Devices and methods for non-invasive capacitive electrical stimulation, and their use for the stimulation of the vagus nerve in a patient's neck

Abstract

To provide a non-invasive electrical stimulator which shapes an elongated electric field effect that can be oriented parallel to a long nerve, such as a vagus nerve in a patient's neck, producing a desired physiological response in the patient.SOLUTION: The stimulator comprises a source of electrical power, at least one electrode, and a continuous electrically conducting medium in contact therein with the electrode(s). The stimulator is configured to produce a peak pulse voltage that is sufficient to produce a physiologically effective electric field in the vicinity of a target nerve, but not to substantially stimulate other nerves or muscles that lie in the vicinity of the target nerve and patient's skin. A current is passed through the electrodes in a burst of preferably 5 sinusoidal pulses. Each pulse within the burst has a duration of preferably 200 microseconds. The burst repeats at preferably 15-50 bursts per second.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of priority of U.S. Patent Application No. 13 / 075,746, filed Mar. 30, 2011, which claims the benefit of priority of U.S. Provisional Patent Application No. 61 / 451,259, filed Mar. 10, 2011. This application also claims the benefit of priority of U.S. Patent Application No. 13 / 183,765, filed Jul. 15, 2011, which claims the benefit of priority of U.S. Provisional Patent Application No. 61 / 488,208, filed May 20, 2011. The disclosures of these are hereby incorporated by reference in their entireties into this specification.

Background Art

[0002] The field of the present invention relates to the delivery of energy impulses (and / or fields) to body tissues for therapeutic purposes. More specifically, it relates to the use of non - invasive devices and methods, particularly transcutaneous electrical nerve stimulation devices using capacitive electrical coupling, and methods of treating patients using the energy delivered by such devices. The disclosed methods and devices can be used to stimulate a patient's vagus nerve to treat a number of diseases, such diseases including headaches such as migraine and cluster headache, rhinitis and sinusitis, depression and anxiety disorders, postoperative ileus, TNF - alpha - related dysfunction in Alzheimer's disease, postoperative cognitive dysfunction, postoperative delirium, rheumatoid arthritis, asthmatic bronchoconstriction, urinary incontinence and / or overactive bladder, and Oddi sphincter dysfunction, as well as neurodegenerative diseases, more generally Alzheimer's disease and its prodromal mild cognitive impairment (MCI), Parkinson's disease (including Parkinson's disease dementia), and multiple sclerosis.

[0003] Treatments for various debilitating conditions may require the destruction of other healthy tissues in order to produce a beneficial effect. Instead of attempting to repair the tissue to its normal function, the dysfunctional tissue is identified and then damaged or otherwise impaired in order to produce a beneficial result. Various techniques and mechanisms have been designed to produce a focused lesion directly within the target nerve tissue, but collateral damage is unavoidable.

[0004] Other treatments for dysfunctional tissue may in fact be drugs, but in many cases, patients become dependent on artificially synthesized chemicals. In many cases, these drug-based approaches have unknown or highly significant side effects. Unfortunately, the beneficial results of surgery and drugs are often achieved at the expense of the function of other tissues or with the risk of side effects.

[0005] The use of electrical stimulation for the treatment of medical conditions has been well known in the art for approximately 2,000 years. Electrical stimulation of the brain and / or peripheral nervous system and / or direct stimulation of the dysfunctional tissue has been recognized as being quite promising for the treatment of many diseases since such stimulation is generally a reversible and non-destructive treatment overall.

[0006] Nerve stimulation is thought to be achieved directly or indirectly by depolarization of the nerve membrane, which causes the discharge of action potentials, or by hyperpolarization of the nerve membrane, which prevents the discharge of action potentials. Such stimulation can occur after electrical energy or similarly other forms of energy have been transmitted near the nerve [F. RATTAY. The basic mechanism for the electrical stimulation of the nervous system. Neuroscience 89(2,1999):335 - 346, Thomas HEIMBURG and Andrew D. JACKSON. On soliton propagation in biomembranes and nerves. PNAS 102(28,2005):9790 - 9795]. Nerve stimulation can be measured directly as an increase, decrease, or modulation of nerve fiber activity, or can be inferred from physiological effects following the transmission of energy to the nerve fiber.

[0007] One of the most successful applications of the modern understanding of the electrophysiological relationship between muscle and nerve is the cardiac pacemaker. The origin of the cardiac pacemaker dates back to the 1800s, but it was not until 1950 that the first practical external bulky pacemaker was developed. In 1957, the first actually functional wearable pacemaker appeared, and in 1960, the first fully implantable pacemaker was developed.

[0008] Around this time, it was also discovered that electrical leads could be connected to the heart through veins, eliminating the need to open the chest and attach the leads to the heart wall. In 1975, the introduction of lithium iodide batteries extended the battery life of pacemakers from a few months to over 10 years. Modern pacemakers can treat various different signaling pathologies in the myocardium and can also act as defibrillators (see U.S. Patent No. 6,738,667 to DENO et al. The disclosure of which is incorporated herein by reference).

[0009] Another example of the electrical stimulation of nerves was the treatment of lower limb radiating pain by stimulating the sacral nerve roots at the base of the spinal cord (see U.S. Patent No. 6,871,099 to WHITEHURST et al., the disclosure of which is incorporated herein by reference).

[0010] Electrical stimulation of the brain with implanted electrodes for use in the treatment of various diseases, including movement disorders such as essential tremor and Parkinson's disease, has also been approved. The principles underlying these techniques involve the disruption and modulation of hyperactive neuronal circuitry at specific sites in the brain. Unlike treatments that cause potentially dangerous lesions where abnormal parts of the brain are physically destroyed, electrical stimulation is achieved by implanting electrodes at these sites. The electrodes are first used to detect abnormal electrical signals and then to send electrical pulses to locally disrupt pathological neuronal transmission and to return it to a normal range of activity. These electrical stimulation treatments are generally performed, along with the invasiveness, by conscious patients and surgical staff.

[0011] However, brain stimulation, and particularly deep brain stimulation, is not without its drawbacks. This procedure requires the use of a catheter-shaped lead wire or the like to penetrate the skull and insert the electrodes into the brain tissue. While monitoring the patient's condition (such as tremor activity), the position of the electrodes is adjusted to achieve significant therapeutic potential. Next, in order to achieve the same therapeutic results, the electrical stimulation signal, such as frequency, periodicity, voltage, current, etc., is adjusted. The electrodes are then permanently implanted and wires are directed from the electrodes to the site of a surgically implanted pacemaker. The pacemaker provides the electrical stimulation signal to the electrodes to maintain the therapeutic effect. Although the treatment results of deep brain stimulation are promising, significant complications can occur with the implantation procedure, including strokes induced by damage to the surrounding tissue and neurovascular structures.

[0012] Most of the above-described applications of electrical stimulation involve surgical implantation of electrodes within a patient's body. In contrast, in the case of embodiments of the present invention, the disclosed devices and medical procedures stimulate nerves by non-invasively transmitting energy to nerves and tissues. They can provide an alternative to patients that does not involve surgery. A medical procedure is defined as non-invasive when it causes no incisions in the skin (or other body surfaces such as a wound bed) through the use of the method, and there is no contact with the body cavity beyond a body opening (e.g., beyond the oral cavity or beyond the ear canal). Such non-invasive procedures are distinguished from invasive procedures (including minimally invasive procedures) in that invasive procedures involve inserting a substance or device into or through the skin or into the body cavity beyond a body opening. For example, transcutaneous electrical nerve stimulation (TENS) is non-invasive because it involves attaching electrodes to the surface of the skin (or using a conductive garment that conforms to the body shape) without causing an incision in the skin. In contrast, percutaneous electrical stimulation of nerves is minimally invasive because it involves inserting electrodes subcutaneously through a skin puncture (see co-pending U.S. Patent Application No. 2010 / 0241188, assigned to the assignee of the present invention for the name Percutaneous Electrical Treatment of Tissue to ERRICO et al., which is hereby incorporated by reference in its entirety).

[0013] The potential advantages of non-invasive medical methods and devices compared to equivalent invasive procedures are as follows. Patients can be more psychologically prepared to undergo a non-invasive procedure and can therefore be more cooperative, leading to better outcomes. Non-invasive procedures can avoid damage to biological tissue such as bleeding, infection, skin or organ injury, vascular injury, and blood clotting in veins or the lungs. Non-invasive procedures generally have fewer issues related to biocompatibility. In cases involving electrode attachment, non-invasive methods are less prone to lead wire breakage and the electrodes can be easily repositioned if necessary. Non-invasive methods can sometimes be performed without pain or with minimal pain and without even the need for local anesthesia. The training required for medical professionals to use non-invasive procedures can be less. Usually, considering the reduced risks associated with non-invasive procedures, some such procedures can be suitable for use by patients or family members at home, or by first responders at home or in the workplace, and the cost of non-invasive procedures can be reduced compared to equivalent invasive procedures.

[0014] There is a long history of electrodes that are non-invasively applied to the body surface and include electrodes used to stimulate underlying nerves [L.A. Geddes. Historical Evolution of Circuit Models for the Electrode-Electrolyte Interface. Annals of Biomedical Engineering 25(1997):1-14]. However, electrical stimulation of nerves was generally disliked in the mid-20th century until the "gate theory of pain" was introduced by Melzack and Wall in 1965. This theory, along with the progress of electronics, revived interest in the use of implanted electrodes to stimulate nerves to control pain for the first time. Then, screening procedures were developed to determine suitable candidates for electrode implantation, which initially involved determining whether the patient responded when stimulated by electrodes applied to the body surface near the possible graft. Subsequently, it was discovered that surface stimulation often controlled pain very well, obviating the need to implant the stimulating electrodes [Charles Burton and Donald D. Maurer. Pain Suppression by Transcutaneous Electronic Stimulation. IEEE Transactions on Biomedical Engineering BME-21(2,1974):81-88]. Such non-invasive transcutaneous electrical nerve stimulation (TENS) was then developed to treat different types of pain, including joint or low back pain, cancer pain, postoperative pain, post-traumatic pain, as well as pain associated with labor and childbirth. [Steven E. Abram. Transcutaneous Electrical Nerve Stimulation, pp1-10 in: Joel B. Myklebust, ed. Neural stimulation (Volume 2). Boca Raton, Fla. CRC Press 1985, WALSH DM, Lowe AS, McCormack K. Willer J-C, Baxter GD, Allen JM.Transcutaneous electrical nerve stimulation: effect on peripheral nerve conduction, mechanical pain threshold, and tactile threshold in humans. Arch Phys Med Rehabil 79(1998):1051-1058, J A CAMPBELL. A critical appraisal of the electrical output characteristics of ten transcutaneous nerve stimulators. Clin.phys.Physiol.Meas. 3(2,1982):141-150, U.S. Patent No. US3817254 for the name Transcutaneous stimulator and stimulation method for Maurer, U.S. Patent No. US4324253 for the name Transcutaneous pain control and / or muscle stimulating apparatus for Greene et al., U.S. Patent No. US4503863 for the name Method and apparatus for transcutaneous electrical stimulation for Katims, U.S. Patent No. US5052391 for the name High frequency high intensity transcutaneous electrical nerve stimulator and method of treatment for Silberstone et al., U.S. Patent No. US6351674 for the name Method for inducing electroanesthesia using high frequency, high intensity transcutaneous electrical nerve stimulation for Silverstone].

[0015] When TENS was developed to treat pain, non-invasive electrical stimulation using surface electrodes was also developed simultaneously for additional therapeutic or diagnostic purposes, which are collectively known as electrotherapy. Neuromuscular electrical stimulation (NMES) stimulates normally innervated muscles to enhance the strength and endurance of normal (e.g., exercising) muscles or injured (e.g., spastic) muscles. Functional electrical stimulation (FES) is used to activate the nerves of muscles affected by paralysis due to spinal cord injury, head trauma, stroke, and other neurological disorders, or muscles affected by foot drop and gait disorders. FES is also used to stimulate muscles as a substitute for orthotic devices, for example, to replace braces or to assist in the management of scoliosis. Other applications of surface electrical stimulation are the stimulation of tissues from the chest to the back, such as emergency defibrillation and cardiac pacing. Surface electrical stimulation has also been used to repair tissues by increasing circulation through vasodilation, controlling edema, healing wounds, and inducing bone growth. Surface electrical stimulation is also used in iontophoresis, in which an electric current is used to drive charged drugs or other ions into the skin, usually to treat inflammation and pain, arthritis, injuries, or scars. Stimulation by surface electrodes is also used diagnostically to elicit responses, for example, in peripheral nerve stimulation (PNS) to evaluate the ability of motor and sensory nerves to conduct reflexes. Surface electrical stimulation is also used in electroconvulsive therapy to treat mental disorders, electrical anesthesia to prevent pain during dental procedures, for example, and electrocutaneous speech processing to convert speech to touch for the hearing impaired.Although all of the above-described application examples of surface electrode stimulation are intended not to cause damage to the patient, when higher currents are used with special electrodes, electrosurgery can be performed as a means for cutting, coagulating, drying, or electrocauterizing tissue [Mark R. Prausnitz. The effects of electric current applied to skin: A review for transdermal drug delivery. Advanced Drug Delivery Reviews 18 (1996) 395-425].

[0016] Despite its appeal, non-invasive electrical stimulation of nerves is not always usable or practical. This is mainly because the stimulating action may inadvertently stimulate nerves other than the target nerve, including the nerves that cause pain, and current state-of-the-art techniques may not be able to selectively stimulate deep nerves without causing excessive pain. For this reason, forms of electrical stimulation other than TENS may be optimal for the treatment of certain types of pain [Paul F. WHITE, Shitong Li and Jen W. Chiu. Electroanalgesia: Its Role in Acute and Chronic Pain Management. Anesth Analg 92 (2001): 505-13].

