1111111111111111 IIIIII IIIII 1111111111 11111 1111111111 111111111111111 111111111111111 11111111
`US 20110152967Al
`
`c19) United States
`c12) Patent Application Publication
`Simon et al.
`
`c10) Pub. No.: US 2011/0152967 Al
`Jun. 23, 2011
`(43) Pub. Date:
`
`(54) NON-INVASIVE TREATMENT OF
`NEURODEGENERATIVE DISEASES
`
`(75)
`
`Inventors:
`
`Bruce Simon, Mountain Lakes, NJ
`(US); Joseph P. Errico, Warren, NJ
`(US); John T. Raffle, Austin, TX
`(US)
`
`(73) Assignee:
`
`ElectroCore, LLC., Morris Plains,
`NJ (US)
`
`(21) Appl. No.:
`
`13/005,005
`
`(22) Filed:
`
`Jan. 12, 2011
`
`Related U.S. Application Data
`
`(63) Continuation-in-part of application No. 12/964,050,
`filed on Dec. 9, 2010, which is a continuation-in-part
`of application No. 12/859,568, filedonAug. 19, 2010,
`said application No. 12/859,568 is a continuation-in(cid:173)
`part of application No. 12/408,131, filed on Mar. 20,
`2009.
`
`(60) Provisional application No. 61/415,469, filed on Nov.
`19, 2010.
`
`Publication Classification
`
`(51)
`
`Int. Cl.
`A61N 1136
`(2006.01)
`(52) U.S. Cl. .......................................................... 607/45
`ABSTRACT
`(57)
`
`Methods and devices are disclosed for the non-invasive treat(cid:173)
`ment of neurodegenerative diseases through delivery of
`energy to target nervous tissue, particularly the vagus nerve.
`The devices include a magnetic stimulator having coils with
`toroidal windings, which are in contact with an electrically
`conducting medium that is adapted to conform to the contour
`of a target body surface of a patient. The coils induce an
`electric current and/or an electric field within the patient,
`thereby stimulating nerve fibers within the patient. The stimu(cid:173)
`lation brings about reduction of neuroinflammation in
`patients suffering from conditions comprising Alzheimer's
`Disease, Parkinson's Disease, Multiple Sclerosis, postopera(cid:173)
`tive cognitive dysfunction and postoperative delirium.
`Reduction in inflammation is effected by enhancing the anti(cid:173)
`inflammatory competence of cytokines such as TGF-beta,
`wherein a retinoid or components of the retinoic acid signal(cid:173)
`ing system provide an anti-inflammatory bias, by enhancing
`anti-inflammatory activity of a neurotrophic factor such as
`NGF, GDNF, BDNF, or MANF, and/or by inhibiting the
`activity of pro-inflammatory cytokines such as TNF-alpha.
`
`NS Device 300
`
`Impulse
`Generator
`310
`
`Control
`Unit
`330
`
`Po\ver
`Source
`320
`
`LUMENIS EX1048
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`Patent Application Publication
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`Jun. 23, 2011 Sheet 1 of 7
`
`US 2011/0152967 Al
`
`350
`
`FIG. 1
`
`NS Device 300
`
`Impulse
`Generator
`310
`
`Centro!
`Unit
`330
`
`Po,ver
`Source
`320
`
`FIG. 2
`
`400
`
`Activity
`
`/
`
`Current
`
`420
`
`Current
`
`Pulses
`410
`
`Time
`
`Time
`
`LUMENIS EX1048
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`Patent Application Publication
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`Jun. 23, 2011 Sheet 2 of 7
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`US 2011/0152967 Al
`
`FIG.3A
`
`FIG. 3B
`
`30
`
`30
`
`FIG.3C
`
`31
`
`FIG. 3D
`
`31
`
`30
`
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`Patent Application Publication
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`Jun. 23, 2011 Sheet 3 of 7
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`US 2011/0152967 Al
`
`FIG.4A
`
`FIG.4C
`
`FIG.4E
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`Patent Application Publication
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`Jun. 23, 2011 Sheet 4 of 7
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`US 2011/0152967 Al
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`FIG. 5
`
`30
`
`39
`
`--38
`
`LUMENIS EX1048
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`Patent Application Publication
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`Jun. 23, 2011 Sheet 5 of 7
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`US 2011/0152967 Al
`
`FIG. 6
`
`---=---=-...:::rr-------'llr-- 7 5
`15·
`'
`---=--,-----...------J
`---------------+-- 7 7
`
`30
`
`LUMENIS EX1048
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`Patent Application Publication
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`Jun. 23, 2011 Sheet 6 of 7
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`US 2011/0152967 Al
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`FIG. 7
`
`66 67 68
`
`76
`
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`Patent Application Publication
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`Jun. 23, 2011 Sheet 7 of 7
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`US 2011/0152967 Al
`
`FIG. 8
`
`81
`
`-
`
`84
`
`!
