U.S. patent application number 16/598127 was filed with the patent office on 2020-02-13 for non-invasive treatment of neurodegenerative diseases.
The applicant listed for this patent is ElectroCore, Inc.. Invention is credited to Joseph P. Errico, John T. Raffle, Bruce J. Simon.
Application Number | 20200046976 16/598127 |
Document ID | / |
Family ID | 69405391 |
Filed Date | 2020-02-13 |
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United States Patent
Application |
20200046976 |
Kind Code |
A1 |
Simon; Bruce J. ; et
al. |
February 13, 2020 |
NON-INVASIVE TREATMENT OF NEURODEGENERATIVE DISEASES
Abstract
Methods and devices are disclosed for the non-invasive treatment
of neurodegenerative diseases through delivery of energy to target
nervous tissue, particularly the vagus nerve. The methods and
devices transmit an electrical impulse transcutaneously through an
outer skin surface of the patient to modulate activity of a
selected nerve at the target region to inhibit inflammation,
enhance an anti-inflammatory competence of a cytokine in the
patient and treat the neurodegenerative disorder. The stimulation
brings about reduction of neuroinflammation in patients suffering
from conditions comprising Alzheimer's Disease, Parkinson's
Disease, Multiple Sclerosis, postoperative cognitive dysfunction
and postoperative delirium.
Inventors: |
Simon; Bruce J.; (Mountain
Lakes, NJ) ; Errico; Joseph P.; (Warren, NJ) ;
Raffle; John T.; (Austin, TX) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ElectroCore, Inc. |
Basking Ridge |
NJ |
US |
|
|
Family ID: |
69405391 |
Appl. No.: |
16/598127 |
Filed: |
October 10, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16388392 |
Apr 18, 2019 |
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16598127 |
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14462605 |
Aug 19, 2014 |
10265523 |
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16388392 |
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13005005 |
Jan 12, 2011 |
8868177 |
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14462605 |
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12964050 |
Dec 9, 2010 |
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13005005 |
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12859568 |
Aug 19, 2010 |
9037247 |
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16388392 |
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61415469 |
Nov 19, 2010 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61N 2/02 20130101; A61N
1/36025 20130101; A61N 2005/0651 20130101; A61N 2/006 20130101;
A61N 5/0618 20130101; A61N 2/002 20130101; A61N 1/40 20130101; A61N
5/0622 20130101; A61N 1/36114 20130101; A61N 1/36034 20170801 |
International
Class: |
A61N 1/36 20060101
A61N001/36; A61N 2/00 20060101 A61N002/00; A61N 2/02 20060101
A61N002/02; A61N 1/40 20060101 A61N001/40 |
Claims
1. An apparatus for applying energy transcutaneously to a target
region within a patient with a neurodegenerative disorder,
comprising: an enclosure; and a power source housed within the
enclosure, wherein the power source generates an energy field
sufficient to transmit an electrical impulse transcutaneously
through an outer skin surface of the patient at or near a target
region sufficient to modulate activity of a selected nerve at the
target region to inhibit inflammation, enhance an anti-inflammatory
competence of a cytokine in the patient and treat the
neurodegenerative disorder.
2. The apparatus of claim 1 further comprising a conduction medium,
wherein the source of energy generates an electric field that
induces an electrical current sufficient to pass through the outer
skin surface of the patient.
3. The apparatus set forth in claim 1 wherein the electrical field
has an amplitude of greater than 10 V/m.
4. The apparatus set forth in claim 1 wherein the electrical field
has a gradient of greater than 2 V/m/mm.
5. The apparatus set forth in claim 1 wherein the electrical field
comprises bursts of pulses with a frequency of 5 Hz to 100 Hz.
6. The apparatus set forth in claim 1 wherein the electrical field
comprises bursts of between 1 and 20 pulses with each pulse 50-1000
microseconds in duration.
7. The apparatus set forth in claim 1 wherein the electrical
impulse is sufficient to inhibit release of a pro-inflammatory
cytokine.
8. The apparatus set forth in claim 7 wherein the pro-inflammatory
cytokine is tumor necrosis factor (TNF)-alpha.
9. The apparatus set forth in claim 7 wherein the cytokine is tumor
growth factor (TGF)-beta.
10. The apparatus set forth in claim 1 wherein a retinoid or a
component of a retinoic acid signaling system biases the competence
of the cytokine towards anti-inflammation.
11. The apparatus set forth in claim 1 wherein the electrical
impulse is sufficient to enhance anti-inflammatory activity of a
neurotrophic factor.
12. The apparatus set forth in claim 11 wherein the neurotrophic
factor is a member of the transforming growth factor (TGF)-beta
superfamily of neurotrophic factors, the nerve growth factor
superfamily of neurotrophic factors, the neurokine superfamily of
neurotrophic factors, or the insulin-like family of non-neuronal
growth factors.
13. The apparatus set forth in claim 1 wherein the selected nerve
is a vagus nerve of the patient.
14. The apparatus set forth in claim 1 wherein the
neurodegenerative disease is Alzheimer's disease, Parkinson's
disease, multiple sclerosis, postoperative cognitive dysfunction or
postoperative delirium.
15. A method for treating a neurodegenerative disorder in a
patient, the method comprising: positioning a contact surface of a
housing in contact with an outer skin surface of a neck of the
patient, wherein the housing comprises an energy source;
transmitting, via the contact surface, an electric current
transcutaneously and non-invasively through the outer skin surface
of the neck of the patient to generate an electrical impulse at or
near a selected nerve within the patient; and modulating the
electric current such that the electrical impulse comprises bursts
of pulses with each of the bursts comprising a frequency from about
5 Hz to about 100 Hz and with each of the pulses comprising a
duration from about 50 microseconds to about 1000 microseconds and
such that the electrical impulse is sufficient to increase an
activity of an anti-inflammatory cytokine in the patient to inhibit
an inflammation and thereby treat the neurodegenerative
disorder.
16. The method of claim 15, wherein the electrical impulse is
sufficient to stimulate a nerve fiber that controls or mediates an
activity of a neurotrophic factor.
17. The method of claim 16, wherein the neurotrophic factor is a
member of a transforming growth factor (TGF) beta superfamily of
neurotrophic factors.
18. The method of claim 16, wherein the neurotrophic factor is a
member of at least one of a nerve growth factor superfamily, a
neurokine superfamily, or an insulin-like family of non-neuronal
growth factors.
19. The method of claim 16, wherein the neurotrophic factor is a
member of a same family as at least one of a nerve growth factor
(NGF), a glial-cell-line-derived neurotrophic factor (GDNF), a
brain-derived neurotrophic factor (BDNF), or a mesencephalic
astrocyte-derived neurotrophic factor (MANF).
20. The method of claim 15, wherein the neurodegenerative disorder
is selected from a group comprising at least one of Alzheimer's
disease, Parkinson's disease, multiple sclerosis, postoperative
cognitive dysfunction, or postoperative delirium.
21. The method of claim 15 wherein the selected nerve is a vagus
nerve.
22. The method of claim 21 wherein the selected nerve is a right
branch of the vagus nerve.
23. The method of claim 15, wherein the electrical impulse is
sufficient to inhibit a release of a pro-inflammatory cytokine.
24. The method of claim 23 wherein the pro-inflammatory cytokine is
tumor necrosis factor (TNF)-alpha.
25. The method of claim 15 wherein the selected nerve is at least
approximately 1-2 cm below an outer skin surface of the
patient.
26. The method of claim 15, wherein the electric current is
modulated such that the patient has decreased measurable pain.
27. An apparatus for applying an electric current to a target
region within a patient with a neurodegenerative disorder, the
apparatus comprising: an enclosure having a contact surface; and a
power source housed within the enclosure, wherein the power source
generates an electric current sufficient to transmit an electrical
impulse transcutaneously and non-invasively through an outer skin
surface of a neck of the patient to a location at or near the
target region when the contact surface is positioned against the
outer skin surface of the neck of the patient, wherein the
electrical impulse comprises bursts of pulses with each of the
bursts comprising a frequency from about 5 Hz to about 100 Hz and
with each of the pulses comprising a duration from about 50
microseconds to about 1000 microseconds and such that the
electrical impulse is sufficient to modulate an activity of a
selected nerve at or near the target region to increase an activity
of an anti-inflammatory cytokine in the patient and thereby treat
the neurodegenerative disorder.
28. The apparatus of claim 27, further comprising a conduction
medium contained within the enclosure, wherein the electrical
impulse passes through the conduction medium, the contact surface,
and the outer skin surface of the patient.
29. The apparatus of claim 27, wherein the electrical impulse is
sufficient to inhibit a release of a pro-inflammatory cytokine.
30. The apparatus of claim 29, wherein the electrical impulse is
sufficient to modulate an activity of a selected nerve at or near
the target region to inhibit a release of a pro-inflammatory
cytokine.
31. The apparatus of claim 30 wherein the pro-inflammatory cytokine
is tumor necrosis factor (TNF)-alpha.
32. The apparatus of claim 27, wherein the anti-inflammatory
cytokine is transforming growth factor (TGF)-beta.
33. The apparatus of claim 27, wherein the selected nerve is a
vagus nerve of the patient.
34. The apparatus of claim 27, wherein the neurodegenerative
disorder comprises at least one of Alzheimer's disease, Parkinson's
disease, multiple sclerosis, postoperative cognitive dysfunction,
or postoperative delirium.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. Nonprovisional
application Ser. No. 16/388,392 filed Apr. 18, 2019, which is a
continuation of U.S. Nonprovisional application Ser. No. 14/462,605
filed Aug. 19, 2014, now U.S. Pat. No. 10,265,523 issued Apr. 23,
2019; which is a continuation of U.S. Nonprovisional application
Ser. No. 13/005,005 filed Jan. 12, 2011, now U.S. Pat. No.
8,868,177 issued Oct. 21, 2014; which is (a) a continuation-in-part
of U.S. Nonprovisional application Ser. No. 12/964,050 filed Dec.
9, 2010, which claims the benefit of priority of U.S. Provisional
Application Ser. No. 61/415,469 filed Nov. 19, 2010, and (b) a
continuation-in-part application of U.S. Nonprovisional application
Ser. No. 12/859,568 filed Aug. 19, 2010, now U.S. Pat. No.
9,037,247 issued May 19, 2015; each of which is incorporated herein
by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] The field of the present invention relates to the delivery
of energy impulses (and/or fields) to bodily tissues for
therapeutic purposes. It relates more specifically to the use of
non-invasive methods and devices, particularly methods that make
use of magnetic stimulation devices, to treat neurodegenerative
disorders, using energy that is delivered by such devices. The
medical disorders include Alzheimer's disease, Parkinson's disease,
multiple sclerosis, postoperative cognitive dysfunction, and
postoperative delirium. The treatment relates to stimulation of the
vagus nerve to reduce neuroinflammation, wherein pathways involving
anti-inflammatory cytokines, the retinoic acid signaling system,
and/or neurotrophic factors are enhanced, and/or pathways involving
pro-inflammatory cytokines are inhibited.
[0003] Treatments for various infirmities sometime require the
destruction of otherwise healthy tissue in order to produce a
beneficial effect. Malfunctioning tissue is identified and then
lesioned or otherwise compromised in order to produce a beneficial
outcome, rather than attempting to repair the tissue to its normal
functionality. A variety of techniques and mechanisms have been
designed to produce focused lesions directly in target nerve
tissue, but collateral damage is inevitable.
[0004] Other treatments for malfunctioning tissue can be medicinal
in nature, but in many cases the patients become dependent upon
artificially synthesized chemicals. In many cases, these medicinal
approaches have side effects that are either unknown or quite
significant. Unfortunately, the beneficial outcomes of surgery and
medicines are often realized at the cost of function of other
tissues, or risks of side effects.
[0005] The use of electrical stimulation for treatment of medical
conditions has been well known in the art for nearly two thousand
years. It has been recognized that electrical stimulation of the
brain and/or the peripheral nervous system and/or direct
stimulation of the malfunctioning tissue holds significant promise
for the treatment of many ailments, because such stimulation is
generally a wholly reversible and non-destructive treatment.
[0006] Nerve stimulation is thought to be accomplished directly or
indirectly by depolarizing a nerve membrane, causing the discharge
of an action potential; or by hyperpolarization of a nerve
membrane, preventing the discharge of an action potential. Such
stimulation may occur after electrical energy, or also other forms
of energy, are transmitted to the vicinity of a nerve [F. RATTAY.
The basic mechanism for the electrical stimulation of the nervous
system. Neuroscience Vol. 89, No. 2, pp. 335-346, 1999; Thomas
HEIMBURG and Andrew D. Jackson. On soliton propagation in
biomembranes and nerves. PNAS vol. 102 (no. 28, Jul. 12, 2005):
9790-9795]. Nerve stimulation may be measured directly as an
increase, decrease, or modulation of the activity of nerve fibers,
or it may be inferred from the physiological effects that follow
the transmission of energy to the nerve fibers.
[0007] Electrical stimulation of the brain with implanted
electrodes has been approved for use in the treatment of various
conditions, including movement disorders such as essential tremor
and Parkinson's disease. The principle underlying these approaches
involves disruption and modulation of hyperactive neuronal circuit
transmission at specific sites in the brain. Unlike potentially
dangerous lesioning procedures in which aberrant portions of the
brain are physically destroyed, electrical stimulation is achieved
by implanting electrodes at these sites. The electrodes are used
first to sense aberrant electrical signals and then to send
electrical pulses to locally disrupt pathological neuronal
transmission, driving it back into the normal range of activity.
These electrical stimulation procedures, while invasive, are
generally conducted with the patient conscious and a participant in
the surgery.
[0008] Brain stimulation, and deep brain stimulation in particular,
is not without some drawbacks. The procedure requires penetrating
the skull, and inserting an electrode into brain matter using a
catheter-shaped lead, or the like. While monitoring the patient's
condition (such as tremor activity, etc.), the position of the
electrode is adjusted to achieve significant therapeutic potential.
Next, adjustments are made to the electrical stimulus signals, such
as frequency, periodicity, voltage, current, etc., again to achieve
therapeutic results. The electrode is then permanently implanted,
and wires are directed from the electrode to the site of a
surgically implanted pacemaker. The pacemaker provides the
electrical stimulus signals to the electrode to maintain the
therapeutic effect. While the therapeutic results of deep brain
stimulation are promising, there are significant complications that
arise from the implantation procedure, including stroke induced by
damage to surrounding tissues and the neuro-vasculature.
[0009] One of the most successful applications of modern
understanding of the electrophysiological relationship between
muscle and nerves is the cardiac pacemaker. Although origins of the
cardiac pacemaker extend back into the 1800's, it was not until
1950 that the first practical, albeit external and bulky, pacemaker
was developed. The first truly functional, wearable pacemaker
appeared in 1957, and in 1960, the first fully implantable
pacemaker was developed.
[0010] Around this time, it was also found that electrical leads
could be connected to the heart through veins, which eliminated the
need to open the chest cavity and attach the lead to the heart
wall. In 1975 the introduction of the lithium-iodide battery
prolonged the battery life of a pacemaker from a few months to more
than a decade. The modern pacemaker can treat a variety of
different signaling pathologies in the cardiac muscle, and can
serve as a defibrillator as well (see U.S. Pat. No. 6,738,667 to
DENO, et al., the disclosure of which is incorporated herein by
reference).
[0011] Another application of electrical stimulation of nerves has
been the treatment of radiating pain in the lower extremities by
stimulating the sacral nerve roots at the bottom of the spinal cord
(see U.S. Pat. No. 6,871,099 to WHITEHURST, et al., the disclosure
of which is incorporated herein by reference).
[0012] Yet another application of electrical stimulation of nerves
has been the treatment of epilepsy and depression by vagus nerve
stimulation (VNS) [U.S. Pat. No. 4,702,254 entitled Neurocybernetic
prosthesis, to ZABARA; U.S. Pat. No. 6,341,236 entitled Vagal nerve
stimulation techniques for treatment of epileptic seizures, to
OSORIO et al; U.S. Pat. No. 5,299,569 entitled Treatment of
neuropsychiatric disorders by nerve stimulation, to WERNICKE et
al]. For this procedure, the left vagus nerve is ordinarily
stimulated at a location on the neck by first implanting an
electrode there, then connecting the electrode to an electrical
stimulator.
[0013] Despite the clinical success of VNS in treating epilepsy and
depression, a specific mechanism underlying VNS relief of symptoms
is not currently known. Vagus afferent fibers innervate several
medullary structures; with the nucleus of the tractus solitarius
(NTS) receiving bilateral inputs totaling approximately eighty
percent of all vagal afferents. The NTS has widespread projections,
including direct or multiple synaptic projections to the
parabrachial nucleus, vermis, inferior cerebellar hemispheres,
raphe nuclei, periaquaductal gray, locus coeruleus, thalamus,
hypothalamus, amygdala, nucleus accumbens, anterior insula,
infralimbic cortex, and lateral prefrontal cortex, making it
difficult to determine the area or neuronal pathway mediating VNS
effects. However, functional imaging studies have concluded that
VNS may bring about changes in several areas of the brain,
including the thalamus, cerebellum, orbitofrontal cortex, limbic
system, hypothalamus, and medulla. The stimulation of particular
areas of the brain has been suggested as a mechanism for the
effects of VNS, but such localized stimulation of the brain may
depend upon the parameters of the stimulation (current, frequency,
pulse width, duty cycle, etc.). Those parameters may also determine
which neurotransmitters are modulated (including norepinephrine,
seratonin, and GABA) [Mark S. George, Ziad Nahas, Daryl E. Bohning,
Qiwen Mu, F. Andrew Kozel, Jeffrey Borckhardt, Stewart Denslow.
Mechanisms of action of vagus nerve stimulation (VNS). Clinical
Neuroscience Research 4 (2004) 71-79; Jeong-Ho Chae, Ziad Nahas,
Mikhail Lomarev, Stewart Denslow, Jeffrey P. Lorberbaum, Daryl E.
Bohning, Mark S. George. A review of functional neuroimaging
studies of vagus nerve stimulation (VNS). Journal of Psychiatric
Research 37 (2003) 443-455; G. C. Albert, C. M. Cook, F. S. Prato,
A. W. Thomas. Deep brain stimulation, vagal nerve stimulation and
transcranial stimulation: An overview of stimulation parameters and
neurotransmitter release. Neuroscience and Biobehavioral Reviews 33
(2009) 1042-1060; GROVES DA, Brown V J. Vagal nerve stimulation: a
review of its applications and potential mechanisms that mediate
its clinical effects. Neurosci Biobehav Rev (2005) 29:493-500;
Reese TERRY, Jr. Vagus nerve stimulation: a proven therapy for
treatment of epilepsy strives to improve efficacy and expand
applications. Conf Proc IEEE Eng Med Biol Soc. 2009;
2009:4631-4].
[0014] To date, the selection of stimulation parameters for VNS has
been highly empirical, in which the parameters are varied about
some initially successful set of parameters, in an effort to find
an improved set of parameters for each patient. A more efficient
approach to selecting stimulation parameters might be to select a
stimulation waveform that mimics electrical activity in the region
of the brain that one is attempting to stimulate, in an effort to
entrain the naturally occurring electrical waveform, as suggested
in patent number U.S. Pat. No. 6,234,953, entitled Electrotherapy
device using low frequency magnetic pulses, to THOMAS et al. and
application number US20090299435, entitled Systems and methods for
enhancing or affecting neural stimulation efficiency and/or
efficacy, to GLINER et al.
[0015] The present disclosure involves devices and medical
procedures that stimulate nerves by transmitting energy to nerves
and tissue non-invasively. A medical procedure is defined as being
non-invasive when no break in the skin (or other surface of the
body, such as a wound bed) is created through use of the method,
and when there is no contact with an internal body cavity beyond a
body orifice (e.g., beyond the mouth or beyond the external
auditory meatus of the ear). Such non-invasive procedures are
distinguished from invasive procedures (including minimally
invasive procedures) in that invasive procedures do involve
inserting a substance or device into or through the skin or into an
internal body cavity beyond a body orifice.
[0016] Potential advantages of such non-invasive medical methods
and devices relative to comparable invasive procedures are as
follows. The patient may be more psychologically prepared to
experience a procedure that is non-invasive and may therefore be
more cooperative, resulting in a better outcome. Non-invasive
procedures may avoid damage of biological tissues, such as that due
to bleeding, infection, skin or internal organ injury, blood vessel
injury, and vein or lung blood clotting. Non-invasive procedures
are sometimes painless or only minimally painful and may be
performed without the need for even local anesthesia. Less training
may be required for use of non-invasive procedures by medical
professionals. In view of the reduced risk ordinarily associated
with non-invasive procedures, some such procedures may be suitable
for use by the patient or family members at home or by
first-responders at home or at a workplace, and the cost of
non-invasive procedures may be reduced relative to comparable
invasive procedures.
[0017] For example, transcutaneous electrical nerve stimulation
(TENS) is non-invasive because it involves attaching electrodes to
the surface of the skin (or using a form-fitting conductive
garment) without breaking the skin. In contrast, percutaneous
electrical stimulation of a nerve is minimally invasive because it
involves the introduction of an electrode under the skin, via
needle-puncture of the skin. Both TENS and percutaneous electrical
stimulation can be to some extent unpleasant or painful, in the
experience of patients that undergo such procedures. In the case of
TENS, as the depth of penetration of the stimulus under the skin is
increased, any pain will generally begin or increase.
[0018] Neurodegenerative diseases result from the deterioration of
neurons, causing brain dysfunction. The diseases are loosely
divided into two groups--conditions affecting memory that are
ordinarily related to dementia and conditions causing problems with
movements. The most widely known neurodegenerative diseases include
Alzheimer (or Alzheimer's) disease and its precursor mild cognitive
impairment (MCI), Parkinson's disease (including Parkinson's
disease dementia), and multiple sclerosis.
[0019] Less well-known neurodegenerative diseases include
adrenoleukodystrophy, AIDS dementia complex, Alexander disease,
Alper's disease, amyotrophic lateral sclerosis (ALS), ataxia
telangiectasia, Batten disease, bovine spongiform encephalopathy,
Canavan disease, cerebral amyloid angiopathy, cerebellar ataxia,
Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob
disease, diffuse myelinoclastic sclerosis, fatal familial insomnia,
Fazio-Londe disease, Friedreich's ataxia, frontotemporal dementia
or lobar degeneration, hereditary spastic paraplegia, Huntington
disease, Kennedy's disease, Krabbe disease, Lewy body dementia,
Lyme disease, Machado-Joseph disease, motor neuron disease,
Multiple systems atrophy, neuroacanthocytosis, Niemann-Pick
disease, Pelizaeus-Merzbacher Disease, Pick's disease, primary
lateral sclerosis including its juvenile form, progressive bulbar
palsy, progressive supranuclear palsy, Refsum's disease including
its infantile form, Sandhoff disease, Schilder's disease, spinal
muscular atrophy, spinocerebellar ataxia,
Steele-Richardson-Olszewski disease, subacute combined degeneration
of the spinal cord, survival motor neuron spinal muscular atrophy,
Tabes dorsalis, Tay-Sachs disease, toxic encephalopathy,
transmissible spongiform encephalopathy, Vascular dementia, and
X-linked spinal muscular atrophy, as well as idiopathic or
cryptogenic diseases as follows: synucleinopathy,
progranulinopathy, tauopathy, amyloid disease, prion disease,
protein aggregation disease, and movement disorder. A more
comprehensive listing may be found at the web site (www) of the
National Institute of Neurological Disorders and Stroke (ninds) of
the National Institutes of Health (nih) of the United States
government (gov) in a subdirectory (/disorder/disorder_index) web
page (htm). It is understood that such diseases often go by more
than one name and that a nosology may oversimplify pathologies that
occur in combination or that are not archetypical.
[0020] Certain other disorders, such as postoperative cognitive
dysfunction have been described only recently, and they too may
involve neuro-degeneration. Other disorders such as epilepsy may
not be primarily neurodegenerative, but at some point in their
progression they might involve nerve degeneration.
[0021] Despite the fact that at least some aspect of the pathology
of each of the neurodegenerative diseases mentioned above is
different from the other diseases, their pathologies ordinarily
share other features, so that they may be considered as a group.
Furthermore, aspects of their pathologies that they have in common
often make it possible to treat them with similar therapeutic
methods. Thus, many publications describe features that
neurodegenerative diseases have in common [Dale E. Bredesen,
Rammohan V. Rao and Patrick Mehlen. Cell death in the nervous
system. Nature 443(2006): 796-802; Christian Haass. Initiation and
propagation of neurodegeneration. Nature Medicine 16(November
2010): 1201-1204; Eng H Lo. Degeneration and repair in central
nervous system disease. Nature Medicine 16(November
2010):1205-1209; Daniel M. Skovronsky, Virginia M.-Y. Lee, and John
Q. Trojanowski. Neurodegenerative Diseases: New Concepts of
Pathogenesis and Their Therapeutic Implications. Annu. Rev. Pathol.
Mech. Dis. 1(2006): 151-70; Michael T. Lin and M. Flint Beal.
Mitochondrial dysfunction and oxidative stress in neurodegenerative
diseases. Nature 443(2006): 787-795; Jorge J. Palop, Jeannie Chin
and Lennart Mucke. A network dysfunction perspective on
neurodegenerative diseases. Nature 443(2006): 768-773; David C.
Rubinsztein. The roles of intracellular protein-degradation
pathways in neurodegeneration. Nature 443(2006): 780-786].
[0022] One such common feature is the presence of inflammation,
wherein the body recognizes the abnormality of the relevant
neuronal tissue and responds to minimize or repair the effects of
the abnormality and/or eventually destroy the abnormal tissue.
[Sandra Amor, Fabiola Puentes, David Baker and Paul van der Valk.
Inflammation in neurodegenerative diseases. Immunology, 129 (2010),
154-169; Mark H. DeLegge. Neurodegeneration and Inflammation.
Nutrition in Clinical Practice 23 (2008):35-41; Tamy C
Frank-Cannon, Laura T Alto, Fiona E McAlpine and Mal G Tansey. Does
neuroinflammation fan the flame in neurodegenerative diseases?
Molecular Neurodegeneration 2009, 4:47-59; Christopher K. Glass,
Kaoru Saijo, Beate Winner, Maria Carolina Marchetto, and Fred H.
Gage. Mechanisms Underlying Inflammation in Neurodegeneration. Cell
140 (2010): 918-934; V. Hugh Perry. The influence of systemic
inflammation on inflammation in the brain: implications for chronic
neurodegenerative disease. Brain, Behavior, and Immunity 18 (2004):
407-413; Marianne Schultzberg, Catharina Lindberg, .ANG.sa Forslin
Aronsson, Erik Hjorth, Stefan D. Spulber, Mircea Oprica.
Inflammation in the nervous system--Physiological and
pathophysiological aspects. Physiology & Behavior 92 (2007)
121-128; Frauke Zipp and Orhan Aktas. The brain as a target of
inflammation: common pathways link inflammatory and
neurodegenerative diseases. Trends in Neurosciences 29 (September
2006) 518-527]. It is understood that inflammation may accompany
not only neurodegenerative disease, but also brain injury that is
caused, for example, by trauma, stroke, or infection. Consequently,
the methods that are disclosed herein may also be applicable to any
situation in which inflammation in the central nervous system
presents a danger to the patient.
[0023] Because excessive and prolonged inflammation may destroy
nervous tissue that is associated with neurodegenerative diseases,
therapies have been proposed to prevent, reduce, or eliminate the
immune response in such inflammation, or to repair damage that may
have been produced by inflammation. Inflammation is modulated by
cytokines, which are small cell-signaling protein or peptide
molecules that are secreted by glial cells of the nervous system,
by numerous cells of the immune system, and by many other cell
types. Some cytokines may regarded as hormones, but in what
follows, the term cytokine is used to refer to any of those
immuno-modulating molecules, with the understanding that they may
also participate in pathways other than immunomodulation.