[0017] Regarding other applications of any other electrotherapy, instead of invasively stimulating the nerve, it was difficult to non-invasively stimulate the nerve. The most relevant therapies to the present invention include electrical stimulation of the cervical vagus nerve to treat epilepsy, depression, and other medical conditions. In the case of these therapies, the left vagus nerve is usually first surgically implanted with electrodes at a location within the neck and then stimulated at that location by connecting the electrodes to an electrical stimulator [U.S. Patent No. US4702254, titled Neurocybernetic prosthesis for ZABARA; U.S. Patent No. US6341236, titled Vagal nerve stimulation techniques for treatment of epileptic seizures for OSORIO et al.; and U.S. Patent No. US5299569, titled Treatment of neuropsychiatric disorders by nerve stimulation for WERNICKE et 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 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 - 4634, Timothy B. MAPSTONE. Vagus nerve stimulation: current concepts. Neurosurg Focus 25(3, 2008): E9, pp. 1 - 4].

[0018] When it is desirable to avoid surgical implantation of electrodes, vagus nerve stimulation (VNS) can be performed, which positions one or more electrodes in the esophagus, trachea, or jugular vein, but can be less invasive by positioning one electrode on the body surface [U.S. Patent No. US7340299 to PUSKAS for the title Methods of indirectly stimulating the vagus nerve to achieve controlled asystole, and U.S. Patent No. US7869884 to SCOTT et al. for the title Non - surgical device and methods for trans - esophageal vagus nerve stimulation]. Despite their advantage of being non - surgical, such methods still present other disadvantages associated with invasive procedures.

[0019] Other patents disclose non-invasive VNS, but at locations other than the neck [e.g., U.S. Patent No. US4865048 to ECKERSON, titled Method and apparatus for drug free neurostimulation; U.S. Patent No. US6609025 to BARRETT et al., titled Treatment of obesity by bilateral sub-diaphragmatic nerve stimulation; U.S. Patent No. US5458625 to KENDALL, titled Transcutaneous nerve stimulation device and method for using same; U.S. Patent No. US7386347 to Chung et al., titled Electric stimulator for alpha-wave derivation; U.S. Patent No. US7797042 to Dietrich et al., titled Device for applying a transcutaneous stimulus or for transcutaneous measuring of a parameter; U.S. Patent Application No. US2010 / 0057154 to Dietrich et al., titled Device and Method for the Transdermal Stimulation of a Nerve of the Human Body; U.S. Patent Application No. US2006 / 0122675 to Libbus et al., titled Stimulator for auricular branch of vagus nerve; U.S. Patent Application No. US2008 / 0288016 to Amurthur et al., titled Systems and Methods for Stimulating Neural Targets]. However, such non-invasive VNS occurs at locations other than the neck and thus cannot be directly compared to invasive VNS in the neck, where the therapeutic results have been well established.Among numerous patents and patent applications, non-invasive VNS is sometimes mentioned in conjunction with invasive VNS methods, but does not address issues such as the unintentional stimulation of nerves other than the vagus nerve, particularly pain-causing nerves [e.g., U.S. Patent Application No. US20080208266 to LESSER et al., entitled System and Method for Treating Nausea and Vomiting by Vagus Nerve Stimulation]. Other patents are vague regarding how non-invasive electrical stimulation near the cervical vagus nerve is achieved [e.g., U.S. Patent No. US7499747 to KIEVAL et al., entitled External baroreflex activation].

SUMMARY OF THE INVENTION

PROBLEM TO BE SOLVED BY THE INVENTION

[0020] In view of the above background, there is a need for a method to electrically stimulate the cervical vagus nerve completely non-invasively, selectively, and essentially without causing pain, which has remained unresolved for many years. Compared to what patients experience with non-invasive stimulation by conventional TENS methods, the present vagus nerve stimulator should cause relatively little pain for a given depth of penetration of the stimulation. Conversely, for a given amount of pain or discomfort on the patient side (e.g., the threshold at which such discomfort or pain begins), the object of the present invention is to achieve a greater depth of penetration of the subcutaneous stimulation. Further, the object is not to stimulate other nerves and muscles near the cervical vagus nerve, but rather to stimulate the vagus nerve to achieve a therapeutic result even in such situations.

MEANS FOR SOLVING THE PROBLEM

[0021] In one aspect of the present invention, a device and method for producing a therapeutic effect in a patient are described by utilizing an energy source that non-invasively transmits energy to neural tissue. Specifically, the disclosed device can transmit energy to a patient's vagus nerve in the neck or in proximity to the nerve in order to temporarily stimulate, block, and / or modulate the electrophysiological signals therein. The methods disclosed herein include stimulating the vagus nerve with specific stimulation waveform parameters, preferably using a nerve stimulator device also disclosed herein.

[0022] In one aspect of the invention, a new stimulator device is used to modulate the electrical activity of the vagus nerve or other nerves or tissues. The stimulator includes a power source and one or more remote electrodes configured to stimulate deep nerves associated with the nerve axis. The device also includes a continuous conductive medium with which the electrodes are in contact. The conductive medium is also in contact with an interface element that makes physical contact with the patient's skin. The interface element can be an electrically insulating (dielectric) material such as a sheet of Mylar, in which case the electrical coupling of the device to the patient is capacitive. In other embodiments, the interface element is a conductive material such as a conductive or permeable membrane, in which case the electrical coupling of the device to the patient is ohmic. The interface element can have a shape that conforms to the contour of the target body surface when the medium is applied to the target body surface of the patient.

[0023] In another aspect of the invention, a new stimulator device is used to modulate the electrical activity of the vagus nerve or other nerves or tissues. The stimulator includes a power source and one or more electrodes configured to stimulate deep nerves associated with the nerve axis. The device also includes a continuous conductive medium with which the electrodes (s) are in contact. The conductive medium provides electrical communication between the electrodes (s) and the patient's tissue, such that the electrodes (s) do not make direct contact with the tissue. The conductive medium preferably has a shape that conforms to the contour of the target body surface when the medium is applied to the target body surface of the patient.

[0024] In the case of current medical applications, the device is typically applied to the patient's neck. In a preferred embodiment of the present invention, the stimulator comprises two electrodes that are parallel within separate stimulator heads, and the electrodes are separated by an electrically insulating material. Each electrode and the patient's skin are in continuous contact with a conductive medium that extends from the interface element of the stimulator to the electrode. The interface element also contacts the patient's skin when the device is in operation. The conductive media of the different electrodes are also separated by an electrically insulating material.

[0025] The power source supplies a pulse of charge to the electrodes, and thus the electrodes generate a current and / or an electric field within the patient's body. The stimulator is configured to induce a peak pulse voltage sufficient to generate an electric field in the vicinity of a nerve, such as the vagus nerve, to depolarize the nerve and reach the threshold of action potential propagation. As an example, the threshold electric field for nerve stimulation can be about 8 V / m at 1000 Hz. For example, the device can generate an electric field of about 10 - 600 V / m within the patient's body and can generate an electric field gradient exceeding 2 V / m / mm.

[0026] The current passing through the electrodes can be about 0 to 40 mA, and the voltage across the entire electrodes is 0 to 30 volts. The current passes through the electrodes in bursts of pulses. There can be 0 to 30 pulses per burst, preferably about 4 to 10 pulses, more preferably 5 pulses. Each pulse within the burst can have a duration of 20 to 1000 microseconds, preferably 100 to 400 microseconds, more preferably about 200 microseconds. The bursts that are followed by an inter-burst silence period repeat at 1 to 5000 bursts per second (bps), preferably 15 to 50 bps. The preferred shape of each pulse is a full sine wave. A suitable stimulator forms an elongated electric field effect that can be oriented parallel to a long nerve such as the vagus nerve in the patient's neck. By selecting a suitable waveform for stimulating the nerve, along with suitable parameters such as current, voltage, pulse width, pulses per burst, inter-burst interval, etc., the stimulator produces the physiological response of the individual patient selected accordingly. Such suitable waveforms and parameters are selected simultaneously so as to avoid substantially stimulating nerves and tissues other than the target nerve, and in particular to avoid stimulating nerves that cause pain.

[0027] The teachings of the present invention demonstrate how the disclosed non-invasive stimulator can be positioned and used relative to the body surface, particularly at a location on the neck of a patient under which the vagus nerve lies. Such teachings also explain the generation of certain beneficial therapeutic effects in the patient. However, it should be understood that the application of the method and device is not limited to the examples given.

[0028] New systems, devices, and methods for treating diseases using the disclosed stimulator or other non-invasive stimulation devices are more fully described in the following detailed description of the invention, reference to the drawings provided therewith, and the claims appended thereto. Other aspects, features, advantages, etc. will become apparent to those skilled in the art when considering the description of the invention herein in conjunction with the accompanying drawings.

[0029] Incorporation by reference By this specification, all issued patents, patent application publications, and non-patent literature described in this specification are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual issued patent, patent application publication, or non-patent literature was specifically and individually indicated to be incorporated by reference.

[0030] For purposes of illustrating various aspects of the present invention, the drawings show forms that are presently preferred and understood, but the present invention is not limited to or by the exact data, methodologies, arrangements, and means shown, but rather is limited only by the claims.

Brief Description of the Drawings

[0031]

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DETAILED DESCRIPTION OF THE INVENTION

[0032] In the present invention, energy is transmitted to the patient non - invasively. The present invention is particularly useful for generating applied electrical impulses that interact with the signals of one or more nerves to achieve a therapeutic result. Specifically, the present disclosure describes devices and methods for non - invasively stimulating the vagus nerve at locations in a patient's neck.

[0033] There has been a need for many years to electrically stimulate the cervical vagus nerve completely non-invasively, selectively, and essentially without causing pain. As will be explained below, this is demonstrated by the fact that other attempts to non-invasively electrically stimulate in the neck to stimulate the vagus nerve at other anatomical locations or to stimulate the vagus nerve non-electrically have failed, and this problem is solved by the invention. Japanese Patent Application No. JP2009233024A, filed on March 26, 2008, for the name Vagus Nerve Stimulation System against Fukui YOSHIHITO, relates to the stimulation of the vagus nerve on the surface of the neck to control the heart rate, rather than epilepsy, depression, or other debilities that are normally intended to be treated. Nevertheless, the technique made by Yoshihito exemplifies the difficulties encountered by non-invasive electrical stimulation of the vagus nerve. Yoshihito emphasizes that since electrical stimulation on the surface of the neck can co-stimulate the phrenic nerve associated with the control of respiration, the patient hiccups and does not breathe normally, resulting in the patient feeling discomfort and uneasiness. Yoshihito's proposed solution to this problem is to adjust the timing and intensity of electrical stimulation in the neck as a function of the respiratory phase in such a way that unwanted respiratory effects are minimized. Thus, Yoshihito's technique is not one to find a way to selectively stimulate the vagus nerve, but rather to compensate for non-selective nerve stimulation. However, such compensatory modulation can also prevent the stimulation from achieving beneficial effects when treating epilepsy, depression, and other debilities that are normally treated by VNS. Furthermore, Yoshihito does not address the problem of pain in the vicinity of the stimulating electrode. Presumably, similar issues can occur in relation to possible co-stimulation of the carotid sinus nerve [Ingrid J.M.Scheffers,Abraham A.Kroon,Peter W.de Leeuw.Carotid Baroreflex Activation:Past,Present,and Future.Curr Hypertens Rep 12(2010):61-66].Side effects can also occur due to the simultaneous activation of muscles controlled by the vagus nerve itself, which exemplifies another type of non-selective stimulation [M. Tosato, K. Yoshida, E. Toft and J. J. Struijk. Quasi-trapezoidal pulses to selectively block the activation of intrinsic laryngeal muscles during vagal nerve stimulation. J. Neural Eng. 4 (2007): 205-212].

[0034] One way to avoid one of the problems solved by the present invention is to non-invasively stimulate the vagus nerve at an anatomical location other than the neck where the nerve is closer to the skin. Suitable alternative locations, although other locations have also been proposed, are in or around the ear (earlobe, ear canal, or concha) [Manuel L. KARELL. TENS in the Treatment of Heroin Dependency. The Western Journal of Medicine 125(5, 1976): 397 - 398, Enrique C. G. VENTUREYRA. Transcutaneous vagus nerve stimulation for partial onset seizure therapy. A new concept. Child’s Nerv Syst 16(2000): 101 - 102, T. KRAUS, K. Hosl, O. Kiess, A. Schanze, J. Kornhuber, C. Forster. BOLD fMRI deactivation of limbic and temporal brain structures and mood enhancing effect by transcutaneous vagus nerve stimulation. J Neural Transm 114(2007): 1485 - 1493, POLAK T, Markulin F, Ehlis AC, Langer JB, Ringel TM, Fallgatter AJ. Far field potentials from brain stem after transcutaneous vagus nerve stimulation: optimization of stimulation and recording parameters.J Neural Transm 116(10,2009):1237-1242, U.S. Patent No. US5458625 to KENDALL, entitled Transcutaneous nerve stimulation device and method for using same, U.S. Patent No. US7797042 to Dietrich et al., entitled Device for applying a transcutaneous stimulus or for transcutaneous measuring of a parameter, U.S. Patent Application No. US2010 / 0057154 to Dietrich et al., entitled Device and Method for the Transdermal Stimulation of a Nerve of the Human Body, and also see the non-invasive methods and devices disclosed by the applicant in the co-pending U.S. Patent Application No. 12 / 859,568, assigned to the assignee of the present invention, entitled Non-invasive Treatment of Bronchial Constriction. However, it is not certain whether the stimulation of these minute branches of the vagus nerve has the same effect as the stimulation of the main vagus nerve in the neck, which usually results in a well-established outcome of VNS treatment with the implantation of VNS electrodes.

[0035] Another strategy for avoiding other problems is to replace electrical stimulation of the vagus nerve in the neck with some other form of stimulation. For example, mechanical stimulation of the vagus nerve in the neck has been proposed as an alternative to electrical stimulation [Jared M. HUSTON, Margot Gallowitsch-Puerta, Mahendar Ochani, Kanta Ochani, Renqi Yuan, Mauricio Rosas-Ballina, Mala Ashok, Richard S. GOLDSTEIN, Sangeeta Chavan, Valentin A. PAVLOV, Christine N. METZ, Huan Yang, Christopher J. Czura, Haichao Wang, Kevin J. TRACEY. Transcutaneous vagus nerve stimulation reduces serum high mobility group box 1 levels and improves survival in murine sepsis. Crit Care Med 35(12, 2007):2762-2768, Artur BAUHOFER and Alexander Torossian. Mechanical vagus nerve stimulation - A new adjunct in sepsis prophylaxis and treatment? Crit Care Med 35(12, 2007):2868-2869, Hendrik SCHMIDT, Ursula Muller-Werdan, Karl Werdan. Assessment of vagal activity during transcutaneous vagus nerve stimulation in mice. Crit Care Med 36(6, 2008):1990, see also the non-invasive methods and devices disclosed by the applicant in the co-pending U.S. patent application Ser. No. 12 / 859,568, entitled Non-invasive Treatment of Bronchial Constriction, assigned to the assignee of the present invention for SIMON].However, such mechanical VNS has only been performed in animal models, and there is no evidence that such mechanical VNS is functionally equivalent to electrical VNS.

