(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY(PCT)
`(19) World Intellectual Property
`Organization
`International Bureau
`
`(43) International Publication Date
`26 November 2015 (26.11.2015) WIPO|PCT
`
`\Za
`
`(10) International Publication Number
`WO 2015/179571 Al
`
`6)
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`(21)
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`(22)
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`(25)
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`(26)
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`(30)
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`(71)
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`(72)
`
`International Patent Classification:
`A6IN 1/36 (2006.01)
`International Application Number:
`nternational
`Application Number: PCT/USD015/031847
`“
`International Filing Date:
`
`.
`Filing Language:
`Publication Language:
`
`20 May2015 (20.05.2015)
`.
`English
`English
`
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY,
`BZ, CA. CH. CL, CN, CO, CR. CU. CZ, DE, DK, DM.
`DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT,
`HN,HR, HU,ID,IL,IN,IR, IS, JP, KE, KG, KN, KP, KR,
`KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG,
`MK,MN, MW,MX, MY, MZ, NA, NG,NI, NO, NZ, OM,
`PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC,
`SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ. TM, TN.
`TR, TT,TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
`.
`oo
`US (84) Designated States (unless otherwise indicated, for every
`US
`kind of regional protection available): ARIPO (BW, GH,
`US
`GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ,
`US
`TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU,
`TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE,
`DK, EE, ES, FI, FR, GB, GR, HR, HU,IE,IS, IT, LT, LU,
`Applicant: ELECTROCORE, LLC [US/US]; 150 Allcn
`LV, MC, MK, MT, NL, NO,PL, PT, RO,RS, SE,SI, SK,
`Road, Suite 201, Basking Ridge, New Jersey 07920 (US).
`ow ON OMaeeRUDeGy CM, GA, GN, GQ,
`Inventors: ERRICO,Joseph P.; 5 Tiffanys Way, Warren,
`° oo »
`NE,
`SN,
`TD,
`TG).
`NewJersey 07059 (US). MENDEZ, Steven; 10 Willow
`Drive, Chester, New Jersey 07930 (US). SIMON, Bruce Published:
`
`Priority Data:
`62/001,004
`14/292,491
`14/335,726
`14/335,784
`
`20 May 2014 (20.05.2014)
`30 May 2014 (30.05.2014)
`18 July 2014 (18.07.2014)
`18 July 2014 (18.07.2014)
`
`us) Pollard Road, Mountain Lakes, New Jersey 07040 _ with international search report (Art. 21(3))
`
`(74)
`
`Agent: BOCK, Joel, N; DENTONS US LLP, P.O. BOX
`061080 Wacker Drive Station, Willis Tower, Chicago,
`Illinois 60606 (US).
`
`(54) Title: NON-INVASIVE NERVE STIMULATION VIA MOBILE DEVICES
`
`Anterior
`Right
`Orbitefrontal p+
`Cingulate
`Cortex
`ortex
`
`
`
`Left & Right |.) Anterior
`Anterior
`Insula
`
`Insula
`
`Mid F
`Posterior
`Dersal
`Insula
`
`
`
`
`Locus
`Ceruleus|
`
`Raphe|
`Nuclei
`
`Periaque-
`ductal Gray|
`
`VMpo
`
`Para-
`brachial
`Nucleus
`
`
`
`
`
`
`
`wo2015/179571A[IMITIMNIINIONTARATEUA
`
`(57) Abstract: Deviccs, systems, and mcthods
`
`
`are disclosed that allow a patient to self-treat a
`medical condition, such as a migraine head-
`ache,an epileptic seizure, a neurodegenerative
`Amyagdalal*
`> +tLe VMb
`disease, such as dementia, Alzheimer's disease,
`ischemic stroke, post-concussion syndrome,
`chronic traumatic encephalopathy or the like,
`
` GABA
`by electrical non-invasive stimulation of a
`
`vagus nerve. The system can comprise a hand-
`oF) Glu
`held stimulator which is applied to a surface of
`OST]
`CHE
`
`4
`
`Dersal
`the patient's neck, wherein the stimulator com-
`Rostral
`Nucleus
`Rastral
`Area
`Nucleus
`Ventral
`Tractus
`Ventral
`Motor||Post-
`
`
`
`
`
`
`Ambiguus
`
`Medial
`prises or is jomed to a mobile device. A camera
`Nucleus)
`[rema
`Medulla|
`
`Slitarius |_,| Lateral
`Medulla
`of the mobile device may be used to position
`
`
`q*
`ao
`Ventra-
`and reposition the stimulator to a particular
`Lateral
`
`
`Medulla
`location on the paticnt's neck. The system may
`
`Al
`also comprise a base station that
`is used to
`\ Modose
`
`
`fF anation
`afferent
`meter the charging of a rechargeable battery
`Stimulation
`within the stimulator. The base station and
`HDesVagus Herve
`
`stimulator transmit data to one another regard-
`
`
`ing the status of a stimulation session.