[0024] In general, one may adopt two approaches to reduce or
prevent inflammation that is modulated by cytokines. First, one may
attempt to inhibit the release or effectiveness of cytokines that
promote inflammation. Those cytokines are called pro-inflammatory,
and the first approach is essentially an anti-pro-inflammatory
strategy. Because pro-inflammatory cytokines may promote the
release of other pro-inflammatory cytokines, the goal is especially
to inhibit the release of the initially released pro-inflammatory
cytokines in an inflammatory cascade. For example, the cytokine
tumor necrosis factor (TNF-alpha) is considered to be a
pro-inflammatory cytokine of central importance, and anti-TNF-alpha
strategies seek to inhibit the release or effectiveness of
TNF-alpha that is released from immune and other cells [Ian A.
Clark, Lisa M. Alleva, Bryce Vissel. The roles of TNF in brain
dysfunction and disease. Pharmacology & Therapeutics 128
(2010): 519-548; Melissa K McCoy and Mal Tansey. TNF signaling
inhibition in the CNS: implications for normal brain function and
neurodegenerative disease. Journal of Neuroinflammation 2008,
5:45].
[0025] A second approach to reducing inflammation that is modulated
by cytokines is to enhance and/or stimulate the release or
effectiveness of cytokines that inhibit inflammation. Those
cytokines are called anti-inflammatory, and the second approach is
essentially a pro-anti-inflammatory strategy. As indicated below,
pro-anti-inflammatory mechanisms are often associated with the
repair of tissue, which may correspond in the adult to mechanisms
that were used in the embryo to create tissue originally. The
cytokine transforming growth factor beta (TGF-beta) is often
regarded as anti-inflammatory, but as described presently, its
anti-inflammatory capabilities are contingent upon certain
conditions being met. According to the second approach, one
endeavors to promote such conditions, as well as to promote the
release of, for example, TGF-beta into a potentially inflammatory
environment.
[0026] In a series of publications, patents, and patent
applications, Kevin J. TRACEY and colleagues described electrical
stimulation of the vagus nerve in an attempt to effect the first,
anti-pro-inflammatory strategy [Kevin J. Tracey. The inflammatory
reflex. Nature 420(2002): 853-859; Kevin J. Tracey. Physiology and
immunology of the cholinergic anti-inflammatory pathway. J. Clin.
Invest. 117(2007): 289-296; Kevin J Tracey. Understanding immunity
requires more than immunology. Nature Immunology 11(2010): 561-564;
G. R. Johnston and N. R. Webster. Cytokines and the
immunomodulatory function of the vagus nerve. British Journal of
Anaesthesia 102(April 2009): 453-462]. U.S. Pat. Nos. 6,610,713 and
6,838,471, entitled Inhibition of inflammatory cytokine production
by cholinergic agonists and vagus nerve stimulation, to TRACEY,
mention treatment of neurodegenerative diseases within a long list
of diseases, in connection with the treatment of inflammation
through stimulation of the vagus nerve. According to those patents,
"Inflammation and other deleterious conditions . . . are often
induced by proinflammatory cytokines, such as tumor necrosis factor
(TNF; also known as TNF.alpha. or cachectin) . . . " The patents go
on to state that "Proinflammatory cytokines are to be distinguished
from anti-inflammatory cytokines, . . . , which are not mediators
of inflammation." It is clear from those patents that the objective
of TRACEY and colleagues is only to suppress the release of
proinflammatory cytokines, such as TNF-alpha. There is no mention
or suggestion that the method is intended to modulate the activity
of anti-inflammatory cytokines, and in fact, the text quoted above
disclaims a role for anti-inflammatory cytokines as mediators of
inflammation. Those patents and applications make a generally
unjustified dichotomy between pro- and anti-inflammatory cytokines,
by suggesting that a cytokine could be one or the other, but not
both. In particular, the patents make no mention of the cytokine
TGF-beta, and there is no suggestion that the role of a cytokine in
regards to its pro- or anti-inflammation competence may be
inherently indeterminate or indefinite unless more information is
provided about the presumed physiological environment in which the
cytokine finds itself.
[0027] Treatment of neurodegenerative diseases is also mentioned
within long lists of diseases in the following related applications
to TRACEY and his colleague HUSTON, wherein stimulation of the
vagus nerve is intended to suppress the release of proinflammatory
cytokines such as TNF-alpha: US20060178703, entitled Treating
inflammatory disorders by electrical vagus nerve stimulation, to
HUSTON et al.; US20050125044, entitled Inhibition of inflammatory
cytokine production by cholinergic agonists and vagus nerve
stimulation, to TRACEY; US20080249439, entitled Treatment of
inflammation by non-invasive stimulation to TRACEY et al.;
US20090143831, entitled Treating inflammatory disorders by
stimulation of the cholinergic anti-inflammatory pathway, to HUSTON
et al; US 20090248097, entitled Inhibition of inflammatory cytokine
production by cholinergic agonists and vagus nerve stimulation, to
TRACEY et al. The same observations made above in connection with
U.S. Pat. Nos. 6,610,713 and 6,838,471 apply to those applications
as well.
SUMMARY OF THE INVENTION
[0028] The present invention discloses methods and devices for the
non-invasive treatment of neurodegenerative conditions, utilizing
an energy source that transmits energy non-invasively to nervous
tissue. In particular, the devices can transmit energy to, or in
close proximity to, a vagus nerve of the patient, in order to
temporarily stimulate, block and/or modulate electrophysiological
signals in that nerve. The neurodegenerative conditions, disorders
or diseases that can be treated with the present invention include
Alzheimer's disease, Parkinson's disease, multiple sclerosis,
postoperative cognitive dysfunction or postoperative delirium.
[0029] In one aspect of the invention, a method for treating a
neurodegenerative disorder in a patient comprises applying energy
transcustaneously through an outer skin surface of the patient to
generate an electrical impulse at or near a selected nerve, such as
the vagus nerve, within the patient. The electrical impulse is
sufficient to inhibit inflammation in the patient and treat the
neurodegenerative disorder. In some embodiments, the electrical
impulse is sufficient to inhibit and/or block the release of
pro-inflammatory cytokines, such as TNF-alpha. In other
embodiments, the electrical impulse is sufficient to increase the
anti-inflammatory competence of certain cytokines to thereby offset
or reduce the effect of pro-inflammatory cytokines.
[0030] In one embodiment, an electrical current is transcutaneously
applied through the outer skin surface of the patient to the vagus
nerve. In another embodiment, a magnetic field is generated
exterior to the patient that is sufficient to induce an electrical
impulse at or near the selected nerve (e.g., the vagus nerve)
within the patient.
[0031] In a preferred embodiment, a time-varying magnetic field is
generated within an enclosed coil outside of the patient that
induces an electrical field. The electrical field is shaped such
that an electrical current is conducted through the outer skin
surface of the patient to modulate the selected nerve. The
electrical field may be shaped by generating a second time-varying
magnetic field within a second enclosed coil positioned near or
adjacent to the first enclosed coil. In other embodiments, the
electrical field may be shaped by positioning a conducting medium
around a portion of the enclosed coil such that the direction of
the electrical field is constrained within the conducting
medium.
[0032] In another aspect of the invention, an apparatus for
applying energy transcutaneously to a target region within a
patient with a neurodegenerative disorder is provided. The
apparatus includes a source of energy for generating an energy
field that is located essentially entirely exterior to an outer
skin surface of the patient. The energy field is sufficient to
transcutaneously pass through the outer skin surface and generate
an electrical impulse at or near the target region. The electrical
impulse modulates activity of a selected nerve at the target region
to inhibit inflammation in the patient and treat the
neurodegenerative disorder. The apparatus preferably also includes
a conduction medium that electrically couples the electric field
with the outer skin surface to facilitate passage of the electric
current therethrough.
[0033] In an exemplary embodiment, a magnetic stimulator is used to
modulate electrical activity of the vagus nerve. The stimulator
comprises a source of electrical power, a magnetically permeable
toroidal core, and a coil that is wound around the core. The device
also comprises a continuous electrically conducting medium with
which the coil and core are in contact, wherein the conducting
medium has a shape that conforms to the contour of a target body
surface of a patient when the medium is applied to the target body
surface. For the present medical applications, the device is
ordinarily applied to the patient's neck. The source of power
supplies a pulse of electric charge to the coil, such that the coil
induces an electric current and/or an electric field within the
patient. The stimulator is configured to induce a peak pulse
voltage sufficient to produce an electric field in the vicinity of
a nerve such as the vagus, to cause the nerve to depolarize and
reach a threshold for action potential propagation. By way of
example, the threshold electric field for stimulation of nerve
terminals may be about 8 V/m at 1000 Hz. For example, the device
may induce an electric field within the patient of about 10 to 600
V/m and an electrical field with a gradient of greater than 2
V/m/mm.
[0034] The preferred magnetic stimulator comprises two toroidal
coils and corresponding cores that lie side-by-side, each
containing a high-permeability material, wherein current passing
through a coil produces a magnetic field within the core of about
0.1 to 2 Tesla. Current passing through a coil may be about 0.5 to
20 amperes, typically 2 amperes, with voltages across each coil of
10 to 100 volts. The current is passed through the coils in bursts
of pulses. The burst repeats at 1 Hz to 5000 Hz, preferably at
15-50 Hz. The pulses have duration of 20 to 1000 microseconds,
preferably 200 microseconds and there may be 1 to 20 pulses per
burst. The preferred magnetic stimulator shapes an elongated
electric field of effect that can be oriented parallel to a long
nerve, such as the vagus nerve.
[0035] By selecting a suitable waveform to stimulate the nerve, the
magnetic stimulator produces a correspondingly selective
physiological response in an individual patient. In general, the
induced electrical signal has a frequency between about 1 Hz to
3000 Hz and a pulse duration of between about 10-1000 microseconds.
By way of example, at least one induced electrical signal may be of
a frequency between about 15 Hz to 35 Hz. By way of example, at
least one induced electrical signal may have a pulsed on-time of
between about 50 to 1000 microseconds, such as between about 100 to
300 microseconds. The induced electrical signal may have any
desired waveform, which may comprise one or more of: a full or
partial sinusoid, a square wave, a rectangular wave, and triangle
wave.
[0036] Teachings of the present invention demonstrate how
non-invasive stimulators may be positioned and used against body
surfaces, particularly at a location on the patient's neck under
which the vagus nerve is situated. Those teachings also provide
methods for treatment of particular neurodegenerative diseases that
involve neurodegeneration, neuroinflammation, or inflammation more
generally. However, it should be understood that application of the
methods and devices is not limited to the examples that are
given.
[0037] Stimulation of the vagus nerve with the magnetic stimulator
brings about reduction of neuroinflammation in patients suffering
from conditions comprising Alzheimer's Disease, Parkinson's
Disease, Multiple Sclerosis, postoperative cognitive dysfunction
and postoperative delirium. The reduction in inflammation is
effected by enhancing the anti-inflammatory competence of cytokines
such as TGF-beta, wherein a retinoid or components of the retinoic
acid signaling system provide an anti-inflammatory bias; by
enhancing anti-inflammatory activity of a neurotrophic factor such
as NGF, GDNF, BDNF, or MANE; and/or by inhibiting the activity of
pro-inflammatory cytokines such as TNF-alpha.
[0038] The novel systems, devices and methods for treating medical
conditions using the disclosed magnetic stimulator or other
non-invasive stimulation devices are more completely described in
the following detailed description of the invention, with reference
to the drawings provided herewith, and in claims appended hereto.
Other aspects, features, advantages, etc. will become apparent to
one skilled in the art when the description of the invention herein
is taken in conjunction with the accompanying drawings.
INCORPORATION BY REFERENCE
[0039] Hereby, all issued patents, published patent applications,
and non-patent publications that are mentioned in this
specification are herein incorporated by reference in their
entirety for all purposes, to the same extent as if each individual
issued patent, published patent application, or non-patent
publication were specifically and individually indicated to be
incorporated by reference.
BRIEF DESCRIPTION OF THE DRAWINGS
[0040] For the purposes of illustrating the various aspects of the
invention, there are shown in the drawings forms that are presently
preferred, it being understood, however, that the invention is not
limited by or to the precise data, methodologies, arrangements and
instrumentalities shown, but rather only by the claims.
[0041] FIG. 1 is a schematic view of a nerve or tissue modulating
device according to the present invention, which supplies
controlled pulses of electrical current to a magnetic stimulator
coil that is continuously in contact with a volume filled with
electrically conducting material.
[0042] FIG. 2 illustrates an exemplary electrical voltage/current
profile for a blocking and/or modulating impulses that are applied
to a portion or portions of a nerve, in accordance with an
embodiment of the present disclosure.
[0043] FIGS. 3A and 3B illustrate top and bottom views respectively
of a toroidal magnetic stimulatorin an embodiment of the present
invention.
[0044] FIGS. 3C and 3D illustrate top and bottom views respectively
of a toroidal magnetic stimulator of an embodiment after sectioning
along its long axis to reveal the inside of the stimulator in an
embodiment.
[0045] FIGS. 4A-4F illustrate different embodiments showing the
geometry of the toroidal core materials around which coils of wire
may be wound in an embodiment of the present disclosure.
[0046] FIG. 5 illustrates the housing and cap of the dual-toroid
magnetic stimulator coils of FIG. 3, attached via cable to a box
containing the device's impulse generator, control unit, and power
source.
[0047] FIG. 6 illustrates the approximate position of the housing
of the magnetic stimulator coil according one embodiment of the
present disclosure, when the coil is used to stimulate the vagus
nerve in the neck of a patient.
[0048] FIG. 7 illustrates the housing of the magnetic stimulator
coil according one embodiment of the present invention, as the coil
is positioned to stimulate the vagus nerve in a patient's neck via
electrically conducting gel (or some other conducting material),
which is applied to the surface of the neck in the vicinity of the
identified anatomical structures.
[0049] FIG. 8 illustrates mechanisms or pathways through which
stimulation of the vagus nerve may reduce inflammation in patients
with neurodegenerative disorders.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0050] In the present invention, energy is transmitted
non-invasively to a patient. In one of the preferred embodiments, a
time-varying magnetic field originating outside of a patient is
generated, such that the magnetic field induces an electromagnetic
field and/or eddy currents within tissue of the patient. The
invention is particularly useful for inducing applied electrical
impulses that interact with the signals of one or more nerves, or
muscles, to achieve a therapeutic result. In particular, the
present disclosure describes devices and methods to treat
neurodegenerative diseases, including Alzheimer's disease,
Parkinson's disease, multiple sclerosis, postoperative cognitive
dysfunction, and postoperative delirium.
[0051] In an exemplary embodiment, the present invention includes
methods and devices for inducing, by a time-varying magnetic field,
electrical fields and current within tissue, in accordance with
Faraday's law of induction. Magnetic stimulation is non-invasive
because the magnetic field is produced by passing a time-varying
current through a coil positioned outside the body, inducing at a
distance an electric field and electric current within
electrically-conducting bodily tissue. Because the induced electric
field and induced current depend not only upon current being passed
through wire of the coil, but also upon the permeability of core
material around which the coil may be wound, the term coil as used
herein refers not only to the current-carrying wire, but also to
the core material, unless otherwise indicated. Large, pulsed
magnetic fields (PMF) can induce significant electric fields in
conducting media, including human tissue. Particular waveforms and
amplitudes can stimulate action potentials in nerves, both in vitro
and in vivo. Due to the noninvasive nature of the stimulation, PMF
devices have found utility in several clinical applications, both
therapeutically, e.g., for treating depression via transcranial
magnetic stimulation (TMS), and diagnostically, for peripheral
nerve stimulation. It is an objective of the present invention to
use magnetic stimulation to produce significantly less pain or
discomfort, as compared with that experienced by the patient
undergoing a treatment with TENS, for a given depth of stimulus
penetration. Or conversely, for a given amount of pain or
discomfort on the part of the patient (e.g., the threshold at which
such discomfort or pain begins), an objective of the present
invention is to achieve a greater depth of penetration of the
stimulus under the skin.
[0052] The principle of operation of magnetic stimulation, along
with a description of commercially available equipment and a list
of medical applications of magnetic stimulation, is reviewed in:
Chris HOVEY and Reza Jalinous, The Guide to Magnetic Stimulation,
The Magstim Company Ltd, Spring Gardens, Whitland, Carmarthenshire,
SA34 0HR, United Kingdom, 2006. The types of the magnetic
stimulator coils that are described there include circular,
parabolic, figure-of-eight (butterfly), and custom designs.
Additional types of the magnetic stimulator coils are described in
U.S. Pat. No. 6,179,770, entitled Coil assemblies for magnetic
stimulators, to MOULD; as well as in Kent DAVEY. Magnetic
Stimulation Coil and Circuit Design. IEEE Transactions on
Biomedical Engineering, Vol. 47 (No. 11, November 2000): 1493-1499
and in HSU K H, Nagarajan S S, Durand D M. Analysis of efficiency
of magnetic stimulation. IEEE Trans Biomed Eng. 2003 November; 50
(11):1276-85.
[0053] The circuits that are used to send pulses or other waveforms
through magnetic stimulator coils are also described by HOVEY and
Jalinous in The Guide to Magnetic Stimulation that was cited above.
Custom magnetic stimulator circuits for control, impulse generator
and power supply have also been described [Eric BASHAM, Zhi Yang,
Natalia Tchemodanov, and Wentai Liu. Magnetic Stimulation of Neural
Tissue: Techniques and System Design. pp. 293-352, In: Implantable
Neural Prostheses 1, Devices and Applications, D. Zhou and E.
Greenbaum, eds., New York: Springer (2009); U.S. Pat. No.
7,744,523, entitled Drive circuit for magnetic stimulation, to
EPSTEIN; U.S. Pat. No. 5,718,662, entitled Apparatus for the
magnetic stimulation of cells or tissue, to JANILOUS; U.S. Pat. No.
5,766,124, entitled Magnetic stimulator for neuro-muscular tissue,
to POLSON].
[0054] As described in the above-cited publications, the circuits
for magnetic stimulators are generally complex and expensive. They
use a high current impulse generator that may produce discharge
currents of 5,000 amps or more, which is passed through the
stimulator coil, and which thereby produces a magnetic pulse.
Typically, a transformer charges a capacitor in the impulse
generator, which also contains circuit elements that limit the
effect of undesirable electrical transients. Charging of the
capacitor is under the control of a control unit, which accepts
information such as the capacitor voltage, power and other
parameters set by the user, as well as from various safety
interlocks within the equipment that ensure proper operation, and
the capacitor is then discharged through the coil via an electronic
switch (e.g., a controlled rectifier) when the user wishes to apply
the stimulus. Greater flexibility is obtained by adding to the
impulse generator a bank of capacitors that can be discharged at
different times. Thus, higher impulse rates may be achieved by
discharging capacitors in the bank sequentially, such that
recharging of capacitors is performed while other capacitors in the
bank are being discharged. Furthermore, by discharging some
capacitors while the discharge of other capacitors is in progress,
by discharging the capacitors through resistors having variable
resistance, and by controlling the polarity of the discharge, the
control unit may synthesize pulse shapes that approximate an
arbitrary function.
[0055] In the preferred embodiments of the present invention, the
disclosed methods use a magnetic stimulation device that requires
significantly less electrical current to be passed through its
coil(s) than magnetic stimulation devices currently known in the
art. That low-current magnetic stimulation device also has control
circuits, impulse generators, and power supplies that are
significantly less complex than magnetic stimulation devices
currently known in the art. In fact, the magnetic stimulation
device used in preferred embodiments of the present invention
requires so little power that it can be operated using conventional
low-voltage batteries, thereby reducing the cost to manufacture the
device and allowing for portability of the device. The low-current
magnetic stimulation device was disclosed in Applicant's co-pending
U.S. patent application Ser. No. 12/964,050 entitled Magnetic
Stimulation Devices and Methods of Therapy, to SIMON et al, which
is hereby incorporated by reference in its entirety for all
purposes.
[0056] A practical disadvantage of conventional magnetic stimulator
coils is that they overheat when used over an extended period of
time, because large coil currents are required to reach threshold
electric fields in the stimulated tissue. At high repetition rates,
currents can heat the coils to unacceptable levels in seconds to
minutes, depending on the power levels and pulse durations and
rates. Accordingly, coil-cooling equipment is used, which adds
complexity to the magnetic stimulator coils. Two approaches to
overcome heating are to cool the coils with flowing water or air or
to increase the magnetic fields using ferrite cores (thus allowing
smaller currents). For some applications where relatively long
treatment times at high stimulation frequencies may be required,
e.g. treating asthma by stimulating the vagus nerve, neither of
these two approaches may be adequate. Water-cooled coils overheat
in a few minutes. Ferrite core coils heat more slowly due to the
lower currents and heat capacity of the ferrite core, but they also
cool slowly and do not allow for water-cooling because the ferrite
core occupies the volume where the cooling water would flow. One
solution to this problem is to use a core that contains ferrofluids
[U.S. Pat. No. 7,396,326 and published applications US20080114199,
US20080177128, and US20080224808, all entitled Ferrofluid cooling
and acoustical noise reduction in magnetic stimulators,
respectively to GHIRON et al., RIEHL et al., RIEHL et al. and
GHIRON et al.]. However, even the use of ferrofluids may be
inadequate when long treatment times at high stimulation
frequencies may be required.
[0057] In preferred embodiments of the present invention,
applicant's above-mentioned low-current magnetic stimulation device
is used, which requires so little electrical current to be passed
through its coil(s) that no special cooling apparatus is required
to operate the device. That device may therefore be operated at
high repetition rates for an indefinite period of time. In other
embodiments or the present invention, higher current magnetic
stimulation coils are used, which may be cooled using methods and
devices that Applicant disclosed in co-pending U.S. patent
application Ser. No. 12/859,568 entitled Non-invasive Treatment of
Bronchial Constriction, to SIMON, which is hereby incorporated by
reference in its entirety for all purposes. That application also
disclosed methods and devices for the stimulation of nerves other
than magnetic stimulation devices and methods, including mechanical
and/or acoustical, optical and/or thermal, and electrode-based
electrical methods and devices, each of which may be used in
alternate embodiments of the present invention in lieu of, or in
addition to, the preferred magnetic stimulation devices and
methods.
[0058] Another problem that is sometimes encountered during
magnetic stimulation is the unpleasantness or pain that is
experienced by the patient in the vicinity of the stimulated
tissue. Little is known about the mechanism that produces the pain,
although it is generally recognized that magnetic stimulation
produces less pain than its electrode-based counterpart. Most
investigations that address this question examine pain associated
with transcranial stimulation.
[0059] ANDERSON et al found that when magnetic stimulation is
repeated over the course of multiple sessions, the patients adapt
to the pain and exhibit progressively less discomfort [Berry S.
ANDERSON, Katie Kavanagh, Jeffrey J. Borckardt, Ziad H. Nahas,
Samet Kose, Sarah H. Lisanby, William M. McDonald, David Avery,
Harold A. Sackeim, and Mark S. George. Decreasing Procedural Pain
Over Time of Left Prefrontal rTMS for Depression: Initial Results
from the Open-Label Phase of a Multisite Trial (OPT-TMS). Brain
Stimul. 2009 Apr. 1; 2(2): 88-92]. Other than waiting for the
patient to adapt, strategies to reduce the pain include: use of
anesthetics placed on or injected into the skin near the
stimulation and placement of foam pads on the skin at the site of
stimulation [Jeffrey J. BORCKARDT, Arthur R. Smith, Kelby
Hutcheson, Kevin Johnson, Ziad Nahas, Berry Anderson, M. Bret
Schneider, Scott T. Reeves, and Mark S. George. Reducing Pain and
Unpleasantness During Repetitive Transcranial Magnetic Stimulation.
Journal of ECT 2006; 22:259-264], use of nerve blockades [V.
HAKKINEN, H. Eskola, A. Yli-Hankala, T. Nurmikko and S.
Kolehmainen. Which structures are sensitive to painful transcranial
stimulation? Electromyogr. clin. Neurophysiol. 1995, 35:377-383],
the use of very short stimulation pulses [V. SUIHKO. Modelling the
response of scalp sensory receptors to transcranial electrical
stimulation. Med. Biol. Eng. Comput., 2002, 40, 395-401], and
providing patients with the amount of information that suits their
personalities [Anthony DELITTO, Michael J Strube, Arthur D Shulman,
Scott D Minor. A Study of Discomfort with Electrical Stimulation.
Phys. Ther. 1992; 72:410-424]. U.S. Pat. No. 7,614,996, entitled
Reducing discomfort caused by electrical stimulation, to RIEHL
discloses the application of a secondary stimulus to counteract
what would otherwise be an uncomfortable primary stimulus.
[0060] However, these methods of reducing pain or discomfort on the
part of the stimulated patient are not always successful or
practical. Accordingly, in the preferred embodiments of the present
invention, applicant's above-mentioned low-current magnetic
stimulation device is used, which produces significantly less pain
or discomfort (if any) to the patient than magnetic stimulator
devices that are currently known in the art.
[0061] To achieve the objectives of the present invention,
applicant's above-mentioned low-current magnetic stimulation device
uses an efficient method to produce electric fields in tissue
noninvasively, namely, to use a toroidal winding around a high
magnetic permeability material core, embedded in a conducting
medium [Rafael CARBUNARU and Dominique M. Durand. Toroidal coil
models for transcutaneous magnetic stimulation of nerves. IEEE
Transactions on Biomedical Engineering. 48 (No. 4, April 2001):
434-441]. The conducting medium must have direct contact with skin
for current to flow from the coil into the tissue. In essence,
Applicant's device produces a transcutaneous current, similar to a
transcutaneous electrical nerve stimulation (TENS) device, but with
greater depth of penetration and virtually no unpleasant peripheral
nerve stimulation. In addition, to generate electric fields
equivalent to other PMF devices, toroidal stimulators require only
about 0.001-0.1 of the current and produce virtually no heating. It
is understood that the magnetic field of a toroidal magnetic
stimulator remains essentially within the toroid, and that when
referring to this device as a magnetic stimulator, it is in fact
the electric fields and/or currents that are induced outside the
stimulator that produce an effect in the patient, not the magnetic
field.
[0062] To the applicant's knowledge, no significant development of
toroidal-coil magnetic stimulators has taken place beyond what was
reported in the above-mentioned CARBUNARU and Durand publication
and the dissertation upon which it was based [Rafael Carbunaru
FAIERSTEIN, Coil Designs for Localized and Efficient Magnetic
Stimulation of the Nervous System. Ph.D. Dissertation, Department
of Biomedical Engineering, Case Western Reserve, May, 1999. (UMI
Microform Number: 9940153, UMI Company, Ann Arbor Mich.)]. Toroidal
coils or partial-toroids were mentioned in the following patents or
patent applications, but they did not develop the use of a
conducting medium in contact with skin: US20080027513, entitled
Systems And Methods For Using A Butterfly Coil To Communicate With
Or Transfer Power To An Implantable Medical Device, to CARBUNARU;
U.S. Pat. No. 7,361,136, entitled Method and apparatus for
generating a therapeutic magnetic field, to PARKER; U.S. Pat. No.
6,527,695, entitled Magnetic stimulation coil and circuit design,
to DAVEY et al.; U.S. Pat. No. 6,155,966, entitled Apparatus and
method for toning tissue with a focused, coherent electromagnetic
field, to PARKER; U.S. Pat. No. 4,915,110, entitled Therapeutic
electrostatic device, to KITOV; US20070032827, entitled Methods and
apparatus for producing therapeutic and diagnostic stimulation, to
KATIMS; US20100222629, entitled Method and apparatus for magnetic
induction therapy, to BURNETT et al. The latter application to
BURNETT et al. only notes that "in the paper titled `Contactless
Nerve Stimulation and Signal Detection by Inductive Transducer`
presented at the 1969 Symposium on Application of Magnetism in
Bioengineering, Maass et al. disclosed that a nerve threading the
lumen of a toroid could be stimulated by a magnetic field."
