I 1111111111111111 11111 1111111111 1111111111 11111 11111 111111111111111 IIII IIII
`US009089719B2
`
`c12) United States Patent
`Simon et al.
`
`(IO) Patent No.:
`(45) Date of Patent:
`
`US 9,089,719 B2
`*Jul. 28, 2015
`
`(54) NON-INVASIVE METHODS AND DEVICES
`FOR INDUCING EUPHORIA IN A PATIENT
`AND THEIR THERAPEUTIC APPLICATION
`
`(75)
`
`Inventors: Bruce J. Simon, Mountain Lakes, NJ
`(US); Joseph P. Errico, Warren, NJ
`(US); John T. Raffle, Austin, TX (US)
`
`(73) Assignee: Electrocore, LLC, Basking Ridge, NJ
`(US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 654 days.
`
`This patent is subject to a terminal dis(cid:173)
`claimer.
`
`(21) Appl. No.: 13/024,727
`
`(22) Filed:
`
`Feb.10,2011
`
`(65)
`
`Prior Publication Data
`
`US 2011/0190569 Al
`
`Aug. 4, 2011
`
`Related U.S. Application Data
`
`(63)
`
`Continuation-in-part of application No. 13/005,005,
`filed on Jan. 12, 2011, now Pat. No. 8,868,177, which
`1s
`a
`continuation-in-part of application No.
`12/964,050, filed on Dec. 9, 2010, which is a
`
`(Continued)
`
`(51)
`
`(52)
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`Int. Cl.
`A61N 1140
`A61N 1118
`A61M 21/00
`A61N 1/36
`U.S. Cl.
`CPC .. A61N 1140 (2013.01); A61N 1118 (2013.01);
`A61M 2021/0055 (2013.01); A61N 1/36017
`(2013.01); A61N 1/36114 (2013.01)
`
`(58) Field of Classification Search
`CPC ... A61N 1/18; A61N 1/36014; A61N 1/0456;
`A61N 1/40; A61N 2/006; A61N 2/008
`USPC .................. 607/2, 45-46, 72, 75, 103; 600/9,
`600/13-15
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4/1980 Bevilacqua
`4,196,737 A
`4,537,195 A * 8/1985 McDonnell ..................... 607/46
`(Continued)
`
`OTHER PUBLICATIONS
`
`International Seaich Report and Written Opinion of the International
`Seaiching Authority dated Dec. 3, 2011, PCT application PCT/
`USl 1/47509, International Filing Date Aug. 12, 2011.
`(Continued)
`
`Primary Examiner - Catherine Voorhees
`(74) Attorney, Agent, or Firm - Dentons US LLP
`
`(57)
`
`ABSTRACT
`
`A novel non-invasive magnetic stimulator is used to modulate
`electrical activity ofa patient's vagus nerve. Parameters of the
`stimulation are selected in such a way as to induce a state of
`euphoria in the patient. The methods and devices may be used
`for anesthesia, or to treat insonmia, depression, or premen(cid:173)
`strual syndromes. They may be used as substitution with(cid:173)
`drawal tools for individuals who otherwise would depend on
`substances and behaviors to achieve a euphoric state of mind,
`particularly individuals who abusively consume drugs, alco(cid:173)
`hol or food, or who exhibit behavioral disorders such as
`compulsive gambling. The devices and methods may also be
`used to prevent, manage, or relieve stress.
`
`27 Claims, 7 Drawing Sheets
`
`1=-"=.-------.,-75
`1-------'<-~~76
`-+---+-77
`
`LUMENIS EX1051
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`US 9,089,719 B2
`Page 2
`
`Related U.S. Application Data
`continuation-in-part of application No. 12/859,568,
`filed on Aug. 19, 2010, which is a continuation-in-part
`of application No. 12/408,131, filed on Mar. 20, 2009,
`now Pat. No. 8,812,112, and a continuation-in-part of
`applicationNo.12/612,177, filed on Nov. 4, 2009, now
`Pat. No. 8,041,428.
`
`(60) Provisional application No. 61/415,469, filed on Nov.
`19, 2010.