`
`Retinoic
`Acid
`
`!85
`
`Vagal
`Nerve
`Stimulation
`
`8?
`.
`~ -
`
`Anti-Inflammatory
`Cytokine, e.g.,
`TGF-13
`
`96
`
`--
`-~
`
`9"
`
`--
`I
`I Pro-Inflammatory
`~I Inflammation I+--
`Cytokine. e.g ..
`86 TNF-u.
`--
`
`97
`
`93
`
`-~
`
`Neurotrophic
`Factor, e.g.,
`BDNF
`
`83 -
`
`91
`
`94
`
`95
`
`LUMENIS EX1048
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`US 2011/0152967 Al
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`Jun. 23, 2011
`
`1
`
`NON-INVASIVE TREATMENT OF
`NEURODEGENERATIVE DISEASES
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`
`[0001] This application is a continuation-in-part applica(cid:173)
`tion of U.S. patent application Ser. No. 12/964,050 filed Dec.
`19, 2010, which claims the benefit of priority of U.S. Provi(cid:173)
`sional Patent Application No. 61/415,469 filed Nov. 19, 2010
`and is a continuation-in-part application of U.S. patent appli(cid:173)
`cation Ser. No. 12/859,568 filed Aug. 9, 2010, which is a
`continuation-in-part of co-pending U.S. patent application
`Ser. No. 12/408,131 filed Mar. 20, 2009, the entire disclosure
`of which is hereby incorporated by reference.
`
`BACKGROUND OF THE INVENTION
`
`[0002] The field of the present invention relates to the deliv(cid:173)
`ery 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 neurode(cid:173)
`generative disorders, using energy that is delivered by such
`devices. The medical disorders include Alzheimer's disease,
`Parkinson's disease, multiple sclerosis, postoperative cogni(cid:173)
`tive dysfunction, and postoperative delirium. The treatment
`relates to stimulation of the vagus nerve to reduce neuro(cid:173)
`inflammation, wherein pathways involving anti-inflamma(cid:173)
`tory cytokines, the retinoic acid signaling system, and/or
`neurotrophic factors are enhanced, and/or pathways involv(cid:173)
`ing 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 inevi(cid:173)
`table.
`[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 ben(cid:173)
`eficial 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 hyperpo(cid:173)
`larization of a nerve membrane, preventing the discharge of
`an action potential. Such stimulation may occur after electri(cid:173)
`cal 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 HEIMBURGand
`
`Andrew D. Jackson. On soliton propagation in biomem(cid:173)
`branes 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 modu(cid:173)
`lation of hyperactive neuronal circuit transmission at specific
`sites in the brain. Unlike potentially dangerous lesioning pro(cid:173)
`cedures 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 stimu(cid:173)
`lation procedures, while invasive, are generally conducted
`with the patient conscious and a participant in the surgery.
`[0008] Brain stimulation, and deep brain stimulation in par(cid:173)
`ticular, 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 sig(cid:173)
`nificant 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 modem
`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(cid:173)
`iodide battery prolonged the battery life of a pacemaker from
`a few months to more than a decade. The modem 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 WHITE(cid:173)
`HURST, 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
`
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`US 2011/0152967 Al
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`Jun. 23, 2011
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`2
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`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 disor(cid:173)
`ders 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 ofVNS in treating epi(cid:173)
`lepsy 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, hypo(cid:173)
`thalamus, 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 con(cid:173)
`cluded 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 neu(cid:173)
`rotransmitters are modulated (including norepinephrine,
`seratonin, and GABA) [Mark S. George, Ziad Nahas, Daryl
`E. Bohning, Qiwen Mu, F. Andrew Kozel, Jeffrey Borck(cid:173)
`hardt, Stewart. Mechanisms of action of vagus nerve stimu(cid:173)
`lation (VNS). Clinical Neuroscience Research 4 (2004)
`71-79; Jeong-Ho Chae, Ziad Nahas, Mikhail Lomarev, Stew(cid:173)
`art Denslow, Jeffrey P. Lorberbaum, Daryl E. Bohning, Mark
`S. George. A review of functional neuroimaging studies of
`vagus nerve stimulation (VNS). Journal of Psychiatric
`Research37 (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. Neuro(cid:173)
`science and Biobehavioral Reviews 33 (2009) 1042-1060;
`GROVES DA, Brown VJ. 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 elec(cid:173)
`trical 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 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 enhanc(cid:173)
`ing 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 inva(cid:173)
`sive 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 proce(cid:173)
`dures are as follows. The patient may be more psychologi(cid:173)
`cally 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 bio(cid:173)
`logical 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 pain(cid:173)
`less 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 pro(cid:173)
`fessionals. 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 compa(cid:173)
`rable invasive procedures.