`Parasympathetic
`
`|}Ganglla Sympathetic |—spinal Card
`ees?
`Ganglia
`
`
`Senses
`
` Organs of the
`within
`Susans
`
`
`
`
`
`Patient's Body
`
`+
`
`
`
`,
`inrer-
`ateral
`imodin-
`tert
`
`at
`“parsal Root
`Ganglion
`
`FIG. 4A
`
`

`

`WO 2015/179571
`
`PCT/US2015/031847
`
`TITLE OF INVENTION
`
`NON-INVASIVE NERVE STIMULATION VIA MOBILE DEVICES
`
`CROSS REFERENCE TO RELATED APPLICATIONS
`
`[0001]
`
`The present application claims the benefit of priority to U.S.
`
`Provisional Application Serial No. 62/001,004 filed 20 May 2014; U.S.
`
`Nonprovisional Application Serial No. 14/292,491 filed 30 May 2014; U.S.
`
`Nonprovisional Application Serial No. 14/335,726 filed 18 July 2014; and U.S.
`
`Nonprovisional Application Serial No. 14/335, 784 filed 18 July 2014; each of which
`
`is incorporated herein by referencein its entirety for all purposes.
`
`BACKGROUND
`
`[0002]
`
`The field of the present disclosure relates to the delivery of energy
`
`impulses (and/or fields) to bodily tissues for therapeutic purposes. The present
`
`disclosure relates more specifically to devices and methods for treating medical
`
`conditions, such as migraine headaches, epilepsy, or others, wherein the patient
`
`uses the devices and methods as self-treatment, without the direct assistance of a
`
`healthcare professional. The energy impulses (and/orfields) that are used to treat
`
`those conditions comprise electrical and/or electromagnetic energy, delivered
`
`non-invasively to the patient, particularly to a vagus nerve of the patient.
`
`[0003]
`
`The use ofelectrical stimulation for treatment of medical conditions is
`
`well known. One of the most successful applications of modern understanding of
`
`the electrophysiological relationship between muscle and nervesis the cardiac
`
`pacemaker. Although origins of the cardiac pacemaker extend backinto 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
`
`appearedin 1957, and in 1960, the first fully implantable pacemaker was
`
`developed.
`
`

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`WO 2015/179571
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`[0004]
`
`Aroundthis time, it was also found that electrical leads could be
`
`connectedto 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 batterylife of a pacemaker from a few months
`
`to more than a decade. The modern pacemakercan treat a variety of different
`
`signaling pathologies in the cardiac muscle, and can serve as a defibrillator as well
`
`(see U.S. Patent Number6,738,667 to DENO, et al., the disclosure of whichis fully
`
`incorporated herein by referencefor all purposes). Because the leads are
`
`implanted within the patient, the pacemaker is an example of an implantable
`
`medical device.
`
`[0005]
`
`Another such example is electrical stimulation of the brain with
`
`implanted electrodes (deep brain stimulation), which has been approvedfor use in
`
`the treatmentof various conditions, including pain and movement disorders such
`
`as essential tremor and Parkinson's disease [Joel S. PERLMUTTER and Jonathan
`
`W. Mink. Deep brain stimulation. Annu. Rev. Neurosci 29 (2006):229-257].
`
`[0006]
`
`Another application of electrical stimulation of nerves is the
`
`treatment of radiating pain in the lower extremities by stimulating the sacral nerve
`
`roots at the bottom of the spinal cord [Paul F. WHITE, Shitong Li and Jen W. Chiu.
`
`Electroanalgesia: Its Role in Acute and Chronic Pain Management. Anesth Analg
`
`92(2001):505—513; patent US6871099, entitled Fully implantable microstimulator
`
`for spinal cord stimulation as a therapy for chronic pain, to WHITEHURST, etal].