[0063] The lack of development is apparently due to the difficulty
of embedding the coil in a practical conducting medium and having
that medium be safely in direct contact with human skin. The only
reported toroidal-coil magnetic stimulation device used to
stimulate human nerves was described in the above-cited
dissertation by Rafael Carbunaru FAIERSTEIN, and it embedded the
coil in agar. Agar degrades in time and is not ideal to use against
skin, presenting difficulties with cleaning it from a patient and
within a device. Furthermore, as disclosed there, the toroid needs
to be surrounded by conducting medium above, below and around it,
making for a relatively bulky device that is difficult to apply to
target tissue having small cross sectional area. Furthermore, the
device that FAIERSTEIN discloses cannot be applied to the surface
of the skin at an arbitrary orientation.
[0064] In preferred embodiments of the present invention,
Applicant's low-current, toroidal-coil magnetic stimulation device
is used. The device may be applied to body surfaces having an
arbitrary orientation with respect to the long-axis of the
component containing the coil. Additional advantages of embodiments
of Applicant's device are that the embodiments are compact and
portable, and that they may be adapted for use in nerve and tissue
stimulation applications that treat diverse medical conditions.
Applicant's co-pending patent application that was mentioned above
Ser. No. 12/964,050 entitled Magnetic Stimulation Devices and
Methods of Therapy, disclosed methods for using the device to treat
such conditions as post-operative ileus, dysfunction associated
with TNF-alpha in Alzheimer's disease, postoperative cognitive
dysfunction, rheumatoid arthritis, bronchoconstriction, urinary
incontinence and/or overactive bladder, and sphincter of Oddi
dysfunction. The present application extends disclosure of the
range of conditions that may be treated by magnetic stimulation or
other non-invasive techniques, by disclosing methods and devices
for treating neurodegenerative diseases more generally.
[0065] The present invention discloses methods for using vagal
nerve stimulation to suppress neuroinflammation. In certain
embodiments, methods and devices of the present invention involve
the inhibition of pro-inflammatory cytokines, or more specifically,
stimulation of the vagus nerve to inhibit and/or block the release
of such pro-inflammatory cytokines. In other embodiments, the
present invention discloses use of vagal nerve stimulation to
increase the concentration or effectiveness of anti-inflammatory
cytokines. TRACEY et al do not consider the modulation of
anti-inflammatory cytokines to be part of the cholinergic
anti-inflammatory pathway that their method of vagal nerve
stimulation is intended to activate. Thus, they explain that
"activation of vagus nerve cholinergic signaling inhibits TNF
(tumor necrosis factor) and other proinflammatory cytokine
overproduction through `immune` a7 nicotinic receptor-mediated
mechanisms" [V. A. PAVLOV and K. J. Tracey. Controlling
inflammation: the cholinergic anti-inflammatory pathway.
Biochemical Society Transactions 34, (2006 June): 1037-1040]. In
contrast, anti-inflammatory cytokines are said to be part of a
different "diffusible anti-inflammatory network, which includes
glucocorticoids, anti-inflammatory cytokines, and other humoral
mediators" [CZURA C J, Tracey K J. Autonomic neural regulation of
immunity. J Intern Med. 257(2005 February): 156-66]. Others make a
similar distinction between vagal and humoral mediation [GUYON A,
Massa F, Rovere C, Nahon J L. How cytokines can influence the
brain: a role for chemokines? J Neuroimmunol 2008; 198:46-55].
[0066] The disclaiming by TRACEY and colleagues of a role for
anti-inflammatory cytokines as mediators of inflammation following
stimulation of the vagus nerve may be due to a recognition that
anti-inflammatory cytokines (e.g., TGF-.beta.) are usually produced
constitutively, while pro-inflammatory cytokines (e.g., TNF-alpha)
are not produced constitutively, but are instead induced. However,
anti-inflammatory cytokines are inducible as well as constitutive,
so that for example, an increase in the concentrations of
potentially anti-inflammatory cytokines such as transforming growth
factor-beta (TGF-.beta.) can in fact be accomplished through
stimulation of the vagus nerve [RA BAUMGARTNER, V A Deramo and MA
Beaven. Constitutive and inducible mechanisms for synthesis and
release of cytokines in immune cell lines. The Journal of
Immunology 157 (1996 September): 4087-4093; CORCORAN, Ciaran;
Connor, Thomas J; O'Keane, Veronica; Garland, Malcolm R. The
effects of vagus nerve stimulation on pro- and anti-inflammatory
cytokines in humans: a preliminary report. Neuroimmunomodulation 12
(May 2005): 307-309].
[0067] An example of a pro-anti-inflammatory mechanism that is
particularly relevant to the treatment of multiple sclerosis is as
follows. TGF-.beta. converts undifferentiated T cells into
regulatory T (Treg) cells that block the autoimmunity that causes
demyelination in multiple sclerosis. However, in the presence of
interleukin-6, TGF-.beta. also causes the differentiation of T
lymphocytes into proinflammatory IL-17 cytokine-producing T helper
17 (TH17) cells, which promote autoimmunity and inflammation. Thus,
it is conceivable that an increase of TGF-.beta. levels might
actually cause or exacerbate inflammation, rather than suppress it.
Accordingly, a step in an embodiment of the methods that are
disclosed herein is to deter TGF-.beta. from realizing its
pro-inflammatory potential, by selecting nerve stimulation
parameters that bias the potential of TGF-.beta. towards
anti-inflammation, and/or by treating the patient with an agent
such as the vitamin A metabolite retinoic acid that is known to
promote such an anti-inflammatory bias [MUCIDA D, Park Y, Kim G,
Turovskaya O, Scott I, Kronenberg M, Cheroutre H. Reciprocal TH17
and regulatory T cell differentiation mediated by retinoic acid.
Science 317(2007, 5835): 256-60; Sheng XIAO, Hulin Jin, Thomas
Korn, Sue M. Liu, Mohamed Oukka, Bing Lim, and Vijay K. Kuchroo.
Retinoic acid increases Foxp3+ regulatory T cells and inhibits
development of Th17 cells by enhancing TGF-.beta.-driven Smad3
signaling and inhibiting IL-6 and IL-23 receptor expression. J
Immunol. 181(2008 April): 2277-2284]. Retinoic acid is a member of
a class of compounds known as retinoids, comprising three
generations: (1) retinol, retinal, retinoic acid (tretinoin,
Retin-A), isotretinoin and alitretinoin; (2) etretinate and
acitretin; (3) tazarotene, bexarotene and Adapalene.
[0068] In one embodiment of the invention, endogenous retinoic acid
that is released by neurons themselves is used to produce the
anti-inflammatory bias. Thus, it is known that vagal nerve
stimulation may induce differentiation through release of retinoic
acid that is produced in neurons from retinaldehyde by
retinaldehyde dehydrogenases, and the disclosed invention promotes
anti-inflammatory regulatory T cell (Treg) differentiation by this
type of mechanism [van de PAVERT S A, Olivier B J, Goverse G,
Vondenhoff M F, Greuter M, Beke P, Kusser K, Hopken U E, Lipp M,
Niederreither K, Blomhoff R, Sitnik K, Agace W W, Randall T D, de
Jonge W J, Mebius R E. Chemokine CXCL13 is essential for lymph node
initiation and is induced by retinoic acid and neuronal
stimulation. Nat Immunol. 10(November, 2009): 1193-1199].
[0069] The retinoic acid so released might also directly inhibit
the release or functioning of proinflammatory cytokines, which
would be an anti-pro-inflammatory mechanism that is distinct from
the one proposed by TRACEY and colleagues [Malcolm Maden. Retinoic
acid in the development, regeneration and maintenance of the
nervous system. Nature Reviews Neuroscience 8(2007), 755-765].
However, if the proinflammatory cytokine that is blocked is
TNF-alpha, its inhibition in multiple sclerosis patients might be
counterproductive. This is because blocking TNF-alpha with the drug
lenercept promotes and exacerbates multiple sclerosis attacks
rather than delaying them, which might be attributable to the fact
that TNF-alpha promotes remyelination and the proliferation of
oligodendrocytes that perform the myelination. [ANONYMOUS. TNF
neutralization in MS: Results of a randomized, placebo controlled
multicenter study. Neurology 1999, 53:457; ARNETT HA, Mason J,
Marino M, Suzuki K, Matsushima G K, Ting J P. TNF alpha promotes
proliferation of oligodendrocyte progenitors and remyelination. Nat
Neurosci 2001, 4:1116-1122].
[0070] In this example, the competence of anti-inflammatory
cytokines may be modulated by the retinoic acid (RA) signaling
system of the nervous system. The most important mechanism of RA
activity is the regulation of gene expression. This is accomplished
by its binding to nuclear retinoid receptors that are
ligand-activated transcription factors. Thus, RA acts as a
transcriptional activator for a large number of other, downstream
regulatory molecules, including enzymes, transcription factors,
cytokines, and cytokine receptors. Retinoic acid is an essential
morphogen in vertebrate development and participates in tissue
regeneration in the adult [Jorg M E Y and Peter MdCaffery. Retinoic
Acid Signaling in the Nervous System of Adult Vertebrates. The
Neuroscientist 10(May 2004): 409-421]. RA also increases synaptic
strength in a homeostatic response (synaptic scaling) to neuronal
inactivity through a mechanism involving protein synthesis that
requires the participation of TNF-alpha. RA is also intimately
involved in the control of the rhythmic electrical activity of the
brain. More generally, all-trans retinoic acid, 9-cis retinoic
acid, and 13-cis retinoic acid are some of a very small number of
entrainment factors that regulate the natural rhythmicity of
metabolic processes in many types of individual cells [Mehdi Tafti,
Norbert B. Ghyselinck. Functional Implication of the Vitamin A
Signaling Pathway in the Brain. Arch Neurol. 64(December 2007):
1706-1711].
[0071] As examples involving other neurodegenerative diseases,
stimulation of nerves to enhance mechanisms involving retinoic acid
or its receptors also promotes the rescue of dopamine producing
cells in Parkinson's disease [Stina Friling, Maria Bergsland and
Susanna Kjellander. Activation of Retinoid X Receptor increases
dopamine cell survival in models for Parkinson's disease. BMC
Neuroscience 2009, 10:146]. Similarly, stimulation of nerves to
release retinoic acid or activate its receptors may also promote
the clearance of beta amyloids in Alzheimer's disease [Camacho I.
E., Serneels L., Spittaels K., Merchiers P., Dominguez D. and De
Strooper B. Peroxisome-proliferator-activated receptor gamma
induces a clearance mechanism for the amyloid-beta peptide. J.
Neurosci. 24(2004), 10908-10917].
[0072] The potentially anti-inflammatory cytokine TGF-beta is a
member of the TGF-beta superfamily of neurotrophic factors.
Neurotrophic factors serve as growth factors for the development,
maintenance, repair, and survival of specific neuronal populations,
acting via retrograde signaling from target neurons by paracrine
and autocrine mechanisms. Other neurotrophic factors also promote
the survival of neurons during neurodegeneration. These include
members of the nerve growth factor (NGF) superfamily, the
glial-cell-line-derived neurotrophic factor (GDNF) family, the
neurokine superfamily, and non-neuronal growth factors such as the
insulin-like growth factors (IGF) family. However, major problems
in using such neurotrophic factors for therapy are their inability
to cross the blood-brain-barrier, adverse effects resulting from
binding to the receptor in other organs of the body and their low
diffusion rate [Yossef S. Levy, Yossi Gilgun-Sherki, Eldad Melamed
and Daniel Offen. Therapeutic Potential of Neurotrophic Factors in
Neurodegenerative Diseases. Biodrugs 2005; 19 (2): 97-127].
[0073] It is known that vagal nerve stimulation and transcranial
magnetic stimulation can increase the levels of at least one
neurotrophic factor in the brain, namely, brain-derived
neurotrophic factor (BDNF) in the NGF superfamily, which has been
studied extensively in connection with the treatment of depression.
However, vagal nerve stimulation to increase levels of neurotrophic
factors has not been reported in connection with neurodegenerative
diseases. Because BDNF may be modulated by stimulating the vagus
nerve, vagal nerve stimulation may likewise promote the expression
of other neurotrophic factors in patients with neurodegenerative
disease, thereby circumventing the problem of blood-brain barrier
blockage [Follesa P, Biggio F, Gorini G, Caria S, Talani G, Dazzi
L, Puligheddu M, Marrosu F, Biggio G. Vagus nerve stimulation
increases norepinephrine concentration and the gene expression of
BDNF and bFGF in the rat brain. Brain Research 1179(2007): 28-34;
Biggio F, Gorini G, Utzeri C, Olla P, Marrosu F, Mocchetti I,
Follesa P. Chronic vagus nerve stimulation induces neuronal
plasticity in the rat hippocampus. Int J Neuropsychopharmacol.
12(September 2009):1209-21; Roberta Zanardini, Anna Gazzoli,
Mariacarla Ventriglia, Jorge Perez, Stefano Bignotti, Paolo Maria
Rossini, Massimo Gennarelli, Luisella Bocchio-Chiavetto. Effect of
repetitive transcranial magnetic stimulation on serum brain derived
neurotrophic factor in drug resistant depressed patients. Journal
of Affective Disorders 91 (2006) 83-86]. Patent application
US20100280562, entitled Biomarkers for monitoring treatment of
neuropsychiatric diseases, to PI et al, disclosed the measurement
of GDNF and other neurotrophic factors following vagal nerve
stimulation. However, that application is concerned with the search
for biomarkers involving the levels of GDNF, rather than a method
for treating a neurodegenerative disease using vagal nerve
stimulation.
[0074] FIG. 1 is a schematic diagram of a nerve
stimulating/modulating device 300 for delivering impulses of energy
to nerves for the treatment of medical conditions. As shown, device
300 may include an impulse generator 310; a power source 320
coupled to the impulse generator 310; a control unit 330 in
communication with the impulse generator 310 and coupled to the
power source 320; and a magnetic stimulator coil 340 coupled via
wires to impulse generator coil 310. The stimulator coil 340 is
toroidal in shape, due to its winding around a toroid of core
material.
[0075] Although the magnetic stimulator coil 340 is shown in FIG. 1
to be a single coil, in practice the coil may also comprise two or
more distinct coils, each of which is connected in series or in
parallel to the impulse generator 310. Thus, the coil 340 shown in
FIG. 1 represents all the magnetic stimulator coils of the device
collectively. In the preferred embodiment that is disclosed below,
coil 340 actually contains two coils that may be connected either
in series or in parallel to the impulse generator 310.
[0076] The item labeled in FIG. 1 as 350 is a volume, surrounding
the coil 340, that is filled with electrically conducting medium.
As shown, the medium not only encloses the magnetic stimulator
coil, but is also deformable such that it is form-fitting when
applied to the surface of the body. Thus, the sinuousness or
curvature shown at the outer surface of the electrically conducting
medium 350 correspond also to sinuousness or curvature on the
surface of the body, against which the conducting medium 350 is
applied, so as to make the medium and body surface contiguous. As
described below in connection with a preferred embodiment, the
volume 350 is electrically connected to the patient at a target
skin surface in order to significantly reduce the current passed
through the coil 340 that is needed to accomplish stimulation of
the patient's nerve or tissue. As also described below in
connection with a preferred embodiment, conducting medium in which
the coil 340 is embedded need not completely surround the
toroid.
[0077] The control unit 330 controls the impulse generator 310 to
generate a signal for each of the device's magnetic stimulation
coils. The signals are selected to be suitable for amelioration of
a particular medical condition, when the signals are applied
non-invasively to a target nerve or tissue via the magnetic
stimulator coil 340. It is noted that nerve stimulating/modulating
device 300 may be referred to by its function as a pulse generator.
Patent application publications US2005/0075701 and US2005/0075702,
both to SHAFER, both of which are incorporated herein by reference,
relating to stimulation of neurons of the sympathetic nervous
system to attenuate an immune response, contain descriptions of
pulse generators that may be applicable to the present invention,
when adapted for use with a magnetic stimulator coil. By way of
example, a pulse generator 300 is also commercially available, such
as Agilent 33522A Function/Arbitrary Waveform Generator, Agilent
Technologies, Inc., 5301 Stevens Creek Blvd Santa Clara Calif.
95051.
[0078] The control unit 330 may also comprise a general purpose
computer, comprising one or more CPU, computer memories for the
storage of executable computer programs (including the system's
operating system) and the storage and retrieval of data, disk
storage devices, communication devices (such as serial and USB
ports) for accepting external signals from the system's keyboard
and computer mouse as well as any externally supplied physiological
signals, analog-to-digital converters for digitizing externally
supplied analog signals, communication devices for the transmission
and receipt of data to and from external devices such as printers
and modems that comprise part of the system, hardware for
generating the display of information on monitors that comprise
part of the system, and busses to interconnect the above-mentioned
components. Thus, the user may operate the system by typing
instructions for the control unit 330 at a device such as a
keyboard and view the results on a device such as the system's
computer monitor, or direct the results to a printer, modem, and/or
storage disk. Control of the system may be based upon feedback
measured from externally supplied physiological or environmental
signals.
[0079] Parameters for the nerve or tissue stimulation include power
level, frequency and train duration (or pulse number). The
stimulation characteristics of each pulse, such as depth of
penetration, strength and accuracy, depend on the rise time, peak
electrical energy transferred to the coil and the spatial
distribution of the electric field. The rise time and peak coil
energy are governed by the electrical characteristics of the
magnetic stimulator and stimulating coil, whereas the spatial
distribution of the induced electric field depends on the coil
geometry and the anatomy of the region of induced current flow. In
one embodiment of the invention, pulse parameters are set in such
as way as to account for the detailed anatomy surrounding the nerve
that is being stimulated [Bartosz SAWICKI, Robert Szmurto,
Przemystaw Ptonecki, Jacek Starzy ski, Stanistaw Wincenciak,
Andrzej Rysz. Mathematical Modelling of Vagus Nerve Stimulation.
pp. 92-97 in: Krawczyk, A. Electromagnetic Field, Health and
Environment: Proceedings of EHE'07. Amsterdam, 105 Press, 2008]. A
single pulse may be monophasic (no current reversal within the
coil), biphasic or polyphasic. For rapid rate stimulators, biphasic
systems may be used wherein energy is recovered from each pulse in
order to help energize the next. Embodiments of the invention
include those that are fixed frequency, where each pulse in a train
has the same inter-stimulus interval, and those that have modulated
frequency, where the intervals between each pulse in a train can be
varied.
[0080] FIG. 2 illustrates an exemplary electrical voltage/current
profile for a stimulating, blocking and/or modulating impulse
applied to a portion or portions of selected nerves in accordance
with an embodiment of the present invention. For the preferred
embodiment, the voltage and current refer to those that are
non-invasively induced within the patient by the magnetic
stimulator. As shown, a suitable electrical voltage/current profile
400 for the blocking and/or modulating impulse 410 to the portion
or portions of a nerve may be achieved using pulse generator 310.
In a preferred embodiment, the pulse generator 310 may be
implemented using a power source 320 and a control unit 330 having,
for instance, a processor, a clock, a memory, etc., to produce a
pulse train 420 to the stimulator coils(s) 340 that deliver the
stimulating, blocking and/or modulating impulse 410 to the nerve.
Nerve stimulating/modulating device 300 may be externally powered
and/or recharged may have its own power source 320.
[0081] The parameters of the modulation signal 400 are preferably
programmable, such as the frequency, amplitude, duty cycle, pulse
width, pulse shape, etc. An external communication device may
modify the pulse generator programming to improve treatment.
[0082] In addition, or as an alternative to the devices to
implement the modulation unit for producing the electrical
voltage/current profile of the stimulating, blocking and/or
modulating impulse to the magnetic stimulator coil, the device
disclosed in patent publication No. US2005/0216062 (the entire
disclosure of which is incorporated herein by reference) may be
employed. U.S. Patent Publication No.: 2005/0216062 discloses a
multifunctional electrical stimulation (ES) system adapted to yield
output signals for effecting electromagnetic or other forms of
electrical stimulation for a broad spectrum of different biological
and biomedical applications, including magnetic stimulators, which
produce a high intensity magnetic field pulse in order to
non-invasively stimulate nerves. The system includes an ES signal
stage having a selector coupled to a plurality of different signal
generators, each producing a signal having a distinct shape, such
as a sine wave, a square or a saw-tooth wave, or simple or complex
pulse, the parameters of which are adjustable in regard to
amplitude, duration, repetition rate and other variables. Examples
of the signals that may be generated by such a system are described
in a publication by LIBOFF [A. R. LIBOFF. Signal shapes in
electromagnetic therapies: a primer. pp. 17-37 in:
Bioelectromagnetic Medicine (Paul J. Rosch and Marko S. Markov,
eds.). New York: Marcel Dekker (2004)]. The signal from the
selected generator in the ES stage is fed to at least one output
stage where it is processed to produce a high or low voltage or
current output of a desired polarity whereby the output stage is
capable of yielding an electrical stimulation signal appropriate
for its intended application. Also included in the system is a
measuring stage which measures and displays the electrical
stimulation signal operating on the substance being treated as well
as the outputs of various sensors which sense conditions prevailing
in this substance whereby the user of the system can manually
adjust it or have it automatically adjusted by feedback to provide
an electrical stimulation signal of whatever type he wishes and the
user can then observe the effect of this signal on a substance
being treated.
[0083] The stimulating, blocking and/or modulating impulse signal
410 preferably has a frequency, an amplitude, a duty cycle, a pulse
width, a pulse shape, etc. selected to influence the therapeutic
result, namely, stimulating, blocking and/or modulating some or all
of the transmission of the selected nerve. For example, the
frequency may be about 1 Hz or greater, such as between about 15 Hz
to 50 Hz, more preferably around 25 Hz. The modulation signal may
have a pulse width selected to influence the therapeutic result,
such as about 20 microseconds or greater, such as about 20
microseconds to about 1000 microseconds. For example, the electric
field induced by the device within tissue in the vicinity of a
nerve is 10 to 600 V/m, preferably around 300 V/m. The gradient of
the electric field may be greater than 2 V/m/mm. More generally,
the stimulation device produces an electric field in the vicinity
of the nerve that is sufficient to cause the nerve to depolarize
and reach a threshold for action potential propagation, which is
approximately 8 V/m at 1000 Hz.
[0084] The preferred embodiment of magnetic stimulator coil 340
comprises a toroidal winding around a core consisting of
high-permeability material (e.g., Supermendur), embedded in an
electrically conducting medium. Toroidal coils with high
permeability cores have been theoretically shown to greatly reduce
the currents required for transcranial (TMS) and other forms of
magnetic stimulation, but only if the toroids are embedded in a
conducting medium and placed against tissue with no air interface.
[Rafael CARBUNARU and Dominique M. Durand. Toroidal coil models for
transcutaneous magnetic stimulation of nerves. IEEE Transactions on
Biomedical Engineering 48 (No. 4, April 2001): 434-441; Rafael
Carbunaru FAIERSTEIN, Coil Designs for Localized and Efficient
Magnetic Stimulation of the Nervous System. Ph.D. Dissertation,
Department of Biomedical Engineering, Case Western Reserve, May,
1999, page 117 (UMI Microform Number: 9940153, UMI Company, Ann
Arbor Mich.)].
[0085] In order to explain some of the novelty of the presently
disclosed invention as compared with the device described in the
above-mentioned Carbunaru and Durand publication, as well as in the
FAIERSTEIN dissertation upon which the publication was based, it is
useful to first summarize the relevant physics of electric fields
and currents that are induced by time-varying magnetic fields, as
produced by current-carrying coils [Richard P. FEYNMAN, Robert B.
Leighton, and Matthew Sands. The Feynman Lectures on Physics.
Volume II. Addison-Wesley Publ. Co. (Reading Mass., 1964), page
15-15; K. P. ESSELLE and M. A. Stuchly, Neural stimulation with
magnetic fields: Analysis of induced electric fields, IEEE Trans.
Biomed. Eng., 39 (July 1992), pp. 693-700; R. BOWTELL and R. M.
Bowley. Analytic Calculations of the E-Fields Induced by
Time-Varying Magnetic Fields Generated by Cylindrical Gradient
Coils. Magnetic Resonance in Medicine 44:782-790 (2000); Feng L I
U, Huawei Zhao, and Stuart Crozier. On the Induced Electric Field
Gradients in the Human Body for Magnetic Stimulation by Gradient
Coils in MRI, IEEE Transactions on Biomedical Engineering 50: (No.
7, July 2003) pp. 804-815].
[0086] The magnetic field B may be represented as the curl of a
vector potential A, where B and A are functions of position and
time: B=.gradient.-A.
[0087] The electric field E, which is also a function of position
and time, consists of two parts, E.sub.1 and E.sub.2:
E=E.sub.1+E.sub.2. For a current-carrying coil, E.sub.1 is obtained
from the vector potential A by:
E 1 = - .differential. A .differential. t = - .intg. 1 4 .pi.
.differential. ( .mu. I ) .differential. t dI r ##EQU00001##
where .mu. is the permeability, I is the current flowing in the
coil, dl is an oriented differential element of the coil, r is the
distance between dl and the point at which the electric field E is
measured, and the integral is performed around all the differential
elements dl of the coil.
[0088] E.sub.2 is obtained from the gradient of a scalar potential
.PHI.: E.sub.2=-.gradient..PHI.. The scalar potential arises
because conductivity changes along the path of a current,
particularly the abrupt change of conductivity at an air/conductor
interface, causes electric charges to separate and accumulate on
the surface of the interface, with the amplitude and sign of the
charges changing as a function of surface position. Thus, no
conduction current can flow across an air/conductor interface, so
according to the interfacial boundary conditions, the component of
any induced current normal to the interface must be zero. The
existence of a scalar potential accounts for these effects.
[0089] The electrical current density J, which is also a function
of position and time, consists of two parts: J=J.sub.1+J.sub.2,
corresponding to the two parts of E: J.sub.1=.sigma.E.sub.1 and
J.sub.2=.sigma.E.sub.2, where the conductivity .sigma. is generally
a tensor and a function of position. If the current flows in
material that is essentially unpolarizable (i.e., is presumed not
to be a dielectric), any displacement current may be ignored, so
the current would satisfy Ampere's law: .gradient..times..mu./B=J.
Because the divergence of the curl is zero, .gradient.J=0. One may
substitute J.sub.1 and J.sub.2 into that equation to obtain:
.gradient.(.sigma.[((E)].sub.11-.gradient..PHI.))=0. The latter
equation has been solved numerically for special cases to estimate
the currents that are induced by a magnetic field that is inserted
into the body [W. WANG, S. R. Eisenberg, A three-dimensional finite
element method for computing magnetically induced currents in
tissues. IEEE Transactions on Magnetics. 30 (6, Nov. 1994):
5015-5023; Bartosz SAWICKI, Robert Szmurto, Przemystaw Ptonecki,
Jacek Starzy ski, Stanistaw Wincenciak, Andrzej Rysz. Mathematical
Modelling of Vagus Nerve Stimulation. pp. 92-97 in: Krawczyk, A.
Electromagnetic Field, Health and Environment: Proceedings of
EHE'07. Amsterdam, IOS Press, 2008]. If the conductivity of
material in the device (or patient) is itself selected to be a
function of the electric field, then the equation becomes
non-linear, which could exhibit multiple solutions, frequency
multiplication, and other such non-linear behavior.