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`nist in Treatment-Resistant Major Depression. Arch Gen Psychiatry.
`2006;63:856-864.
`Zeki. The neurobiology of love. FEBS Letters 581 (2007): 2575-
`2579.
`Zobel et al. Changes in regional cerebral blood flow by therapeutic
`vagus nerve stimulation in depression: An exploratory approach.
`Psychiatry Research: Neuroirnaging 139 (2005) 165-179.
`
`* cited by examiner
`
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`

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`U.S. Patent
`
`Jul. 28, 2015
`
`Sheet 1 of 7
`
`US 9,089,719 B2
`
`FIG. 1
`
`NS Dev'ice 300
`
`Impulse
`Generator
`3i0
`
`Control
`Unit
`330
`
`Pov1er
`Source
`320
`
`FIG. 2
`
`400
`
`Current
`
`~,,.---------~---...."--.... ...., .. _.,_ .. ,, ..
`
`Time
`
`420
`
`Current rl
`
`I
`
`4~G-
`
`/' ___ ,
`
`/'"""'""'-"-"-"-'"._ ............ ,,,,"v·-
`
`Time
`
`LUMENIS EX1051
`Page 5
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`

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`U.S. Patent
`
`Jul. 28, 2015
`
`Sheet 2 of 7
`
`US 9,089,719 B2
`
`FIG. 3A
`
`FIG. 3B
`
`30
`
`FIG. 3C
`
`30
`
`FIG. 3D
`
`30-
`
`34
`
`34
`
`34
`
`33
`
`30
`
`34
`
`32
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`LUMENIS EX1051
`Page 6
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`U.S. Patent
`
`Jul. 28, 2015
`
`Sheet 3 of 7
`
`US 9,089,719 B2
`
`FIG.4A
`
`FIG.4D
`
`FIG.4E
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`Page 7
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`U.S. Patent
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`Jul. 28, 2015
`
`Sheet 4 of 7
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`US 9,089,719 B2
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`FIG. 5
`
`30
`
`39
`
`--38
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`Page 8
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`U.S. Patent
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`Jul. 28, 2015
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`Sheet 5 of 7
`
`US 9,089,719 B2
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`FIG. 6
`
`----=-----"=-------75
`~------------7 6
`- - - - -+ - - 77
`
`30
`
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`U.S. Patent
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`Jul. 28, 2015
`
`Sheet 6 of 7
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`US 9,089,719 B2
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`FIG. 7
`
`66 67 68
`
`76
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`U.S. Patent
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`Jul. 28, 2015
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`Sheet 7 of 7
`
`US 9,089,719 B2
`
`FIG. 8
`
`81
`
`.
`
`Vagal
`Nerve
`Stimulation
`
`82
`
`84
`
`!
`
`Retinoic
`Acid
`
`Anti-Inflammatory
`
`Pro-lnflamrnatory
`
`!
`.
`Cytokine, e.g., HI Inflammation 1..- Cytokine, e.g.,
`TNF-,:1_.
`-~
`-~
`
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`
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`
`83
`
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`
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`FactN, e.g ..
`BDNF
`
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`US 9,089,719 B2
`
`1
`NON-INVASIVE METHODS AND DEVICES
`FOR INDUCING EUPHORIA IN A PATIENT
`AND THEIR THERAPEUTIC APPLICATION
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`
`2
`discharge of an action potential; or by hyperpolarization of a
`nerve membrane, preventing the discharge of an action poten(cid:173)
`tial. Such stimulation may occur after electrical energy, or
`also other forms of energy, are transmitted to the vicinity of a
`5 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].
`10 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.
`Electrical stimulation of the brain with implanted elec-
`trodes 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
`20 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
`25 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.
`Brain stimulation, and deep brain stimulation in particular,
`is not without some drawbacks. The procedure requires pen(cid:173)
`etrating 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
`35 position of the electrode is adjusted to achieve significant
`therapeutic potential. Next, adjustments are made to the elec(cid:173)
`trical stimulus signals, such as frequency, periodicity, volt(cid:173)
`age, current, etc., again to achieve therapeutic results. The
`electrode is then permanently implanted, and wires are
`40 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
`45 from the implantation procedure, including stroke induced by
`damage to surrounding tissues and the neuro-vasculature.