`
`[0007]
`
`Vagus nervestimulation (VNS, also known as vagal nerve
`
`stimulation) is a form of electrical stimulation. It was developedinitially for the
`
`treatment of partial onset epilepsy and was subsequently developed for the
`
`treatment of depression and other disorders. The left vagus nerveis ordinarily
`
`stimulated at a location within the neck byfirst surgically implanting an electrode
`
`there and then connecting the electrode to an electrical stimulator [Patent numbers
`
`US4702254 entitled Neurocybernetic prosthesis, to ZABARA; US6341236 entitled
`
`Vagal nerve stimulation techniquesfor treatment of epileptic seizures, to OSORIO
`
`

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`WO 2015/179571
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`et al; US5299569 entitled Treatment of neuropsychiatric disorders by nerve
`
`stimulation, to WERNICKEet al; 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 VJ. Vagal nerve stimulation: a review ofits applications and potential
`
`mechanisms that mediateits clinical effects. Neurosci Biobehav Rev
`
`29(2005):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 MedBiol Soc. 2009; 2009:4631-4634; Timothy B. MAPSTONE.
`
`Vagus nervestimulation: current concepts. Neurosurg Focus 25 (3,2008):E9, pp.
`
`1-4; ANDREWS, R.J. Neuromodulation. |. Techniques-deep brain stimulation,
`
`vagus nerve stimulation, and transcranial magnetic stimulation. Ann. N. Y. Acad.
`
`Sci. 993(2003):1-13; LABINER, D.M., Ahern, G.L. Vagus nervestimulation
`
`therapy in depression and epilepsy: therapeutic parameter settings. Acta. Neurol.
`
`Scand. 115(2007):23-33].
`
`[0008]
`
`Chronic daily headache bydefinition occurs with a frequency of at
`
`least 15 headache days per month for greater than 3 months duration. Chronic
`
`migraine sufferers comprise a subset of the population of chronic headache
`
`sufferers, as do those who suffer other primary headache disorders such as
`
`chronic tension-type headache [Bert B.VARGAS, David W. Dodick. The Face of
`
`Chronic Migraine: Epidemiology, Demographics, and Treatment Strategies.
`
`Neurol Clin 27 (2009) 467-479; Peter J. GOADSBY,Richard B. Lipton, Michel D.
`
`Ferrari. Migraine - Current understanding and treatment. N Engl J Med 346
`
`(4,2002): 257- 270; Stephen D SILBERSTEIN. Migraine. LANCET 363
`
`(2004):38 1-391].
`
`[0009]
`
`A migraine headache typically passes through the following stages:
`
`prodrome, aura, headache pain, and postdrome. All these phases do not
`
`necessarily occur, and there is not necessarily a distinct onset or end of each stage,
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`with the possible exception of the aura. An interictal period follows the postdrome,
`
`unless the postrome of one migraine attack overlaps the prodrome of the next
`
`migraine attack.
`
`[0010]
`
`The prodrome stage comprisestriggering events followed by
`
`premonitory symptoms. The prodrome is often characterized byfatigue,
`
`sleepiness, elation, food cravings, depression, and irritability, among other
`
`symptoms. Triggers (also called precipitating factors) such as excessivestress or
`
`sensory barrage usually precede the attack by less than 48 h. The average
`
`duration of the prodrome is 6 to 10 hours, but in half of migraine attacks, the
`
`prodrome is less than two hours(or absent), and in approximately 15% of migraine
`
`attacks, the prodrome lasts for 12 hours to 2 days.
`
`[0011]
`
`The aura is due to cortical spreading depression within the brain.
`
`Approximately 20-30% of migraine sufferers experience an aura, ordinarily a
`
`visual aura, which is perceived as a scintillating scotoma (zig-zag line) that moves
`
`within the visual field. However, aura symptoms, regardlessof their form, vary to a
`
`great extent in duration and severity from patient to patient, and also within the
`
`same individual.
`
`[0012]
`
`Although the headache phase can begin at any hour, it most
`
`commonly begins as mild pain when the patient awakens in the morning. It then
`
`gradually builds at variable rates to reach a peak at which the pain is usually
`
`described as moderate to severe. Migraine headachesoften occur on both sides
`
`of the head in children, but an adult pattern of unilateral pain often emergesin
`
`adolescence. The pain is often reported as starting in the occipital/neck regions,
`
`later becoming frontotemporal. It is throbbing and aggravated by physical effort,
`
`with all stimuli tending to accentuate the headache. The pain phase lasts 4—72 h in
`
`adults and 1-72 h in children, with a mean duration generally of less than 1 day.