[0090] If the displacement current cannot be ignored, the
displacement appears as a term involving the time-derivative of the
electric field in the more general expression:
.gradient. ( .differential. ( E ) .differential. t + .sigma. [ ( (
E ) ] 1 1 - .gradient. .PHI. ) ) = 0 , ##EQU00002##
where .di-elect cons. is the permittivity, which is a function of
position and is generally a tensor. As a consequence of such a
term, the waveform of the electric field at any point will
generally be altered relative to the waveform of the current I(t)
that is passed through the coils. Furthermore, if the permittivity
of a material in the device is itself selected to be a function of
the electric field, then the equation becomes non-linear, which
could exhibit multiple solutions, frequency multiplication, and
other such non-linear behavior.
[0091] The above-mentioned publication by CARBUNARU and Durand, as
well as the FAIERSTEIN dissertation upon which the publication was
based, are heretofore unique in that they describe a magnetic
stimulation device that does not create a magnetic field within the
tissues that the device is intended to stimulate. Their device
instead confines the magnetic field to a toroid, which is the only
coil geometry known to create a magnetic field that is completely
limited to part of space. With such a device, the electric field
alone penetrates the patient to stimulate nerves or tissue, which
they calculate using device-specific equations for the fields
E.sub.1 and E.sub.2 that were defined above. Unlike conventional
magnetic stimulation devices, their device's electric field
orientation is not limited to fields at the skin that are parallel
to the skin surface, due to the presence of conducting material
that extends from the skin to (and beyond) the stimulator's coil.
The boundary conditions giving rise to E.sub.2 were those of an
infinite half-space. Thus, their toroidal coil was immersed in a
homogeneous continuous conducting material that had an
air/conductor interface along an infinite plane parallel to the
toroid, located at a variable distance from the toroid, and the
toroid and conducting material were in contact with a patient's
skin.
[0092] In their investigations, Carbunaru and Durand varied E.sub.1
by only changing the coil geometry (integral over dl) as follows.
They investigated winding the coil around different core geometries
(round, quarter circle, square) and changed the radius and
thickness of the core. They also varied E.sub.2 by varying the
thickness of the conducting layer in which the toroid was immersed,
thereby changing boundary conditions only in that manner. Although
Carbunaru and Durand demonstrated that it is possible to
electrically stimulate a patient transcutaneously with such a
device, they made no attempt to develop the device in such a way as
to generally shape the electric field that is to stimulate the
nerve. In particular, the electric fields that may be produced by
their device are limited to those that are radially symmetric at
any given depth of stimulation into the patient (i.e., z and p are
used to specify location of the field, not x, y, and z). This is a
significant limitation, and it results in a deficiency that was
noted in FIG. 6 of their publication: "at large depths of
stimulation, the threshold current [in the device's coil] for long
axons is larger than the saturation current of the coil.
Stimulation of those axons is only possible at low threshold points
such as bending sites or tissue conductivity inhomogeneities".
Thus, for their device, varying the parameters that they
considered, in order to increase the electric field or its gradient
in the vicinity of a nerve, may come at the expense of limiting the
field's physiological effectiveness, such that the spatial extent
of the field of stimulation may be insufficient to modulate the
target nerve's function. Yet, such long axons are precisely what we
may wish to stimulate in therapeutic interventions, such as the
ones disclosed herein. Accordingly, it is an objective of the
present invention to shape an elongated electric field of effect
that can be oriented parallel to such a long nerve. The term "shape
an electric field" as used herein means to create an electric field
or its gradient that is generally not radially symmetric at a given
depth of stimulation in the patient, especially a field that is
characterized as being elongated or finger-like, and especially
also a field in which the magnitude of the field in some direction
may exhibit more than one spatial maximum (i.e. may be bimodal or
multimodal) such that the tissue between the maxima may contain an
area across which induced current flow is restricted. Shaping of
the electric field refers both to the circumscribing of regions
within which there is a significant electric field and to
configuring the directions of the electric field within those
regions.
[0093] Thus, the present invention differs from the device
disclosed by CARBUNARU and Durand by deliberately shaping an
electric field that is used to transcutaneously stimulate the
patient. Our invention does so by configuring elements that are
present within the equations that were summarized above, comprising
(but not limited to) the following exemplary configurations that
may be used alone or in combination.
[0094] First, the contours of the coil differential elements dl
that are integrated in the above equation for E.sub.1 are shaped
into a geometry other than a single planar toroid. For example, two
separate toroidal coils are used so that E.sub.1 becomes the sum of
two integrals, or the shape of a single toroid is twisted to
resemble a figure-of-8 rather than a planar toroid.
[0095] Second, the value of the current I in the above equation for
E.sub.1 is manipulated to shape the electric field. For example, if
the device contains two toroidal coils, the current in one toroid
may be the negative of the current in the other toroid. As another
example, the magnitude of the current in a left toroidal coil may
be varied relative to the magnitude of the current in a right
toroidal coil, so that the location of their superimposed induced
electric fields may be correspondingly moved (focused) in the left
or right directions. As another example, the waveform of the
current in a left toroidal coil may be different than the waveform
of the current in a right toroidal coil, so that their superimposed
induced electric fields may exhibit beat frequencies, as has been
attempted with electrode-based stimulators [U.S. Pat. No.
5,512,057, entitled Interferential stimulator for applying
localized stimulation, to REISS et al.], and acoustic stimulators
[U.S. Pat. No. 5,903,516, entitled Acoustic force generator for
detection, imaging and information transmission using the beat
signal of multiple intersecting sonic beams, to GREENLEAF et
al].
[0096] Third, the scalar potential .PHI. in the above equation for
E.sub.2 is manipulated to shape the electric field. For example,
this is accomplished by changing the boundaries of conductor/air
(or non-conductor) interfaces, thereby creating different boundary
conditions. Whereas the toroid in the CARBUNARU and Durand
publication was immersed in a homogeneous conducting half-space,
this is not necessarily the case for our invention. Although our
invention will generally have some continuously conducting path
between the device's coil and the patient's skin, the conducting
medium need not totally immerse the coil, and there may be
insulating voids within the conducting medium. For example, if the
device contains two toroids, conducting material may connect each
of the toroids individually to the patient's skin, but there may be
an insulating gap (from air or some other insulator) between the
surfaces at which conducting material connected to the individual
toroids contact the patient. Furthermore, the area of the
conducting material that contacts the skin may be made variable, by
using an aperture adjusting mechanism such as an iris diaphragm. As
another example, if the coil is wound around core material that is
laminated, with the core in contact with the device's electrically
conducting material, then the lamination may be extended into the
conducting material in such a way as to direct the induced
electrical current between the laminations and towards the surface
of the patient's skin. As another example, the conducting material
may pass through apertures in an insulated mesh before contacting
the patient's skin, creating thereby an array of electric field
maxima.
[0097] Fourth, the conductivity .sigma. (in the equations
J.sub.1=.sigma.E.sub.1 and J.sub.2=.sigma.E.sub.2) may be varied
spatially within the device by using two or more different
conducting materials that are in contact with one another, for
given boundary conditions. The conductivity may also be varied by
constructing some conducting material from a semiconductor, which
allows for adjustment of the conductivity in space and in time by
exposure of the semiconductor to agents to which they are
sensitive, such as electric fields, light at particular
wavelengths, temperature, or some other environmental variable over
which the user of the device has control. For the special case in
which the semiconductor's conductivity may be made to approach
zero, that would approximate the imposition of an interfacial
boundary condition as described in the previous paragraph. As
another example, the conducting material of the device may be
selected to have a three-dimensional conductivity structure that
approximates that of the conducting tissue under the patient's
skin, but oriented in the opposite and/or mirror image directions,
in such a way that the conductivity is symmetrical on either side
of the patient's skin. Such an arrangement will allow for
essentially symmetrical electrical stimulation of the patient's
tissue and the conducting material within the device.
[0098] Fifth, a dialectric material having a high permittivity
.di-elect cons., such as Mylar, neoprene, titanium dioxide, or
strontium titanate, may be used in the device, for example, in
order to permit capacitative electrical coupling to the patient's
skin.
[0099] Sixth, the present invention is more general than the device
described in the above-mentioned publication of CARBUNARU and
Durand in that, although the magnetic field produced by the present
invention does not effectively penetrate the patient's tissue, that
feature need not be due to the use of a toroidal coil. The magnetic
field will not effectively penetrate the patient's tissue if the
field's de minimis existence within the patient would produce no
significant physiological effect. For example, it would not produce
a significant physiological effect if the magnitude of the magnetic
field were of the same order of magnitude as the earth's magnetic
field. The magnetic field of our disclosed device may be produced
by a coil other than a toroid, wherein the magnetic field outside
the coil falls rapidly as a function of distance from the coil. For
example, the coil may be a solenoid that has an approximately
centrally-confined magnetic field as the density of coil turns and
the length of the solenoid increase. As another example, the coil
may be a partial toroid, which would also have a magnetic field
that approximates that of a complete toroid as the gap within the
partial-toroid decreases to zero. As another example, even if one
is attempting to construct a complete toroidal winding, the
presence of lead wires and imperfections of the winding may cause
the device in practice to deviate from the ideal toroid. Such
non-toroidal windings may be used in the present invention if they
are backed away and/or oriented relative to the patient's skin in
such a way that the magnetic field that is produced by the device
does not effectively penetrate the patient's tissue. Alternatively,
magnetic shielding, such as mumetal, supermalloy, supermumetal,
nilomag, sanbold, molybdenum permalloy, Sendust, M-1040, Hipernom
and HyMu-80, may be interposed between the patient and coil of the
device in such a way that the magnetic field that is produced by
the device does not effectively penetrate the patient's tissue.
[0100] In the dissertation cited above, Carbunaru-FAIERSTEIN made
no attempt to use conducting material other than agar in a KCl
solution, and he made no attempt to devise a device that could be
conveniently and safely applied to a patient's skin, at an
arbitrary angle without the conducting material spilling out of its
container. It is therefore an objective of the present invention to
disclose conducting material that can be used not only to adapt the
conductivity .sigma. and select boundary conditions, thereby
shaping the electric fields and currents as described above, but
also to create devices that can be applied practically to any
surface of the body. The volume of the container containing
electrically conducting medium is labeled in FIG. 1 as 350. Use of
the container of conducting medium 350 allows one to generate
(induce) electric fields in tissue (and electric field gradients
and electric currents) that are equivalent to those generated using
current magnetic stimulation devices, but with about 0.001 to 0.1
of the current conventionally applied to a magnetic stimulation
coil. This allows for minimal heating and deeper tissue
stimulation. However, application of the conducting medium to the
surface of the patient is difficult to perform in practice because
the tissue contours (head for TMS, arms, legs, neck, etc. for
peripheral nerve stimulation) are not planar. To solve this
problem, in the preferred embodiment of the present invention, the
toroidal coil is embedded in a structure which is filled with a
conducting medium having approximately the same conductivity as
muscle tissue, as now described.
[0101] In one embodiment of the invention, the container contains
holes so that the conducting material (e.g., a conducting gel) can
make physical contact with the patient's skin through the holes.
For example, the conducting medium 350 may comprise a chamber
surrounding the coil, filled with a conductive gel that has the
approximate viscosity and mechanical consistency of gel deodorant
(e.g., Right Guard Clear Gel from Dial Corporation, 15501 N. Dial
Boulevard, Scottsdale Ariz. 85260, one composition of which
comprises aluminum chlorohydrate, sorbitol, propylene glycol,
polydimethylsiloxanes Silicon oil, cyclomethicone, ethanol/SD
Alcohol 40, dimethicone copolyol, aluminum zirconium
tetrachlorohydrex gly, and water). The gel, which is less viscous
than conventional electrode gel, is maintained in the chamber with
a mesh of openings at the end where the device is to contact the
patient's skin. The gel does not leak out, and it can be dispensed
with a simple screw driven piston.
[0102] In another embodiment, the container itself is made of a
conducting elastomer (e.g., dry carbon-filled silicone elastomer),
and electrical contact with the patient is through the elastomer
itself, possibly through an additional outside coating of
conducting material. In some embodiments of the invention, the
conducting medium may be a balloon filled with a conducting gel or
conducting powders, or the balloon may be constructed extensively
from deformable conducting elastomers. The balloon conforms to the
skin surface, removing any air, thus allowing for high impedance
matching and conduction of large electric fields in to the tissue.
A device such as that disclosed in U.S. Pat. No. 7,591,776,
entitled Magnetic stimulators and stimulating coils, to PHILLIPS et
al. may conform the coil itself to the contours of the body, but in
the preferred embodiment, such a curved coil is also enclosed by a
container that is filled with a conducting medium that deforms to
be contiguous with the skin.
[0103] Agar can also be used as part of the conducting medium, but
it is not preferred, because agar degrades in time, is not ideal to
use against skin, and presents difficulties with cleaning the
patient and stimulator coil. Use of agar in a 4M KCl solution as a
conducting medium was mentioned in the above-cited dissertation:
Rafael Carbunaru FAIERSTEIN, Coil Designs for Localized and
Efficient Magnetic Stimulation of the Nervous System. Ph.D.
Dissertation, Department of Biomedical Engineering, Case Western
Reserve, May, 1999, page 117 (UMI Microform Number: 9940153, UMI
Company, Ann Arbor Mich.). However, that publication makes no
mention or suggestion of placing the agar in a conducting
elastomeric balloon, or other deformable container so as to allow
the conducting medium to conform to the generally non-planar
contours of a patient's skin having an arbitrary orientation. In
fact, that publication describes the coil as being submerged in a
container filled with an electrically conducting solution. If the
coil and container were placed on a body surface that was oriented
in the vertical direction, then the conducting solution would spill
out, making it impossible to stimulate the body surface in that
orientation. In contrast, the present invention is able to
stimulate body surfaces having arbitrary orientation. Examples
making use of the present device show the body surface as having
many different orientations that are incompatible with the
disclosure in the above-cited dissertation.
[0104] That dissertation also makes no mention of a dispensing
method whereby the agar would be made contiguous with the patient's
skin. A layer of electrolytic gel is said to have been applied
between the skin and coil, but the configuration was not described
clearly in the publication. In particular, no mention is made of
the electrolytic gel being in contact with the agar.
[0105] Rather than using agar as the conducting medium, the coil
can instead be embedded in a conducting solution such as 1-10%
NaCl, contacting an electrically conducting interface to the human
tissue. Such an interface is used as it allows current to flow from
the coil into the tissue and supports the medium-surrounded toroid
so that it can be completely sealed. Thus, the interface is
material, interposed between the conducting medium and patient's
skin, that allows the conducting medium (e.g., saline solution) to
slowly leak through it, allowing current to flow to the skin.
Several interfaces are disclosed as follows.
[0106] One interface comprises conducting material that is
hydrophilic, such as Tecophlic from The Lubrizol Corporation, 29400
Lakeland Boulevard, Wickliffe, Ohio 44092. It absorbs from 10-100%
of its weight in water, making it highly electrically conductive,
while allowing only minimal bulk fluid flow.
[0107] Another material that may be used as an interface is a
hydrogel, such as that used on standard EEG, EKG and TENS
electrodes [Rylie A GREEN, Sungchul Baek, Laura A Poole-Warren and
Penny J Martens. Conducting polymer-hydrogels for medical electrode
applications. Sci. Technol. Adv. Mater. 11 (2010) 014107 (13pp)].
For example it may be the following hypoallergenic, bacteriostatic
electrode gel: SIGNAGEL Electrode Gel from Parker Laboratories,
Inc., 286 Eldridge Rd., Fairfield N.J. 07004.
[0108] A third type of interface may be made from a very thin
material with a high dielectric constant, such as those used to
make capacitors. For example, Mylar can be made in submicron
thicknesses and has a dielectric constant of about 3. Thus, at
stimulation frequencies of several kilohertz or greater, the Mylar
will capacitively couple the signal through it because it will have
an impedance comparable to that of the skin itself. Thus, it will
isolate the toroid and the solution it is embedded in from the
tissue, yet allow current to pass.
[0109] The preferred embodiment of the magnetic stimulator coil 340
in FIG. 1 reduces the volume of conducting material that must
surround a toroidal coil, by using two toroids, side-by-side, and
passing electrical current through the two toroidal coils in
opposite directions. In this configuration, the induced current
will flow from the lumen of one toroid, through the tissue and back
through the lumen of the other, completing the circuit within the
toroids' conducting medium. Thus, minimal space for the conducting
medium is required around the outside of the toroids at positions
near from the gap between the pair of coils. An additional
advantage of using two toroids in this configuration is that this
design will greatly increase the magnitude of the electric field
gradient between them, which is crucial for exciting long, straight
axons such as the vagus nerve and certain peripheral nerves.
[0110] This preferred embodiment of the invention is shown in FIG.
3. FIGS. 3A and 3B respectively provide top and bottom views of the
outer surface of the toroidal magnetic stimulator 30. FIGS. 3C and
3D respectively provide top and bottom views of the toroidal
magnetic stimulator 30, after sectioning along its long axis to
reveal the inside of the stimulator.
[0111] FIGS. 3A-3D all show a mesh 31 with openings that permit a
conducting gel to pass from the inside of the stimulator to the
surface of the patient's skin at the location of nerve or tissue
stimulation. Thus, the mesh with openings 31 is the part of the
stimulator that is applied to the skin of the patient.
[0112] FIGS. 3B-3D show openings at the opposite end of the
stimulator 30. One of the openings is an electronics port 32
through which wires pass from the stimulator coil(s) to the impulse
generator (310 in FIG. 1). The second opening is a conducting gel
port 33 through which conducting gel may be introduced into the
stimulator 30 and through which a screw-driven piston arm may be
introduced to dispense conducting gel through the mesh 31. The gel
itself will be contained within cylindrical-shaped but
interconnected conducting medium chambers 34 that are shown in
FIGS. 3C and 3D. The depth of the conducting medium chambers 34,
which is approximately the height of the long axis of the
stimulator, affects the magnitude of the electric fields and
currents that are induced by the device [Rafael CARBUNARU and
Dominique M. Durand. Toroidal coil models for transcutaneous
magnetic stimulation of nerves. IEEE Transactions on Biomedical
Engineering. 48 (No. 4, April 2001): 434-441].
[0113] FIGS. 3C and 3D also show the coils of wire 35 that are
wound around toroidal cores 36, consisting of high-permeability
material (e.g., Supermendur). Lead wires (not shown) for the coils
35 pass from the stimulator coil(s) to the impulse generator (310
in FIG. 1) via the electronics port 32. Different circuit
configurations are contemplated. If separate lead wires for each of
the coils 35 connect to the impulse generator (i.e., parallel
connection), and if the pair of coils are wound with the same
handedness around the cores, then the design is for current to pass
in opposite directions through the two coils. On the other hand, if
the coils are wound with opposite handedness around the cores, then
the lead wires for the coils may be connected in series to the
impulse generator, or if they are connected to the impulse
generator in parallel, then the design is for current to pass in
the same direction through both coils.
[0114] As seen in FIGS. 3C and 3D, the coils 35 and cores 36 around
which they are wound are mounted as close as practical to the
corresponding mesh 31 with openings through which conducting gel
passes to the surface of the patient's skin. As seen in FIG. 3D,
each coil and the core around which it is wound is mounted in its
own housing 37, the function of which is to provide mechanical
support to the coil and core, as well as to electrically insulate a
coil from its neighboring coil. With this design, induced current
will flow from the lumen of one toroid, through the tissue and back
through the lumen of the other, completing the circuit within the
toroids' conducting medium.
[0115] Different diameter toroidal coils and windings may be
preferred for different applications. For a generic application,
the outer diameter of the core may be typically 1 to 5 cm, with an
inner diameter typically 0.5 to 0.75 of the outer diameter. The
coil's winding around the core may be typically 3 to 250 in number,
depending on the core diameter and depending on the desired coil
inductance.
[0116] The embodiment shown in FIG. 3 contains two toroids, in
which the outer surface of the toroids are planar, the toroids lie
side-by-side, and the corresponding outer surfaces for both toroids
lie essentially in the same plane. Many different embodiments are
also contemplated, each of which may be better suited to the
stimulation of particular nerves or tissues. Examples of such
alternate embodiments are illustrated in FIG. 4, showing the
geometry of the toroidal core material around which coils of wire
(not shown) would be wound. The darkened faces of the figures shown
there indicate the faces that would be oriented towards the
patient's skin. Instead of placing the toroids side-by-side as in
FIG. 3, a pair of toroids may be placed concentrically as shown in
FIG. 4A. Instead of using two toroids, any number could be used, as
illustrated by FIG. 4B that shows four concentrically positioned
toroids. Individual planar toroids need not all lie in the same
plane, as shown in FIG. 4C. In fact, the toroids themselves need
not have a planar structure, as illustrated in FIGS. 4D and 4E.
Furthermore, the toroids need not have a round structure or a
structure comprising arcs, as illustrated in FIG. 4F, which shows a
pair of concentrically positioned square toroids. The examples
shown here have toroids that are rectangular or square when
sectioned perpendicular to their perimeters. In other embodiments,
the sectioned toroid could have any other closed geometry, such as
a circle or an ellipse or a geometry that changes from one part of
the toroid to another.
[0117] Thus, the geometrical configuration of the disclosed device
is general. For example, it may comprise a plurality of toroids. It
may comprise two toroids wherein one toroid lies within the
aperture of the second toroid. A surface having a minimum area that
fills an aperture of a toroid need not lie within a plane. The
projection of the volume of a toroidal core onto a plane need not
produce a circular shape around any perimeter of any such
projection. For a plurality of toroids, a plane having a greatest
area of intersection through one toroid among the plurality may,
but need not, be parallel to a plane having a greatest area of
intersection through some second toroid among the plurality.
[0118] The design and methods of use of impulse generators, control
units, and stimulator coils for magnetic stimulators are informed
by the designs and methods of use of impulse generators, control
units, and electrodes (with leads) for comparable completely
electrical nerve stimulators, but design and methods of use of the
magnetic stimulators must take into account many special
considerations, making it generally not straightforward to transfer
knowledge of completely electrical stimulation methods to magnetic
stimulation methods. Such considerations include determining the
anatomical location of the stimulation and determining the
appropriate pulse configuration [OLNEY R K, So Y T, Goodin D S,
Aminoff Mt A comparison of magnetic and electric stimulation of
peripheral nerves. Muscle Nerve 1990:13:957-963; J. NILSSON, M.
Panizza, B. J. Roth et al. Determining the site of stimulation
during magnetic stimulation of the peripheral nerve,
Electroencephalographs and clinical neurophysiology. vol 85, pp.
253-264, 1992; Nafia AL-MUTAWALY, Hubert de Bruin, and Gary Hasey.
The Effects of Pulse Configuration on Magnetic Stimulation. Journal
of Clinical Neurophysiology 20(5):361-370, 2003].
[0119] In the preferred embodiment of the invention, electronic
components of the stimulator (impulse generator, control unit, and
power source) are compact, portable, and simple to operate. The
preferred simplicity is illustrated in FIG. 5, which shows the
stimulator coil housing 30 (illustrated in more detail as 30 in
FIG. 3), which is connected by electrical cable to a circuit
control box 38. As shown in FIG. 5, the circuit control box 38 will
generally require only an on/off switch and a power controller,
provided that the parameters of stimulation described in connection
with FIG. 2 have already been programmed for the particular
application of the device. For such a portable device, power is
provided by batteries, e.g., a 9 volt battery or two to six 1.5V AA
batteries. A covering cap 39 is also provided to fit snugly over
the mesh (31 in FIG. 3) of the stimulator coil housing 30, in order
to keep the housing's conducting medium from leaking or drying when
the device is not in use.
[0120] In the preferred embodiment for a generic therapeutic
application, the currents passing through the coils of the magnetic
stimulator will saturate the core (e.g., 0.1 to 2 Tesla magnetic
field strength for Supermendur core material). This will require
approximately 0.5 to 20 amperes of current being passed through
each coil, typically 2 amperes, with voltages across each coil of
10 to 100 volts. The current is passed through the coils in bursts
of pulses. The burst repeats at 1 Hz to 5000 Hz, preferably at
15-50 Hz. The pulses have duration of 20 to 1000 microseconds,
preferably 200 microseconds and there may be 1 to 20 pulses per
burst. Other waveforms described above in connection with FIG. 2
are also generated, depending on the nerve or tissue stimulation
application.
[0121] Examples in the remaining disclosure will be directed to use
of the disclosed toroidal magnetic stimulation device for treatment
of specific medical conditions. These applications involve
stimulating a patient in and around the patient's neck. However, it
will be appreciated that the systems and methods of the present
invention can be applied equally well to other tissues and nerves
of the body, including but not limited to parasympathetic nerves,
sympathetic nerves, spinal or cranial nerves, and brain tissue. In
addition, the present invention can be used to directly or
indirectly stimulate or otherwise modulate nerves that innervate
smooth or skeletal muscle, endocrine glands, and organs of the
digestive system.
[0122] In some preferred embodiments of methods that make use of
the disclosed toroidal-coil magnetic stimulation device, selected
nerve fibers are stimulated. These include stimulation of the vagus
nerve at a location in the patient's neck. At that location, the
vagus nerve is situated within the carotid sheath, near the carotid
artery and the interior jugular vein. The carotid sheath is located
at the lateral boundary of the retopharyngeal space on each side of
the neck and deep to the sternocleidomastoid muscle. The left vagus
nerve is ordinarily selected for stimulation because stimulation of
the right vagus nerve may produce undesired effects on the
heart.
[0123] The three major structures within the carotid sheath are the
common carotid artery, the internal jugular vein and the vagus
nerve. The carotid artery lies medial to the internal jugular vein,
and the vagus nerve is situated posteriorly between the two
vessels. Typically, the location of the carotid sheath or interior
jugular vein in a patient (and therefore the location of the vagus
nerve) will be ascertained in any manner known in the art, e.g., by
feel or ultrasound imaging. Proceeding from the skin of the neck
above the sternocleidomastoid muscle to the vagus nerve, a line may
pass successively through the sternocleidomastoid muscle, the
carotid sheath and the internal jugular vein, unless the position
on the skin is immediately to either side of the external jugular
vein. In the latter case, the line may pass successively through
only the sternocleidomastoid muscle and the carotid sheath before
encountering the vagus nerve, missing the interior jugular vein.
Accordingly, a point on the neck adjacent to the external jugular
vein might be preferred for non-invasive stimulation of the vagus
nerve. The magnetic stimulator coil may be centered on such a
point, at the level of about the fifth to sixth cervical
vertebra.
[0124] FIG. 6 illustrates use of the device shown in FIG. 3 and
FIG. 5 to stimulate the vagus nerve at that location in the neck,
in which the stimulator device 30 is applied to the target location
on the patient's neck as described above. For reference, locations
of the following vertebrae are also shown: first cervical vertebra
71, the fifth cervical vertebra 75, the sixth cervical vertebra 76,
and the seventh cervical vertebra 77.
[0125] FIG. 7 provides a more detailed view of use of the toroidal
magnetic stimulator device, when positioned to stimulate the vagus
nerve at the neck location that is indicated in FIG. 6. As shown,
the toroidal magnetic stimulator 30 touches the neck indirectly, by
making electrical contact through conducting gel 29 (or other
conducting material) that is dispensed through mesh openings of the
stimulator (identified as 31 in FIG. 3). The layer of conducting
gel 29 in FIG. 7 is shown to connect the device to the patient's
skin, but it is understood that the actual location of the gel
layer(s) is generally determined by the location of mesh 31 shown
in FIG. 3A. It is also understood that the device 30 is connected
via wires or cables (not shown) to an impulse generator 310 as in
FIG. 1. The vagus nerve 60 is identified in FIG. 7, along with the
carotid sheath 61 that is identified there in bold peripheral
outline. The carotid sheath encloses not only the vagus nerve, but
also the internal jugular vein 62 and the common carotid artery 63.
Features that may be identified near the surface of the neck
include the external jugular vein 64 and the sternocleidomastoid
muscle 65. Additional organs in the vicinity of the vagus nerve
include the trachea 66, thyroid gland 67, esophagus 68, scalenus
anterior muscle 69, and scalenus medius muscle 70. The sixth
cervical vertebra 76 is also shown in FIG. 7, with bony structure
indicated by hatching marks.