[0036] Another strategy for avoiding problems is to use magnetism rather than simply electrical stimulation of 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, A. Shafik, "Functional magnetic stimulation of the vagus nerve enhances colonic transit time in healthy volunteers."See also the non-invasive methods and devices disclosed by the applicant in U.S. Patent Application No. 12 / 859,568, a continuation-in-part of U.S. Patent Application No. 12 / 859,568, titled Non-invasive Treatment of Bronchial Constriction, and U.S. Patent Application No. 12 / 964,050, a continuation-in-part of U.S. Patent Application No. 12 / 964,050, titled Magnetic Stimulation Devices and Methods of Therapy. Magnetic stimulation can be functionally similar to electrical stimulation. However, magnetic stimulation has disadvantages such as usually requiring complex and expensive equipment, and the duration of stimulation can be limited by overheating of the magnetic stimulator. Additionally, in some cases, magnetic stimulation of the neck can also inadvertently stimulate nerves other than the vagus nerve, such as the phrenic nerve [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]. Furthermore, magnetic stimulation can also stimulate the nerves that cause pain. Other stimulators that utilize magnetic fields can also be used, but they are also complex and expensive and can share many other disadvantages with many conventional magnetic stimulators [U.S. Patent No. US7699768 for the name Device and method for non-invasive, localized neural stimulation utilizing hall effect phenomenon against Kishawi et al.].

[0037] Transcutaneous electrical stimulation (as well as magnetic stimulation) can be unpleasant or painful in the experience of patients undergoing such treatment. The quality of the sensation produced by the stimulation strongly depends on the current and frequency, thus a current slightly above the perception threshold generally produces a painless sensation expressed as tingling, itching, vibration, buzzing, contact, pressure, or twitching, while higher currents can produce sharp or burning pain. As the penetration depth of the subcutaneous stimulation increases (e.g., up to deeper nerves such as the vagus nerve), generally some pain starts or increases. Methods for reducing pain include the use of anesthetic agents placed on or injected into the skin near the stimulation site, and the placement of a foam pad on the skin of the stimulation site [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], the use of nerve blocks [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], reducing the current density by increasing the electrode size [Kristof VERHOEVEN, and J. Gert van Dijk.Reducing pain in electrical nerve stimulation. [Clinical Neurophysiology 117(2006)972-978], use of high-impedance electrodes [N. SHA, L. P. J. Kenney, B. W. Heller, A. T. Barker, D. Howard, and W. Wang. The effect of the impedance of a thin hydrogel electrode on sensation during functional electrical stimulation. Medical Engineering & Physics 30(2008):739-746], and providing patients with an amount of information tailored to the individual patient [Anthony DELITTO, Michael J Strube, Arthur D Shulman, Scott D Minor. A Study of Discomfort with Electrical Stimulation. Phys. Ther. 1992;72:410-424] can be mentioned. U.S. Patent No. US7614996 for the name Reducing discomfort caused by electrical stimulation to RIEHL discloses the application of a second stimulus to cancel out the main stimulus that would otherwise cause discomfort. Other methods of reducing pain are intended to be used with invasive nerve stimulation. [U.S. Patent No. US7904176 for the name Techniques for reducing pain associated with nerve stimulation to Ben-Ezra et al.].

[0038] Further considerations related to pain caused by stimulation are as follows. When the stimulation is repeated over multiple sessions, the patient may adapt to the pain and exhibit progressively less discomfort. Patients can be non-uniform with respect to their thresholds for the pain caused by the stimulation, including non-uniformities related to gender and age. The electrical properties of an individual's skin vary from day to day and can be affected by the cleaning, wear, and application of various electrode gels and pastes. The properties of the skin can also be affected by the stimulation itself as a function of the duration of the stimulation, the recovery time between stimulation sessions, the transcutaneous voltage, the current density, and the power density. The application of multiple electrical pulses can result in different perception thresholds or pain thresholds and sensation levels depending on the intervals and rates at which the pulses are applied. The separation distance between two electrodes determines whether the sensations from the electrodes are separate, partially overlapping, or fused. The limit of acceptable sensation is said to correspond to a current density of 0.5 mA / cm 2 2, but in reality, the functional relationship between pain and current density is very complex. The maximum local current density can be more important than the average current density in causing pain, and the local current density generally varies under the electrode, for example, the current density is greater along the edge of the electrode or at "hot spots". Furthermore, the pain threshold can have a thermal component and / or an electrochemical component, as well as a current density component. The pulse frequency plays an important role in the perception of pain, with muscle contraction occurring at some frequencies and not at others, and the spatial spread of the pain sensation is also a function of the frequency. Sensation is also a function of the waveform (square wave, sine wave, trapezoidal wave, etc.), especially when the pulse has a duration of less than 1 millisecond. [Mark R. PRAUSNITZ. The effects of electric current applied to skin: A review for transdermal drug delivery. Advanced Drug Delivery Reviews 18 (1996): 395 - 425].

[0039] Considering that there are a very large number of variables that can affect the likelihood of pain during non-invasive electrical stimulation (detailed stimulation waveforms, frequencies, current densities, types and geometries of electrodes, skin preparations, etc.), and considering that these same variables must be selected simultaneously in order to independently produce the desired therapeutic results by stimulating the vagus nerve, and also considering that it is desirable to selectively stimulate the vagus nerve (e.g., avoid stimulating the phrenic nerve), it can be understood that no one has previously disclosed, more fully than the present disclosure, a device and method for electrically stimulating the cervical vagus nerve completely non-invasively, selectively, and essentially without causing pain.

[0040] In the experimental process with the magnetic stimulation device disclosed in the co-pending U.S. Patent Application No. 12 / 964,050, which was assigned to the assignee of the present invention for the application named Magnetic Stimulation Devices and Methods of Therapy by SIMON et al., the applicant discovered the disclosed device and method. The stimulator uses a magnetic coil and is embedded in a safe and practical conductive medium that is in direct contact with the arbitrarily oriented skin of the patient, which has not been described in recent technologies [Rafael CARBUNARU, and Dominique M. Durand. Toroidal coil models for transcutaneous magnetic stimulation of nerves. IEEE Transactions on Biomedical Engineering 48(4, 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 (UMI Microform Number: 9940153, UMI Company, Ann Arbor MI)]. Such a design, which is adapted to be used with surface electrodes herein, enables the formation of an electric field that is used to selectively stimulate deep nerves such as the vagus nerve in the neck. Further, this design causes significantly less pain or discomfort (if applicable) to the patient than the stimulator devices currently known in the art. Conversely, for a given amount of pain or discomfort on the patient side (e.g., the threshold at which such discomfort or pain begins), this design achieves a greater depth of penetration of subcutaneous stimulation.

[0041] FIG. 1 is a schematic view of a nerve stimulation / regulation device 300 for delivering an energy impulse to a nerve for the treatment of a medical condition. As shown, the device 300 can include an impulse generator 310, a power supply 320 coupled to the impulse generator 310, a control unit 330 in communication with the impulse generator 310 and coupled to the power supply 320, and an electrode 340 coupled to the impulse generator 310 via a wire 345.

[0042] Although a pair of electrodes 340 are shown in FIG. 1, in practice, the electrodes can also comprise three or more separate electrode elements, each of which is connected to the impulse generator 310 in series or in parallel. Thus, the electrodes 340 shown in FIG. 1 represent all of the electrodes of the device collectively.

[0043] The item labeled 350 in FIG. 1 is a volume adjacent to the electrode 340 filled with a conductive medium. As shown in the preferred embodiment, the medium is also deformable to conform to the body shape when applied to the body surface. Thus, the waves or curves shown on the outer surface of the conductive medium 350 also correspond to waves or curves on the body surface to which the conductive medium 350 is applied so as to abut the medium and the body surface. As will be described below in connection with the preferred embodiment, the volume 350 is electrically connected to the patient at the target skin surface to form a current density passing through the electrode 340 that is necessary to achieve stimulation of the patient's nerve or tissue. Also, as will be described below in connection with an exemplary embodiment of the present invention, the conductive medium in which the electrode 340 is embedded need not completely surround the electrode.

[0044] The control unit 330 controls the impulse generator 310 to generate respective signals for the electrodes of the device. When the signals are non-invasively applied to the target nerve or tissue via the electrodes 340, the signals are selected to be suitable for improving a particular medical condition. Note that the nerve stimulation / regulation device 300 may be referred to as a pulse generator by its function. Both are incorporated herein by reference, and both U.S. Patent Application Publication Nos. US2005 / 0075701 and US2005 / 0075702 to SHAFER relate to the stimulation of neurons of the sympathetic nervous system for attenuating the immune response and include descriptions of pulse generators that may be applicable to the present invention. As an example, the pulse generator 300 is also commercially available, such as the Agilent 33522A function / arbitrary waveform generator, Agilent Technologies, Inc., 5301 Stevens Creek Blvd Santa Clara CA 95051, etc.

[0045] The control unit 330 may also include a general-purpose computer having one or more CPUs, a computer memory for storing and reading executable computer programs (including the system's operating system) and data, a disk storage device, a communication device (such as a serial port and a USB port) for receiving external signals from the system's keyboard and computer mouse, as well as any externally supplied physiological signals, an analog-to-digital converter for digitizing externally supplied analog signals, a communication device for transmitting data to and receiving data from external devices such as printers and modems that form part of the system, hardware for generating a display of information on a monitor forming part of the system, and a bus for interconnecting the above-described components. Thus, a user can operate the system by inputting instructions to the control unit 330 using a device such as a keyboard, 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. The control of the system may be based on feedback measured from externally supplied physiological or environmental signals. Alternatively, the control unit 330 may have a compact and simple structure. For example, a user may operate the system using only an on / off switch and an output control wheel or knob.

[0046] Parameters for nerve stimulation or tissue stimulation include power level, frequency, and train duration (or number of pulses). The stimulation characteristics of each pulse, such as penetration depth, intensity, and selectivity, depend on the rise time and peak electrical energy transferred to the electrode, as well as the spatial distribution of the electric field generated by the electrode. The rise time and peak energy are governed by the electrical characteristics of the stimulator and electrode, as well as the anatomical structure of the region in the patient's body where the current flows. In one embodiment of the present invention, the pulse parameters are set in a manner that complements the detailed anatomical structure surrounding the nerve being stimulated [Bartosz SAWICKI, Robert Szmurto, Przemystaw Ptonecki, Jacek Starzynski, 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]. The pulses can be single - phase, two - phase, or multi - phase. Embodiments of the present invention include those having a fixed frequency where each pulse in the train has the same inter - stimulus interval, and those having a modulated frequency where the interval between each pulse in the train can be varied.

[0047] Figure 2A illustrates an exemplary voltage / current profile of a stimulation, blocking, and / or modulation impulse applied to one or more portions of a selected nerve, in accordance with an embodiment of the present invention. For a preferred embodiment, the voltage and current refer to those that occur non-invasively within the patient's body by an electrode. As shown, a suitable voltage / current profile 400 for a blocking and / or modulation impulse 410 to one or more portions of a nerve can be achieved using a pulse generator 310. In a preferred embodiment, the pulse generator 310 can be implemented using a power source 320 and a control unit 330 having, for example, a processor, a clock, a memory, etc., to generate a pulse train 420 for the electrode 340 that delivers the stimulation, blocking, and / or modulation impulse 410 to the nerve. The nerve stimulation / modulation device 300 can be powered externally, can be recharged, and / or can have its own power source 320. The parameters of the modulation signal 400, such as frequency, amplitude, duty cycle, pulse width, pulse shape, etc., are preferably programmable. An external communication device can modify the program of the pulse generator so as to improve the treatment.

[0048] In addition to, or alternatively to, a device implementing a modulation unit for generating voltage / current profiles of stimulation, blocking, and / or modulation impulses for an electrode, a device disclosed in U.S. Patent Publication No. US2005 / 0216062 (the entire disclosure of which is incorporated herein by reference) may be employed. That patent publication is adapted to obtain an output signal for providing electromagnetic or other forms of electrical stimulation for a wide range of different biological and biomedical applications, and discloses a multifunctional electrical stimulation (ES) system that generates an electric field pulse for non-invasively stimulating nerves. This system includes an ES signal stage having a selector coupled to a plurality of different signal generators, each generating a signal having a different shape such as a sine wave, square wave, or sawtooth wave, or a simple or complex pulse, the parameters of which are adjustable with respect to amplitude, duration, repetition rate, and other variables. Examples of 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 an output of high voltage or low voltage or high current or low current of a desired polarity, whereby the output stage can obtain an electrical stimulation signal appropriate for its intended use. This system also includes a measurement stage for measuring and displaying the output of an electrical stimulation signal operating on the substance being treated, as well as the outputs of various sensors sensing the dominant conditions within this substance, whereby the user of the system can manually adjust the system or cause the system to be automatically adjusted by feedback to provide any electrical stimulation signal desired by the user, and the user can then observe the effect of this signal on the substance being treated.

[0049] The stimulating, blocking, and / or modulating impulse signal 410 is preferably selected to have a frequency, amplitude, duty cycle, pulse width, pulse shape, etc., that affect the treatment outcome, i.e., stimulate, block, and / or modulate some or all of the transmission of the selected nerve. For example, the frequency can be about 1 Hz or more, such as from about 15 Hz to 50 Hz, more preferably about 25 Hz. The modulation signal can have a pulse width selected to affect the treatment outcome, such as about 20 microseconds or more, such as from about 20 microseconds to about 1000 microseconds. For example, the electric field induced by the device within the tissue near the nerve is 10 - 600 V / m, preferably about 300 V / m. The gradient of the electric field can be greater than 2 V / m / mm. More generally, the stimulating device creates an electric field near the nerve that is sufficient to depolarize the nerve and reach the threshold for action potential propagation, and this electric field is about 8 V / m at 1000 Hz.