`
`The pain intensity usually follows a smooth curve with a crescendo with a
`
`diminuendo. After the headache has resolved, many patients are left with a
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`postdrome that lingers for one to two days. The main complaints during the
`
`prodrome are cognitive difficulties, such as mental tiredness.
`
`[0013]
`
`For more background information on the use of noninvasive vagus
`
`nerve stimulation to treat migraine/sinus headaches, refer to co-pending,
`
`commonly assigned application number US 13/109,250 with publication number
`
`US20110230701, entitled Electrical and magnetic stimulators used to treat
`
`migraine/sinus headache and comorbid disorders to SIMON etal; and application
`
`number US 13/183,721 with publication number US201 10276107, entitled
`
`Electrical and magnetic stimulators used to treat migraine/sinus headache, rhinitis,
`
`sinusitis, rhinosinusitis, and comorbid disorders, to SIMON etal, which arefully
`
`incorporated by referencefor all purposes.
`
`[0014]
`
`Dementia is a clinical diagnosis that is based on evidence of
`
`cognitive dysfunction in both the patient's history and in successive mental status
`
`examinations. The diagnosis is made when thereis impairment in two or more of
`
`the following: learning and retaining newly acquired information (episodic
`
`declarative memory); handling complex tasks and reasoning abilities (executive
`
`cognitive functions); visuospatial ability and geographic orientation; and language
`
`functions. The diagnosis may be made after excluding potentially treatable
`
`disorders that may otherwise contribute to cognitive impairment, such as
`
`depression, vitamin deficiencies, hypothyroidism, tumor, subdural hematomas,
`
`central nervous system infection, a cognitive disorder related to human
`
`immunodeficiencyvirus infection, adverse effects of prescribed medications, and
`
`substance abuse [McKHANN G, Drachman D, Folstein M, Katzman R, Price D,
`
`Stadian EM. Clinical diagnosis of Alzheimer's disease: report of the
`
`NINCDS-ADRDA Work Group under the auspices of Department of Health and
`
`Human Services Task Force on Alzheimer's Disease. Neurology
`
`34(7,1984):939-44; David S. KNOPMAN. Alzheimer's Disease and other
`
`dementias. Chapter 409 (pp. 2274-2283) In: Goldman's Cecil Medicine, 24th Edn.
`
`(Lee Goldman and Andrew |. Schafer, Eds.). Philadelphia : Elsevier-Saunders,
`
`

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`2012; THOMPSON SB. Alzheimers Disease: Comprehensive ReviewofAetiology,
`
`Diagnosis, Assessment Recommendations and Treatment. Webmed Central
`
`AGING 2011; 2(3): WMC001681, pp. 1-42].
`
`[0015]
`
`Dementia prevalence increases with age, from 5 % of those aged
`
`71-79 years to 37%of those aged 90 and older. However, despite their
`
`prevalence in old age, dementias such as Alzheimer's disease are not an integral
`
`part of the aging process [NELSON PT, Head E, Schmitt FA, Davis PR, Neltner JH,
`
`Jicha GA, Abner EL, Smith CD, Van Eldik LJ, Kryscio RJ, Scheff SW. Alzheimer's
`
`disease is not "brain aging": neuropathological, genetic, and epidemiological
`
`human studies. Acta Neuropathol 121(5,2011):571-87]. Genetics plays a role in
`
`early-onset AD (less than 1% of cases). The most powerful genetic risk factor for
`
`the more commonforms of AD is the APOE e4 gene, one or more copies of which
`
`are carried by 60% of AD patients in some populations. Otherwise, the risk of AD
`
`may be increased by a low level of education, severe head injury, cerebrovascular
`
`disease, diabetes and obesity.
`
`[0016]
`
`The principal diseases that cause dementia are three
`
`neurodegenerative diseases (Alzheimer’s disease, Lewy body disease, and
`
`frontotemporal lobar degeneration) and cerebrovascular disease. In the United
`
`States, Alzheimer’s disease accounts for approximately 70% of cases of dementia,
`
`and vascular dementia accounts for 17% of cases. Lewy body dementia and
`
`frontotemporal lobar dementia accountfor the remaining 13% of cases, along with
`
`less common causes(e.g., alcoholic/toxic dementia, traumatic brain injury,
`
`normal-pressure hydrocephalus, Parkinson’s dementia, Creutzfeldt—-Jakob
`
`disease, and undetermined etiology). In absolute numbers, it is estimated that
`
`about 5.4 million Americans are currently living with Alzheimer's disease, and
`
`Lewy Body dementia affects about 1.3 million Americans.