[0126] Magnetic stimulation has been used by several investigators
to non-invasively stimulate the vagus nerve, in the neck and at
other locations. In a series of articles beginning in 1992, Aziz
and colleagues describe using non-invasive magnetic stimulation to
electrically stimulate the vagus nerve in the neck. [Q. AZIZ et al.
Magnetic Stimulation of Efferent Neural Pathways to the Human
Oesophagus. Gut 33: S53-S70 (Poster Session F218) (1992); AZIZ, Q.,
J. C. Rothwell, J. Barlow, A. Hobson, S. Alani, J. Bancewicz, and
D. G. Thompson. Esophageal myoelectric responses to magnetic
stimulation of the human cortex and the extracranial vagus nerve.
Am. J. Physiol. 267 (Gastrointest. Liver Physiol. 30): G827-G835,
1994; Shaheen HAMDY, Qasim Aziz, John C. Rothwell, Anthony Hobson,
Josephine Barlow, and David G. Thompson. Cranial nerve modulation
of human cortical swallowing motor pathways. Am. J. Physiol. 272
(Gastrointest. Liver Physiol. 35): G802-G808, 1997; Shaheen HAMDY,
John C. Rothwell, Qasim Aziz, Krishna D. Singh, and David G.
Thompson. Long-term reorganization of human motor cortex driven by
short-term sensory stimulation. Nature Neuroscience 1 (issue 1, May
1998):64-68.] SIMS and colleagues stimulated the vagus nerve at and
near the mastoid tip. [H. Steven SIMS, Toshiyuki Yamashita, Karen
Rhew, and Christy L. Ludlow. Assessing the clinical utility of the
magnetic stimulator for measuring response latencies in the
laryngeal muscles. Otolaryngol Head Neck Surg 1996; 114:761-7].
KHEDR and colleagues also used a magnetic stimulator to stimulate
the vagus nerve at the tip of the mastoid bone [E. M. KHEDR and
E-E. M. Aref Electrophysiological study of vocal-fold mobility
disorders using a magnetic stimulator. European Journal of
Neurology 2002, 9: 259-267; KHEDR, E. M., Abo-Elfetoh, N., Ahmed,
M. A., Kamel, N. F., Farook, M., El Karn, M. F. Dysphagia and
hemispheric stroke: A transcranial magnetic study. Neurophysiologie
Clinique/Clinical Neurophysiology (2008) 38, 235-242)]. SHAFIK
stimulated the vagus nerve in the neck, placing the magnetic
stimulator on the neck between the sternomastoid muscle and the
trachea. [A. SHAFIK. Functional magnetic stimulation of the vagus
nerve enhances colonic transit time in healthy volunteers. Tech
Coloproctol (1999) 3:123-12]. Among these investigations, the one
by SHAFIK stimulated the vagus nerve for the longest period of
time. He stimulated at 175 joules per pulse, 40 Hz frequency, 10
seconds on, 10 seconds off for 20 minutes duration and followed by
60 minutes of rest, and this sequence was performed for 5 cycles in
each subject.
[0127] The vagus is not the only nerve that may be stimulated
non-invasively in the neck using magnetic stimulation. For example,
the phrenic nerve has also been magnetically stimulated.
[SIMILOWSKI, T., B. Fleury, S. Launois, H. P. Cathala, P. Bouche,
and J. P. Derenne. Cervical magnetic stimulation: a new painless
method for bilateral phrenic nerve stimulation in conscious humans.
J. Appl. Physiol. 67(4): 1311-1318, 1989; Gerrard F. RAFFERTY, Anne
Greenough, Terezia Manczur, Michael I. Polkey, M. Lou Harris, Nigel
D. Heaton, Mohamed Rela, and John Moxham. Magnetic phrenic nerve
stimulation to assess diaphragm function in children following
liver transplantation. Pediatr Crit Care Med 2001, 2:122-126; W.
D-C. MAN, J. Moxham, and M. I. Polkey. Magnetic stimulation for the
measurement of respiratory and skeletal muscle function. Eur Respir
J 2004; 24: 846-860]. If one intends to stimulate only the vagus
nerve, careful positioning of the stimulator coil should be
undertaken in order to avoid co-stimulation of the phrenic nerve,
or the magnetic stimulation waveform may be designed to minimize
the effect of any co-stimulation of the vagus and phrenic nerves
[patent application JP2008/081479A, entitled Vagus nerve
stimulation system, to YOSHIHOTO].
[0128] If it is desired to maintain a constant intensity of
stimulation in the vicinity of the vagus nerve (or any other nerve
or tissue that is being stimulated), methods may also be employed
to modulate the power of the stimulator in order to compensate for
patient motion or other mechanisms that would otherwise give rise
to variability in the intensity of stimulation. In the case of
stimulation of the vagus nerve, such variability may be
attributable to the patient's breathing, which may involve
contraction and associated change in geometry of the
sternocleidomastoid muscle that is situated close to the vagus
nerve (identified as 65 in FIG. 7). Methods for compensating for
motion and other confounding factors were disclosed by the present
applicant in co-pending application Ser. No. 12/859,568 entitled
Non-Invasive Treatment of Bronchial Constriction, to SIMON, which
is hereby incorporated by reference.
[0129] Several examples follow, exemplifying therapies for
neurodegenerative disorders that involve stimulation of the vagus
nerve in the neck using magnetic stimulation devices. However, it
is understood that stimulation of the vagus nerve could also be
performed at locations other than the neck [Polak T, Markulin F,
Ehlis A C, Langer J B, Ringel T M, Fallgatter A J. Far field
potentials from brain stem after transcutaneous vagus nerve
stimulation: optimization of stimulation and recording parameters.
J Neural Transm. 2009 October; 116(10):1237-42]. It is also
understood that non-invasive methods other than magnetic
stimulation may also be used to stimulate the vagus nerve, in order
to achieve the intended therapeutic effects. In particular, the
non-invasive methods and devices that Applicant disclosed in
co-pending U.S. patent application Ser. No. 12/859,568 entitled
Non-invasive Treatment of Bronchial Constriction, to SIMON, may
also be used. It is also understood that stimulation of nerves
other than the vagus nerve may also achieve the intended
therapeutic results, including those in the sympathetic nervous
system, particularly the splenic nerve.
[0130] FIG. 8 illustrates mechanisms or pathways through which
stimulation of the vagus nerve may be used to reduce inflammation
in patients with neurodegenerative disorders. In what follows, each
of the mechanisms or pathways is described in connection with
treatment of particular disorders, namely, Alzheimer's disease,
Parkinson's disease, multiple sclerosis, and postoperative
cognitive dysfunction and/or postoperative delirium. However, it is
understood that the treatment of other neurodegenerative disorders
using vagal nerve stimulation may also make use of methods
involving these mechanisms or pathways. It is also understood that
not all of the pathways or mechanisms may be used in the treatment
of a particular patient and that pathways or mechanisms that are
not shown in FIG. 8 may also be used. Thus, particular pathways or
mechanisms are invoked by the selection of particular stimulation
parameters, such as current, frequency, pulse width, duty cycle,
etc. Nevertheless, as an aid to understanding the applications that
follow, it is useful to consider at once all the mechanisms shown
in FIG. 8.
[0131] Two types of pathways are shown in FIG. 8. The pathways that
stimulate or upregulate are indicated with an arrow (.dwnarw.). The
pathways that inhibit or downregulate are indicated with a blockage
bar (.perp.). Pathways resulting from stimulation of the vagus
nerve are shown to stimulate retinoic acid 81, anti-inflammatory
cytokines 82 such as TGF-beta, and neurotrophic factors 83 such as
BDNF. The patient may also be treated with retinoic acid or some
other retinoid by administering it as a drug 84. For cytokines that
may have both anti-inflammatory and pro-inflammatory capabilities,
the retinoic acid biases such cytokines to exhibit their
anti-inflammatory potential, as shown in the pathway labeled as 85.
Pro-inflammatory cytokines, on the other hand, promote inflammation
by pathways labeled as 86. Stimulation of the vagus nerve inhibits
the release of pro-inflammatory cytokines 91 directly through
pathways that have been described by TRACEY and colleagues. The
other pathways shown in FIG. 8 to inhibit inflammation following
stimulation of the vagus nerve are novel to this disclosure, and
include inhibition of inflammation via anti-inflammatory cytokine
pathways 92 including those that inhibit the release of
pro-inflammatory cytokines 93, inhibition via neurotrophic factors
94 including those that inhibit the release of pro-inflammatory
cytokines 95, and inhibition via retinoic acid pathways 96
including those that inhibit the release of pro-inflammatory
cytokines 97.
[0132] It is understood that the labels in FIG. 8 that are used for
simplicity to describe the pathways actually refer to a large set
of related pathways. For example, the box labeled as "retinoic
acid" actually refers to not only retinoic acid but also to a
larger class of retinoids, as well as to retinaldehyde
dehydrogenases, retinoic acid receptors (RAR), retinoid X receptors
(RXR), retinoic acid response elements (RAREs), and more generally
to the retinoic acid signaling system of the nervous system and
related pathways.
[0133] Furthermore, it is understood that the box labeled
"Anti-Inflammatory Cytokine, e.g., TGF-beta" can actually be placed
within the box entitled "Neurotrophic Factor", because TFG-beta is
a member of the superfamily of TGF-beta neurotrophic factors
[Yossef S. Levy, Yossi Gilgun-Sherki, Eldad Melamed and Daniel
Offen. Therapeutic Potential of Neurotrophic Factors in
Neurodegenerative Diseases. Biodrugs 2005; 19 (2): 97-127].
However, because TGF-beta is ordinarily referred to simply as a
cytokine, and because its anti-inflammatory competence is known to
be influenced by retinoic acid, it was placed in a separate box to
avoid undue confusion.
Example: Stimulation of the Vagus Nerve to Treat Alzheimer
Disease
[0134] Alzheimer (or Alzheimer's) disease (AD) is the most common
cause of dementia, affecting more than 5 million individuals in the
United States. AD clinical decline and pathological processes occur
gradually. Dementia is the end stage of many years of accumulation
of pathological changes, which begin to develop decades before the
earliest clinical symptoms occur. A pre-symptomatic phase occurs
first, in which individuals are cognitively normal but some have AD
pathological changes. This is followed by a second prodromal phase
of AD, commonly referred to as mild cognitive impairment (MCI). The
final phase in the evolution of AD is dementia, defined as
impairments that are severe enough to produce loss of function.
[0135] Until recently, a definitive diagnosis of AD could only be
made at the autopsy or by brain biopsy of an individual, by
identifying amyloid plaques and neurofibrillary tangles (NFTs) in
the association regions of the individual's brain, particularly in
the medial aspect of the temporal lobe. Additional evidence of AD
from an individual's autopsy or biopsy would include the presence
of the following: the granulovacuolar degeneration of Shimkowicz,
the neuropil threads of Braak, and neuronal loss with synaptic
degeneration.
[0136] Amyloid precursor protein (APP) is a membrane protein that
is concentrated in the synapses of neurons. APP is the precursor
molecule whose proteolysis generates .beta.-amyloid (A.beta.), a
peptide whose amyloid fibrillar form is the primary component of
amyloid plaques found in the brains of AD patients.
[0137] Tau proteins, which are abundant in the central nervous
system, stabilize microtubules. When tau proteins are defective and
no longer stabilize microtubules properly, they can produce
dementias, including AD. Defective tau protein will aggregate and
twist into neurofibrillary tangles (NFTs), so that the protein is
no longer available the stabilization of microtubules. As a result,
the neuronal cytoskeleton falls apart, contributing to neuronal
malfunction and cell death.
[0138] AD begins when cells abnormally process the amyloid
precursor protein (APP), which then leads to excess production or
reduced clearance of .beta.-amyloid (A.beta.) in the cortex. Excess
of one or more forms of A.beta. leads to a cascade, characterized
by abnormal tau protein aggregation, synaptic dysfunction, cell
death, and brain shrinkage. The detailed molecular mechanism of tau
protein aggregation is unknown, but it is thought that
extracellular deposits of A.beta. in the brains of AD patients
promote tau polymerization.
[0139] Inflammation and the immune system play a significant role
in AD pathogenesis. The inflammatory components in AD include
microglia and astrocytes, the complement system, and various
inflammatory mediators (including cytokines and chemokines).
Microglia are the resident immune cell types of the central nervous
system, and in AD, microglia may cause damage by secretion of
neurotoxins. When microglia become activated during inflammation,
they also secrete a variety of inflammatory mediators including
cytokines (TNF and interleukins IL-1.beta. and IL-6) and chemokines
(macrophage inflammatory protein MIP-1a, monocyte chemoattractant
protein MCP-1 and interferon inducible protein IP-10) that promote
the inflammatory state.
[0140] Microglia accumulate in locations that contain A.beta. and
are associated with the local toxicity of A.beta. plaques. Whether
the accumulated microglia contribute to the removal or deposition
of plaque is now thought to depend on the detailed microenvironment
of the accumulated microglia. Microglial cell activation and
migration toward .beta.-amyloid plaques precede the appearance of
abnormally shaped neurites and the formation of neurofibrillary
tangles. It has been shown that following microglial migration to
the plaques, microglial-derived proinflammatory cytokine TNF-alpha
is induced, which in turn induces accumulation of the
aggregation-prone tau molecules in neurites via reactive oxygen
species. [GORLOVY, P., Larionov, S., Pham, T. T. H., Neumann, H.
Accumulation of tau induced in neurites by microglial
proinflammatory mediators. FASEB J. 23, 2502-2513 (2009)]. Elevated
levels of TNF-alpha also induce an increased expression of
interleukin-1, which in turn increases production of the precursors
that may be necessary for formation of .beta.-amyloid plaques and
neurofibrillary tangles. Thus, the secretion of TNF-alpha by
microglia contributes to a cycle wherein tau aggregates to form
tangles, .beta.-amyloid plaques are formed, microglia aggregate to
those plaques, and more TNF-alpha is secreted by microglia
cells.
[0141] In addition to its proinflammatory functions, TNF-alpha is a
gliotransmitter that regulates synaptic function in neural
networks. In particular, TNF-alpha has been shown to mediate the
disruption in synaptic memory mechanisms. Etanercept, a biologic
antagonist of TNF-alpha, when delivered by perispinal
administration, has been shown to improve the cognitive abilities
of AD patients, even within minutes of its administration [Edward L
TOBINICK and Hyman Gross. Rapid cognitive improvement in Alzheimer
disease following perispinal etanercept administration. Journal of
Neuroinflammation 2008, 5:2; W Sue T GRIFFIN. Perispinal
etanercept: Potential as an Alzheimer therapeutic. Journal of
Neuroinflammation 2008, 5:3; Edward TOBINICK. Tumour Necrosis
Factor Modulation for Treatment of Alzheimer's Disease Rationale
and Current Evidence. CNS Drugs 2009; 23 (9): 713-725].
Furthermore, in a population of adults with rheumatoid arthritis,
CHOU et al. observed that the risk of AD was significantly reduced
by TNF inhibitor therapy for the rheumatoid arthritis, but not by
other disease modifying agents used for treatment of rheumatoid
arthritis. It may therefore be concluded that TNF may be an
important component in the pathogenesis of AD [Richard C. CHOU,
Michael A. Kane, Shiva Gautam and Sanjay Ghirmire. Tumor Necrosis
Factor Inhibition Reduces the Incidence of Alzheimer's Disease in
Rheumatoid Arthritis Patients. Program abstracts of the American
College of Rheumatology/Association of Rheumatology Health
Professionals Scientific Meeting, Nov. 8, 2010, Atlanta Ga.,
Presentation No. 640].
[0142] With the ability to better stage the progression of AD
through use of biomarkers, treatment of AD may be justified at
stages prior to actual dementia. With a better understanding of the
pathogenesis of AD, those treatments might be directed to slowing,
stopping, or reversing the pathophysiological processes underlying
AD.
[0143] Biomarkers are cognitive, physiological, biochemical, and
anatomical variables that can be measured in a patient that
indicate the progression of AD. The most commonly measured
biomarkers are decreased A.beta.42 in the cerebrospinal fluid
(CSF), increased CSF tau, decreased fluorodeoxyglucose uptake on
PET (FDG-PET), PET amyloid imaging, and structural MRI measures of
cerebral atrophy. Biomarkers of A.beta. deposition become abnormal
early, before neurodegeneration and clinical symptoms occur.
Biomarkers of neuronal injury, dysfunction, and neurodegeneration
become abnormal later in the disease. Cognitive symptoms are
directly related to biomarkers of neurodegeneration, rather than to
biomarkers of A.beta. deposition.
[0144] At the present time, other than physical and mental
exercise, only symptomatic therapies for AD are available. All
approved drugs for the symptomatic treatment of AD modulate
neurotransmitters--either acetylcholine or glutamate:
cholinesterase inhibitors and partial N-methyl-D-aspartate
antagonists. Psychotropic medications are also used to treat
secondary symptoms of AD such as depression, agitation, and sleep
disorders.
[0145] Therapies directed to modifying AD progression itself are
considered investigational. These include treatment of the intense
inflammation that occurs in the brains of patients with AD,
estrogen therapy, use of free-radical scavengers, therapies
designed to decrease toxic amyloid fragments in the brain
(vaccination, anti-amyloid antibodies, selective amyloid-lowering
agents, chelating agents to prevent amyloid polymerization, brain
shunting to improve removal of amyloid, and beta-secretase
inhibitors to prevent generation of the A-beta amyloid fragment),
and agents that may prevent or reverse excess tau phosphorylation
and thereby diminish formation of neurofibrillary tangles.
[0146] However, it is increasingly recognized that a single target
or pathogenic pathway for the treatment of AD is unlikely to be
identified. The best strategy is a multi-target therapy that
includes multiple types of treatments [Mangialasche F, Solomon A,
Winblad B, Mecocci P, Kivipelto M. Alzheimer disease: clinical
trials and drug development. Lancet Neurol. 2010 July;
9(7):702-16]. Targets in that multi-target approach will include
inflammatory pathways, and several therapeutic agents have been
proposed to target them--nonsteroidal anti-inflammatory drugs,
statins, RAGE antagonists and antioxidants [Stuchbury G, Munch G.
Alzheimer associated inflammation, potential drug targets and
future therapies. J Neural Transm. 2005 March; 112(3):429-53].
Another such agent, Etanercept, was mentioned above as targeting
TNF-alpha, but its use has the disadvantage that because it does
not pass the blood-brain barrier (BBB), its administration is via a
painful spinal route or via an experimental method to get through
the BBB [U.S. Pat. No. 7,640,062, entitled Methods and systems for
management of alzheimer's disease, to SHALEV]. One TNF-inhibitor
that does not have this disadvantage is thalidomide [Tweedie D,
Sambamurti K, Greig N H: TNF-alpha Inhibition as a Treatment
Strategy for Neurodegenerative Disorders: New Drug Candidates and
Targets. Curr Alzheimer Res 2007, 4(4):375-8]. However, thalidomide
is well known by the public to cause birth defects, and in a small
trial, its use did not appear to improve cognition in AD patients
[Peggy PECK. IADRD: Pilot Study of Thalidomide for Alzheimer's
Disease Fails to Detect Cognitive Benefit but Finds Effect on
TNF-alpha. Doctor's Guide Global Edition, Jul. 26, 2002]. There is
therefore a need in the art for new therapies that target
TNF-alpha, including its physiological activity for a given amount,
as a component of a multi-target approach to treating AD
[0147] In 2002, it was reported that electrical stimulation of the
vagus nerve has a beneficial effect on cognition in patients with
AD [Sjogren M J, Hellstrom P T, Jonsson M A, Runnerstam M, Silander
H C, Ben-Menachem E. Cognition-enhancing effect of vagus nerve
stimulation in patients with Alzheimer's disease: a pilot study. J
Clin Psychiatry. 2002 November; 63(11):972-80]. The rationale for
the trial was that vagus nerve stimulation had previously been
found to enhance the cognitive abilities of patients that were
undergoing vagus nerve stimulation for other conditions such as
epilepsy and depression, as well cognitive abilities observed in
animal studies. Results concerning the AD patients' improved
cognitive abilities over a longer period of time, along with
improvement in tau protein of cerebrospinal fluid, were
subsequently reported [Merrill C A, Jonsson M A, Minthon L, Ejnell
H, C-son Silander H, Blennow K, Karlsson M, Nordlund A, Rolstad S,
Warkentin S, Ben-Menachem E, Sjogren M J. Vagus nerve stimulation
in patients with Alzheimer's disease: Additional follow-up results
of a pilot study through 1 year. J Clin Psychiatry. 2006 August;
67(8):1171-8]. Stimulation of the vagus nerve to treat dementia
might be more effective than stimulation of nerves found in
locations such as the spine, forehead, and earlobes [Cameron M H,
Lonergan E, Lee H. Transcutaneous Electrical Nerve Stimulation
(TENS) for dementia. Cochrane Database of Systematic Reviews 2003,
Issue 3. Art. No.: CD004032. (2009 update)]. The method of using
vagal nerve stimulation to treat AD had been disclosed earlier in
U.S. Pat. No. 5,269,303, entitled Treatment of dementia by nerve
stimulation, to WERNICKE et al., but neither that patent nor the
clinical trials proposed any physiological intermediary through
which vagal nerve stimulation may result in clinical improvement to
AD patients.
[0148] It has been proposed that electrical stimulation of the
vagus nerve may attenuate an inflammatory response. In particular,
methods involving electrical stimulation of the vagus nerve have
been disclosed for attenuating or inhibiting the release of the
pro-inflammatory cytokine TNF-alpha, including AD as one disease in
a long list of diseases involving inflammation [U.S. Pat. Nos.
6,610,713 and 6,838,471, entitled Inhibition of inflammatory
cytokine production by cholinergic agonists and vagus nerve
stimulation, to TRACEY; Kevin J. TRACEY. The inflammatory reflex.
Nature 420(2002): 853-859; Kevin J. TRACEY. Physiology and
immunology of the cholinergic anti-inflammatory pathway. J. Clin.
Invest. 117(2007):289-296]. It has also been proposed that
electrical stimulation of nerves of the sympathetic nervous system
(particularly the splenic nerve) may also attenuate an inflammatory
response, by attenuating or inhibiting the release of TNF-alpha,
including AD as a one disease in a long list of diseases involving
inflammation [U.S. Pat. No. 7,769,442, entitled Device and method
for inhibiting release of pro-inflammatory mediator, to SHAFER].
PROLO et al. noted the above-mention vagal nerve stimulation
investigations and predicted that interventions based on
attenuation of inflammation would be useful for the treatment of AD
[Paolo PROLO, Francesco Chiappelli, Alberto Angeli, Andrea Dovio,
Maria Luisa Sartori, Fausto Fanto, Negoita Neagos, Ercolano
Manfrini. Putative Neurolmmune Mechanisms in Alzheimer's Disease:
Modulation by Cholinergic Anti-Inflammatory Reflex (CAIR).
International Journal of Integrative Biology 2007, Vol 1 (No.
2):88-95].
[0149] However, as noted above, TNF-alpha is involved in more than
inflammation in AD [Ian A. CLARK, Lisa M. Alleva and Bryce Vissel.
The roles of TNF in brain dysfunction and disease. Pharmacology
& Therapeutics, 128 (Issue 3, December 2010): 519-548]. It is
also a gliotransmitter that regulates synaptic function in neural
networks [Gertrudis PEREA and Alfonso Araque. GLIA modulates
synaptic transmission. Brain Research Reviews. 63 (Issues 1-2, May
2010):93-102]. In that capacity, TNF-alpha has been shown to
mediate the disruption in synaptic memory mechanisms. None of the
above-mentioned citations have proposed that stimulation of the
vagus nerve modulates the capacity of TNF-alpha to function as a
gliotransmitter, which can be released from any glial cell,
including oligodendrocytes, astrocytes, and microglia. Such
modulation in capacity can be due to a change in the amount of
TNF-alpha or in the activity of a given amount of TNF-alpha or in
the activity of the cells between which TNF-related
gliotransmission occurs. In fact, the above-mentioned citations are
concerned only with the attenuation or inhibition of the release of
TNF-alpha as a pro-inflammatory mediator, but not with its
degradation or modification or with changes in its activity for a
given amount.
[0150] Stimulation of the vagus nerve may also antagonize the
pro-inflammatory capabilities of TNF-alpha and other
pro-inflammatory cytokines through mechanisms that are different
from those proposed by TRACEY and colleagues. In particular, it has
been observed that stimulation of the vagus nerve may enhance the
release of retinoic acid (RA) from nerve locations that produce RA
from retinaldehyde using retinaldehyde dehydrogenases [van de
PAVERT SA, Olivier B J, Goverse G, Vondenhoff M F, Greuter M, Beke
P, Kusser K, Hopken U E, Lipp M, Niederreither K, Blomhoff R,
Sitnik K, Agace W W, Randall T D, de Jonge W J, Mebius R E.
Chemokine CXCL13 is essential for lymph node initiation and is
induced by retinoic acid and neuronal stimulation. Nat Immunol.
10(November 2009): 1193-1199]. The retinoic acid so released may
directly inhibit the release or functioning of proinflammatory
cytokines, which would be an anti-pro-inflammatory mechanism that
is distinct from the one proposed by TRACEY and colleagues [Malcolm
Maden. Retinoic acid in the development, regeneration and
maintenance of the nervous system. Nature Reviews Neuroscience
8(2007), 755-765]. Because RA strongly suppresses the production of
IL6, inhibits amyloid-beta-induced TNF-alpha production, and
inhibits expression of inducible NO synthase (iNOS) in activated
microglia, the release of RA following stimulation of the vagus
nerve will also serve to inhibit inflammation [K. SHUDO, H.
Fukasawa, M. Nakagomi and N. Yamagata. Towards Retinoid Therapy for
Alzheimer's Disease. Current Alzheimer Research, 2009, 6, 302-311].
Retinoic acid can also regulate the expression of the tau protein,
and in particular the level of phosphorylated forms of tau [Andrea
MALASPINA and Adina T. Michael-Titus. Is the modulation of retinoid
and retinoid associated signaling a future therapeutic strategy in
neurological trauma and neurodegeneration? J. Neurochem. (2008)
104, 584-595]. Furthermore, stimulation of nerves to release
retinoic acid or activate its receptors may also promote the
clearance of beta amyloids in AD by RA activation of the
heterodimeric complex formed by PPAR-RXR [Camacho I. E., Serneels
L., Spittaels K., Merchiers P., Dominguez D. and De Strooper B.
Peroxisome-proliferator-activated receptor gamma induces a
clearance mechanism for the amyloid-beta peptide. J. Neurosci.
24(2004), 10908-10917].
[0151] The cytokine TGF-beta acts in a highly contextual manner,
and depending on cell type and environment, TGF-beta may promote
cell survival or induce apoptosis, stimulate cell proliferation or
induce differentiation, and initiate or resolve inflammation. In
the presence of RA, TGF-beta is biased towards anti-inflammation,
so the release of RA following vagal nerve stimulation may inhibit
inflammation by that pro-anti-inflammatory mechanism as well [Tony
Wyss-Coray. TGF-beta Pathway as a Potential Target in
Neurodegeneration and Alzheimer's. Current Alzheimer Research,
3(2006): 191-195]. Treating the patient with oral retinoic acid may
also promote an anti-inflammatory bias for TGF-beta. Furthermore,
vagal nerve stimulation may also stimulate the production of the
TGF-beta that can act as an anti-inflammatory agent [CORCORAN,
Ciaran; Connor, Thomas J; O'Keane, Veronica; Garland, Malcolm R.
The effects of vagus nerve stimulation on pro- and
anti-inflammatory cytokines in humans: a preliminary report.
Neuroimmunomodulation 12 (May 2005): 307-309].