[0050] The object of the disclosed stimulator is to provide both nerve fiber selectivity and spatial selectivity. Spatial selectivity can be achieved, in part, through the design of the electrode configuration, and nerve fiber selectivity can be achieved, in part, through the design of the stimulation waveform, but these two types of selectivity are related to each other. This is because, for example, the waveform can selectively stimulate only one of two nerves, regardless of whether the two nerves are near each other, so there is no need to concentrate the stimulation signal on only one of the nerves [GRILL W, and Mortimer J T. Stimulus waveforms for selective neural stimulation. IEEE Eng. Med. Biol. 14 (1995): 375 - 385]. These methods supplement or partially overlap with other methods used to achieve selective nerve stimulation, such as the use of local anesthetics, application of pressure, induction of ischemia, cooling, use of ultrasound, stepwise increase in stimulation intensity, utilization of the absolute refractory period of axons, and application of stimulation blockers [John E. SWETT, and Charles M. Bourassa. Electrical stimulation of peripheral nerve. In: Electrical Stimulation Research Techniques, Michael M. Patterson and Raymond P. Kesner, eds. Academic Press. (New York, 1981) pp. 243 - 295].

[0051] So far, the selection of stimulation waveform parameters for vagus nerve stimulation (VNS) has been highly empirical, in which parameters are varied with respect to some initially successful parameter sets for the purpose of finding an improved set of parameters for each patient. A more efficient approach to selecting stimulation parameters could be to select a stimulation waveform that mimics the electrical activity in the region of the brain being indirectly stimulated, for the purpose of synchronizing with the naturally occurring electrical waveforms, as proposed in U.S. Patent No. US6234953, entitled "Electrotherapy device using low frequency magnetic pulses" to THOMAS et al., and U.S. Patent Application No. US20090299435, entitled "Systems and methods for enhancing or affecting neural stimulation efficiency and / or efficacy" to GLINER et al. Also, it is possible to vary the stimulation parameters iteratively in search of an optimal setting [U.S. Patent No. US7869885, entitled "Threshold optimization for tissue stimulation therapy" to Begnaud et al.]. However, some VNS stimulation waveforms, such as those described herein, are discovered by trial and error and then carefully refined accordingly.

[0052] Invasive vagus nerve stimulation generally uses square-wave pulse signals. Standard waveform parameter values for VNS treatment of epilepsy and depression are a current of 1 to 2 mA, a frequency of 20 - 30 Hz, a pulse width of 250 - 500 microseconds, and a duty cycle of 10% (30 seconds of signal on-time and 5 minutes of signal off-time). The output current is increased stepwise from 0.25 mA to the maximum allowable level (up to 3.5 mA), and in a typical treatment setting, it is in the range of 1.0 - 1.5 mA. Larger output currents are associated with an increased incidence of side effects, including voice alteration, cough, throat constriction, and dyspnea. The frequency is generally 20 Hz for depression and 30 Hz for epilepsy. Treatment is adjusted in a stepwise and systematic manner to individualize treatment for each patient. For treating migraine, typical VNS parameters are a current of 0.25 - 1 mA, a frequency of 30 Hz, a pulse width of 500 microseconds, and an "on" time of 30 seconds every 5 minutes. For treating migraine and epilepsy, typical parameters are 1.75 mA, a frequency of 20 Hz, a pulse width of 250 microseconds, and an "on" time of 7 seconds followed by a 12-second "off" time.To treat mild to moderate Alzheimer's disease, typical VNS waveform parameters are a current of 0.25 - 0.5 mA, a frequency of 20 Hz, a pulse width of 500 microseconds, and an "on" time of 30 seconds every 5 minutes [ANDREWS, A.J., 2003. Neuromodulation. I, Techniques - deep brain stimulation, vagus nerve stimulation, and transcranial magnetic stimulation. Ann. N.Y. Acad. Sci. 993, 1 - 13, LABINER, D.M., Ahern, G.L., 2007. Vagus nerve stimulation therapy in depression and epilepsy: therapeutic parameter settings. Acta. Neurol. Scand. 115, 23 - 33, 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]. The Applicant has found that these square waveforms are not ideal for non - invasive VNS stimulation as they cause excessive pain.

[0053] Prepulses and similar waveform modifications have been proposed as a method to improve the selectivity of the stimulation waveform of the vagus nerve and other nerves, but the applicant has not found them to be optimal [Aleksandra VUCKOVIC, Marco Tosato, and Johannes J Struijk. A comparative study of three techniques for diameter selective fiber activation in the vagal nerve: anodal block, depolarizing prepulses and slowly rising pulses. J. Neural Eng. 5 (2008): 275-286, Aleksandra VUCKOVIC, Nico J.M.Rijkhoff, and Johannes J.Struijk. Different Pulse Shapes to Obtain Small Fiber Selective Activation by Anodal Blocking - A Simulation Study. IEEE Transactions on Biomedical Engineering 51 (5, 2004): 698-706, Kristian HENNINGS, Selective Electrical Stimulation of Peripheral Nerve Fibers: Accommodation Based Methods. Ph.D. Thesis, Center for Sensory-Motor Interaction, Aalborg University, Aalborg, Denmark, 2004].

[0054] The Applicant has also found that a stimulation waveform consisting of a burst of square pulses is not ideal for non-invasive VNS stimulation [M.I. JOHNSON, C.H. Ashton, D.R.Bousfield and J.W. Thompson. Analgesic effects of different pulse patterns of transcutaneous electrical nerve stimulation on cold-induced pain in normal subjects. Journal of Psychosomatic Research 35(2 / 3, 1991): 313-321, U.S. Patent No. US7734340 entitled Stimulation design for neuromodulation to De Ridder]. However, as shown in FIGS. 2B and 2C, a burst of sine wave pulses is the preferred stimulation waveform. As can be seen, the individual sine wave pulses have a period of τ, and the burst consists of N such pulses. This is followed by a period (inter-burst period) without any signal. The pattern in which an inter-burst silence period follows a burst repeats itself with a period of T. For example, the sine wave period τ can be from about 50 μs to about 1 ms, preferably from about 100 μs to 400 μs, more preferably about 200 microseconds, the number of pulses per burst (N) can be from about 2 to 20 pulses, preferably from about 4 to 10 pulses, more preferably 5 pulses, and the entire pattern of bursts followed by an inter-burst silence period can have a period (T) of from about 1 to 100 Hz, preferably from about 10 to 35 Hz, more preferably about 25 Hz, or 40,000 microseconds (in FIG. 2C, a very small value of T is shown in order to be able to distinguish the bursts). The Applicant is not aware that such waveforms have been used in vagus nerve stimulation, but similar waveforms have been used to stimulate muscles as a means of enhancing the muscle strength of elite athletes. However, for muscle strengthening applications, the current used (200 mA) can be very painful and can be two orders of magnitude greater than the magnitudes disclosed herein for VNS.

[0055] When these exemplary values are used for T and τ, the waveform contains a significant Fourier component at a higher frequency (1 / 200 microseconds = 5000 / sec) compared to the Fourier components contained in transcutaneous nerve stimulation waveforms as currently practiced. Further, the signal used for muscle strengthening can be other than a sine wave (e.g., a triangular wave), and the parameters τ, N, and T can also be different from the values exemplified above [A. DELITTO, M. Brown, M. J. Strube, S. J. Rose, and R. C. Lehman. Electrical stimulation of the quadriceps femoris in an elite weight lifter: a single subject experiment. Int J Sports Med 10(1989):187 - 191, Alex R WARD, Nataliya Shkuratova. Russian Electrical Stimulation: The Early Experiments. Physical Therapy 82(10,2002):1019 - 1030, Yocheved LAUFER and Michal Elboim. Effect of Burst Frequency and Duration of Kilohertz - Frequency Alternating Currents and of Low - Frequency Pulsed Currents on Strength of Contraction, Muscle Fatigue, and Perceived Discomfort. Physical Therapy 88(10,2008):1167 - 1176, Alex R WARD. Electrical Stimulation Using Kilohertz - Frequency Alternating Current. Physical Therapy 89(2,2009):181 - 190, J. PETROFSKY, M. Laymon, M. Prowse, S. Gunda, and J. Batt.The transfer of current through skin and muscle during electrical stimulation with sine, square, Russian and interferential waveforms. Journal of Medical Engineering and Technology 33(2, 2009): 170 - 181, U.S. Patent No. US4177819 for the name Muscle stimulating apparatus against KOFSKY et al. As an example, the electric fields shown in FIGS. 2B and 2C can have an Emax value of 17 V / m, which is sufficient to stimulate the vagus nerve but significantly lower than the threshold required to stimulate the surrounding muscles.

[0056] To compare the stimulator disclosed herein having existing electrodes with stimulators used for non - invasive electrical stimulation, it is first useful to summarize the relevant physical properties of the electric fields and currents generated by the electrodes. According to Maxwell's equations (Ampere's law with Maxwell's correction),

Equation

[0057] where B is the magnetic field, J is the current density, E is the electric field, ε is the permittivity, and t is time [Richard P. FEYNMAN, Robert B. Leighton, and Matthew Sands. The Feynman Lectures on Physics. Volume II. Addison - Wesley Publ. Co. (Reading MA, 1964), page 15 - 15].[[]END]]

[0058] According to Faraday's law,

Equation

[0059] However, in the case of this objective, since the change in the magnetic field B may be ignored,

Number

[0060] which results in, and thus, E can be obtained from the gradient of the scalar potential Φ

Number

[0061] Generally, the scalar potential Φ and the electric field E are functions of the position (r) and time (t).

[0062] The current density J is also a function of the position (r) and time (t), which is determined by the electric field and the conductivity as follows. In the formula, the conductivity σ is generally a tensor quantity and a function of the position (r).

Number

[0063]

Number

[0064] Therefore, Ampere's law with Maxwell's correction is expressed as the following equation.

Number

[0065] When a current flows through a material that is basically non-polar (i.e., it is presumed not to be a dielectric, so ε = 0), substituting the equation for J into the above equation regarding Ampere's law gives

Number

[0066] gives, and this equation is in the form of Laplace's equation. If the conductivity of the material of the device (or patient) itself is a function of the electric field or potential, the equation becomes non-linear, which can exhibit multiple solutions, frequency multiplexing, and other such non-linear behaviors. The equation has been solved analytically for special electrode configurations, but for more general electrode configurations, it must be analyzed numerically [Petrus J. CILLIERS. Analysis of the current density distribution due to surface electrode stimulation of the human body. Ph.D. Dissertation, Ohio State University, 1988. (UMI Microform Number: 8820270, UMI Company, Ann Arbor MI), Martin REICHEL, Teresa Breyer, Winfried Mayr, and Frank Rattay. Simulation of the Three-Dimensional Electrical Field in the Course of Functional Electrical Stimulation. Artificial Organs 26(3, 2002):252 - 255, Cameron C. McINTYRE and Warren M. Grill. Finite Element Analysis of the Current-Density and Electric Field Generated by Metal Microelectrodes. Annals of Biomedical Engineering 29(2001):227 - 235, A. PATRICIU, T.P. DeMonte, M.L.G.Joy, J.J. Struijk. Investigation of current densities produced by surface electrodes using finite element modeling and current density imaging.Proceedings of the 23rd Annual EMBS International Conference, October 25 - 28, 2001, Istanbul, Turkey: 2403 - 2406, Yong HU, XB Xie, LY Pang, XH Li, KDK Luk. Current Density Distribution Under Surface Electrode on Posterior Tibial Nerve Electrical Stimulation. Proceedings of the 2005 IEEE Engineering in Medicine and Biology 27th Annual Conference Shanghai, China, September 1 - 4, 2005: 3650 - 3652]. The equations have also been numerically analyzed to compare different electrode shapes and numbers [Abhishek DATTA, Maged Elwassif, Fortunato Battaglia and Marom Bikson. Transcranial current stimulation focality using disc and ring electrode configurations: FEM analysis. J. Neural Eng. 5(2008)163 - 174, Jay T. RUBENSTEIN, Francis A. Spelman, Mani Soma and Michael F. Suesserman. Current Density Profiles of Surface Mounted and Recessed Electrodes for Neural Prostheses. IEEE Transactions on Biomedical Engineering BME - 34(11, 1987): 864 - 875, David A. KSIENSKI. A Minimum Profile Uniform Current Density Electrode.IEEE Transactions on Biomedical Engineering 39(7,1992):682-692, Andreas KUHN, Thierry Keller, Silvestro Micera, Manfred Morari. Array electrode design for transcutaneous electrical stimulation: A simulation study. Medical Engineering & Physics 31(2009)945-951]. The calculated electric field can be verified using measurements made with the model [A.M. SAGI_DOLEV, D. Prutchi and R.H. Nathan. Three-dimensional current density distribution under surface stimulation electrodes. Med. and Biol. Eng. and Comput. 33(1995):403-408].

[0067] When the capacitive effects cannot be ignored, an additional term containing the time derivative of the potential gradient appears in the more general equation, as obtained by substituting the equations for J and E into the divergence of Ampere's law with Maxwell's corrections:

Equation

[0068] The permittivity ε is a function of position (r) and is generally a tensor quantity. It can be due to the properties of the body and can also be due to the properties of the electrode design [L.A. Geddes, M. Hinds and K.S. Foster. Stimulation with capacitor electrodes. Med. and Biol. Eng. and Comput. 25 (1987): 359-360]. As a result of such terms, the waveform of the potential at multiple locations within the body generally varies relative to the waveform of the voltage signal(s) applied to the electrode(s). Further, if the permittivity of the material of the device (or patient) itself is a function of the electric field or potential, the equations become non-linear, which can exhibit multiple solutions, frequency multiplexing, and other such non-linear behavior.This time-dependent equation has been numerically solved [KUHN A, Keller T.A 3D transient model for transcutaneous functional electrical stimulation. Proc. 10th Annual Conference of the International FES Society July 2005 - Montreal, Canada: pp. 1 - 3, Andreas KUHN, Thierry Keller, Marc Lawrence, Manfred Morari. A model for transcutaneous current stimulation: simulations and experiments. Med Biol Eng Comput 47(2009):279 - 289, N. FILIPOVIC, M. Nedeljkovic, A. Peulic. Finite Element Modeling of a Transient Functional Electrical Stimulation. Journal of the Serbian Society for Computational Mechanics 1(1,2007):154 - 163, Todd A. KUIKEN, Nikolay S. Stoykov, Milica Popovic, Madeleine Lowery and Allen Taflove. Finite Element Modeling of Electromagnetic Signal Propagation in a Phantom Arm. IEEE Transactions on Neural Systems and Rehabilitation Engineering 9(4,2001):346 - 354].