`
`[0017]
`
`Patients with each type of dementia exhibit certain typical symptoms.
`
`In Alzheimer’s disease, anterograde amnesia is a dominant symptom -- loss of the
`
`ability to create new memories of events occurring after the onset of the disease.
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`Dementia with Lewybodiesis characterized by parkinsonism, visual hallucinations,
`
`and a rapid-eye-movementsleep disorder. Frontotemporal lobar degeneration is
`
`characterized by prominent behavioral and personality changes or by prominent
`
`language difficulties early in the course of the disease. Cerebrovascular dementia,
`
`which may be a sequela of atherosclerosis, is due to one or more cerebral
`
`infarctions (ischemic strokes) in brain locations that are responsible for the
`
`cognitive deficits. The simultaneous presence of Alzheimer’s disease with
`
`vascular dementia is common, and it may be difficult to distinguish these two
`
`dementia on the basis of symptoms alone.
`
`[0018]
`
`Hour-to-hour and day-to-day changesin cognition may also be
`
`exhibited by individuals with dementia. Thus, caregivers of patients with dementia
`
`often notice that the patient may be confused and incoherent at one time, and only
`
`a few hourslater, or the next day, the patient is alert and coherent. The
`
`time-course and situational antecedent of those so-called cognitive fluctuations
`
`may also be helpful in distinguishing one form of dementia from the others, using
`
`clinical scales have been developed to analyze suchfluctuations (Clinician
`
`Assessment of Fluctuation, One Day Fluctuation Assessment Scale, Mayo
`
`Fluctuation Questionnaire). Dementia with Lewy bodiesis associated with
`
`transient and spontaneous episodes of confusion and an inability to engage in
`
`meaningful cognitive activity, followed by reversion to a near normal level of
`
`function, often within hours. In contrast, cognitive fluctuations in Alzheimer’s
`
`diseaseare often elicited by situations in which an underlying cognitive impairment
`
`manifestsitself, typically as repetitiveness in conversation, forgetfulnessin relation
`
`to a recent task or event, or other behavioral consequences of poor memory. In
`
`addition to this situational triggering aspect of a cognitive fluctuation in patients
`
`with Alzheimer’s disease, the confusion is often a more enduring state shift (good
`
`days/bad days), rather than an hour-to-hour shift.
`
`[0019]
`
`The mechanism of cognitive fluctuation is unknown, either for the
`
`hour-to-hour type that is common in dementia with Lewy bodies, or the day-to-day
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`type that is not uncommon among Alzheimer patients. However, the mechanism is
`
`clearly different than the ones involvedin circadian phenomena, such as
`
`"“sundowning," because the cognitive fluctuation need not occur around a
`
`particular time of day. Whatever the mechanism of cognitive fluctuations, it would
`
`be very beneficial to be able to prevent or reverse them, if only as a prophylactic or
`
`symptomatic treatment, so as to spare the patient and caregiver of the stress
`
`associated with fluctuating cognitive impairmentas it relates to impairment of
`
`activities of daily living [Jorge J. PALOP, Jeannie Chin and Lennart Mucke. A
`
`network dysfunction perspective on neurodegenerative diseases. Nature
`
`443(7113,2006):768-73; WALKER MP, Ayre GA, Cummings JL, Wesnes K,
`
`McKeith IG, O'Brien JT, Ballard CG. The Clinician Assessment of Fluctuation and
`
`the One Day Fluctuation Assessment Scale. Two methods to assessfluctuating
`
`confusion in dementia. Br J Psychiatry 177(2000):252-6; BRADSHAW J, Saling M,
`
`Hopwood M, Anderson V, Brodtmann A. Fluctuating cognition in dementia with
`
`Lewy bodies and Alzheimer's diseaseis qualitatively distinct. J Neurol Neurosurg
`
`Psychiatry 75(3,2004):382-7; BALLARD C, Walker M, O'Brien J, Rowan E,
`
`McKeith |. The characterisation and impactof ‘fluctuating’ cognition in dementia
`
`with Lewy bodies and Alzheimer's disease. Int J Geriatr Psychiatry
`
`16(5,2001 ):494-8; CUMMINGSJL. Fluctuations in cognitive function in dementia
`
`with Lewy bodies. Lancet Neurol 3(5,2004):266; David R. LEE, John-Paul Taylor,
`
`Alan J. Thomas. Assessment of cognitive fluctuation in dementia: a systematic
`
`review ofthe literature. International Journal of Geriatric Psychiatry 27(10, 2012):
`
`989-998; BACHMAND, Rabins P. "Sundowning" and other temporally associated
`
`agitation states in dementia patients. Annu Rev Med 57(2006):499-51 1].