[0152] TGF-beta is a member of the TGF-beta superfamily of
neurotrophic factors. Neurotrophic factors serve as growth factors
for the development, maintenance, repair, and survival of specific
neuronal populations, acting via retrograde signaling from target
neurons by paracrine and autocrine mechanisms. Nerve growth factor
(NGF) is the most widely examined neurotrophin in experimental
models of AD, and of all the factors tested, NGF appears to be the
most effective in improving the survival and maintenance of
cholinergic neurons. It is therefore considered to be a promising
therapeutic agent for AD [Yossef S. LEVY, Yossi Gilgun-Sherki,
Eldad Melamed and Daniel Offen. Therapeutic Potential of
Neurotrophic Factors in Neurodegenerative Diseases. Biodrugs 2005;
19 (2): 97-127; Mark H. TUSZYNSKI. Nerve Growth Factor Gene Therapy
in Alzheimer Disease. Alzheimer Dis Assoc Disord 21 (February
2007): 179-189]. However, major problems in using neurotrophic
factors for therapy are their inability to cross
blood-brain-barrier, adverse effects resulting from binding to the
receptor in other organs of the body and their low diffusion
rate.
[0153] It is known that vagal nerve stimulation and transcranial
magnetic stimulation can increase the levels of at least one
neurotrophic factor in the brain, brain-derived neurotrophic factor
(BDNF), which has been studied extensively in connection with the
treatment of depression. However, it has never been suggested that
vagal nerve stimulation may be utilized to increase BDNF levels in
AD patients. BDNF is known to be reduced in AD brains, and the
introduction of BDNF into the brain of animal models of AD promotes
regeneration [Alan H NAGAHARA et al. Neuroprotective effects of
brain-derived neurotrophic factor in rodent and primate models of
Alzheimer's disease. Nat Med. 15(March 2009): 331-337]. Vagal nerve
stimulation may likewise promote the expression of other
neurotrophic factors such as NGF, which circumvents the problem of
blood-brain barrier blockage [Follesa P, Biggio F, Gorini G, Caria
S, Talani G, Dazzi L, Puligheddu M, Marrosu F, Biggio G. Vagus
nerve stimulation increases norepinephrine concentration and the
gene expression of BDNF and bFGF in the rat brain. Brain Research
1179(2007): 28-34; Biggio F, Gorini G, Utzeri C, Olla P, Marrosu F,
Mocchetti I, Follesa P. Chronic vagus nerve stimulation induces
neuronal plasticity in the rat hippocampus. Int J
Neuropsychopharmacol. 12(September 2009):1209-21; Roberta
Zanardini, Anna Gazzoli, Mariacarla Ventriglia, Jorge Perez,
Stefano Bignotti, Paolo Maria Rossini, Massimo Gennarelli, Luisella
Bocchio-Chiavetto. Effect of repetitive transcranial magnetic
stimulation on serum brain derived neurotrophic factor in drug
resistant depressed patients. Journal of Affective Disorders 91
(2006) 83-86]. Patent application US20100280562, entitled
Biomarkers for monitoring treatment of neuropsychiatric diseases,
to PI et al, disclosed the measurement of BDNF following vagal
nerve stimulation. However, that application is concerned with the
search for biomarkers involving the levels of BDNF, rather than a
method for treating a neurodegenerative disease using vagal nerve
stimulation.
[0154] Magnetic stimulation of AD patients has been performed, but
its use has been intended to affect cognitive skills using
transcranial magnetic stimulation [Mamede de Carvalho, Alexandre de
Mendonca, Pedro C. Miranda, Carlos Garcia and Maria Lourdes Sales
Luis. Magnetic stimulation in Alzheimer's disease. Journal of
Neurology 244 (1997 May): 304-307; Cotelli M, Manenti R, Cappa S F,
Zanetti O, Miniussi C. Transcranial magnetic stimulation improves
naming in Alzheimer disease patients at different stages of
cognitive decline. Eur J Neurol. 15(December 2008):1286-92; Guse B,
Falkai P, Wobrock T. Cognitive effects of high-frequency repetitive
transcranial magnetic stimulation: a systematic review. J Neural
Transm. 117(January 2010):105-22].
[0155] Accordingly, methods are disclosed here to treat AD
patients, preferably as part of a multi-target therapy. The
foregoing review of AD disclosed six novel mechanisms by which
stimulation of the vagus nerve may be used to treat AD: (1)
stimulate the vagus nerve in such a way as to enhance the
availability or effectiveness of TGF-beta or other
anti-inflammatory cytokines; (2) stimulate the vagus nerve in such
a way as to enhance the availability or effectiveness of retinoic
acid; (3) stimulate the vagus nerve in such a way as to promote the
expression of the neurotrophic factors such as BDNF; (4) stimulate
the vagus nerve to modulate the capacity of TNF-alpha to function
as a gliotransmitter, including modulating the activity of the
cells between which TNF-related gliotransmission occurs; (5)
stimulate the vagus nerve in such a way as to suppress the release
or effectiveness of pro-inflammatory cytokines, through a mechanism
that is distinct from the one proposed by TRACEY and colleagues;
(6) stimulate the vagus nerve to modulate the degradation of
TNF-alpha, and/or modify the activity of existing TNF-alpha
molecules as a pro-inflammatory mediator.
[0156] In the preferred embodiment, the method stimulates the vagus
nerve as indicated in FIGS. 6 and 7, using the toroidal magnetic
stimulation device that is disclosed herein. The position and
angular orientation of the device are adjusted about that location
until the patient perceives stimulation when current is passed
through the stimulator coils. The applied current is increased
gradually, first to a level wherein the patient feels sensation
from the stimulation. The power is then increased, but is set to a
level that is less than one at which the patient first indicates
any discomfort. Straps, harnesses, or frames are used to maintain
the stimulator in position (not shown in FIG. 6 or 7). The
stimulator signal may have a frequency and other parameters that
are selected to influence the therapeutic result. For example, a
pulse width may be from about 0.01 ms to 500.0 ms, typically 200
ms. The pulses may be delivered at a frequency of 0.5 to 500 Hz.,
typically 20 Hz. The stimulation may be performed for 1 to 200
minutes, typically for 30 minutes. Typically, the treatment is
performed repeatedly, e.g., once a week for six months. However,
parameters of the stimulation may be varied in order to obtain a
beneficial response, as indicated, for example, by the measurement
of levels and/or activities of TGF-beta, neurotrophic factors,
retinoic acid, and/or TNF-alpha in the patient's peripheral
circulation and/or in the patient's cerebrospinal fluid, during and
subsequent to each treatment.
Example: Stimulation of the Vagus Nerve to Treat Parkinson's
Disease
[0157] Parkinson's disease (PD) is a chronic neurodegenerative
disease that is characterized by problems with movement,
particularly tremor at rest, slowness of gait, joint and muscle
rigidity, and unstable posture. The disease is also commonly
accompanied by cognitive, autonomic, and sensory dysfunctions. PD
symptoms result from dopamine insufficiency in dopaminergic neurons
of the substantia nigra and other portions of the midbrain. In PD,
neuromelanin-pigmented, dopamine-secreting neurons in those regions
die, at locations where there is an abnormal accumulation and
aggregation of misfolded alpha-synuclein protein in the form of
so-called Lewy bodies.
[0158] Definite diagnosis of PD is made only at autopsy with a
finding of substantial nerve cell depletion with accompanying
gliosis in the substantia nigra, of at least one Lewy body in the
substantia nigra or in the locus coeruleus, and of no pathological
evidence for other diseases that produce symptoms of Parkinsonism.
Diagnosis of PD based upon symptoms alone is considered to be only
probable, with up to 20% of the probable PD diagnoses not confirmed
after autopsy. The onset and progression of probable PD in an
individual is commonly quantified using a scoring device known as
the Unified Parkinson's Disease Rating Scale (UPDRS), which
incorporates considerations used to diagnose PD. The scoring of
symptoms follows standard neurological examination practice, in
which finding of the following contribute to the diagnosis of
PD--tremor (especially if more pronounced at rest); slowing of
motion and muscle rigidity; onset of symptoms on only one side of
the body; and improvement with administration of levodopa [J
JANKOVIC. Parkinson's disease: clinical features and diagnosis. J
Neurol Neurosurg Psychiatry 79(2008):368-376; Christopher G. GOETZ
et al. Movement Disorder Society-Sponsored Revision of the Unified
Parkinson's Disease Rating Scale (MDS-UPDRS): Scale Presentation
and Clinimetric Testing Results. Movement Disorders 23 (No. 15,
2008): 2129-2170].
[0159] Currently, there are no laboratory tests that can confirm a
neurological diagnosis of probable PD. Blood and cerebrospinal
fluid tests of PD patients are often normal, electroencephalography
is not able to detect PD, and the MRI and CAT scans of PD patients
appear normal. However, experimental biomarkers for diagnosing PD
are available [A. W. Michell, S. J. G. Lewis, T. Foltynie and R. A.
Barker. Biomarkers and Parkinson's disease. Brain (2004), 127,
1693-1705; Manuel B. Graeber. Biomarkers for Parkinson's disease.
Experimental Neurology 216 (2009) 249-253].
[0160] PD is the second most common neurodegenerative disease after
Alzheimer's disease and is the most common movement disorder. Some
movement disorders resemble PD but belong to a more general
category of disorder referred to as Parkinsonian syndrome or
Parkinsonism. Other movement disorders may involve
neurodegeneration at some point in their pathogenesis, including
multiple system atrophy, progressive supranuclear palsy,
corticobasal degeneration, tremor, dystonia (including torticollis,
spasmodic dysphonia and blepharospasm), restless leg syndrome, tic
and Tourette syndrome, chorea, spasticity and tardive dyskinesia.
It is understood that the methods disclosed herein for the
treatment of PD may be used to treat such other movement disorders
as well.
[0161] PD usually appears in people between 40 and 70 years of age,
with the incidence of PD peaking in people in their sixties. More
than one million individuals in the North America have PD, and in
industrialized societies, greater than 1% of the population over
the age of 65 years have the disease. Increasing age beyond 60
years is a strong risk factor for PD. Currently, there is no clear
evidence that PD is found preferentially in a particular sex or
geographical location. Exposure to the neurotoxin MPTP causes
permanent symptoms that are similar to those in PD, and exposure to
toxic chemicals such as pesticides (e.g., rotenone), herbicides
(e.g., paraquat), and fungicides (e.g., maneb) greatly increase the
risk of developing PD. Only 5-15% of the cases of PD are related to
the patient having a predisposing gene, but some such genes lead to
early-onset PD. Use of tobacco, coffee, non-steroidal
anti-inflammatory drugs and calcium channel blocker drugs have been
found to protect against PD. [Lonneke M L DELAU, Monique M B
Breteler. Epidemiology of Parkinson's disease. Lancet Neurol
5(2006): 525-35; SHIN, J.-H., V. L. Dawson, T. M. Dawson, SnapShot:
Parkinson's disease pathogenesis. Cell 139 (2009):440-440].
[0162] BRAAK and colleagues present evidence that PD ordinarily
begins in the dorsal motor nucleus of the vagus nerve (in the
medulla) and not in the midbrain dopaminergic neurons as has been
generally assumed. Furthermore, since this site is connected to the
periphery by the vagus nerve, they propose that toxic factors
enters the central nervous system via the vagus nerve, and the
pathological process then progresses up the neuroaxis, during which
components of the olfactory, autonomic, limbic, and somatomotor
systems become progressively involved [BRAAK H, Bohl J R, Muller C
M, Rub U, de Vos R A, Del Tredici K., Stanley Fahn Lecture 2005:
The staging procedure for the inclusion body pathology associated
with sporadic Parkinson's disease reconsidered. Mov Disord 2006;
21(12):2042-51]. Accordingly, methods for preventing or treating PD
are to stimulate the vagus nerve in such a way as to prevent toxins
(environmental toxin, virus, or alpha-synuclein clusters) from
reaching the dorsal motor nucleus of the vagus nerve, to serve as
an antidote to toxins that have already reached that location, and
to prevent the pathology from progressing up the neuroaxis.
[0163] The pathophysiological origins of dopaminergic nerve
depletion in the substantia nigra of PD patients are thought to
involve mitochondrial dysfunction, oxidative and nitrosative
stress, and impairment of the the ubiquitinproteasome system (UPS)
and the autophagy-lysosome pathway (ALP), with attendant aberrant
protein handling. Nerve depletion occurs in dopamine producing
cells of the substantia nigra because those cell are uniquely
susceptible to damage, as a result of their high energy
requirements and their expression of a unique Cav 1.3 calcium
channel protein. The calcium channel protein causes sustained
elevations in cytosolic calcium concentration, particularly in
dendrites, which stimulates mitochondrial respiratory metabolism
and generates reactive oxygen species (ROS). Generation of ROS or
damage from environmental toxins leads to inhibition of the first
enzyme complex of the mitochondrial electron-transfer chain
(mitochondrial complex I). For example, the Parkinson-producing
toxin MPTP specifically inhibits mitochondrial complex I. This
leads to eventual depolarization of the mitochondrial membrane and
opening of the mitochondrial permeability transition pore. A
by-product of such mitochondrial impairment is increased production
of more ROS, producing a vicious cycle of more oxidative damage
within the neurons of PD patients [Chan C S, Guzman J N, Ilijic E,
Mercer J N, Rick C, Tkatch T, Meredith G E, Surmeier D J (2007)
`Rejuvenation` protects neurons in mouse models of Parkinson's
disease. Nature 447: 1081-1086].
[0164] Alpha-synuclein (alpha-SN) is a cytoplasmic protein that is
highly expressed in dopaminergic neuronal cells and that interacts
with pre-synaptic membranes, suggesting that its function is to
regulate synaptic vesicle pools, including control of dopamine
levels. As noted above, alpha-SN deposits in the form of Lewy
Bodies are a defining characteristic of PD. Oxidation and nitration
of alpha-SN in the environment of dysfunctional mitochondria lead
to the formation of alpha-SN aggregates and the stabilization of
assembled alpha-SN filaments. Such abnormal alpha-SN might also
damage mitochondria directly, contributing to even greater
oxidative stress and mitochondrial dysfunction. The conversion of
alpha-SN from soluble monomers to aggregated amyloid-like insoluble
forms is a key event in PD pathogenesis.
[0165] Protein mishandling due to dysfunction in the
ubiquitinproteasome system (UPS) and the autophagy-lysosome pathway
(ALP) are major pathways leading to neuronal degeneration in PD.
The UPS pathway targets and rapidly destroy misfolded proteins in
cells, through attachment of ubiquitin to target proteins. The
ubiquitin tag serves as a signal for their degradation by a
proteasome, which is an abundant ATP-dependent protease. The second
pathway is autophagy, which is a catabolic process involving the
degradation of a cell's own components through lysosomal machinery.
It comprises several types: macroautophagy, microautophagy, and
chaperone-mediated autophagy. Although the UPS and ALP pathways may
clear damaged cell components in early stages of PD, eventually
they may themselves become damaged and contribute to the
progression of PD.
[0166] Abnormal alpha-SN is thought to cause UPS dysfunction
through binding and inhibiting the 20/26S proteasome, and abnormal
or aggregated forms of alpha-SN may also overwhelm the degradative
capacity of the proteasome, leading to UPS impairment beyond that
which is attributable to oxidation of UPS components.
[0167] Once the UPS has become dysfunctional, autophagy is
upregulated as a compensatory mechanism for degrading aggregated,
misfolded and abnormal proteins. However, lysosomal malfunction has
been found to accompany alpha-SN aggregation, supporting the view
that ALP dysfunction is an important mechanism of
neurodegeneration. Furthermore, dysfunction of the ALP is thought
to occur naturally as a consequence of aging, so that clearance of
aggregating alpha-SN might fail in the cells of elderly individuals
irrespective of whether the abnormal alpha-SN promotes ALP
dysfunction.
[0168] Autophagy has a dual role: to promote cell survival through
removal of abnormal cellular components, and to promote cell death
when intracellular damage is beyond repair. Inappropriate or
prolonged activation of autophagy may therefore lead to the
complete death and destruction of some cells in PD. Other
mechanisms for the death of the defective dopamine-producing cells
include caspase-dependent and caspase-independent pathways,
endoplasmic-reticulum stress, neuronal nitric oxide synthase (nNOS)
activation, DNA damage, poly(ADP-ribose) polymerase (PARP)
activation, and GAPDH modification [Dale E. BREDESEN, Rammohan V.
Rao and Patrick Mehlen. Cell death in the nervous system. Nature
443(7113, 2006):796-802; Tianhong P A N, Seiji Kondo, Weidong Le,
Joseph Jankovic. The role of autophagy-lysosome pathway in
neurodegeneration associated with Parkinson's disease. Brain 131
(2008): 1969-1978].
[0169] Another mechanism leading to the death of dopamine-producing
cells in PD is inflammatory, through microglial activation. The
activation begins with microglia detecting stimulatory signaling
molecules such as the active form of MMP-3, alpha-SN and
neuromelanin that have leaked from intact cells or that are
extracellular after the destruction of dopamine-producing cells by
mechanisms that were described above. Activated microglia cause
dopamine neuronal degeneration either by superoxide, NO and other
proinflammatory cytokines or by direct phagocytosis against neurons
that are in the process of becoming dysfunctional or even normal
(bystander) neurons. Products derived from microglia and astrocytes
act in a combinatorial manner to promote neurotoxicity. The
inflammatory response becomes a vicious cycle because additional
microglial activating factors are leaked or released from the cells
that are attacked during the inflammation [Kim Y S, Joh T H.
Microglia, major player in the brain inflammation: their roles in
the pathogenesis of Parkinson's disease. Exp Mol Med 38(2006):
333-347].
[0170] Neutralizing the proinflammatory cytokine tumor necrosis
factor (TNF-alpha) has been found to reduce nigral degeneration in
an animal model of PD. [Melissa K. McCOY, Terina N. Martinez, Kelly
A. Ruhn, David E. Szymkowski, Christine G. Smith, Barry R.
Botterman Keith E. Tansey and Malu' G. Tansey. Blocking Soluble
Tumor Necrosis Factor Signaling with Dominant-Negative Tumor
Necrosis Factor Inhibitor Attenuates Loss of Dopaminergic Neurons
in Models of Parkinson's Disease. The Journal of Neuroscience
26(37, 2006):9365-9375]. U.S. Pat. Nos. 6,610,713 and 6,838,471,
entitled Inhibition of inflammatory cytokine production by
cholinergic agonists and vagus nerve stimulation, to TRACEY, also
suppress the release of proinflammatory cytokines, such as
TNF-alpha, by vagal nerve stimulation. The methods described in
those patents might therefore substitute for the anti-TNF treatment
that was used by McCOY and colleagues. However, there is no mention
or suggestion that the methods described in those patents are
intended to modulate the activity of anti-inflammatory cytokines
such as TGF-beta or to antagonize TNF-alpha by some other
mechanism. One such mechanism involves the release of retinoic acid
from cells [Malcolm Maden. Retinoic acid in the development,
regeneration and maintenance of the nervous system. Nature Reviews
Neuroscience 8(2007), 755-765] and is discussed below.
[0171] Under normal physiologic conditions, microglia are
maintained quiescent by the coordinate action of neurons and
astrocytes. Astrocytes are able to suppress microglial activation
by releasing TGF-beta or IL-10 [Vincent V A, Tilders F J, Van Dam A
M. Inhibition of endotoxin-induced nitric oxide synthase production
in microglial cells by the presence of astroglial cells: a role for
transforming growth factor beta. Glia. 1997 March; 19(3):190-8].
TGF-beta is also produced by, and promotes the survival of, neurons
in the substantia nigra and the striatum [Kerstin Krieglstein.
Factors promoting survival of mesencephalic dopaminergic neurons.
Cell Tissue Res (2004) 318: 73-80].
[0172] The orphan nuclear receptor Nurr1 also inhibits expression
of proinflammatory neurotoxic mediators in microglia and
astrocytes. A heterodimer between the retinoid X receptor and Nurr1
also rescues dopamine-producing neurons from degeneration [Stina
Friling, Maria Bergsland and Susanna Kjellander. Activation of
Retinoid X Receptor increases dopamine cell survival in models for
Parkinson's disease. BMC Neuroscience 2009, 10:146; Kaoru Saijo,
Beate Winner, Christian T. Carson, Jana G. Collier, Leah Boyer,
Michael G. Rosenfeld, Fred H. Gage, and Christopher K. Glass. A
Nurr1/CoREST Pathway in Microglia and Astrocytes Protects
Dopaminergic Neurons from Inflammation-Induced Death. Cell 137,
47-59, Apr. 3, 2009].
[0173] This implicates retinoic acid in the response to
inflammatory and other damage through the following mechanism.
Retinoic acid acts by binding to heterodimers of the retinoic acid
receptor (RAR) and the retinoid X receptor (RXR), which then bind
to retinoic acid response elements (RAREs) to activate
transcription in the regulatory regions of target survival and
repair genes. Retinoic acid signaling is also involved in normal
nigrostriatal functioning, as evidenced by the fact that
disulphiram, which blocks the synthesis of retinoic acid, induces
Parkinsonism by producing lesions. The dopaminergic neurons of the
nigrostriatal system contain high levels of retinaldehyde
dehydrogenase that generate retinoic acid in the axon terminals,
which in turn acts on neurotransmission in an autocrine fashion or
on the striatal cells in a paracrine fashion [Malcolm Maden.
Retinoic acid in the development, regeneration and maintenance of
the nervous system Nature Reviews Neuroscience 8 (2007),
755-765].
[0174] Thus, the enhanced availability of TGF-beta and retinoic
acid are thought to have anti-inflammatory effects in PD, and both
have been reported to be enhanced by stimulation of the vagus nerve
[CORCORAN, Ciaran; Connor, Thomas J; O'Keane, Veronica; Garland,
Malcolm R. The effects of vagus nerve stimulation on pro- and
anti-inflammatory cytokines in humans: a preliminary report.
Neuroimmunomodulation 12 (May 2005): 307-309; van de PAVERT SA,
Olivier B J, Goverse G, Vondenhoff M F, Greuter M, Beke P, Kusser
K, Hopken U E, Lipp M, Niederreither K, Blomhoff R, Sitnik K, Agace
W W, Randall T D, de Jonge W J, Mebius R E. Chemokine CXCL13 is
essential for lymph node initiation and is induced by retinoic acid
and neuronal stimulation. Nat Immunol. 10(November 2009):
1193-1199].
[0175] TGF-beta is a member of the TGF-beta superfamily of
neurotrophic factors. Neurotrophic factors serve as growth factors
for the development, maintenance, repair, and survival of specific
neuronal populations, acting via retrograde signaling from target
neurons by paracrine and autocrine mechanisms. Other neurotrophic
factors, such as glial cell line-derived neurotrophic factor (GDNF)
and neurturin also strongly promote the survival of
dopamine-producing neurons. However, major problems in using
neurotrophic factors for therapy are their inability to cross
blood-brain-barrier, adverse effects resulting from binding to the
receptor in other organs of the body and their low diffusion rate.
A recently discovered neurotrophic factor, mesencephalic
astrocyte-derived neurotrophic factor (MANF), is able to diffuse
more rapidly but is also unable to cross the blood-brain barrier
[Yossef S. Levy, Yossi Gilgun-Sherki, Eldad Melamed and Daniel
Offen. Therapeutic Potential of Neurotrophic Factors in
Neurodegenerative Diseases. Biodrugs 2005; 19 (2): 97-127;
Voutilainen M H, Back S, Porsti E, Toppinen L, Lindgren L, Lindholm
P, Peranen J, Saarma M, Tuominen R K. Mesencephalic
Astrocyte-Derived Neurotrophic Factor Is Neurorestorative in Rat
Model of Parkinson's Disease. The Journal of Neuroscience, Jul. 29,
2009, 29(30):9651-9659].
[0176] However, it is known that vagal nerve stimulation and
transcranial magnetic stimulation can increase the levels of at
least one neurotrophic factor in the brain, brain-derived
neurotrophic factor (BDNF), which has been studied extensively in
connection with the treatment of depression. It is therefore
possible that vagal nerve stimulation may likewise promote the
expression of the neurotrophic factors such as GDNF and MANF that
are known to promote the survival of dopamine-producing cells in
PD, thereby circumventing the problem of blood-brain barrier
blockage [Follesa P, Biggio F, Gorini G, Caria S, Talani G, Dazzi
L, Puligheddu M, Marrosu F, Biggio G. Vagus nerve stimulation
increases norepinephrine concentration and the gene expression of
BDNF and bFGF in the rat brain. Brain Research 1179(2007): 28-34;
Biggio F, Gorini G, Utzeri C, Olla P, Marrosu F, Mocchetti I,
Follesa P. Chronic vagus nerve stimulation induces neuronal
plasticity in the rat hippocampus. Int J Neuropsychopharmacol.
12(September 2009):1209-21; Roberta Zanardini, Anna Gazzoli,
Mariacarla Ventriglia, Jorge Perez, Stefano Bignotti, Paolo Maria
Rossini, Massimo Gennarelli, Luisella Bocchio-Chiavetto. Effect of
repetitive transcranial magnetic stimulation on serum brain derived
neurotrophic factor in drug resistant depressed patients. Journal
of Affective Disorders 91 (2006) 83-86]. Patent application
US20100280562, entitled Biomarkers for monitoring treatment of
neuropsychiatric diseases, to PI et al, disclosed the measurement
of GDNF following vagal nerve stimulation. However, that
application is concerned with the search for biomarkers involving
the levels of GDNF, rather than a method for treating a
neurodegenerative disease using vagal nerve stimulation.
[0177] It is known that the levels of BDNF are rapidly regulated by
sensory input during development and in adulthood, particularly the
presence or absence of bright light [Eero CASTREN, Francisco Zafra,
Hans Thoenen, and Dan Lindholm. Light regulates expression of
brain-derived neurotrophic factor mRNA in rat visual cortex. Proc.
Nad. Acad. Sci. USA 89 (1992): 9444-9448]. The levels of other
neurotrophic factors may also be regulated by sensory input.
Accordingly, it may be possible to enhance the effect of vagal
nerve stimulation on the levels of neurotrophic factors by
simultaneously presenting the waveform of the vagal nerve
stimulation to the patient by a second route, in the form of bright
light that is fluctuating in intensity with the vagal stimulation
waveform. The bright light waveform may be presented without any
delay, or it may be presented after a delay such that the vagal and
light waveforms can best entrain one another within the patient's
brain. Considering that bright light therapy and vagal nerve
stimulation are established treatments for depression, such a novel
combined therapy may be most successful for treating depression.
However, bright light therapy has also been used successfully to
treat PD, and its success with PD patients may be attributable to
the regulation of neurotrophic factors in addition to BDNF
[Sebastian Paus, Tanja Schmitz-Hubsch, Ullrich Wullner, Antje
Vogel, Thomas Klockgether and Michael Abele. Bright Light Therapy
in Parkinson's Disease: A Pilot Study. Movement Disorders
22(October 2007): 1495-1498]. It is understood that other forms of
sensory input may also be used in place of, or in addition to,
bright light, e.g., audio or tactile input that is presented with
the waveform of the vagal nerve stimulator.
[0178] To understand how PD symptoms of abnormal movement relate to
dopaminergic nerve depletion in the substantia nigra, it is
necessary to appreciate how the substantia nigra connects
functionally and neuroanatomically to regions of the brain that
control movement. Basically, dopaminergic depletion in PD disrupts
corticostriatal neuroelectrical balance, leading to increased
activity in an indirect circuit and reduced activity in a direct
circuit. Those imbalanced corticostriatal connections result in
excessive thalamic inhibition, which leads to suppression of the
cortical motor system, resulting in akinesia, rigidity, and tremor;
and inhibitory descending projection to brain-stem locomotor areas
contribute to abnormalities of gait and posture [Lang A E, Lozano A
M. Parkinson's disease. Second of two parts. N Engl J Med 339 (No.
16, 1998): 1130-1143; OBESO JA, Rodriguez-Oroz M C, Benitez-Temino
B, et al. Functional organization of the basal ganglia: therapeutic
implications for Parkinson's disease. Mov. Disord. 23 (Suppl 3,
2008): S548-59]. That understanding provides a rationale for the PD
treatments involving deep brain stimulation or ablation that are
summarized below.