`One of the most successful applications of modern under(cid:173)
`standing of the electrophysiological relationship between
`muscle and nerves is the cardiac pacemaker. Although origins
`50 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, wear(cid:173)
`able pacemaker appeared in 1957, and in 1960, the first fully
`implantable pacemaker was developed.
`Around this time, it was also found that electrical leads
`could be connected to the heart through veins, which elimi(cid:173)
`nated 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
`60 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).
`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
`
`The present application is a Continuation-In-Part of U.S.
`application Ser. No. 13/005,005 filed Jan. 12, 2011 which
`published as US2011-0152967 on Jun. 23, 2011; which is a
`Continuation-In-Part ofU.S. application Ser. No. 12/964,050
`filed Dec. 19, 2010 which published as US2011-0125203 on
`May 26, 2011; which claims the benefit of U.S. Provisional
`Application No. 61/415,469 filed Nov. 19, 2010; each of
`which is incorporated herein by reference in its entirety. The 15
`present application is also a Continuation-In-Part of U.S.
`application Ser. No. 12/859,568 filed Aug. 9, 2010 which
`published as US201 l-0046432 on Feb. 24, 2011; which is a
`Continuation-In-Part ofU.S. application Ser. No. 12/612,177
`filed Nov. 9, 2009 now U.S. Pat. No. 8,041,428 issued on Oct.
`18, 2011; which is a Continuation-In-Part ofU.S. application
`Ser. No. 12/408,131 filed Mar. 20, 2009 which published as
`US2009-0187231 on Jul. 23, 2009; each of which is incorpo(cid:173)
`rated herein by reference in its entirety
`
`BACKGROUND OF THE INVENTION
`
`The field of the present invention relates to the delivery of
`energy impulses ( and/or fields) to bodily tissues for therapeu-
`tic purposes. It relates more specifically to the use of non- 30
`invasive methods and devices, particularly methods that make
`use of magnetic stimulation devices, to treat depression and/
`or induce in a patient a euphoric affect or sense of well-being,
`using energy that is delivered by such devices. The disclosed
`methods involve stimulation of the vagus nerve to induce
`euphoria, for example, in individuals needing relief from
`mental and physical stress, depression, premenstrual syn(cid:173)
`drome, substance abuse and withdrawal including overeating,
`and behavioral disorders including compulsive gambling.
`The disclosed methods and devices may also be used for
`purposes of anesthesia or as a sleep aid for insonmia.
`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.
`Other treatments for malfunctioning tissue can be medici(cid:173)
`nal in nature, but in many cases the patients become depen(cid:173)
`dent upon artificially synthesized chemicals. In many cases,
`these medicinal approaches have side effects that are either
`unknown or quite significant. Unfortunately, the beneficial 55
`outcomes of surgery and medicines are often realized at the
`cost of function of other tissues, or risks of side effects.
`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 stimu(cid:173)
`lation of the brain and/or the peripheral nervous system and/
`or direct stimulation of the malfunctioning tissue holds sig(cid:173)
`nificant promise for the treatment of many ailments, because
`such stimulation is generally a wholly reversible and non(cid:173)
`destructive treatment.
`Nerve stimulation is thought to be accomplished directly or
`indirectly by depolarizing a nerve membrane, causing the
`
`65
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`US 9,089,719 B2
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`4
`US20090299435, entitled Systems and methods for enhanc(cid:173)
`ing or affecting neural stimulation efficiency and/or efficacy,
`to GLINER et al. However, some effects ofVNS stimulation,
`such as effects described herein, are simply discovered by
`5 serendipity, then improved upon deliberately.
`
`SUMMARY OF THE INVENTION
`
`3
`spinal cord (see U.S. Pat. No. 6,871,099 to WHITEHURST,
`et al., the disclosure of which is incorporated herein by ref(cid:173)
`erence).
`Yet another application of electrical stimulation of nerves
`has been the treatment of epilepsy and depression b