`
`[0020]
`
`Early staging of the patient's disease progression makesuse of
`
`biomarkers, which are cognitive, physiological, biochemical, and anatomical
`
`variables that can be measured in a patient that indicate the progression of a
`
`dementia such as AD. The most commonly measured biomarkers for AD include
`
`decreased AR42 in the cerebrospinal fluid (CSF), increased CSF tau, decreased
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`fluorodeoxyglucose uptake on PET (FDG-PET), PET amyloid imaging, and
`
`structural MRI measuresof cerebral atrophy. Use of biomarkers to stage AD has
`
`developed to the point that biomarkers can be used with revised criteria for
`
`diagnosing the disease [MASDEU JC, Kreisl WC, Berman KF. The neurobiology of
`
`Alzheimer disease defined by neuroimaging. Curr Opin Neurol
`
`25(4,2012):410-420; DUBOIS B, Feldman HH, Jacova C, Dekosky ST,
`
`Barberger-Gateau P, Cummings J, Delacourte A, Galasko D, Gauthier S, Jicha G,
`
`Meguro K, O'brien J, Pasquier F, Robert P, Rossor M, Salloway S, Stern Y, Visser
`
`PJ, Scheltens P. Research criteria for the diagnosis of Alzheimer's disease:
`
`revising the NINCDS-ADRDAcriteria. Lancet Neurol 6(8,2007):734-46;
`
`GAUTHIER 8, Dubois B, Feldman H, Scheltens P. Revised research diagnostic
`
`criteria for Alzheimer's disease. Lancet Neurol 7 (8,2008): 668-670].
`
`[0021]
`
`In the remainder of this background section, current methods of
`
`treating AD are described. As summarized here, they include methods to treat
`
`cognitive symptoms of AD patients, as well as methods that are intendedto treat
`
`the underlying pathophysiological progression of AD. Because the methods
`
`described in the publications cited below have not been demonstrated to exhibit
`
`more than very modestsuccessin treating only symptoms of AD, and no methodis
`
`knownto stop the progression of AD, additional methods are clearly needed. Due
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`to the effect of vagus nerve stimulation on the patient's locus ceruleus, and the
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`consequencesofthat effect, the literature below is relevant to those subjects and
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`is emphasized in whatfollows.
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`[0022]
`
`Before the currently favored amyloid cascade hypothesis of AD (and
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`subsequent variants of that hypothesis), the focus of AD research was the search
`
`for a clearly defined neurochemical abnormality in AD patients, which would
`
`provide the basis for the development of rational therapeutic interventions that are
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`analogous to levodopa treatment of Parkinson’s disease. This led to the
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`cholinergic hypothesis of Alzheimer’s disease, which proposed that degeneration
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`of cholinergic neurons in the basal forebrain and the associated loss of cholinergic
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`neurotransmission in the cerebral cortex and other areas contributed significantly
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`to the deterioration in cognitive function seen in patients with Alzheimer’s disease.
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`The symptomatic drug treatments that arose from that research are currently the
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`mainstay of AD treatment, even though their effectiveness is very modest, and no
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`drug delays the progression of the disease. Approved drugs for the symptomatic
`
`treatment of AD modulate neurotransmitters -- either acetylcholine or glutamate:
`
`cholinesterase inhibitors (tacrine, rivastigmine, galantamine and donepezil) and
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`partial N -methyl-D-aspartate antagonists (memantine) [FRANCIS PT, Ramirez
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`MJ, Lai MK. Neurochemical basis for symptomatic treatment of Alzheimer's
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`disease. Neuropharmacology 59(4-5,2010):221-229; FRANCIS PT, Palmer AM,
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`Snape M, Wilcock GK. The cholinergic hypothesis of Alzheimer's disease: a
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`review of progress. J Neurol Neurosurg Psychiatry 66(2,1999):137-47; MESULAM
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`M.The cholinergic lesion of Alzheimer's disease: pivotal factor or side show? Learn
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`Mem 11(1,2004):43-49].