[0069] In any case, the Dirichlet (D) boundary condition defines the power source, and the Neumann (N) boundary condition represents the behavior of the electric field at the intersection boundary line from the skin to the air, as follows.

Number

[0070] and

Number

[0071] In the formula, n represents an outward normal vector, that is, a vector perpendicular to the boundary curve, and V(t) represents the voltage applied to the electrode. Therefore, since no conductive current can flow across the air / conductor interface, according to the interface boundary condition, any component of the current perpendicular to the air / conductor interface should be zero. When constructing the above differential equation for Φ as a function of time, the divergence of J is taken, which satisfies the following continuity equation

Number

[0072] In the formula, ρ is the charge density. The law of charge conservation requires that both sides of this equation be zero anywhere outside the surface of the electrode where charge is added (injected or received) to the system.

[0073] An object of the present invention is to form an elongated electric field effect that can be oriented parallel to a long nerve such as the vagus nerve in the neck. As used herein, the term "forming an electric field" refers to an electric field or its gradient that is generally not radially symmetric at a given depth of stimulation in a patient, particularly an electric field characterized as elongated or finger-like, and particularly an electric field in which the magnitude of the electric field in several directions can exhibit two or more spatial maxima (i.e., can be bimodal or multimodal) such that the tissue between the highest points can include a region where the flow of current is restricted. Forming an electric field refers to both forming the boundary of a region having a significant electric field therein and configuring the direction of the electric field within such a region. The present invention is made by constructing elements present in the equations summarized above, including the following exemplary configurations (but not limited thereto) that can be used alone or in combination.

[0074] First, different contours or shapes of the electrodes [Number]

[0075] have an impact. For example, when the electrodes are curved with respect to the plane or there are two or more electrodes in the system, the charges are applied (injected or received) differently depending on the system.

[0076] Second, the value of the voltage V(t) under the above boundary conditions is manipulated to form an electric field. For example, if the device includes two pairs of electrodes that are perpendicular to each other or at variable angles to each other, the waveform of the voltage across one pair of electrodes can be different from the waveform of the voltage across the second pair, and thus, the superimposed electric fields they generate exhibit a beat frequency, which has been attempted in electrode-based stimulators [U.S. Patent No. US5512057 to REISS et al., titled Interferential stimulator for applying localized stimulation] and acoustic stimulators [U.S. Patent No. US5903516 to GREENLEAF et al., titled Acoustic force generator for detection, imaging and information transmission using the beat signal of multiple intersecting sonic beams].

[0077] Third, the above equation [Number]

[0078] The scalar potential Φ in can be manipulated to form an electric field. For example, this is achieved by changing the boundary of the conductor / air (or non-conductor) interface, thereby creating different boundary conditions. For example, a conductive material can pass through the conductive openings of an insulated mesh before contacting the patient's skin, thereby creating a series of electric field maxima. As another example, electrodes can be placed at the ends of a long tube filled with a conductive material, or the electrodes can be positioned at the bottom of a curved cup filled with a conductive material. In such cases, the dimensions of the tube or cup affect the resulting electric field and current.

[0079] Fourthly, (in Equation

Number

[0080] the conductivity σ (in ) can vary spatially within the device by using two or more different conductive materials that are in contact with each other for a given boundary condition. Conductivity can also vary by constructing some conductive materials from semiconductors, which allows for spatial and temporal adjustment of conductivity by exposing the semiconductors to agents that are susceptible to their effects, such as an electric field, light of a specific wavelength, temperature, or any other environmental variable over which the user of the device has control. In the special case where the conductivity of the semiconductor can be brought to zero, it approaches the application of interface boundary conditions as described in the previous paragraph.

[0081] Fifthly, for example, a dielectric material having a high dielectric constant ε, such as Mylar, neoprene, titanium dioxide, or strontium titanate, can be used in the device to enable capacitive electrical connection to the patient's skin. Changing the dielectric constant, along with changing the waveform V(t), affects the operation of the device, especially since the dielectric constant appears in terms that are functions of the time derivative of the potential.

Number

[0082] In the configuration of the present invention, the electrode is located within a container filled with a conductive material. In one embodiment, the container includes pores, such that the conductive material (e.g., conductive gel) can make physical contact with the patient's skin through the pores. For example, the conductive medium 350 of FIG. 1 surrounds the electrode and is filled with a conductive gel having a viscosity and mechanical integrity similar to that of a gel deodorant (e.g., Right Guard Clear Gel by Dial Corporation, 15501 N. Dial Boulevard, Scottsdale AZ 85260, one of whose compositions includes aluminum chlorohydrate, sorbitol, propylene glycol, polydimethylsiloxane silicone oil, cyclomethicone, ethanol / SD alcohol 40, dimethicone copolyol, aluminum zirconium tetrachlorohydrex glycine, and water). The gel has less viscosity than conventional electrode gels and is held within a chamber having an aperture mesh at the end of the device where it contacts the patient's skin. The gel does not leak and can be dispensed with a simple screw-driven piston.

[0083] In another embodiment, the container itself is made of a conductive elastomer (e.g., dry carbon-filled silicone elastomer), and electrical contact with the patient is made through the elastomer itself, optionally through an additional outer coating of a conductive material. In some embodiments of the present invention, the conductive medium can be a balloon filled with a conductive gel or conductive powder, or the balloon can be largely composed of a deformable conductive elastomer. The balloon conforms to the skin surface and removes any air, thus enabling high impedance matching and conduction of a large electric field into the tissue.

[0084] Agar can be used as part of the conductive medium, but agar degrades over time, is not ideal for use on the skin, and is not preferred because it is difficult for the patient to wash. Instead of using agar as the conductive medium, the electrodes can be contacted in a conductive solution such as 1-10% NaCl, which also contacts the conductive interface to human tissue. Such an interface is useful because it allows current to flow from the electrode into the tissue and supports the conductive medium, and the device can be completely sealed. Thus, the interface is a material that is interposed between the conductive medium and the patient's skin, allows the conductive medium (e.g., saline) to slowly leak through the interface, and allows current to flow through the skin. A plurality of interfaces (351 in FIG. 1) are disclosed as follows.

[0085] One interface includes a hydrophilic conductive material such as Tecophlic by The Lubrizol Corporation, 29400 Lakeland Boulevard, Wickliffe, Ohio 44092. This material absorbs water up to 10-100% by weight, making it extremely conductive while allowing only a minimal amount of fluid flow.

[0086] Another material that can be used as an interface is a hydrogel, such as that used in 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 can be a low-allergenic and bacteriostatic electrode gel, such as SIGNAGEL Electrode Gel by Parker Laboratories, Inc., 286 Eldridge Rd., Fairfield NJ 07004. Another example is the KM10T hydrogel by Katecho Inc., 4020 Gannett Ave., Des Moines IA 50321.

[0087] A third type of interface can be made from a very thin material with a high dielectric constant, such as the material used to fabricate a capacitor. For example, Mylar can be fabricated with a submicron thickness and has a dielectric constant of about 3. Thus, at stimulation frequencies above a few kilohertz, Mylar has an impedance equivalent to that of the skin itself, so signals can be capacitively coupled through it. Thus, it isolates the electrode and the conductive solution within it from the tissue, but current can pass through.

[0088] The stimulator 340 in FIG. 1 shows two parallel and equivalent electrodes, and current passes through these two electrodes in opposite directions. Thus, current flows from one electrode, through the tissue, back through the other electrode, and completes the circuit within the conductive medium of the electrodes separated from each other. The advantage of using two equivalent electrodes in this configuration is that this design increases the magnitude of the electric field gradient between the electrodes, which is essential for exciting long and straight axons, such as the vagus nerve in the neck and other deep peripheral nerves.

[0089] A preferred embodiment of the stimulator is shown in FIG. 3A. A cross-sectional view of the stimulator along its long axis is shown in FIG. 3B. As shown, the stimulator (30) comprises two heads (31) and a body (32) joining the heads. Each head (31) includes a stimulating electrode. The body (32) of the stimulator includes electronic components and a battery (not shown) used to generate a signal for driving the electrodes, which are located on the back side of the insulating plate (33) shown in FIG. 3B. However, in other embodiments of the present invention, the electronic components for generating the signal applied to the electrodes may be separated but can be connected to the electrode heads (31) using wires. Further, other embodiments of the present invention may include a single such head, or more than two heads.

[0090] The heads (31) of the stimulator are applied to the surface of the patient's body, during which the stimulator can be held in place by a strap or frame (not shown), or the stimulator can be held against the patient's body by hand. In either case, the level of the stimulating power can be adjusted by a wheel (34) that also serves as an on / off switch. When power is supplied to the stimulator, the illumination (35) lights up. An optional cap may be provided to cover each of the heads (31) of the stimulator, to protect the device when not in use, to prevent accidental stimulation, and to prevent the materials inside the head from leaking or drying out. Thus, in this embodiment of the present invention, the mechanical and electronic components (impulse generator, control device, and power source) of the stimulator are compact, portable, and easy to operate.

[0091] The configurations of different embodiments of the stimulator head are shown in more detail in FIG. 4. Referring here to the exploded view shown in FIG. 4A, the electrode head is assembled from a snap-on cap (41) that serves as a tumbler for a dielectric or conductive film (42), a disk (43) without a window or alternatively a disk (43') with a window, a head cup (44), and an electrode (45) that is also a screw. Two embodiments of the disk (43) are shown. The preferred embodiment (43) is a solid, usually uniformly conductive disk (e.g., a metal such as stainless steel), and in some embodiments, it may be flexible. The material of the conductive interface can generally be any biocompatible conductive material that remains solid at body temperature and does not chemically react with water or conductive fluids, such as stainless steel, germanium, titanium, etc. An alternative embodiment of the disk (43') is also shown, which is a non-conductive (e.g., plastic) aperture screen that allows current to pass through its opening. The electrodes (45, also 340 in FIG. 1) found in each stimulator head have a screw shape with a flat tip. Pointing the tip makes the electrode more of a point source, and thus the equations regarding the potential described above may have solutions that more closely correspond to the far-field approximation. Rounding the electrode surface or shaping the electrode differently will similarly affect the boundary conditions. The assembly of the completed stimulator head is shown in FIG. 4B, and also shows how the head is attached to the body (47) of the stimulator.

[0092] The membrane (42) typically serves as an interface, shown as 351 in FIG. 1. For example, the membrane (42) can be made of a dielectric (non-conductive) material such as a thin sheet of Mylar (biaxially oriented polyethylene terephthalate, also known as BoPET). In other embodiments, the membrane can be made of a conductive material, such as a sheet of Tecophlic material by Lubrizol Corporation, 29400 Lakeland Boulevard, Wickliffe, Ohio 44092. In one embodiment shown in FIG. 4A, the opening of the alternative disk (43’) can be opened or plugged with a conductive material, such as KM10T hydrogel by Katecho Inc., 4020 Gannett Ave., Des Moines IA 50321. When the opening is plugged in such a manner and the membrane (42) is made of a conductive material, the membrane is optional and the plug serves as the interface 351 shown in FIG. 1.

[0093] The head cup (44) is filled with a conductive material (350 in FIG. 1), such as SIGNAGEL Electrode Gel by Parker Laboratories, Inc., 286 Eldridge Rd., Fairfield NJ 07004. The snap-on cap (41) of the stimulator, the opening screen disk (43’), the head cup (44), and the body are made of a non-conductive material such as acrylonitrile butadiene styrene. The depth of the head cup from its top surface to the electrode can be from 1 to 6 centimeters. The head cup can have a curvature different from that shown in FIG. 4, or can be tubular or conical, or can have some other inner geometry that affects the Neumann boundary conditions.

[0094] An alternative embodiment of the stimulator head shown in FIG. 4C also includes a snap-on cap (41), a membrane (42) made of a dielectric or conductive material, a head cup (44), and an electrode (45) that is also a screw. This alternative embodiment differs from the embodiments shown in FIGS. 4A and 4B with respect to the mechanical support provided to the membrane (42). While the disc (43) or (43’) provided mechanical support to the membrane in other embodiments, in the alternative embodiment, a reinforcing ring (40) is provided to the membrane. The reinforcing ring is rested on a non-conductive strut (49) disposed within the head cup (44), and a non-conductive strut ring (48) is disposed within a notch of the strut (49) to hold the strut in place. The advantage of the alternative embodiment is that, without the disc (43) or (43’), particularly when the membrane is made of a conductive material, the flow of current through the membrane (42) cannot be overly restricted. Further, while the strut and strut ring are made of non-conductive material in this alternative embodiment, the design can be adapted to position additional electrodes or other conductive elements within the head cup for more specialized configurations of the stimulator head, and including this can affect the electric field generated by the device. The completed alternative stimulator head assembly is shown in FIG. 4D, although its attachment to the body of the stimulator is not shown. In fact, leads can be inserted under the head of the electrode (45), and many other methods of attaching the electrode to the signal generating electronics of the stimulator are known in the art.

[0095] When the membrane (42) is made of a conductive material and the disk (43) of FIG. 4A is made of a solid conductive material such as stainless steel, the membrane is optional and the disk serves as the interface 351 shown in FIG. 1. Thus, embodiments without a membrane are shown in FIGS. 4E and 4F. FIG. 4E, which shows this version of the device, includes a solid (but in some embodiments, optionally flexible) conductive disk (43) that cannot absorb fluid, a non-conductive stimulator head (44) in or on which the disk is disposed, and an electrode (45) that is also a screw. As is apparent in FIG. 4F, these items are assembled to form a sealed stimulator head that is attached to the body (47) of the stimulator. The disk (43) can be screwed into the stimulator head (44), attached to the head with an adhesive, or attached by other methods known in the art. The chamber of the stimulator head cup is filled with a conductive gel, fluid, or paste, and the disk (43) and electrode (45) are tightly sealed against the stimulator head cup (44), so that the conductive material within the stimulator head cannot leak out.