`[0017] For example, transcutaneous electrical nerve stimu(cid:173)
`lation (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 deterio(cid:173)
`ration 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 Alzhe(cid:173)
`imer'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 scle(cid:173)
`rosis (ALS), ataxia telangiectasia, Batten disease, bovine
`spongiform encephalopathy, Canavan disease, cerebral amy(cid:173)
`loid angiopathy, cerebellar ataxia, Cockayne syndrome, cor(cid:173)
`ticobasal degeneration, Creutzfeldt-Jakob disease, diffuse
`myelinoclastic sclerosis, fatal familial insomnia, Fazio(cid:173)
`Londe disease, Friedreich's ataxia, frontotemporal dementia
`
`LUMENIS EX1048
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`US 2011/0152967 Al
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`Jun. 23, 2011
`
`3
`
`or lobar degeneration, hereditary spastic paraplegia, Hunting(cid:173)
`ton disease, Kennedy's disease, Krabbe disease, Lewy body
`dementia, Lyme disease, Machado-Joseph disease, motor
`neuron disease, Multiple systems atrophy, neuroacanthocy(cid:173)
`tosis, 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, spinoc(cid:173)
`erebellar ataxia, Steele-Richardson-Olszewski disease, sub(cid:173)
`acute combined degeneration of the spinal cord, survival
`motor neuron spinal muscular atrophy, Tabes dorsalis, Tay(cid:173)
`Sachs disease, toxic encephalopathy, transmissible spongi(cid:173)
`form encephalopathy, Vascular dementia, and X-linked spinal
`muscular atrophy, as well as idiopathic or cryptogenic dis(cid:173)
`eases as follows: synucleinopathy, progranulinopathy, tau(cid:173)
`opathy, amyloid disease, prion disease, protein aggregation
`disease, and movement disorder. A more comprehensive list(cid:173)
`ing 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 gov(cid:173)
`ermnent (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 no so logy may oversimplify
`pathologies that occur in combination or that are not arche(cid:173)
`typical.
`[0020] Certain other disorders, such as postoperative cog(cid:173)
`nitive 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 men(cid:173)
`tioned 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 dis(cid:173)
`eases have in common [Dale E. Bredesen, Rammohan V. Rao
`and Patrick Mehl en. Cell death in the nervous system. Nature
`443 (2006): 796-802; Christian Haass. Initiation and propa(cid:173)
`gation of neurodegeneration. Nature Medicine 16(November
`2010): 1201-1204; Eng H Lo. Degeneration and repair in
`central nervous system disease. Nature Medicine 16(Novem(cid:173)
`ber 2010):1205-1209; Dahiel M. Skovronsky, Virginia M.-Y.
`Lee, and John Q. Trojanowski. Neurodegenerative Diseases
`New Concepts of Pathogenesis and Their Therapeutic Impli(cid:173)
`cations. 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 Len(cid:173)
`nart Mucke. A network dysfunction perspective on neurode(cid:173)
`generative 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 ofinflam(cid:173)
`mation, 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 neurodegen-
`
`erative 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 Mahi G Tansey. Does
`neuroinflammation fan the flame in neurodegenerative dis(cid:173)
`eases? Molecular Neurodegeneration 2009, 4:47-59; Chris(cid:173)
`topher K. Glass, Kaoru Saijo, Beate Winner, Maria Carolina
`Marchetta, 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 neuro(cid:173)
`degenerative disease. Brain, Behavior, and Immunity 18
`(2004): 407-413; Marianne Schultzberg, Catharina Lindberg,
`Asa Forslin Arons son, Erik Hjorth, Stefan D. Spulber, Mircea
`Oprica. Inflammation in the nervous system-Physiological
`and pathophysiological aspects. Physiology & Behavior 92
`(2007) 121-128; Franke Zipp and OrhanAktas. The brain as
`a target of inflammation: common pathways link inflamma(cid:173)
`tory and neurodegenerative diseases. Trends in Neuro(cid:173)
`sciences 29 (9, 2006) 518-527]. It is understood that inflam(cid:173)
`mation 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 dis(cid:173)
`closed 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 neurode(cid:173)
`generative diseases, therapies have been proposed to prevent,
`reduce, or eliminate the immune response in such inflamma(cid:173)
`tion, 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 immuno(cid:173)
`modulation.