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`[0023]
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`The symptomatic treatment of AD by modulating neurotransmitters
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`other than acetylcholine or glutamate has also been considered. One such
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`neurotransmitter is norepinephrine (noradrenaline), which in the brain is principally
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`synthesized in the locus ceruleus. A rationale for therapeutic modulation of
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`norepinephrine levels has been that in AD, there is loss of noradrenergic neurons
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`in the locus ceruleus, and the treatment would compensatefor that loss
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`[HAGLUND M, Sjébeck M, Englund E. Locus ceruleus degeneration is ubiquitous
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`in Alzheimer's disease: possible implications for diagnosis and treatment.
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`Neuropathology 26(6,2006):528-32; SAMUELS ER, Szabadi E. Functional
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`neuroanatomyof the noradrenergic locus coeruleus: its roles in the regulation of
`
`arousal and autonomic function part Il: physiological and pharmacological
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`manipulations and pathological alterations of locus coeruleus activity in humans.
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`Curr Neuropharmacol 6(3,2008):254-85; Patricia SZOT. Common factors among
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`Alzheimer’s disease, Parkinson’s disease, and epilepsy: Possible role of the
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`noradrenergic nervous system. Epilepsia 53(Suppl. 1,2012):61—66].
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`[0024]
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`Accordingly, several investigators proposedto increasebrain
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`norepinephrine as a therapy for AD patients [EM VAZEY, VK Hinson, AC
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`Granholm, MA Eckert, GA Jones. Norepinephrine in Neurodegeneration: A
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`Coerulean Target. J Alzheimers Dis Parkinsonism 2(2,2012):1000e114, pp. 1-3].
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`Administration of norepinephrineitself is not feasible as a method for increasing its
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`levels in the central nervous system because norepinephrine, as with other
`
`catecholamines, cannot cross the blood-brain barrier. Many other drugs such as
`
`amphetamines and methylphenidate can increase norepinephrine brain levels, but
`
`they affect other neurotransmitter systems as well and havesignificant side effects.
`
`Consequently, less direct methods have been used or suggested as waysto
`
`increase norepinephrine levels in the central nervous system, orto activate
`
`adrenergic signaling. They include the use of special drugs that mimic
`
`norepinephrine, that serve as precursors of norepinephrine, that block the
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`reuptake of norepinephrine, and that serve as adrenoceptor antagonists that
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`enhancesnorepinephrine release [MISSONNIER P, Ragot R, Derouesné C, Guez
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`D, Renault B. Automatic attentional shifts induced by a noradrenergic drug in
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`Alzheimer's disease: evidence from evoked potentials. Int J Psychophysiol
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`33(3,1999): 243-51; FRIEDMAN JI, Adler DN, Davis KL. The role of
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`norepinephrine in the pathophysiology of cognitive disorders: potential
`
`applications to the treatment of cognitive dysfunction in schizophrenia and
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`Alzheimer's disease. Biol Psychiatry. 46(9,1999):1243-52; KALININ S, Polak PE,
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`Lin SX, Sakharkar AJ, Pandey SC, Feinstein DL. The noradrenaline precursor
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`L-DOPS reduces pathology in a mouse model of Alzheimer's disease. Neurobiol
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`Aging 33(8,2012):1651-1663; MOHS, R.C., Shiovitz, T.M., Tariot, P.N.,
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`Porsteinsson, A.P., Baker, K.D., Feldman, P.D., 2009. Atomoxetine augmentation
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`of cholinesterase inhibitor therapy in patients with Alzheimer disease: 6-month,
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`randomized, double-blind, placebo-controlled, parallel-trial study. Am. J. Geriatr.
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`Psychiatry 17, 752-759; SCULLION GA,Kendall DA, Marsden CA, Sunter D,
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`Pardon MC. Chronic treatment with the a2-adrenoceptor antagonist fluparoxan
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`prevents age-related deficits in spatial working memory in APPxPS1 transgenic
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`mice without altering &-amyloid plaque load or astrocytosis. Neuropharmacology
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`60(2-3,201 1):223-34]. Other agents that are thought to alter norepinephrine levels,
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`via locus ceruleus activity, include chronic stress, chronic opiate treatment, and
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`anti-depressant treatment [NESTLER Eu, Alreja M, Aghajanian GK. Molecular
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`control of locus coeruleus neurotransmission. Biol Psychiatry
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`46(9,1999):1131-1139; SAMUELS, E.R., and Szabadi, E. Functional
`
`neuroanatomyof the noradrenergic locus coeruleus: its roles in the regulation of
`
`arousal and autonomic function part Il: physiological and pharmacological
`
`manipulations and pathological alterations of locus coeruleus activity in humans.