[0096] In a preferred embodiment of the present invention, the interface (351 in FIG. 1 or 42 in FIG. 4) is made of a very thin material having a high dielectric constant, such as the material used to fabricate the capacitor. For example, this interface can be Mylar having a submicron thickness (preferably in the range of 0.5 to 1.5 microns) and having a dielectric constant of about 3. Since one side of the Mylar is smooth and the other side is microscopically rough, the present invention aims at the following two different configurations. That is, one of the configurations is that the smooth side is oriented towards the patient's skin and the other is that the rough side is oriented in the same way. Thus, at stimulation Fourier frequencies above a few kilohertz, the dielectric interface has an impedance equivalent to that of the skin and capacitively couples the signal through itself. Thus, the dielectric interface isolates the electrodes of the stimulator from the tissue, yet the current can still pass through. In a preferred embodiment of the present invention, non-invasive electrical stimulation of the nerves is essentially achieved substantially capacitively, reducing the amount of ohmic stimulation and thereby reducing the sensation felt by the patient at the tissue surface. This is because, for example, at least 30%, preferably at least 50% of the energy used to stimulate the nerves is due to capacitive coupling through the stimulator interface rather than ohmic coupling. In other words, a substantial portion (e.g., 50%) of the voltage drop is across the dielectric interface while the remaining portion is through the tissue.

[0097] In certain exemplary embodiments, the interface and / or the mechanical support thereunder also provide a substantial or complete seal of the interior space of the device. This prevents any leakage of conductive materials, such as gels, from the interior space of the device and also prevents any fluid ingress into the device. Additionally, this feature allows the user to easily clean the surface of the dielectric material (e.g., with isopropyl alcohol or a similar disinfectant), avoiding potential contamination during subsequent use of the device. One such material is a thin sheet-like Mylar supported by a stainless steel disc as described above.

[0098] The selection of a material for the dielectric constant involves at least the following two important variables. That is, (1) the thickness of the interface, and (2) the dielectric constant of the material. The thinner the interface and / or the higher the dielectric constant of the material, the lower the voltage drop across the entire dielectric interface (thus, the lower the required driving voltage). For example, for Mylar, the thickness can be about 0.5 to 5 microns (preferably about 1 micron), and the dielectric constant can be about 3. In the case of a piezoelectric material such as barium titanate or PZT (lead zirconate titanate), since the dielectric constant exceeds 1000, the thickness can be about 100 to 400 microns (preferably about 200 microns, or 0.2 mm).

[0099] In another embodiment, the interface includes a fluid-permeable material that allows current to pass through the permeable portion of the material. In this embodiment, the conductive medium (such as a gel) is preferably located between the electrode(s) and the permeable interface. The conductive medium provides a conductive path for electrons to pass from the permeable interface to the outer surface of the interface and the patient's skin.

[0100] One of the novel features of the disclosed non-invasive capacitive stimulator (hereinafter more generally referred to as a capacitive electrode) results from its use of a low voltage (generally less than 100 volts) power source, which is made possible by the use of suitable stimulation waveforms such as the waveforms disclosed herein (Figures 2B and 2C). In addition, the capacitive electrode allows for the use of an interface that provides a more complete hermetic seal of the internal space of the device. The capacitive electrode can be used by applying a small amount of conductive material (e.g., a conductive gel as described above) to its outer surface. In some embodiments, the capacitive electrode can also be used by contacting dry skin, thereby avoiding the inconvenience of applying an electrode gel, paste, or other electrolyte material to the patient's skin and also avoiding problems associated with the drying of electrode pastes and gels. Such dry electrodes are particularly suitable for use by patients who develop dermatitis after the electrode gel has been placed in contact with the skin. [Ralph J. COSKEY. Contact dermatitis caused by ECG electrode jelly. Arch Dermatol 113 (1977): 839-840]. The capacitive electrode can also be used to contact wet skin (e.g., with tap water or more conventional electrolyte materials) in order to make the contact (here, the permittivity) between the electrode and the skin more uniform. [A L ALEXELONESCU, G Barbero, F C M Freire, and R Merletti. Effect of composition on the dielectric properties of hydrogels for biomedical applications. Physiol. Meas. 31 (2010) S169-S182].

[0101] As described below, capacitive biomedical electrodes are known in the art, but when used to non-invasively stimulate nerves, high voltage power supplies are currently used to effect the stimulation. Otherwise, the prior uses of capacitive biomedical electrodes have been limited to invasive implantable applications, non-invasive applications including signal monitoring or recording but not tissue stimulation, non-invasive applications including some stimulation other than nerves (e.g., tumors), or use as a dispersive electrode in electro-surgery.

[0102] Evidence of a need that has remained unresolved for many years, and evidence that others have failed to solve the problems solved by the present invention (non-invasive capacitive stimulation of nerves at low voltage), was provided by KELLER and Kuhn. They reexamined the previous high-voltage capacitive stimulation electrodes of GEDDES et al. and stated that "Capacitive stimulation would be a preferred way to activate muscle nerves and fibers if the inherent danger of high-voltage breakdown of the dielectric material could be eliminated. The goal of future research could be the development of improved ultrathin dielectric foils so that the high stimulation voltage can be reduced." [L.A. GEDDES, M. Hinds, and K.S. Foster. Stimulation with capacitor electrodes. Medical and Biological Engineering and Computing 25 (1987): 359-360, Thierry KELLER and Andreas Kuhn. Electrodes for transcutaneous (surface) electrical stimulation. Journal of Automatic Control, University of Belgrade 18 (2, 2008): 35-45, on page 39]. In the United States, it should be understood that according to the 2005 US Electrical Code, high voltage is any voltage exceeding 600V. US Patent No. US3077884 for the name Electro-physiotherapy apparatus to BARTROW et al., and US Patent No. US4144893 for the name Neuromuscular therapy device to HICKEY also describe high-voltage capacitive electrodes. US Patent No. US7904180 for the name Capacitive medical electrode to JUOLA et al. describes capacitive electrodes, including transcutaneous nerve stimulation as one intended use, but the patent does not describe the stimulation voltage or stimulation waveform and frequency used for transcutaneous stimulation.U.S. Patent No. US7715921, titled Electrodes for applying an electric field in-vivo over an extended period of time with respect to PALTI, and U.S. Patent No. US7805201, titled Treating a tumor or the like with an electric field with respect to PALTI, also describe capacitive stimulating electrodes, but they are intended for the treatment of tumors and do not disclose the use including nerves, nor do they teach a stimulation frequency in the range of 50 kHz to about 500 kHz.

[0103] Rather than developing an ultra-thin dielectric foil, the present invention uses a different method to lower the stimulation voltage, i.e., to use a suitable stimulation waveform such as the waveforms disclosed herein (Figures 2B and 2C). That waveform has a significant Fourier component at a higher frequency than the waveforms used for transcutaneous nerve stimulation as currently practiced. Thus, those skilled in the art did not combine the elements recited in the claims because transcutaneous nerve stimulation is performed with waveforms having a significant Fourier component only at lower frequencies and non-invasive capacitive nerve stimulation is performed at higher voltages. In fact, the combined elements not only perform the functions that each element performs separately. The dielectric material can be placed in contact with the skin alone for pacemaker-free or dry stimulation and has a current density that is more uniform than the current density associated with ohmic stimulation, but the stimulation voltage is high [L.A. Geddes, M. Hinds, and K.S. Foster. Stimulation with capacitor electrodes. Medical and Biological Engineering and Computing 25 (1987): 359-360, Yongmin KIM, H. Gunter Zieber, and Frank A. Yang. Uniformity of current density under stimulating electrodes. Critical Reviews in Biomedical Engineering 17 (1990, 6): 585-619]. With regard to the waveform element, a waveform having a significant Fourier component at a higher frequency than the waveforms currently used for transcutaneous nerve stimulation, as disclosed herein for both non-capacitive and capacitive electrodes, can be used to selectively stimulate deep nerves and avoid stimulating other nerves. However, it is a combination of two elements (the dielectric interface and the waveform) that enables capacitive stimulation of nerves without using the high stimulation voltages as currently practiced.

[0104] The use of high dielectric constant materials to coat electrodes for biocompatible applications was first disclosed in 1940 by PATZOLD et al. for diathermy applications [U.S. Patent No. US2220269 for PATZOLD et al. titled Electrode means]. In the 1960s and early 1970s, the fact that other (non-capacitive, ohmic) electrodes used invasively as prosthetic implants exhibit undesirable electrochemical polarization motivated the disclosure of capacitive electrodes. When the electrodes are made of noble metals, polarization wastes the stimulation energy, which becomes a problem when the electrodes are used as battery-powered implants (e.g., cardiac pacemakers). When the electrodes are made of non-noble metals, an electrolytic corrosion reaction also occurs at the surface of the electrodes, so the electrodes can be destroyed and potentially toxic substances can accumulate in the patient's body. Furthermore, in the case of polarizable electrodes, the nature of the interaction between the electrode and the electrolyte is such that undesirable electronic non-linearity occurs. The use of non-polarizable Ag / AgCl electrodes for invasive stimulation is not a solution to these problems due to the toxicity of silver [Wilson GREATBATCH, Bernard Piersma, Frederick D. Shannon and Stephen W. Calhoun, Jr. Polarization phenomena relating to physiological electrodes. Annals New York Academy of Science 167(1969,2):722-44].

[0105] Considering the above considerations, multiple researchers have described capacitive electrodes where the implantation of the capacitive electrode does not generate toxic products at the location where it contacts the body fluid. Such toxic electrolytic products are avoided in capacitive electrodes because the metal of the electrode is surrounded by insulating the dielectric material. MAURO has described a capacitive electrode where the insulated wire is surrounded by saline, such that the electrode communicates directly with the electrolyte contacting the nerve or tissue. The communication of the electrolyte is provided by plastic tubes or holes in a single conduit for the fluid. In 1971, SCHALDACH described an implantable cardiac pacing electrode where a thin dielectric layer of tantalum oxide covers the surface of the metal electrode tip. In 1973 and 1974, GUYTON and Hambrecht considered using other dielectric materials to coat implantable stimulating electrodes, including barium titanate and related ceramic dielectrics, Teflon®, parylene and Mylar, and organic dielectric materials such as parylene C [Alexander MAURO.Capacity electrode for chronic stimulation.Science 132(1960):356, Max SCHALDACH.New pacemaker electodes.Transactionsactions of the American Society for Artificial Internal Organs 17(1971):29-35, David L.GUYTON and F.Terry Hambrecht.Capacitor electrode stimulates nerve or muscle without oxidation-reduction reaction.Science 181(1973,4094):74-76, David L.GUYTON and F.Terry Hambrecht.Theory and design of capacitor electrodes for chronic stimulation.Medical and Biological Engineering 12(1974,5):613-620].However, the use of such implantable capacitive electrodes was limited because they provided little improvement over some non-capacitive implantable electrodes with respect to corrosion and generation of poisoning products. This is because for noble metal electrodes, particularly those made of platinum and platinum-iridium alloys, the Faraday reaction is limited to a single layer on the surface, and thus these electrodes are often described as pseudocapacitive despite the fact that electron transfer occurs across the entire noble metal electrode interface [Stuart F. Cogan. Neural Stimulation and Recording Electrodes. Annu. Rev. Biomed. Eng. 10 (2008): 275-309].

[0106] During the first half of the 1970s, while implantable capacitive electrodes were being developed for stimulation, non-invasive capacitive electrodes for monitoring or recording were also developed to avoid the use of electrode paste or jelly. Such paste-free electrodes are desired for situations involving long-term monitoring or recording of physiological signals from ambulatory patients, critical care patients, pilots, or astronauts. LOPEZ and Richardson (1969) described capacitive electrodes for recording ECG. POTTER (1970) described capacitive electrodes with a pyren wax dielectric for recording EMG. POTTER and Portnoy (1972) described capacitive electrodes with an integrated impedance transformer. MATSUO et al. (1973) described capacitive electrodes for measuring EEG. Patents were issued to EVERETT et al., KAUFMAN, and FLETCHER et al. for capacitive electrodes or systems.[Alfredo LOPEZ, Jr. and Philip C. Richardson. Capacitive electrocardiographic and bioelectric electrodes. IEEE Trans Biomed Eng. 16(1969,1):99, Allan POTTER. Capacitive type of biomedical electrode. IEEE Trans Biomed Eng. 17(1970,4):350 - 351, U.S. Patent No. US3568662 for EVERETT et al. titled Method and apparatus for sensing bioelectric potentials, R.M. DAVID and W.M. Portnoy. Insulated electrocardiogram electrodes. Med Biol Eng. 10(1972,6):742 - 51, U.S. Patent No. US3744482 for KAUFMAN et al. titled Dry contact electrode with amplifier for physiological signals, MATSUOT, Iinuma K, Esashi M. A barium - titanate - ceramics capacitive - type EEG electrode. IEEE Trans Biomed Eng 20(1973,4):299 - 300, U.S. Patent No. US3882846 for FLETCHER et al. titled Insulated electrocardiographic electrodes].

[0107] Non-invasive capacitive electrodes can be used as dry paste-less electrodes, but it should be understood that they can also be used to contact the skin moistened (e.g., with tap water or more conventional electrolyte materials) in order to make the contact between the electrode and the skin (here, the dielectric constant) more uniform. In fact, sweat from the skin provides some moisture at the boundary of the electrode-skin interface. Furthermore, not all non-invasive paste-less electrodes are capacitive electrodes [BERGEY, George E., Squires, Russell D., and Sipple, William C. Electrocardiogram recording with pasteless electrodes. IEEE Trans Biomed Eng. 18(1971,3):206-211, GEDDES LA, Valentinuzzi ME. Temporal changes in electrode impedance while recording the electrocardiogram with “dry” electrodes. Ann Biomed Eng. 1(1973,3):356-67, DELUCA CJ, Le Fever RS, Stulen FB. Pasteless electrode for clinical use. Med Biol Eng Comput. 17(1979,3):387-90, GONDRAN C, Siebert E, Fabry P, Novakov E, Gumery PY. Non-polarisable dry electrode based on NASICON ceramic. Med Biol Eng Comput. 33(1995,3 Spec No):452-457, Yu Mike CHI, Tzyy-Ping Jung, and Gert Cauwenberghs. Dry-Contact and noncontact biopotential electrodes: methodological review.IEEE Reviews in Biomedical Engineering 3(2010):106-119, Benjamin Blankertz, Michael Tangermann, Carmen Vidaurre, Siamac Fazli, Claudia Sannelli, Stefan Haufe, Cecilia Maeder, Lenny Ramsey, Irene Sturm, Gabriel Curio and Klaus-Robert Muller. The Berlin brain-computer interface: non-medical uses of BCI technology. Front Neurosci. 4(2010):198. doi:10.3389 / fnins.2010.00198, pp1-17]. Furthermore, it should be noted that some dry electrodes, which are said to be non-invasive, are actually minimally invasive because they have tiny tips that pierce the skin [N.S. Dias, J.P. Carmo, A. Ferreira da Silva, P.M. Mendes, J.H. Correia. New dry electrodes based on iridium oxide (IrO) for non-invasive biopotential recordings and stimulation. Sensors and Actuators A 164(2010):28-34, U.S. Patent No. US4458696 for the name T.E.N.S. Electrode for Larimore, U.S. Patent No. US5003978 for the name Non-polarizable dry biomedical electrode for Dunseath Jr.].