[0179] Currently there is no cure for PD, but therapies are
available to treat its symptoms and retard its progression. The
drug levodopa (L-DOPA) is the most commonly used treatment. It is
transformed into dopamine in dopaminergic neurons and therefore
compensates for the lack of dopamine in the substantia nigra.
Because L-DOPA may be metabolized before crossing the blood-brain
barrier, its metabolite(s) may cause significant side-effects by
virtue of their effects outside the brain. Therefore, peripheral
dopa decarboxylase inhibitors (carbidopa and benserazide) are often
co-administered with L-DOPA to reduce the side effects.
Furthermore, administered L-DOPA inhibits the endogenous formation
of dopamine, so its administration eventually becomes
counterproductive, such that the PD patient exhibits periods of
unresponsiveness to L-DOPA (the so-called "off" periods). At that
point, dopamine agonists may be administered, which activate
dopamine receptors even in the absence of dopamine. The dopamine
agonists include bromocriptine, pergolide, pramipexole, ropinirole,
piribedil, cabergoline, apomorphine, and lisuride. In late PD they
are useful for reducing the "off" periods. They may also be
administered as an initial treatment depending on the age of the
patient, before using L-DOPA. In lieu of dopamine agonists, MAO-B
inhibitors (selegiline and rasagiline) may also be administered.
They increase dopamine levels by inhibiting the rate at which
dopamine is degraded.
[0180] Excessive muscle contraction in PD occurs when cholinergic
function (which increases muscle contraction) is more powerful than
dopaminergic function (which decreases muscle contraction).
Anti-muscarinics reduce cholinergic function and are therefore
sometimes prescribed to bring about more balanced muscular
contraction.
[0181] Deep brain stimulation (DBS) is currently performed on
patients whose PD symptoms cannot be controlled by medication and
patients for whom the medications produce unacceptable side
effects. DBS is a surgical procedure that electrically stimulates
the brain at the sites of implanted electrodes, most often in
subthalamic nucleus, the globus pallidus internus, or the ventralis
intermedius nucleus of the thalamus. The battery-powered
neurostimulator to which the electrodes are attached may be turned
off, making DBS effectively reversible, in contrast to irreversible
surgical ablation (pallidotomy) at those sites of the brain.
Experimental stimulators may also turn themselves off, but
stimulate only when the onset of tremors is detected by the device.
Use of DBS makes it possible for the PD patients to reduce their
medications, thereby also reducing side effects from them.
Complications from DBS include those associated with the surgery
itself (bleeding, reaction to anesthesia), infection, and cable
breakage and migration, as well as problems resulting from the
stimulation (e.g., cognitive problems, numbness, double vision,
etc. that cannot be corrected by adjusting stimulation parameters)
[GARCIA, L., D'Alessandro, G., Bioulac, B., Hammond, C., 2005.
High-frequency stimulation in Parkinson's Disease: More or less?
Trends Neurosci. 28, 209-216; BITTAR, R. G. Neuromodulation for
movement disorders. J. Clin. Neurosci. 13 (2006), 315-318].
[0182] Vagal nerve stimulation has been performed on one PD patient
who also had epilepsy. When the stimulation intensity was
insufficient to control epileptic seizure, the PD symptoms
nevertheless improved: resting tremor resolved, bradykinesia
improved and the UPDRS score decreased to from 22 to 16. However,
the mechanism of that improvement was not addressed. Furthermore,
considering that the stimulation parameters were those that had
been optimized to treat epilepsy, it is likely that other
stimulation parameters may be more suitable for the treatment of PD
[S. BOKKALA-PINNINTI, N. Pinninti and S. Jenssen. Vagus nerve
stimulation effective for focal motor seizures and focal interictal
parkinsonian symptoms--A case report. Journal of Neurology 255(2008
February): 301-302].
[0183] Other forms of non-invasive stimulation are commonly used to
treat the motor dysfunction of PD patients--repetetive transcranial
magnetic stimulation (rTMS) and electroconvulsive therapy (ECT).
These methods stimulate the brain directly rather stimulate the
vagus nerve [F FREGNI, D K Simon, A Wu, A Pascual-Leone.
Non-invasive brain stimulation for Parkinson's disease: a
systematic review and meta-analysis of the literature. J Neurol
Neurosurg Psychiatry 2005; 76:1614-1623; LEFAUCHEUR, J. P., Drouot,
X., Von Raison, F., Menard-Lefaucheur, I., Cesaro, P., Nguyen, J.
P., 2004. Improvement of motor performance and modulation of
cortical excitability by repetitive transcranial magnetic
stimulation of the motor cortex in Parkinson's Disease. Clin.
Neurophysiol. 115, 2530-2541]. Although the reported rTMS protocols
for treating PD were generally found to improve motor function,
interpretation of their results is complicated by heterogeneity of
the patients' medication status, the use of circular versus
figure-of-eight stimulation coils, stimulation at different
anatomical locations, the use of low-frequency stimulation (from
0.2 to 1 Hz) versus high-frequency stimulation (5, 10 or 20 Hz),
the use of sub-threshold stimulation versus supra-threshold
stimulation, and the use of different methods of assessing benefit.
One such protocol demonstrated that improved motor performance in
PD after repeated sessions of rTMS may be related to an elevation
of serum dopamine concentration [KHEDR, E. M., Rothwell, J. C.,
Shawky, O. A., Ahmed, M. A., Foly, N., Hamdy, A., 2007. Dopamine
levels after repetitive transcranial magnetic stimulation of motor
cortex in patients with Parkinson's Disease: preliminary results.
Mov. Disord. 22, 1046-1050]. In primates, ECT has also been shown
to increase dopaminergic neurotransmission [Anne M LANDAU, M Mallar
Chakravarty, Campbell M Clark, Athanasios P Zis and Doris J Doudet.
Electroconvulsive Therapy Alters Dopamine Signaling in the Striatum
of Non-human Primates. Neuropsychopharmacology, (13 Oct. 2010, Epub
ahead of print)].
[0184] The foregoing review of PD disclosed six novel mechanisms by
which stimulation of the vagus nerve may be used to treat PD: (1)
stimulate the vagus nerve in such a way as to prevent toxins
(environmental toxin, virus, or alpha-synuclein clusters) from
reaching the dorsal motor nucleus of the vagus nerve, to serve as
an antidote to toxins that have already reached that location, and
to prevent the pathology from progressing up the neuroaxis; (2)
stimulate the vagus nerve in such a way as to enhance the
availability or effectiveness of TGF-beta or other
anti-inflammatory cytokines; (3) stimulate the vagus nerve in such
a way as to enhance the availability or effectiveness of retinoic
acid; (4) stimulate the vagus nerve in such a way as to suppress
the release or effectiveness of pro-inflammatory cytokines, such as
TNF-alpha, through a mechanism that is distinct from the one
proposed by TRACEY and colleagues; (5) stimulate the vagus nerve in
such a way as to promote the expression of the neurotrophic factors
such as GDNF and MANE; and (6) present bright light to the patient
in such a way that the light varies in intensity with the same
waveform as the vagal nerve stimulation waveform.
[0185] Embodiments of the invention in which toxins are prevented
from affecting the dorsal motor nucleus of the vagus nerve and
other locations along the neuroaxis are like embodiments described
below for treating PD at or near the substantia nigra, except that
parameters of the stimulation (current, frequency, pulse width,
duty cycle, etc.) are chosen in such a way as to preferentially
treat the selected neuroanatomical locations
[0186] Thus, in one embodiment of the invention, the vagus nerve in
such a way as to enhance the availability or effectiveness of
TGF-beta or other anti-inflammatory cytokines. In a related
embodiment of the invention, vagal nerve stimulation promotes
release of neuron-synthesized retinoic acid. In another embodiment
of the invention, patients may be co-treated with all-trans
retinoic acid (ATRA), wherein oral retinoic acid is first
administered at a dose of 0.1 to 200 mg/sq. m, typically 20 mg/sq.
m. If retinoic acid syndrome or other side effects are not observed
in the patient, ATRA is thereafter administered daily until vagal
nerve stimulation is performed, typically after one week of ATRA
administration and no more than about 45 days of ATRA
administration. It is understood that other retinoids, such as
9-cis-retinoic acid and 13-cis-retinoic acid, and any other agent
that biases TGF-.beta. towards its anti-inflammatory potential, may
be substituted for ATRA, and that if side effects are found, a
reduced dose may be administered [ADAMSON, P. C., Bailey, J.,
Pluda, J., Poplack, D. G. Bauza, S., Murphy, R. F., Yarchoan, R.,
and Balis, F. M. Pharmacokinetics of all-trans-retinoic acid
administered on an intermittent schedule. J. Clin. Oncol., 13:
1238-1241, 1995].
[0187] In another embodiment of the invention, the vagus nerve is
stimulated in such a way as to promote the expression of the
neurotrophic factors such as GDNF and MANF. This may be performed
with or without the additional presentation of bright light to the
patient in such a way that the light varies in intensity with the
same waveform as the vagal nerve stimulation waveform. If
co-treatment with light is performed, the luminance is greater than
2500 lux, typically 7500 lux. The light source preferentially
produces white or short wavelength light, such as blue light.
Furthermore, output of light from the light source follows the
supply of energy to the light source, such that when power is
supplied or removed, the light rapidly appears or disappears
without any significant lag. In the preferred embodiment, the light
source comprises light-emitting diodes (LEDs). In another
embodiment of the invention, the vagus nerve in such a way as to
suppress the release or effectiveness of pro-inflammatory
cytokines, such as TNF-alpha, via anti-inflammatory cytokine,
retinoic acid and neurotrophic pathways.
[0188] In the preferred embodiment of treating PD, the method
stimulates the vagus nerve as indicated in FIGS. 6 and 7, using the
magnetic stimulation devices that are disclosed herein. The
position and angular orientation of the device are adjusted about
that location until the patient perceives stimulation when current
is passed through the stimulator coils. The applied current is
increased gradually, first to a level wherein the patient feels
sensation from the stimulation. The power is then increased, but is
set to a level that is less than one at which the patient first
indicates any discomfort. Straps, harnesses, or frames are used to
maintain the stimulator in position (not shown in FIG. 6 or 7). The
stimulator signal may have a frequency and other parameters that
are selected to influence the therapeutic result. For example, a
pulse width may be from about 0.01 ms to 500.0 ms, typically 200
ms. The pulses may be delivered at a frequency of 0.5 to 500 Hz,
typically 20 Hz. The stimulation may be performed for 1 to 200
minutes, typically for 30 minutes. Typically, the treatment is
performed repeatedly, e.g., once a month for six months. However,
parameters of the stimulation may be varied in order to obtain a
beneficial response, as indicated, for example, by the measuring
levels and/or activities of anti-inflammatory cytokines,
pro-inflammatory cytokines, retinoic acid, and/or neurotrophic
factors in the patient's peripheral circulation and/or in the
patient's cerebrospinal fluid and/or tissue, before, during or
subsequent to each treatment. A beneficial response may also be
determined through use of standard diagnosis and treatment
evaluation tools for PD, such as the Unified Parkinson's Disease
Rating Scale (UPDRS).
Example: Stimulation of the Vagus Nerve to Treat Multiple
Sclerosis
[0189] Myelin is a dielectric material that forms a natural layer
(sheath) around the axon of certain neurons. The presence of a
myelin sheath increases the speed at which electrical impulses
propagate along those axons, through a process known as saltation.
Myelin is composed of about 80% lipid (principally
galactocerebroside and sphingomyelin) and about 20% protein
(principally myelin basic protein, myelin oligodendrocyte
glycoprotein, and proteolipid protein). Myelin is formed and
maintained by Schwann cells for axons within the peripheral nervous
system and by interfascicular oligodendrocytes for axons within the
central nervous system.
[0190] Demyelination is the loss of myelin sheaths around axons. It
is the primary cause of a category of neurodegenerative autoimmune
diseases in which the immune system pathologically damages the
nervous system by destroying myelin. These demyelinating diseases
include multiple sclerosis, acute disseminated encephalomyelitis,
transverse myelitis, chronic inflammatory demyelinating
polyneuropathy, Guillain-Barre Syndrome, central pontine
myelinosis, leukodystrophy, and Charcot Marie Tooth disease. In
what follows, methods of treating multiple sclerosis (MS) are
disclosed, but it is understood that the disclosure applies also to
other demyelinating neurodegenerative diseases.
[0191] MS has no generally accepted formal definition, so that a
large number of so-called idiopathic inflammatory demyelinating
diseases, also known as borderline forms of MS, may also be treated
by the disclosed methods, to the extent that autoimmunity is
involved in their pathophysiology (e.g., optic-spinal MS, Devic's
disease, acute disseminated encephalomyelitis, Balo concentric
sclerosis, Schilder disease, Marburg M S, tumefactive MS, pediatric
and pubertal MS, and venous MS). To that same extent, the disclosed
methods would also apply to dysmyelination disease, viz., diseases
involving the formation of defective myelin without the formation
of plaques, including leukodystrophies (Pelizaeus-Merzbacher
disease, Canavan disease, phenylketonuria) and schizophrenia.
[0192] In MS, nerves of the brain and spinal cord not only become
demyelinated, but there is also scarring (formation of scleroses,
also known as plaques or lesions) of the nervous tissue,
particularly in the white matter of the brain and spinal cord,
which is mainly composed of myelin. The neurons in white matter
carry signals between grey matter areas of the central nervous
system (where information processing is performed) and the rest of
the body. In MS, the demyelination is found only rarely in the
peripheral nervous system [COMPSTON A and Coles A. Multiple
sclerosis. Lancet 372 (9648, October 2008): 1502-1517].
[0193] The destruction of myelin takes place concomitantly with
destruction of the oligodendrocytes that are responsible for the
formation and maintenance of myelin sheaths. As the body's own
immune system attacks and damages the myelin, myelin sheaths are
damaged or lost, and axons can no longer effectively conduct
signals. The inability to conduct nerve signals leads to symptoms
that correspond to the particular nervous tissue that has been
damaged [Kenneth J. SMITH and W. I. McDonald. The pathophysiology
of multiple sclerosis: the mechanisms underlying the production of
symptoms and the natural history of the disease. Philos Trans R Soc
Lond B Biol Sci. 1999 Oct. 29; 354(1390): 1649-1673].
[0194] Because the demyelination can occur essentially anywhere in
the white matter of the brain and spinal cord, the MS patient can
initially exhibit almost any neurological symptom, making an
initial diagnosis of MS difficult. Such symptoms include impairment
of the central nervous system (fatigue, depression and moodiness,
or cognitive dysfunction), visual problems (inflammation of the
optic nerve, double vision, or involuntary eye movement), inability
to articulate or swallow, muscle problems (weakness, spasm, or lack
of coordination), sensation problems (pain, insensitivity,
tingling, prickliness, or numbness), bowel problems (constipation,
diarrhea, or incontinence), and urinary problems (incontinence,
overactive bladder, or retention). In order of frequency, the most
common initial MS symptoms are changes in sensation, vision loss,
weakness, double vision, unsteady walking, and imbalance. Fifteen
percent of MS patients have multiple initial symptoms.
[0195] Following the initial symptoms, a period of months to years
of remission may elapse. Thereafter, acute periods of relapse may
occur, followed by another remission or a gradual deterioration of
neurologic function. New symptoms may also arise during each
relapse. Progression of the disease is heterogeneous among MS
patients, and subtypes of MS are recognized, based upon the
regularity of the acute relapse and subsequent remission, the
magnitude of the relapse, and the extent to which progressive
deterioration occurs between acute relapses. The most common
pattern of MS is known as relapsing-remitting MS (RRMS), in which
unpredictable acute relapses may sometimes produce little or no
lasting symptoms, followed by periods of no change, followed by
another relapse, etc. RRMS usually begins with a clinically
isolated syndrome (CIS) attack that only suggests MS, which
develops into MS in only 30 to 70 percent of CIS patients.
[0196] Standard diagnostic tools for MS are neuroimaging, analysis
of cerebrospinal fluid, and evoked potentials. The neuroimaging
includes the use of MRI to show plaque location. The analysis of
cerebrospinal fluid measures factors that would indicate the
presence of chronic inflammation. The evoked potentials comprise
neural stimulation that seeks to determine the existence of a
reduced neural response that would indicate demyelination.
[0197] Many potential triggers of MS acute relapses have been
examined, but only a few of them are often acknowledged as being
likely triggers, such as the season of the year (spring and
summer), viral infection, and stress.
[0198] Epidemiological studies have also examined the likelihood
that an individual will ever have MS. More than 300 thousand
individuals suffer from MS in North America. Worldwide, incidence
of MS is significantly higher at locations closer to the north and
south poles. Migration studies show that if the exposure to a
higher risk environment occurs before the age of 15 years, the
migrant assumes the higher risk of the earlier environment.
Epidemics of MS have been reported, most notably in the Faroe
Islands, but no causative agent has been identified.
[0199] The disease onset usually occurs in young adulthood, peaking
between the ages of 20 and 30, and it is 1.4 to 3.1 times more
common in females than males. Known genetic variations predispose
an individual to have MS, with Caucasian populations being at
greater risk than Asian or African populations. Although there is a
tendency for MS to run in families, only 35% of monozygotic twins
both have MS. Some environmental factors also increase the risk of
MS, such as decreased exposure to sunlight and infection with the
Epstein-Barr virus at a young age. However, there is no set of risk
factors that can reliably predict the onset of MS.
[0200] It is generally recognized that MS is an autoimmune disease
in which T cells of the immune system gain entrance to the brain
when the blood-brain barrier (BBB) is compromised, leading to
inflammation in the brain and spinal cord. A deficiency in uric
acid is implicated in compromise of the BBB, and individuals with
elevated uric acid (e.g., gout patients) are at decreased risk of
developing MS. The T cells recognize myelin as foreign and attack
it, triggering inflammatory processes and stimulating other immune
cells and soluble factors such as cytokines and antibodies.
Myelinating oligodendrocytes (either mature or derived from stem
cells) can repair some of the demyelination, but if the
inflammation is prolonged or frequent, the damage eventually
becomes unrepairable, and a scarring (sclerosis) accumulates around
the demyelinated neurons. Furthermore, the axons of the
corresponding neurons may also be damaged, probably by B-Cells of
the immune system.
[0201] There is no known cure for MS. The current therapeutic
practice is to relieve symptoms during and between acute attacks
and to attempt to reduce the likelihood of relapses, thereby
slowing progression of the disease. Symptomatic treatment involves
administration of corticosteroids, such as methylprednisolone, to
reduce inflammation during attacks. Other drugs are used to treat
the symptoms of spasticity (baclofen, tizanidine, diazepam,
clonazepam, dantrolene), optic neuritis (methylprednisolone and
oral steroids), fatigue (amantadine, pemoline), pain (codeine),
trigeminal neuralgia (carbamazepine), and sexual dysfunction
(papaverine for men).
[0202] To prevent relapses, the following drugs are currently used:
Interferon beta-1a, interferon beta-lb, glatiramer acetate,
mitoxantrone, and natalizumab. These interferons are anti-viral
proteins that may suppress the immune system. Mitoxantrone is also
an immunosuppressant that suppresses the proliferation of T cells
and B cells. Natalizumab is a monoclonal antibody that blocks the
ability of inflammatory immune cells to attach to and pass through
the cell layers lining the blood-brain barrier, by binding to the
cellular adhesion molecule a4-integrin. Glatiramer acetate is an
immunomodulator drug that shifts the population of T cells from
pro-inflammatory Th1 cells to regulatory Th2 cells, by virtue of
its resemblance to myelin basic protein. Each of these drugs
produces significant side effects. For example, glatiramer acetate
and the interferon treatments produce irritation at the injection
site. Interferons also produce flu-like symptoms and may cause
liver damage. Mitoxantrone may cause cardiotoxicity. Natalizumab
may cause multifocal leukoencephalopathy.
[0203] Experimental treatments for MS include plasma exchange, bone
marrow transplantation, potassium channel blockers to improve the
conduction of nerve impulses, the inducement of an immune attack
against myelin-destroying T cells (vaccination and peptide
therapy), protein antigen feeding to release the protective
cytokine TGF-beta, administration of TGF-beta, use of monoclonal
antibodies to promote remyelination, and various dietary therapies.
Many such experimental treatments are motivated by experiments
using an animal model of brain inflammation diseases including MS,
namely, experimental allergic encephalomyelitis (EAE) [HAFLER DA,
Kent S C, Pietrusewicz M J, Khoury S J, Weiner H L and Fukaura H.
Oral administration of myelin induces antigen-specific TGF-beta 1
secreting T cells in patients with multiple sclerosis. Ann N Y Acad
Sci 1997; 56:120-131; MIRSHAFIEY A, Mohsenzadegan M. TGF-beta as a
promising option in the treatment of multiple sclerosis.
Neuropharmacology 56(6-7, 2009):929-36].
[0204] To date, electrical stimulation therapies have stimulated
nerves of MS patients other than the vagus nerve, primarily to
treat symptoms such as urinary incontinence and spasticity [KRAUSE
P, Szecsi J, Straube A. FES cycling reduces spastic muscle tone in
a patient with multiple sclerosis. NeuroRehabilitation. 2007;
22(4):335-7]; P. KETELAER, G. Swartenbroekx, P. Deltenre, H. Carton
and J. Gybels. Percutaneous epidural dorsal cord stimulation in
multiple sclerosis. Acta Neurochirurgica 49 (1979): 95-101; L. S.
ILLIS and E. M. Sedgwick. Dorsal column stimulation in multiple
sclerosis. Br Med J. (1980 Aug. 16); 281(6238): 518]. Electrical
stimulation of the vagus nerve of MS patients has been reported in
connection with treatment of tremor and dysphagia [F. MARROSU, A.
Maleci, E. Cocco, M. Puligheddu, and M. G. Marrosu. Vagal nerve
stimulation effects on cerebellar tremor in multiple sclerosis.
Neurology 65 (2005): 490; F MARROSU, A Maleci, E Cocco, M
Puligheddu, L Barberini and M G Marrosu. Vagal nerve stimulation
improves cerebellar tremor and dysphagia in multiple sclerosis.
Multiple Sclerosis 2007; 13: 1200-1202].
[0205] Patent application US20040249416, entitled Treatment of
conditions through electrical modulation of the autonomic nervous
system, to YUN et al. mentions treatment of multiple sclerosis
within a long list of diseases, in connection with stimulation of
the vagus and other nerves. However, it makes no mention of
modulating the activity of cytokines or neurotrophic factors.
[0206] U.S. Pat. Nos. 6,610,713 and 6,838,471, entitled Inhibition
of inflammatory cytokine production by cholinergic agonists and
vagus nerve stimulation, to TRACEY, mention treatment of multiple
sclerosis within a long list of diseases, in connection with the
treatment of inflammation through stimulation of the vagus nerve.
According to those patents, "Inflammation and other deleterious
conditions . . . are often induced by proinflammatory cytokines,
such as tumor necrosis factor (TNF; also known as TNF.alpha. or
cachectin) . . . " The patents goes on to state that
"Proinflammatory cytokines are to be distinguished from
anti-inflammatory cytokines, . . . , which are not mediators of
inflammation." It is clear from those patents that their objective
is only to suppress the release of proinflammatory cytokines, such
as TNF-alpha. There is no mention or suggestion that the method is
intended to stimulate the release of anti-inflammatory cytokines,
and in fact the text quoted above disclaims a role for
anti-inflammatory cytokines as mediators of inflammation. Those
patents make a generally unjustified dichotomy between pro- and
anti-inflammatory cytokines, by indicating that a cytokine could be
one or the other but not both. In particular, the patents make no
mention of the cytokine TGF-beta, and there is no suggestion that
the role of a cytokine in regards to its pro- or anti-inflammation
competence may be inherently indeterminate or indefinite unless
more information is provided about the presumed physiological
environment in which the cytokine finds itself.
[0207] Treatment of multiple sclerosis is also mentioned within
long lists of diseases in the following related applications to
TRACEY and his colleague HUSTON, wherein stimulation of the vagus
nerve is intended to suppress the release of proinflammatory
cytokines such as TNF-alpha: US20060178703, entitled Treating
inflammatory disorders by electrical vagus nerve stimulation, to
HUSTON et al.; US20050125044, entitled Inhibition of inflammatory
cytokine production by cholinergic agonists and vagus nerve
stimulation, to TRACEY; US20080249439, entitled Treatment of
inflammation by non-invasive stimulation to TRACEY et al.;
US20090143831, entitled Treating inflammatory disorders by
stimulation of the cholinergic anti-inflammatory pathway, to HUSTON
et al; US 20090248097, entitled Inhibition of inflammatory cytokine
production by cholinergic agonists and vagus nerve stimulation, to
TRACEY et al. The same observations made above in connection with
U.S. Pat. Nos. 6,610,713 and 6,838,471 apply to those applications
as well.
[0208] The present invention discloses methods for using vagal
nerve stimulation to suppress inflammation. However, unlike the
patents and applications to TRACEY and to HUSTON, the present
invention discloses use of vagal nerve stimulation to increase the
concentration or effectiveness of anti-inflammatory cytokines.
TRACEY et al do not consider the modulation of anti-inflammatory
cytokines to be part of the cholinergic anti-inflammatory pathway
that their method of vagal nerve stimulation is intended to
activate. Thus, they explain that "activation of vagus nerve
cholinergic signaling inhibits TNF (tumor necrosis factor) and
other proinflammatory cytokine overproduction through `immune` a7
nicotinic receptor-mediated mechanisms" [V. A. PAVLOV and K. J.
Tracey. Controlling inflammation: the cholinergic anti-inflammatory
pathway. Biochemical Society Transactions 34, (2006 June):
1037-1040]. In contrast, anti-inflammatory cytokines are said to be
part of a different "diffusible anti-inflammatory network, which
includes glucocorticoids, anti-inflammatory cytokines, and other
humoral mediators" [CZURA O, Tracey K J. Autonomic neural
regulation of immunity. J Intern Med. 257(2005 February): 156-66].
Their disclaiming of a role for anti-inflammatory cytokines as
mediators of inflammation following stimulation of the vagus nerve
may be due to a recognition that anti-inflammatory cytokines (e.g.
TGF-.beta.) are produced constitutively while pro-inflammatory
cytokines (e.g., TNF-alpha) are not, but are instead induced.
However, anti-inflammatory cytokines are inducible as well as
constitutive, so that for example, an increase in the
concentrations of potentially anti-inflammatory cytokines such as
transforming growth factor-beta (TGF-.beta.) can in fact be
accomplished through stimulation of the vagus nerve [RA
BAUMGARTNER, V A Deramo and MA Beaven. Constitutive and inducible
mechanisms for synthesis and release of cytokines in immune cell
lines. The Journal of Immunology 157 (1996 September): 4087-4093;
CORCORAN, Ciaran; Connor, Thomas J; O'Keane, Veronica; Garland,
Malcolm R. The effects of vagus nerve stimulation on pro- and
anti-inflammatory cytokines in humans: a preliminary report.
Neuroimmunomodulation 12 (May 2005): 307-309].
[0209] In MS, the strategy of inhibiting pro-inflammatory cytokines
rather than enhancing anti-inflammatory cytokines might even be
counterproductive. Thus, blocking TNF-alpha with the drug lenercept
promotes and exacerbates MS attacks rather than delaying them,
which might be attributable in part to the fact that TNF-alpha
promotes remyelination and the proliferation of oligodendrocytes
that perform the myelination. [ANONYMOUS. TNF neutralization in MS:
Results of a randomized, placebo controlled multicenter study.