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`Curr. Neuropharmacol. 6(2008), 254-285].
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`[0025]
`
`However, for several reasons, it is not settled that a
`
`pharmacologically-induced increase of norepinephrine, or increased signaling
`
`through the adrenergic receptors in the central nervous system, will substantially
`
`benefit AD patients. First, in patients with AD, clonidine (a centrally acting alpna2
`
`adrenergic agonist) was reported to have no effect on cognitive functions, and may
`
`even impair sustained attention and memory. Another putative
`
`alpha2-adrenoceptor agonist, guanfacine, has consistently been shown to be
`
`without effect on cognitive functions. Thus, administration of clonidine or
`
`guanfacine does not appear to provide any consistent improvement in cognitive
`
`functions, either in normal subjects or in patients with AD or other cognitive
`
`impairments. On the other hand, the alpha2-adrenoceptor antagonist, idazoxan,
`
`improved planning, sustained attention, verbal fluency, and episodic memory but
`
`impaired spatial working memory in patients with dementia of the frontal type
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`[MARIEN MR, Colpaert FC, Rosenquist AC. Noradrenergic mechanisms in
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`neurodegenerative diseases: a theory. Brain Res Brain Res Rev
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`45(1,2004):38-78].
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`[0026]
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`Second, norepinephrine significantly worsens agitation and anxiety
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`in AD patients, such that any potential benefits of increased norepinephrine levels
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`may be offset by behavioral side effects, as well as cardiovascular side effects
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`[HERRMANN N, Lanctét KL, Knan LR. The role of norepinephrine in the
`
`behavioral and psychological symptoms of dementia. J Neuropsychiatry Clin
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`Neurosci 16(3,2004):261-76; PESKIND, E.R., Tsuang, D.W., Bonner,L.T.,
`
`Pascualy, M., Riekse, R.G., Snowden, M.B., Thomas, R., Raskind, M.A..
`
`Propranolol for disruptive behaviors in nursing home residents with probable or
`
`possible Alzheimer disease: a placebo-controlled study. Alzheimer Dis. Assoc.
`
`Disord. 19(2005): 23-28].
`
`[0027]
`
`Third, loss of locus ceruleus cells in AD may lead to compensatory
`
`production of norepinephrine in other cells, such that there may actually be an
`
`increase in norepinephrine levels in some AD patients [Fitzgerald PJ. Is elevated
`
`norepinephrine an etiological factor in some casesof Alzheimer's disease? Curr
`
`Alzheimer Res 7(6,2010):506-16; ELROD R, Peskind ER, DiGiacomo L, Brodkin
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`KI, Veith RC, Raskind MA. Effects of Alzheimer's disease severity on
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`cerebrospinal fluid norepinephrine concentration. Am J Psychiatry
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`154(1,1997):25-30].
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`[0028]
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`Even if there is a decreasein overall brain norepinephrine levels in
`
`AD, this decrease does not necessarily occur uniformly among brain regions that
`
`are modulated by the locus ceruleus, and patterns of compensatory receptor
`
`alterations may also be complicated, with selective decreases and increases of
`
`noradrenergic receptors subtypesin different regions of the brain [HOOGENDIJK
`
`WJ, Feenstra MG, Botterblom MH, Gilhuis J, Sommer IE, Kamphorst W,
`
`Eikelenboom P, Swaab DF. Increasedactivity of surviving locus ceruleus neurons
`
`in Alzheimer's disease. Ann Neurol 45(1,1999):82-91; SZOT P, White SS,
`
`Greenup JL, Leverenz JB, Peskind ER, Raskind MA. Compensatory changesin
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`the noradrenergic nervous system in the locus coeruleus and hippocampus of
`
`postmortem subjects with Alzheimer’s disease and dementia with Lewy Bodies. J
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`Neurosci 26(2006):467-478; SZOT P, White SS, Greenup JL, Leverenz JB,
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`Peskind ER, Raskind MA. Changesin adrenoreceptors in the prefrontal cortex of
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`subjects with dementia: evidence of compensatory changes.Neuroscience
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`146(2007):471-480].
`
`[0029]
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`Therefore, what is needed is not a pharmacological method that
`
`increases norepinephrine levels indiscriminately throughout the central nervous
`
`system of AD patients, but rather a method tha