[0108] As the disadvantages of the non-invasive capacitive electrodes described above, it can be mentioned that they are easily affected by motion artifacts, have a high inherent noise level, and are easily affected by changes due to the presence of sweat. In fact, they tend to outweigh the advantages of the electrodes being paste-free or in a dry state and exhibiting a uniform current density. However, in recent years, such electrodes have been improved for the purpose of being used without contacting the skin, and the electrodes can record an individual's ECG or EEG when the electrodes are placed in clothes, headbands, chest bands, chairs, beds, etc. [Yu Mike CHI, Tzyy-Ping Jung, and Gert Cauwenberghs. Dry-Contact and noncontact biopotential electrodes: methodological review. IEEE Reviews in Biomedical Engineering 3 (2010): 106-119, Jaime M. LEE, Frederick Pearce, Andrew D. Hibbs, Robert Matthews, and Craig Morrissette. Evaluation of a Capacitively-Coupled, Non-Contact (through Clothing) Electrode or ECG Monitoring and Life Signs Detection for the Objective Force Warfighter. Paper presented at the RTO HFM Symposium on “Combat Casualty Care in Ground Based Tactical Situations: Trauma Technology and Emergency Medical Procedures”, held in St. Pete Beach, USA, 16-18 August 2004, and published in RTO-MP-HFM-109: pp 25-1 to 25-10, HEUER S., Martinez, D.R., Fuhrhop, S., Ottenbacher, J.Motion artefact correction for capacitive ECG measurement. Biomedical Circuits and Systems Conference (BioCAS) Proceedings 26 - 28 Nov. 2009, pp113 - 116, Enrique SPINELLI and Marcelo Haberman. Insulating electrodes: a review on biopotential front ends for dielectric skin - electrode interfaces. Physiol. Meas. 31(2010) S183 - S198, A SEARLE and L Kirkup. A direct comparison of wet, dry and insulating bioelectric recording electrodes. Physiol. Meas. 21(2000): 271 - 283, US Patent No. US7173437 for the name Garment incorporating embedded physiological sensors against HERVIEUX et al., US Patent No. US7245956 for the name Unobtrusive measurement system for bioelectric signals against MATTHEWS et al. Such disclosures address the issues of motion artefact and noise. Regarding the contact of capacitive electrodes, the problem of sweating can be addressed by arranging channels with uneven surfaces on the skin - side surface of the dielectric material parallel to the electrode surface, arranging absorbent material around the electrode, and sucking sweat through the channels into the absorbent material.

[0109] Capacitive electrodes have also been used to stimulate tissues other than nerves. They are used as dispersive electrodes in electro-surgery [U.S. Patent No. US4304235, titled Electrosurgical electrode for KAUFMAN; U.S. Patent No. US4387714, titled Electrosurgical dispersive electrode for GEDDES et al.; U.S. Patent No. US4669468, titled Capacitively coupled indifferent electrode for CARTMELL et al.; Yongmin KIM, H. Gunter Zieber, and Frank A. Yang. Uniformity of current density under stimulating electrodes. Critical Reviews in Biomedical Engineering 17(1990,6)585 - 619]. Capacitive electrodes have also been used to invasively treat tumors by inserting a pair of insulated wires near the tumor [Eilon D. Kirson, Zoya Gurvich, Rosa Schneiderman, Erez Dekel, Aviran Itzhaki, Yoram Wasserman, Rachel Schatzberger, and Yoram Palti. Disruption of cancer cell replication by alternating electric fields. Cancer Research 64(2004):3288 - 3295]. Similarly, capacitive electrodes have also been used to non-invasively treat tumors [U.S. Patent No. US7715921, titled Electrodes for applying an electric field in-vivo over an extended period of time for PALTI; U.S. Patent No. US7805201, titled Treating a tumor or the like with an electric field for PALTI].However, none of these application examples involving stimulating tissues other than nerves, none of the other non-invasive recording application examples, nor any of the invasive application examples disclose a method or device demonstrating how capacitive electrodes are used to non-invasively stimulate nerves using a low voltage stimulator.

[0110] Another embodiment of the disclosed stimulator is shown in FIG. 5 and shows a device in which a conductive material is dispensed from the device onto the patient's skin. In this embodiment, the interface (351 in FIG. 1) is the conductive material itself. FIGS. 5A and 5B provide, respectively, a top view and a bottom view of the outer surface of the electrical stimulator 50. FIG. 5C provides a bottom view of the stimulator 50 after being cut along its long axis to reveal the interior of the stimulator.

[0111] FIGS. 5A and 5C show a mesh 51 having an opening that allows a conductive gel to pass from the interior of the stimulator to the surface of the patient's skin at the nerve or tissue stimulation site. Thus, the mesh having the opening 51 is part of the stimulator applied to the patient's skin through which the conductive material can be dispensed. It should be understood that in any given stimulator, the distance between the two mesh openings 51 in FIG. 5A is constant, but different stimulators can be constructed with different inter-mesh distances to accommodate the anatomical structure and physiological function of individual patients. Alternatively, the inter-mesh distance can be made variable, such as that of the eyepiece of binoculars. A cover cap (not shown) is also provided to fit snugly over the top of the stimulator housing and the mesh opening 51 to prevent leakage or drying of the conductive medium in the housing when the device is not in use.

[0112] Figures 5B and 5C show the bottom of the self - contained stimulator 50. The on / off switch 52 is attached through port 54, and the power level controller 53 is attached through another port 54. The switch is connected to the battery power supply (320 in FIG. 1), and the power level controller is attached to the control unit of the device (330 in FIG. 1). The battery power supply, the electrode level controller, and the impulse generator (310 in FIG. 1) are located in the rear compartment 55 of the housing of the stimulator 50 (not shown).

[0113] Individual wires (not shown) connect the impulse generator (310 in FIG. 1) to the electrodes 56 of the stimulator. Here, two electrodes 56 are shown as elliptical metal discs located between the head compartment 57 and the rear compartment 55 of the stimulator 50. The partition 58 separates each of the two head compartments 57 from each other and from one rear compartment 55. Each partition 58 also holds its corresponding electrode in place. However, each electrode 56 can be removed to add conductive gel (350 in FIG. 1) to each head compartment 57. Each partition 58 can also slide towards the head of the device to dispense the conductive gel through the mesh opening 51. Thus, the position of each partition 58 determines the distance 59 between its electrode 56 and the mesh opening 51 and is variable to obtain an optimally uniform current density through the mesh opening 51. The outside of the housing of the stimulator 50, as well as each head compartment 57 of the housing and its partition 58, are made of an electrically insulating material such as acrylonitrile - butadiene - styrene, so that the two head compartments are electrically insulated from each other.

[0114] The embodiment of FIG. 5 is shown as a non - capacitive stimulator, but it should be understood that it can be converted to a capacitive stimulator by replacing the mesh opening 51 with a dielectric material such as sheet - like Mylar or by covering the mesh opening 51 with a sheet - like such dielectric material.

[0115] In a preferred embodiment, the electrode is made of a metal such as stainless steel. However, in other embodiments, the electrode can have many other sizes and shapes, and the electrode can be made of other materials [Thierry KELLER and Andreas Kuhn. Electrodes for transcutaneous (surface) electrical stimulation. Journal of Automatic Control, University of Belgrade, 18(2,2008):35-45, G.M. LYONS, G.E. Leane, M. Clarke-Moloney, J.V. O’Brien, P.A. Grace. An investigation of the effect of electrode size and electrode location on comfort during stimulation of the gastrocnemius muscle. Medical Engineering&Physics 26(2004)873-878, Bonnie J. FORRESTER and Jerrold S. Petrofsky. Effect of Electrode Size, Shape, and Placement During Electrical Stimulation. The Journal of Applied Research 4,(2,2004):346-354, Gad ALON, Gideon Kantor and Henry S. Ho. Effects of Electrode Size on Basic Excitatory Responses and on Selected Stimulus Parameters. Journal of Orthopaedic and Sports Physical Therapy.20(1,1994):29-35].

[0116] For example, there can be two or more electrodes, the electrodes can comprise a plurality of concentric rings, the electrodes can be disc-shaped, or can have a non-planar geometry. The electrodes can be made of other metals or resistive materials such as silicon rubber impregnated with carbon having different conductive properties [Stuart F. COGAN. Neural Stimulation and Recording Electrodes. Annu. Rev. Biomed. Eng. 2008. 10:275-309, Michael F. NOLAN. Conductive differences in electrodes used with transcutaneous electrical nerve stimulation devices. Physical Therapy 71(1991):746-751].

[0117] The electrodes can consist of rows of conductive material, but the embodiments shown in FIGS. 3-5 avoid the complexity and expense of row or grid electrodes [Ana POPOVIC-BIJELIC, Goran Bijelic, Nikola Jorgovanovic, Dubravka Bojanic, Mirjana B. Popovic, and Dejan B. Popovic. Multi-Field Surface Electrode for Selective Electrical Stimulation. Artificial Organs 29(6, 2005):448-452, Dejan B. POPOVIC and Mirjana B. Popovic. Automatic determination of the optimal shape of a surface electrode: Selective stimulation. Journal of Neuroscience Methods 178(2009)174-181, Thierry KELLER, Marc Lawrence, Andreas Kuhn, and Manfred Morari. New Multi-Channel Transcutaneous Electrical Stimulation Technology for Rehabilitation. Proceedings of the 28th IEEE EMBS Annual International Conference New York City, USA, Aug 30-Sept 3, 2006(WeC14.5):194-197]. This is because the designs shown in FIGS. 3-5 provide a uniform surface current density, which is otherwise a potential advantage of electrode arrays and a feature not common to most electrode designs [Kenneth R. BRENNEN. The Characterization of Transcutaneous Stimulating Electrodes. IEEE Transactions on Biomedical Engineering BME-23(4, 1976):337-340, Andrei PATRICIU, Ken Yoshida, Johannes J.Struijk, Tim P., De Monte, Michael L. G., Joy, Hans, & Stodkilde-Jorgensen, Hans. Current Density Imaging and Electrically Induced Skin Burns Under Surface Electrodes. IEEE Transactions on Biomedical Engineering, 52(12), 2005, 2024 - 2031. R. H. Geuze. Two methods for homogeneous field defibrillation and stimulation. Med. and Biol. Eng. and Comput., 21, 1983, 518 - 520. J. Petrofsky, E. Schwab, M. Cuneo, J. George, J. Kim, A. Almalty, D. Lawson, E. Johnson, & W. Remigo. Current distribution under electrodes in relation to stimulation current and skin blood flow: are modern electrodes really providing the current distribution during stimulation we believe they are? Journal of Medical Engineering and Technology, 30(6), 2006, 368 - 381. Russell G. Maus, Erin M. McDonald, & R. Mark Wightman. Imaging of Nonuniform Current Density at Microelectrodes by Electrogenerated Chemiluminescence. Anal. Chem.71(1999):4944 - 4950]. In fact, patients found that the designs shown in FIGS. 3 - 5 were less painful in a direct comparison with commercially available grid - pattern electrodes [UltraStim grid - pattern electrode, Axelggard Manufacturing Company, 520 Industrial Way, Fallbrook CA, 2011]. Embodiments of electrodes using capacitive coupling are particularly suitable for generating a uniform stimulating current [Yongmin KIM, H. Gunter Zieber, and Frank A. Yang. Uniformity of current density under stimulating electrodes. Critical Reviews in Biomedical Engineering 17(1990,6):585 - 619].

[0118] The stimulator designs shown in FIGS. 3-5 position the electrodes away from the surface of the skin within a chamber, and a conductive material is disposed within the chamber between the skin and the electrodes. Such chamber designs were used prior to the availability of flexible, flat, disposable electrodes [U.S. Patent No. US3659614 to Jankelson, titled Adjustable headband carrying electrodes for electrically stimulating the facial and mandibular nerves; U.S. Patent No. US3590810 to Kopecky, titled Biomedical body electode; U.S. Patent No. US3279468 to Le Vine, titled Electrotherapeutic facial mask apparatus; U.S. Patent No. US6757556 to Gopinathan et al., titled Electrode sensor; U.S. Patent No. US4383529 to Webster, titled Iontophoretic electrode device, method and gel insert; U.S. Patent No. US4220159 to Francis et al., titled Electrode; U.S. Patents Nos. US3862633, US4182346, and US3973557 to Allison et al., titled Electrode; U.S. Patent No. US4215696 to Bremer et al., titled Biomedical electrode with pressurized skin contact; and U.S. Patent No. US4166457 to Jacobsen et al., titled Fluid self-sealing bioelectrode]. The stimulator designs shown in FIGS. 3-5 are also self-contained units that house the electrodes, signal electronics, and a power source. Portable stimulators are also known in the art, such as U.S. Patent No. US7171266 to Gruzdowich, titled Electro-acupuncture device with stimulation electrode assembly.One or more aspects of the present invention are configured such that two or more remote electrodes are disposed relative to the axis of a long, deep nerve, such that the stimulator forms an electric field and stimulates the nerve with a suitable stimulation waveform in response thereto, thereby producing a selective physiological response while avoiding substantial stimulation of nerves and tissues other than the target nerve, and in particular, avoiding stimulation of nerves that cause pain.