`[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-inflamma(cid:173)
`tory cytokines may promote the release of other pro-inflam(cid:173)
`matory 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-inflam(cid:173)
`matory cytokine of central importance, and anti-TNF-alpha
`strategies seek to inhibit the release or effectiveness ofTNF(cid:173)
`alpha that is released from immune and other cells [Ian A.
`Clark, Lisa M. Alleva, Bryce Vissel. The roles ofTNF in brain
`dysfunction and disease. Pharmacology & Therapeutics 128
`(2010): 519-548; Melissa K McCoy and Mali, G Tansey. TNF
`signaling inhibition in the CNS: implications for normal brain
`function and neurodegenerative disease. Journal ofNeuroin(cid:173)
`flammation 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 inflamma(cid:173)
`tion. Those cytokines are called anti-inflammatory, and the
`
`LUMENIS EX1048
`Page 11
`
`

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`US 2011/0152967 Al
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`Jun. 23, 2011
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`4
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`second approach is essentially a pro-anti-inflannnatory strat(cid:173)
`egy. As indicated below, pro-anti-inflannnatory 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-in(cid:173)
`flannnatory, but as described presently, its anti-inflannnatory
`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 inflannnatory environ(cid:173)
`ment.
`[0026]
`In a series of publications, patents, and patent appli(cid:173)
`cations, Kevin J. TRACEY and colleagues described electri(cid:173)
`cal stimulation of the vagus nerve in an attempt to effect the
`first, anti-pro-inflannnatory strategy [Kevin J. Tracey. The
`inflannnatory reflex. Nature 420 (2002): 853-859; Kevin J.
`Tracey. Physiology and innnunology of the cholinergic anti(cid:173)
`inflannnatory pathway. J. Clin. Invest. 117 (2007): 289-296;
`Kevin 1 Tracey. Understanding innnunity requires more than
`immunology. Nature Innnunology 11 (2010): 561-564; G. R.
`Johnston and N. R. Webster. Cytokines and the immuno(cid:173)
`modulatory function of the vagus nerve. British Journal of
`Anaesthesia 102(April 2009): 453-462]. U.S. Pat. No. 6,610,
`713 and U.S. Pat. No. 6,838,471, entitled Inhibition of
`inflannnatory 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 inflannnation through
`stimulation of the vagus nerve. According to those patents,
`"Inflannnation and other deleterious conditions ... are often
`induced by proinflannnatory cytokines, such as tumor necro(cid:173)
`sis factor (TNF; also known as TNF.alpha. or cachectin) ... "
`The patents go on to state that "Proinflannnatory cytokines
`are to be distinguished from anti-inflannnatory 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 proinflannnatory cytokines,
`such as TNF-alpha. There is no mention or suggestion that the
`method is intended to modulate the activity of anti-inflam(cid:173)
`matory cytokines, and in fact, the text quoted above disclaims
`a role for anti-inflannnatory cytokines as mediators ofinflam(cid:173)
`mation. Those patents and applications make a generally
`unjustified dichotomy between pro- and anti-inflannnatory
`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-inflannnation
`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 HUS(cid:173)
`TON, wherein stimulation of the vagus nerve is intended to
`suppress the release of proinflannnatory cytokines such as
`TNF-alpha: US20060178703, entitled Treating inflannna(cid:173)
`tory disorders by electrical vagus nerve stimulation, to HUS(cid:173)
`TON et al.; US20050125044, entitled Inhibition of inflam(cid:173)
`matory cytokine production by cholinergic agonists and
`vagus nerve stimulation, to TRACEY; US20080249439,
`entitled Treatment of inflannnation by non-invasive stimula(cid:173)
`tion to TRACEY et al.; US20090143831, entitled Treating
`inflannnatory disorders by stimulation of the cholinergic anti-
`
`inflammatory pathway, to HUSTON et al; US 20090248097,
`entitled Inhibition of inflannnatory cytokine production by
`cholinergic agonists and vagus nerve stimulation,
`to
`TRACEY et al. The same observations made above in con(cid:173)
`nection with patents U.S. Pat. No. 6,610,713 and U.S. Pat.
`No. 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-invasivelyto 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 neu(cid:173)
`rodegenerative conditions, disorders or diseases that can be
`treated with the present invention include Alzheimer's dis(cid:173)
`ease, 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 elec(cid:173)
`trical impulse is sufficient to inhibit inflannnation 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-inflannnatory cytokines, such
`as TNF-alpha. In other embodiments, the electrical impulse is
`sufficient to increase the anti-inflannnatory competence of
`certain cytokines to thereby offset or reduce the effect of
`pro-inflannnatory cytokines.
`[0030]
`In one embodiment, an electr