Neurology 1999, 53:457; ARNETT HA, Mason J, Marino M, Suzuki K,
Matsushima G K, Ting J P. TNF alpha promotes proliferation of
oligodendrocyte progenitors and remyelination. Nat Neurosci 2001,
4:1116-1122].
[0210] TGF-.beta. is currently used as an experimental treatment
for multiple sclerosis [MIRSHAFIEY A, Mohsenzadegan M.TGF-beta as a
promising option in the treatment of multiple sclerosis.
Neuropharmacology. 56 (2009, 6-7): 929-36]. In the method disclosed
herein, it is applied directly as a drug, indirectly through
stimulation of the vagus nerve without pharmacological
administration to the patient, or both directly and indirectly.
[0211] TGF-.beta. converts undifferentiated T cells into regulatory
T (Treg) cells that block autoimmunity. However, in the presence of
interleukin-6, TGF-.beta. also causes the differentiation of T
lymphocytes into proinflammatory IL-17 cytokine-producing T helper
17 (TH17) cells, which promote autoimmunity and inflammation. Thus,
it is conceivable that an increase of TGF-.beta. levels might
actually cause or exacerbate inflammation, rather than suppress it.
Accordingly, a step in the method that is disclosed here is to
deter TGF-.beta. from realizing its pro-inflammatory potential, by
selecting electrical stimulation parameters that bias the potential
of TGF-.beta. towards anti-inflammation, and/or by treating the
patient with an agent such as the vitamin A metabolite retinoic
acid that is known to promote such an anti-inflammatory bias
[MUCIDA D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M,
Cheroutre H. Reciprocal TH17 and regulatory T cell differentiation
mediated by retinoic acid. Science 317(2007, 5835): 256-60; Sheng
XIAO, Hulin Jin, Thomas Korn, Sue M. Liu, Mohamed Oukka, Bing Lim,
and Vijay K. Kuchroo. Retinoic acid increases Foxp3+ regulatory T
cells and inhibits development of Th17 cells by enhancing
TGF-.beta.-driven Smad3 signaling and inhibiting IL-6 and IL-23
receptor expression. J Immunol. 181(2008 April): 2277-2284].
[0212] In one embodiment of the invention, endogenous retinoic acid
that is produced and released by neurons themselves is used to
produce the anti-inflammatory bias. Thus, it is known that vagal
nerve stimulation may induce differentiation through release of
retinoic acid that is produced in neurons from retinaldehyde by
retinaldehyde dehydrogenases, and the disclosed invention claims to
induce anti-inflammatory regulatory T cell (Treg) differentiation
by this type of mechanism [van de PAVERT SA, Olivier B J, Goverse
G, Vondenhoff M F, Greuter M, Beke P, Kusser K, Hopken U E, Lipp M,
Niederreither K, Blomhoff R, Sitnik K, Agace W W, Randall T D, de
Jonge W J, Mebius R E. Chemokine CXCL13 is essential for lymph node
initiation and is induced by retinoic acid and neuronal
stimulation. Nat Immunol. 2009 November; 10(11):1193-9]. It is
understood that the methods that are disclosed here in connection
with the treatment of MS may be applied to the treatment of other
diseases that involve inflammation, such as post-operative
ileus.
[0213] Thus, the present invention comprises a
pro-anti-inflammatory mechanism because it biases the competence of
TGF-beta towards that of an anti-inflammatory cytokine. An increase
in the concentrations of potentially anti-inflammatory cytokines
such as TGF-.beta. can also be accomplished through stimulation of
the vagus nerve, which is also a pro-anti-inflammatory mechanism
when TGF-.beta. is biases towards anti-inflammation [CORCORAN,
Ciaran; Connor, Thomas J; O'Keane, Veronica; Garland, Malcolm R.
The effects of vagus nerve stimulation on pro- and
anti-inflammatory cytokines in humans: a preliminary report.
Neuroimmunomodulation 12 (May 2005): 307-309]. As mentioned above,
inhibiting the pro-inflammatory cytokine TNF-alpha is considered to
be counterproductive in MS patients, there may be circumstances in
which the inhibition of other pro-inflammatory cytokines may be
useful therapeutically. In that case, stimulation of the vagus
nerve in an attempt to produce the anti-pro-inflammatory response
advocated by TRACEY and colleagues may be attempted. However, an
anti-pro-inflammatory response may be produced by another mechanism
involving stimulation of the vagus nerve, because as indicated
above, vagal nerve stimulation may result in the release of
retinoic acid, and the retinoic acid itself inhibits
pro-inflammatory cytokines [Malcolm Maden. Retinoic acid in the
development, regeneration and maintenance of the nervous system.
Nature Reviews Neuroscience 8(2007), 755-765].
[0214] The potentially anti-inflammatory cytokine TGF-beta is a
member of the TGF-beta superfamily of neurotrophic factors.
Neurotrophic factors serve as growth factors for the development,
maintenance, repair, and survival of specific neuronal populations,
acting via retrograde signaling from target neurons by paracrine
and autocrine mechanisms. Other neurotrophic factors also promote
the survival of neurons during neurodegeneration. These include
members of the nerve growth factor (NGF) superfamily, the
glial-cell-line-derived neurotrophic factor (GDNF) family, the
neurokine superfamily, and non-neuronal growth factors such as the
insulin-like growth factors (IGF) family. However, major problems
in using such neurotrophic factors for therapy are their inability
to cross the blood-brain-barrier, adverse effects resulting from
binding to the receptor in other organs of the body and their low
diffusion rate [Yossef S. Levy, Yossi Gilgun-Sherki, Eldad Melamed
and Daniel Offen. Therapeutic Potential of Neurotrophic Factors in
Neurodegenerative Diseases. Biodrugs 2005; 19 (2): 97-127].
[0215] It is known that vagal nerve stimulation and transcranial
magnetic stimulation can increase the levels of at least one
neurotrophic factor in the brain, brain-derived neurotrophic factor
(BDNF), which has been studied extensively in connection with the
treatment of depression [Follesa P, Biggio F, Gorini G, Caria S,
Talani G, Dazzi L, Puligheddu M, Marrosu F, Biggio G. Vagus nerve
stimulation increases norepinephrine concentration and the gene
expression of BDNF and bFGF in the rat brain. Brain Research
1179(2007): 28-34; Biggio F, Gorini G, Utzeri C, Olla P, Marrosu F,
Mocchetti I, Follesa P. Chronic vagus nerve stimulation induces
neuronal plasticity in the rat hippocampus. Int J
Neuropsychopharmacol. 12(September 2009):1209-21; Roberta
Zanardini, Anna Gazzoli, Mariacarla Ventriglia, Jorge Perez,
Stefano Bignotti, Paolo Maria Rossini, Massimo Gennarelli, Luisella
Bocchio-Chiavetto. Effect of repetitive transcranial magnetic
stimulation on serum brain derived neurotrophic factor in drug
resistant depressed patients. Journal of Affective Disorders 91
(2006) 83-86]. It has never been proposed before the present
disclosure that vagal nerve stimulation may be utilized to increase
BDNF levels in MS patients. BDNF is known to reduce clinical
inflammation and cell death in an animal model of MS [Makar T K,
Trisler D, Sura K T, Sultana S, Patel N, Bever C T. Brain derived
neurotrophic factor treatment reduces inflammation and apoptosis in
experimental allergic encephalomyelitis. J Neurol Sci. 270(1-2,
2008):70-6]. Vagal nerve stimulation may likewise promote the
expression of other beneficial neurotrophic factors as well, which
circumvents the problem of blood-brain barrier blockage by being
induced through vagal nerve stimulation. Patent application
US20100280562, entitled Biomarkers for monitoring treatment of
neuropsychiatric diseases, to PI et al, disclosed the measurement
of BDNF following vagal nerve stimulation. However, that
application is concerned with the search for biomarkers involving
the levels of BDNF, rather than a method for treating a
neurodegenerative disease using vagal nerve stimulation.
[0216] The foregoing review of MS disclosed four novel mechanisms
by which stimulation of the vagus nerve may be used to treat MS:
(1) stimulate the vagus nerve in such a way as to enhance the
availability or effectiveness of TGF-beta or other
anti-inflammatory cytokines; (2) stimulate the vagus nerve in such
a way as to enhance the availability or effectiveness of retinoic
acid; (3) stimulate the vagus nerve in such a way as to suppress
the release or effectiveness of pro-inflammatory cytokines, through
a mechanism that is distinct from the one proposed by TRACEY and
colleagues; (4) stimulate the vagus nerve in such a way as to
promote the expression of the neurotrophic factors such as
BDNF.
[0217] In one embodiment of the invention, patients may be
co-treated with all-trans retinoic acid (ATRA), wherein oral
retinoic acid is first administered at a dose of 0.1 to 200 mg/sq.
m, typically 20 mg/sq. m. If retinoic acid syndrome or other side
effects are not observed in the patient, ATRA is thereafter
administered daily until vagal nerve stimulation is performed,
typically after one week of ATRA administration and no more than
about 45 days of ATRA administration. It is understood that other
retinoids, such as 9-cis-retinoic acid and 13-cis-retinoic acid,
and any other agent that biases TGF-.beta. towards its
anti-inflammatory potential, may be substituted for ATRA, and that
if side effects are found, a reduced dose may be administered
[ADAMSON, P. C., Bailey, J., Pluda, J., Poplack, D. G. Bauza, S.,
Murphy, R. F., Yarchoan, R., and Balis, F. M. Pharmacokinetics of
all-trans-retinoic acid administered on an intermittent schedule.
J. Clin. Oncol., 13: 1238-1241, 1995].
[0218] In another embodiment of the invention, vagal nerve
stimulation itself promotes release of neuron-synthesized retinoic
acid, thereby inducing the differentiation undifferentiated T cells
into anti-inflammatory regulatory T cells (Treg) in the presence of
the cytokineTGF-beta. In yet another embodiment of the invention,
both endogenous (induced by vagal nerve stimulation) and exogenous
retinoic acid (administered as a drug) are used to induce
differentiation of undifferentiated T cells into regulatory T
(Treg) cells. Other aspects of the invention are that TGF-beta
itself may be induced by the vagal nerve stimulation, the release
of proinflammatory cytokines such as TNF-alpha may be blocked by
the vagal nerve stimulation, and neurotrophic factors such as BDNF
may be induced by the vagal nerve stimulation.
[0219] In the preferred embodiment of treating MS, the method
stimulates the vagus nerve as indicated in FIGS. 6 and 7, using the
magnetic stimulation devices that are disclosed herein. The
position and angular orientation of the device are adjusted about
that location until the patient perceives stimulation when current
is passed through the stimulator coils. The applied current is
increased gradually, first to a level wherein the patient feels
sensation from the stimulation. The power is then increased, but is
set to a level that is less than one at which the patient first
indicates any discomfort. Straps, harnesses, or frames are used to
maintain the stimulator in position (not shown in FIG. 6 or 7). The
stimulator signal may have a frequency and other parameters that
are selected to influence the therapeutic result. For example, a
pulse width may be from about 0.01 ms to 500.0 ms, typically 200
ms. The pulses may be delivered at a frequency of 0.5 to 500 Hz,
typically 20 Hz. The stimulation may be performed for 1 to 200
minutes, typically for 30 minutes. Typically, the treatment is
performed repeatedly, e.g., once a month for six months or
throughout a period of remission. However, parameters of the
stimulation may be varied in order to obtain a beneficial response,
as indicated, for example, by measuring levels and/or activities of
TGF-.beta. or other anti-inflammatory cytokines, pro-inflammatory
cytokines, and/or neurotrophic factors such as BDNF in the
patient's peripheral circulation and/or in the patient's
cerebrospinal fluid, before, during and subsequent to each
treatment. A beneficial response may also be determined through use
of standard diagnostic tools for MS, including neuroimaging,
analysis of cerebrospinal fluid, and evoked potentials. The
treatment is primarily intended to prevent MS relapses during
remission, but it may also be administered to patients while a MS
relapse is in progress, so as to hasten entry into remission.
Example: Stimulation of the Vagus Nerve to Treat Postoperative
Cognitive Dysfunction and/or Postoperative Delirium
[0220] Postoperative cognitive dysfunction (POCD) is a loss in
cognitive function after surgery. The loss may include memory, the
ability to learn, the ability to concentrate, and/or the ability to
reason and comprehend. The cognitive decline may be subtle, such
that psychological testing is needed to detect it, or it may be
profound and obvious.
[0221] POCD does not refer to delirium that may occur immediately
after surgery, but instead refers to cognitive loss that may
persist weeks, months, or permanently after the surgery. However,
postoperative cognitive dysfunction and postoperative delirium
(POD) are not mutually exclusive. They may in fact have risk
factors, mechanisms, and treatment options in common. Accordingly,
background information pertaining to POD is presented below, after
first discussing POCD and disclosing methods for treating POCD.
[0222] A limited number of studies have been conducted to evaluate
whether certain demographic populations are at higher risk to
suffer from POCD, whether the risk is contingent on the type of
surgery, whether the risk depends on the anesthesia that was used,
how the medical condition of the patient prior to the surgery
influences the risk, whether drug sensitivity is involved, and
whether these variables influence the duration of the POCD, its
preventability, or its treatability. Elderly patients are at
greatest risk for developing POCD. A low level of education
predisposes a risk of POCD. Patients undergoing cardiac surgery are
at greatest risk, especially those with progressive
atherosclerosis. However, major surgery in general poses a greater
risk of developing POCD than minor surgery. The incidence of
prolonged POCD is apparently similar regardless of the anesthetic
technique used, suggesting that nonanesthetic factors are likely to
be important. However, use of regional anesthesia decreases the
incidence of POCD early after surgery. [Lars S. RASMUSSEN.
Postoperative cognitive dysfunction: Incidence and prevention. Best
Practice & Research Clinical Anesthesiology 20(2006, No. 2):
315-330; Ola A. SELNES and Guy M. McKhann. Neurocognitive
Complications after Coronary Artery Bypass Surgery. Ann Neurol
2005; 57:615-621; Ramesh RAMAIAH and Arthur M. Lam. Postoperative
Cognitive Dysfunction in the Elderly. Anesthesiology Clin 27(2009):
485-496; Anne-Mette SAUER, Cornelis Kalkman and Diederik van Dijk.
Postoperative cognitive decline. J Anesth (2009) 23:256-259].
[0223] The pathophysiology of POCD has been investigated in view of
the above clinical findings and in the context of cellular
responses to surgery in general [Niamh Ni CHOILEAIN and H. Paul
Redmond. Cell response to surgery. Arch Surg 2006; 141:1132-40; XIE
GL, Zhang W, Chang Y Z, Chu Q J. Relationship between perioperative
inflammatory response and postoperative cognitive dysfunction in
the elderly. Med Hypotheses 2009; 73:402-3; HU Z, Ou Y, Duan K,
Jiang X. Inflammation: a bridge between postoperative cognitive
dysfunction and Alzheimer's disease. Med Hypotheses. 2010 April;
74(4):722-4].
[0224] Although the cause of POCD appears to be multifactorial, the
response of the body to the surgery itself appears to be a primary
contributing factor. This is because decreased surgical trauma is
associated with a decreased risk of POCD, and the stress of surgery
triggers an inflammatory response with release of cytokines that
may be responsible for changes in brain function and recovery.
Furthermore, a correlation has been observed in patients'
interleukin-6, cortisol and late functional recovery. Animal
experiments also indicate that there is a relation between
cytokine-mediated inflammation and POCD [Y WAN, J Xu, D Ma, Y Zeng,
M Cibelli, M Maze. Postoperative impairment of cognitive function
in rats: a possible role for cytokine-mediated inflammation in the
hippocampus. Anesthesiology 2007; 106:436-43].
[0225] There is currently no generally agreed-upon treatment for
POCD. Primary prevention by providing good oxygenation and cerebral
perfusion during surgery, and adequate analgesia and emotional
support after surgery have been suggested, including the use of
occupational therapy and biofeedback. Medical conditions that could
also contribute to POCD should also be treated, such as
hypothyroidism. Otherwise, there are few treatment options. XIONG
et al suggested that transcutaneous stimulation of the vagus nerve
may attenuate the inflammatory response that appears to be
associated with POCD. Their suggestion was that the stimulation be
transcutaneous because implantation of a vagal nerve stimulator by
surgery may exacerbate the very surgery-induced problem that the
stimulation is intended to treat. [XIONG J, Xue F S, Liu J H, Xu Y
C, Liao X, Zhang Y M, Wang W L, Li S. Transcutaneous vagus nerve
stimulation may attenuate postoperative cognitive dysfunction in
elderly patients. Medical Hypotheses 73 (2009) 938-941].
[0226] However, the site of transcutaneous vagal stimulation that
XIONG et al suggest is the external auditory canal. This may not be
as effective as stimulating at the site where vagus nerve
stimulators are ordinarily implanted, namely, in the neck.
Furthermore, XIONG et al do not suggest stimulation parameters that
should be used. Accordingly, methods are disclosed here to better
treat POCD patients. The methods counteract inflammation by any of
the mechanisms shown in FIG. 8.
[0227] In the preferred embodiment, the method stimulates the vagus
nerve in the neck as indicated in FIGS. 6 and 7, using the magnetic
stimulation devices that are disclosed herein. The position is
adjusted about that location, and the angular orientation of the
device is also rotated about that location, until the patient
perceives stimulation when current is passed through the stimulator
coils. The applied current is increased gradually, first to a level
wherein the patient feels sensation from the stimulation. The power
is then increased, but is set to a level that is less than one at
which the patient first indicates any discomfort. Straps,
harnesses, or frames are used to maintain the stimulator in
position (not shown in FIG. 6 or 7). The stimulator signal may have
a frequency and other parameters that are selected to influence the
therapeutic result. For example, a pulse width may be from about
0.01 ms to 500.0 ms, typically 200 ms. The pulses may be delivered
at a frequency of 0.5 to 500 Hz., typically 20 Hz. The stimulation
may be performed for 1 to 200 minutes, typically for 30 minutes.
Typically, the treatment is performed repeatedly, e.g., once a week
for six months. However, parameters of the stimulation may be
varied in order to obtain a beneficial response, as indicated, for
example, by the measurement of levels and/or activities of
TGF-beta, neurotrophic factors, retinoic acid, and/or TNF-alpha in
the patient's peripheral circulation and/or in the patient's
cerebrospinal fluid, during and subsequent to each treatment, or by
psychological evaluation of the extent of the patient's cognitive
dysfunction.
[0228] If a patient experiences postoperative delirium before
experiencing POCD, the disclosed method of treatment is initially
somewhat different, as now described. According to the American
Psychiatric Association diagnostic manual (DSM-IV-TR), delirium is
a potentially reversible state of acute brain failure with
disturbance of consciousness accompanied by cognitive deficits that
cannot be accounted for by past or evolving dementia and is
associated with evidence of physiological disturbance owing to a
medical condition. It is characterized by the inability to focus
attention, disorientation that is not attributable to dementia,
sleep disturbance, and sometimes disruptive behavior. However, in
the elderly, the earliest signs of delirium may be withdrawal
rather than agitation.
[0229] Postoperative delirium (POD) is delirium that develops
acutely after surgery, usually within hours to days, and its
severity often fluctuates during the course of the day. The
physiological disturbance with which the delirium is associated is
the surgery itself. The time-course of POD is typically a shock
phase of several hours after surgery in which the patient is
hypometabolic, followed by a hypermetabolic inflammatory phase that
ordinarily peaks two days after surgery, followed by a return to
normal within a week. If the problem does not resolve itself
completely within this time frame, the patient may be considered to
suffer from postoperative cognitive dysfunction (POCD) rather than
POD.
[0230] POD occurs in 10 to 50% of postoperative patients and in 80%
of elderly patients who require intensive care. Patients undergoing
cardiovascular, major abdominal and orthopedic surgery are most
prone to develop POD. Twenty five percent of elderly patients who
exhibit POD die within six months.
[0231] Factors that may predispose to the development of POD
include exposure to toxins (including CNS-active drugs and alcohol
abuse), infection, inflammation (resulting, for example, from
autoimmune disease), trauma including postoperative trauma,
decreased cardiac output and/or oxygen saturation, vascular
disease, metabolic derangement, vitamin deficiency, central nervous
system states such as epilepsy, hydrocephalus, and central nervous
system lesions. Prevention or treatment of POD will initially
involve the identification, management and/or elimination of such
predisposing factors [Yu-Ling CHANG, Yun-Fang Tsai, Pyng-Jing Lin,
Min-Chi Chen, and Chia-Yih Liu. Prevalence and risk factors for
postoperative delirium in a cardiovascular intensive care unit.
American Journal of Critical Care. 2008; 17:567-575; RUDRA A,
Chatterjee S, Kirtania J, Sengupta S, Moitra G, Sirohia S, Wankhade
R, Banerjee S. Postoperative delirium. Indian J Crit Care Med 2006;
10:235-40].
[0232] Behavior suggestive of delirium includes the inability to
focus attention, incoherent speech, hallucination, withdrawal or
hypervigilance. In contrast to dementia, such behavior with POD may
fluctuate significantly over the course of even a few hours. The
Delirium Symptom Interview, the Confusion Assessment Method, the
Delirium Scale, the Delirium Rating Scale and the Memorial Delirium
Assessment Scale are formal psychological measurements that are
useful for forming an initial diagnosis of patients who are not
agitated.
[0233] The antidopaminergic drug haloperidol is often administered
intravenously to counter the neuronal dysfunction associated with
delirium, especially when agitation is present. This is because
psychotic fear in delirium may originate in the amygdala, which
abnormally excites dopamine subpopulations that project to limbic
areas and to cognitive regions of the cortex and striatum. Thus,
fear in delirium requires the use of dopamine-blocking neuroleptics
rather than benzodiazepines. However, careful monitoring of the
cardiovascular system is necessary because of the potential for
ventricular arrhythmia following use of haloperidol [Gregory L.
FRICCHIONE, Shamim H. Nejad, Justin A. Esses, Thomas J. Cummings,
Jr., John Querques, Ned H. Cassem, and George B. Murray.
Postoperative Delirium. Am J Psychiatry 165 (7, Jul. 2008):
803-812].
[0234] POD is thought to arise initially because leukocytes adhere
to surgically damaged endothelial cells and become activated. Their
degranulation releases free oxygen radicals and enzymes, which in
turn leads to endothelial cell membrane destruction, loosening of
intercellular tights, extravascular fluid shift, and formation of
perivascular edema. The immune response in the brain is amplified
in patients whose predisposing factors cause the blood-brain
barrier to have compromised integrity [James L. RUDOLPH, Basel
Ramlawi, George A. Kuchel, Janet E. McElhaney, Dongxu Xie, Frank W.
Sellke, Kamal Khabbaz, Sue E. Levkoff, and Edward R. Marcantonio.
Chemokines are Associated with Delirium after Cardiac Surgery. J
Gerontol A Biol Sci Med Sci. 2008 February; 63(2): 184-189]. The
edema in turn produces longer diffusion distance for oxygen to
reach nerve cells. Furthermore, the blood flow in individual
capillaries may become disrupted. Synthesis and release of the
neurotransmitter acetylcholine (ACH) is particularly sensitive to
the resulting hypoxia, especially in the elderly.
[0235] Such oxidative stress may produce localized neuronal
dysfunction in the hippocampus and amygdala, which subsequently
progresses to dysfunction in the brainstem, gray matter, and
cerebellum. The neuronal dysfunction is associated with
neurotransmitter disequilibrium corresponding to decreased
acetylcholine and GABA, as well as increased dopamine and
glutamate. That neurotransmitter dysfunction ultimately produces
the symptoms of delirium. Thus, the decreased ACH leads to a
relative excess of dopaminergic transmission, wherein the amygdala
projects to dopamine subpopulations in limbic and cognitive areas
of the brain that produce fear in delirious patients. [Martin Hala.
Pathophysiology of postoperative delirium: Systemic inflammation as
a response to surgical trauma causes diffuse microcirculatory
impairment. Medical Hypotheses (2007) 68, 194-196].
[0236] Accordingly, applicants disclose herein a method for
preventing or minimizing excessive development of the perioperative
inflammation that leads to POD. The method is like that used to
treat POCD in that involves stimulation of the vagus nerve in the
neck to increase reserve levels of the neurotransmitter
acetylcholine, in such a way as to promote a normal balance of
neurotransmitter levels. However, the method differs from that used
to treat POCD in that the parameters of the stimulation are
selected to specifically promote normal neurotransmitter levels in
the amygdala and in the limbic and cognitive areas of the brain to
which the amygdala projects. Vagal afferents traverse the brainstem
in the solitary tract, with terminating synapses particularly
located in the nucleus of the tractus solitarius (NTS). The NTS
projects to a wide variety of structures including the parabrachial
nucleus, which in turn projects to the hypothalamus, the thalamus,
the amygdala, the anterior insular, and infralimbic cortex, lateral
prefrontal cortex, and other cortical regions. Through its
projection to the amygdala, the NTS gains access to
amygdala-hippocampus-entorhinal cortex pathways of the limbic
system. Thus, the disclosed treatment of POD by vagal nerve
stimulation uses parameters (intensity, pulse-width, frequency,
duty cycle, etc.) that preferentially activate the limbic system
via the amygdala [Jeong-Ho CHAE, Ziad Nahas, Mikhail Lomarev,
Stewart Denslow, Jeffrey P. Lorberbaum, Daryl E. Bohning, Mark S.
George. A review of functional neuroimaging studies of vagus nerve
stimulation (VNS). Journal of Psychiatric Research 37 (2003)
443-455] or by other routes [G. C. Albert, C. M. Cook, F. S. Prato,
A. W. Thomas. Deep brain stimulation, vagal nerve stimulation and
transcranial stimulation: An overview of stimulation parameters and
neurotransmitter release. Neuroscience and Biobehavioral Reviews 33
(2009) 1042 1060].
[0237] In the preferred embodiment, the method stimulates the vagus
nerve in the neck as indicated in FIGS. 6 and 7, using the magnetic
stimulation devices that are disclosed herein. Any of the
anti-inflammatory mechanisms shown in FIG. 8 may be induced by the
stimulation.
[0238] The position of the device is adjusted and the angular
orientation of the device is also rotated about an initial
location, until the patient perceives stimulation when current is
passed through the stimulator coils. The applied current is
increased gradually, first to a level wherein the patient feels
sensation from the stimulation. The power is then increased, but is
set to a level that is less than one at which the patient first
indicates any discomfort. Straps, harnesses, or frames are used to
maintain the stimulator in position (not shown in FIG. 6 or 7). The
stimulator signal may have a frequency and other parameters that
are selected to influence the therapeutic result. For example, a
pulse width may be from about 0.01 ms to 500.0 ms, typically 200
ms. The pulses may be delivered at a frequency of 0.5 to 500 Hz.,
typically 20 Hz. The stimulation may be performed for 1 to 200
minutes, typically for 30 minutes. Typically, the treatment is
performed repeatedly, e.g., before surgery, and daily after
surgery. However, parameters of the stimulation may be varied in
order to obtain a beneficial response, as indicated, for example,
by the measurement of levels and/or activities of TGF-beta,
neurotrophic factors, retinoic acid, and/or TNF-alpha in the
patient's peripheral circulation and/or in the patient's
cerebrospinal fluid, during and subsequent to each treatment, or by
psychological evaluation of the extent of the patient's
delirium.
[0239] Although the invention herein has been described with
reference to particular embodiments, it is to be understood that
these embodiments are merely illustrative of the principles and
applications of the present invention. It is therefore to be
understood that numerous modifications may be made to the
illustrative embodiments and that other arrangements may be devised
without departing from the spirit and scope of the present
invention as defined by the appended claims.
* * * * *