained in this disclosure, the systems, devices and methods of
this disclosure are configured to minimize current penetration into
the brain.
[0053] Dimensions of one embodiment of the electrode assembly are
shown in FIG. 3B. The surface area, relationship between the
electrode contacts and the midline, and the inter-electrode
distances are each important factors to minimize the potential for
skin or nerve injury, for ensuring adequate stimulation of each
nerve, and to minimize current flow (penetration) through the skull
and into the brain tissue. The current flow to the electrode, the
on/off time, time of use and frequency of stimulation are also
important to ensure adequate safety and efficacy. The electrode
dimensions are scalable for use with different output currents and
pulse duration.
[0054] As can be understood from FIG. 3B, each contact 12a, 12b,
14a, 14b is sized to deliver an electrical pulse over a large
enough surface area to minimize any skin injury due to excess
charge density, and to minimize current penetration beyond the
inner surface of the skull bone. The distance between the first
contact pair 12a, 12b and the second contact pair 14a, 14b is
configured to stimulate the ophthalmic nerves while minimizing any
current delivery to the surface of the brain. In one embodiment,
the mid-point of each of the electrodes is approximately 2.5 cm
(range 2.1-2.6 cm) from the nasal midline. The electrode size and
the inter-electrode distance may vary for children and adults, and
for males and females. In one embodiment, the electrode is
approximately 32.5 mm in length by 12 5 mm in height and the
inter-electrode distance between, for example, the upper pair of
electrodes 12a, 14a is 17 5 mm and the inter-electrode distance
between, for example, the upper electrode 12a and the lower
electrode 12b is 20 mm In other embodiments, the length of the
electrode may be greater than or less than 32.5 mm and greater than
or less than 12.5 mm in height. In still other embodiments, the
inter electrode distance can be in a range greater than 20 mm
and/or less than 17.5 mm 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.
[0055] Those skilled in the art will appreciate that various
adaptations and modifications of the above-described embodiments of
the electrode assembly 10 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. Also, the instant
electrode assembly can also be configured for the stimulation of
the maxillary nerves or the mandibular nerves or other nerves as
disclosed herein. As yet another example, an electrode assembly
configured for the simultaneous stimulation of a plurality of
trigeminal nerve branches is also within the scope of the present
disclosure.
[0056] In use, the electrode assembly 10 is positioned over the
forehead of the patient 5 such that the insulative connection
region 16 lines up with the midline of the nose of the patient 5.
In some embodiments, the electrode assembly 10 is placed over the
supraorbital foramina, located over the orbital ridge approximately
2.1-2.6 cm lateral to nasal midline. In one embodiment, the
electrode assembly 10 is then connected to a pulse generator 15 via
the electrical cable 20. In other embodiments, the electrode
assembly is connected to the pulse generator 15 via a wireless
connection. Stimulation according to patient specific operational
parameters as determined according to the methods described herein
is then applied.
[0057] According to one aspect of the present disclosure, a method
of treatment of epilepsy and related seizure disorders and other
neurological disorders and conditions using the electrode assembly
10, as described above, is described. In one embodiment, the method
of treating these neurological disorders and conditions includes
positioning the electrode assembly 10 to the forehead of a patient,
connecting the electrode assembly 10 to a stimulator, and
stimulating the electrode assembly 10 at defined values of the
operational parameters as disclosed herein to minimize current
penetration into the brain/below the skull bone. In some
embodiments, the electrode assembly is connected to the stimulator
via wire 20 and/or lead wires. In some embodiments, the electrode
assembly is wirelessly connected to the stimulator.
[0058] In one embodiment, the bilateral supraorbital electrode 10
illustrated in FIGS. 2-3B is stimulated at a stimulus frequency
between about 20 Hz and about 300 Hz, at a pulse duration between
50 microseconds (.mu.sec) to 250 .mu.sec, at an output current
density of less than approximately 25 mA/cm.sup.2 and at no or
negligible charge densities at the cerebral cortex, or calculated
or measured charge densities at the cerebral cortex of less than 10
.mu.C/cm.sup.2 to reduce the risk of brain injury, and less than
1.0 .mu.C/cm.sup.2, and even 0.001-0.01 .mu.C/cm.sup.2 in some
embodiments, and at combinations of charge density and charge per
phase not known to cause brain injury for at least one-half to one
hour per day or may be provided for up to 24 hours per day. It is
possible that even lower charge densities may be desirable. Those
of skill in the art will recognize that one or more of the above
parameters can be used as a border of a range of parameters.
[0059] According to one aspect of the present disclosure, the
method of treating epilepsy and related seizure disorders and other
neurological disorders and conditions by TNS comprises selecting
optimal values for the operational parameters for the stimulation
of each individual patient. In one embodiment, the neurostimulation
is provided using an electrical stimulator at the following
exemplary settings: frequency 20-150 Hz, current 5-15 mA, pulse
duration of 50-250 microseconds, a duty cycle of 10% to 50%, for at
least one hour per day. In another embodiment, the neurostimulation
is provided using an electrical stimulator at the following
exemplary settings: frequency 20-150 Hz, current 1-10 mA, pulse
duration of 50-250 microseconds, a duty cycle of 10% to 50%, for at
least one hour per day.
[0060] In various embodiments, the stimulation is delivered at a
specific pulse width or range of pulse widths (or pulse duration).
The stimulation can be set to deliver pulse widths in the range
greater than 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.
[0061] 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 various embodiments, the
amplitude can be in a range greater than 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 IgA, 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, 1 mA, 12 mA, 13 mA,
14 mA, 15 mA, 16 mA, 17 mA, 18 mA, 19 mA and 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.
[0062] 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,
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,
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.
[0063] 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
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.
[0064] In other embodiments, different values of the operational
parameters may be used. 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 and scalp without being in discomfort or in pain. The
neurostimulation parameters are important factors in the treatment
method. In one embodiment, the values of the operational parameters
are selected to minimize skin irritation, burns, undesired effects
on the brain and/or the ophthalmic nerves. In one embodiment, the
method of selecting operational parameters comprises evaluating
variables such as the configuration and size of the electrode, the
pulse duration, the electrode current, the duty cycle and the
stimulation frequency, each of which are important factors in
ensuring that the total charge, the charge density, and charge per
phase are well within accepted safety limits for the skin, nerve
and brain. For example, to minimize skin irritation, it is not
sufficient to merely consider the total current, but the current
density needs to be defined. Additionally, it is important to
select the electrical stimulation parameters, electrode design, and
inter-electrode distance, such that the electrical stimulation zone
includes the ophthalmic nerve (approximately 3-4 mm deep) or other
desired nerve branch, while preventing or minimizing current
penetration beneath the skull bone and into the brain.
[0065] The stimulation is carried out at the above-described values
of the operational parameters. The values of the operational
parameters are advantageously selected such that a patient will
experience a stimulation sensation, such as mild tingling over the
forehead and scalp, without causing the patient unbearable
discomfort or pain and to minimize current penetration into the
brain. These values may vary according to the treatment of
interest.
[0066] 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 an implanted electrode assembly. 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.
[0067] In addition, the use of external electrodes for stimulation
of the trigeminal nerve may identify individuals who are likely to
derive therapeutic benefit from a 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 a
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.
[0068] 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 cutaneous
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, and
implanting the subcutaneous electrode assembly or system in the
patient for treatment of a neurological disorder.
[0069] 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 cutaneous 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, implanting the subcutaneous electrode
assembly or system 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.
[0070] 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 for the treatment of neurological
disorders and conditions. In the examples, patients with epilepsy
were treated by TNS with external cutaneous electrodes.
Example 1
[0071] FIG. 5 illustrates the results from a pilot study of
external trigeminal nerve stimulation. Subjects with epilepsy who
met inclusion and exclusion criteria for a pilot feasibility study
of external trigeminal nerve stimulation 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.
[0072] Subjects underwent stimulation using an electrical
stimulator, such as the EMS Model 7500 commercially available from
TENS Products, Inc. at a frequency of 120 Hertz, a current less
than 20 mA, pulse duration of 250 .mu.sec, and a duty cycle at 30
seconds on and 30 seconds off, for a minimum of 8 hours.
[0073] FIG. 5 illustrates the 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 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 and 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
[0074] FIG. 6 summarizes current, charge, current density and
charge density in a subject exposed to cutaneous 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.
[0075] Cutaneous 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, and patients typically are stimulated at an
amplitude setting well below 25 mA (6-10 mA).
[0076] 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.r.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.
[0077] 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.sup.2 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.A 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.
[0078] As shown in FIG. 6, stimulation intensity responses in a
subject with electrodes of surface area 7.92 cm.sup.2, 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).
[0079] 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 cutaneous 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.
* * * * *