[0119] The remaining disclosure embodiments are directed to methods of using the disclosed electrical stimulation devices to treat patients. These applications include stimulating the patient in and around the patient's neck. However, it should be recognized that the systems and methods of the present invention can be equally suitably applied to other nerves of the body, including but not limited to the parasympathetic, sympathetic, and spinal or cranial nerves. By way of example, the disclosed device can be used to treat certain medical conditions by substituting the stimulator disclosed in the following patent applications with the device disclosed herein.

[0120] The co-pending U.S. Patent Application No. 12 / 964,050, assigned to the assignee of the present invention and having the name Toroidal Magnetic Stimulation Devices and Methods of Therapy, discloses methods for using a device to treat diseases such as postoperative intestinal obstruction, TNF-alpha-related dysfunction in Alzheimer's disease, postoperative cognitive dysfunction, rheumatoid arthritis, bronchoconstriction, urinary incontinence and / or overactive bladder, and Oddi sphincter dysfunction.

[0121] Another co-pending U.S. patent application No. 13 / 005,005, assigned to the assignee of the present invention and having the title "Non-invasive Treatment of Neurodegenerative Diseases", discloses methods and devices for treating neurodegenerative diseases, including Alzheimer's disease and its prodromal mild cognitive impairment (MCI), Parkinson's disease (including Parkinson's disease dementia), and multiple sclerosis, as well as postoperative cognitive dysfunction and postoperative delirium. These devices and methods can also be used to treat diseases not disclosed in such patent applications, such as allergic rhinitis, headache, particularly tension headache, cluster headache, sinus headache, and migraine [Alberto Proietti CECCHINI, Eliana Mea, Vincenzo Tullo, Marcella Curone, Angelo Franzini, Giovanni Broggi, Mario Savino, Gennaro Bussone, Massimo Leone. Vagus nerve stimulation in drug-resistant daily chronic migraine with depression: preliminary data. Neurol Sci (2009) 30 (Suppl 1): S101-S104].

[0122] Another co-pending U.S. patent application No. 13 / 024,727, assigned to the assignee of the present invention and having the title "Non-invasive methods and devices for inducing euphoria in a patient and their therapeutic application", discloses methods and devices for treating depression, premenstrual symptoms, behavioral disorders, and insomnia, as well as uses for performing anesthesia.

[0123] Another co-pending U.S. patent application Ser. No. 13 / 109,250, assigned to the assignee of the present invention and entitled Electrical and magnetic stimulators used to treat migraine / sinus headache and comorbid disorders, disclosed methods and devices for treating headaches, including migraine and cluster headaches, and anxiety disorders.

[0124] Another co-pending U.S. patent application Ser. No. 13 / 109,250, assigned to the assignee of the present invention and entitled Electrical and magnetic stimulators used to treat migraine / sinus headache, rhinitis, sinusitis, rhinosinusitis, and comorbid disorders, disclosed methods for treating rhinitis, sinusitis, and rhinosinusitis.

[0125] Selected nerve fibers are stimulated in different embodiments of the disclosed method of using an electrical stimulation device, including stimulation of the vagus nerve at a location in the patient's neck. At that location, the vagus nerve is within the carotid sheath, near the carotid artery, and near the internal jugular vein. The carotid sheath is the lateral boundary of the retropharyngeal space on both sides of the neck and is located deep to the sternocleidomastoid muscle. Stimulation of the right vagus nerve can produce undesirable effects on the heart, so sometimes the left vagus nerve is selected for stimulation, but depending on the application, the right vagus nerve, or both the right and left vagus nerves, can be stimulated instead.

[0126] The three main structures within the carotid sheath are the common carotid artery, the internal jugular vein, and the vagus nerve. The carotid artery is in the middle of the internal jugular vein, and the vagus nerve is located posteriorly between the two blood vessels. Generally, the location of the patient's carotid sheath or internal jugular vein (and thus the location of the vagus nerve) is confirmed by any method known in the art, such as palpation or ultrasound imaging. When proceeding from the skin of the neck above the sternocleidomastoid muscle to the vagus nerve, the line can pass continuously through the sternocleidomastoid muscle, the carotid sheath, and the internal jugular vein, provided that the position on the skin does not approach either side of the external jugular vein. In the latter case, the line can pass continuously through only the sternocleidomastoid muscle and the carotid sheath before encountering the vagus nerve, and the internal jugular vein can be removed. Thus, a position on the neck adjacent to the external jugular vein can be favorable for non-invasive stimulation of the vagus nerve. The magnetic stimulator coil can be centered at a position such as at approximately the level of the 5th to 6th cervical vertebrae.

[0127] Figure 6 illustrates the use of the device shown in FIGS. 3 - 5 for stimulating the vagus nerve at that location in the neck. In this figure, the stimulator device 50 of FIG. 5 is shown as being applied to the target location on the patient's neck as described above. For reference, the location of the vertebrae is also shown. That is, the first cervical vertebra 71, the fifth cervical vertebra 75, the sixth cervical vertebra 76, and the seventh cervical vertebra 77.

[0128] FIG. 7 provides a more detailed view of the use of the electrical stimulator when positioned to stimulate the vagus nerve at the location of the neck shown in FIG. 6. As shown, the stimulator 50 of FIG. 5 makes indirect contact with the neck by electrically contacting through a conductive gel 29 (or other conductive material), which gel can be dispensed through the mesh openings (identified as 51 in FIG. 5) of the stimulator or applied as an electrode gel or paste. The layer of conductive gel 29 in FIG. 7 is shown connecting the device to the patient's skin, but it should be understood that the actual location of the gel layer(s) can generally be determined by the location of the mesh 51 shown in FIG. 5. Further, for other embodiments of the present invention, it should be understood that the conductive head of the device may not require the use of additional conductive material applied to the skin. The vagus nerve 60 is identified along with the carotid sheath 61, which is identified by the thick outlined line in FIG. 7. The carotid sheath surrounds not only the vagus nerve but also the internal jugular vein 62 and the common carotid artery 63. Features that can 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, the thyroid gland 67, the esophagus 68, the anterior scalene muscle 69, and the middle scalene muscle 70. The sixth cervical vertebra 76 is also shown in FIG. 7 by the bone structure indicated by the hatching marks.

[0129] If it is desirable to maintain a certain intensity of stimulation in the vicinity of the vagus nerve (or any other nerve or tissue being stimulated), the method can also be used to adjust the power of the stimulator to compensate for patient movement or other mechanisms that would otherwise cause variability in the intensity of the stimulation. In the case of vagus nerve stimulation, such variability can be due to the patient's breathing, which can include contraction of the geometry of the sternocleidomastoid muscle (identified as 65 in FIG. 7) located near the vagus nerve and related changes. Methods for compensating for movement and other confounding factors are disclosed by the applicant in co-pending U.S. patent application Ser. No. 12 / 859,568, entitled Non-invasive Treatment of Bronchial Constriction to SIMON, which is assigned to the assignee of the present invention and is incorporated herein by reference.

[0130] A method of treating a patient includes stimulating the vagus nerve as shown in FIGS. 6 and 7 using an electrical stimulation device disclosed herein. The position and angular orientation of the device are adjusted around the location until the patient notices the stimulation when current passes through the electrodes of the stimulator. The current applied is increased stepwise, initially at a level where the patient senses the stimulation. Then the power is increased but set at a level below that at which the patient first exhibits any discomfort. Straps, harnesses, or frames (not shown in FIGS. 6 or 7) are used to maintain the stimulator in place. The signal of the stimulator may have a frequency and other parameters that are selected to produce a treatment result in the patient. The stimulation parameters for each patient are adjusted on an individual basis. Typically, the amplitude of the stimulation signal is set at the maximum value that is comfortable for the patient, and then the other stimulation parameters are adjusted.

[0131] In other embodiments of the present invention, vagus nerve stimulation can be paired with a temporally varying sensory stimulus. The paired sensory stimulus can be bright light, sound, tactile stimulation, or electrical stimulation of the tongue to simulate smell / taste, and for example, pulsates at the same frequency as the electrical stimulation of the vagus nerve. The rationale for the paired sensory stimulus is the same as for the simultaneous paired stimulation of both the left and right vagus nerves, i.e., pairs of signals that interact with each other in the brain can result in the formation of longer and more coherent neural assemblies than the neural assemblies associated with the individual signals, thereby enhancing the therapeutic effect. For example, since the hypothalamus is well known to respond to the presence of bright light, a patient can be exposed to bright light that varies at the same stimulation frequency (or multiple thereof) as the vagus nerve in order to enhance the role of the hypothalamus in producing the desired therapeutic effect. Such paired stimuli do not rely on neural plasticity, in that sense being different from the reports of other paired stimuli [Navzer D.ENGINEER,Jonathan R.Riley,Jonathan D.Seale,Will A.Vrana,Jai A.Shetake,Sindhu P.Sudanagunta,Michael S.Borland and Michael P.Kilgard.Reversing pathological neural activity using targeted plasticity.Nature(2011):published online doi:10.1038 / nature09656].

[0132] Kit

[0133] The devices described herein can be packaged in the form of a kit. In one embodiment, the kit includes a hand-held battery-powered portable stimulator device useful for stimulating a nerve of a subject and instructions for using it. The kits of the present invention can include any of a nerve stimulator, a conductive gel or fluid, and instructions, either separately or in combination.

[0134] Each stimulator kit provides a fully operational stimulator and is suitable for storage or immediate use. The kit may optionally provide additional components, such as a conductive solution or gel, that are useful in the practice of the method, the training, and the treatment of the present embodiment.

[0135] An example of a kit includes a stimulator device and instructions regarding the use of the device. The instructions are generally recorded on a suitable recording medium. For example, the instructions can be printed on a substrate such as paper or plastic. Thus, the instructions can be present in the kit as an attached document, in the label of the kit's container, or in the components of the kit (i.e., the associated packaging material, or sub-packaging material). In other embodiments, the instructions exist as an electronic storage data file on a suitable computer-readable storage medium, such as a CD-ROM, a diskette, etc. The instructions can take any form, including complete instructions regarding the use of the device or a reference that teaches the user to use a further information source regarding the instructions, such as a website address having instructions posted on the World Wide Web.

[0136] The following exemplary instructions are provided for illustrative purposes and not for purposes of limitation.

[0137] Instructions

[0138] A stimulator device adapted for use on the vagus nerve can be non-invasively placed on the right side of the subject's neck by a healthcare provider, the subject, or a third-party administrator. In some embodiments, the device operates as follows. The healthcare provider, the subject, or the third-party administrator removes the protective cap from the two simulation surfaces located on the stimulator. When using the stimulator for the first time, it may also be necessary to remove the protective plastic cover or protective film from the stimulation surface.

[0139] The subject shall assume a sitting position with the head of the subject tilted to the upper left, thereby exposing the right side of the subject's neck. All gemstones in the head and neck regions of the subject shall be removed. The stimulator device shall be aligned with the following anatomical structures and positions of the subject. That is, in front of the sternocleidomastoid muscle, directly below the mandibular contour, and parallel to the trachea. Before actually placing the simulator on the subject, a small amount (about 1 cc) of a suitable electrode gel shall be placed on each of the stimulation surfaces.

[0140] Next, prepare to turn on the stimulator device. A healthcare provider, the subject, or a caregiver shall slowly rotate the thumb wheel towards the surface of the stimulator until a clicking sound is heard. When the stimulator is ready for use, i.e., operational, the LED illuminator turns green and the device emits an audible or beeping sound. A healthcare provider, the subject, or a caregiver shall position the stimulator on the right side of the subject's neck in the area described above. With the stimulator in place, the user shall slowly increase the stimulation intensity by rotating the thumb wheel stepwise towards the subject's neck until the subject reaches a maximum allowable level of comfort. The subject may experience a slight tremor of the muscle under the stimulation surface. If the muscle contraction is too strong or uncomfortable, the stimulation level can be reduced by adjusting the thumb wheel.

[0141] Due to anatomical differences between the subject and the positioning of the stimulator, it may be appropriate to adjust the stimulation intensity to the highest setting that can be comfortably tolerated by the subject. However, the treatment may still be effective at a level where the subject perceives a slight tremor of the subcutaneous muscle or at a level just before that. Once the correct intensity is set, the stimulator shall be held in place for the entire treatment period (in one embodiment, 90 seconds). Note that the stimulator can operate for up to 120 seconds after it is turned on to give the subject, the healthcare provider, or a third - party caregiver sufficient time to position the device and set the appropriate stimulation intensity.

[0142] If an unpleasant skin or muscle sensation persists to the extent that the subject cannot tolerate treatment for 90 seconds, follow the following procedures: (a) remove the stimulator from the subject's neck, (b) reduce the stimulation intensity by rotating the thumb wheel away from the stimulation surface, (c) reposition the stimulator on the subject's neck, and (d) if the stimulation still cannot be tolerated, turn off the stimulator and interrupt the treatment.

[0143] After the treatment is completed, the stimulator shall be turned off by rotating the thumb wheel until a clicking sound is heard. Any excess gel shall be removed from the stimulation surface with a soft, dry cloth. The protective cap shall be replaced, and the stimulator shall be stored in a clean and dry place for the next use.

[0144] In various embodiments, the total treatment period can be a fixed period, for example, 30 seconds, 40 seconds, 50 seconds, 60 seconds, 70 seconds, 80 seconds, 90 seconds, 100 seconds, 110 seconds, 120 seconds, or more than 120 seconds, or the total treatment period can be a variable period depending on various factors such as, for example, the patient's weight, the patient's medical condition (including those based on pulse, blood pressure, blood oxygen level, etc.), the type of disease being treated, or any other factor. The stimulator can operate over the total treatment period or over a period longer than the total treatment period.

[0145] Although the present invention has been described herein with respect to specific embodiments, it should be understood that these embodiments are merely illustrative of the principles and applications of the present invention. Therefore, it should be understood that numerous changes can be made to the exemplary embodiments and that other configurations can be devised without departing from the spirit and scope of the present invention as defined by the appended claims.

Claims

1. An apparatus for treating a patient's medical condition, comprising: a housing having an energy source and an electrode for contacting the outer surface of the patient's skin within the housing; a signal generator coupled to the energy source and the electrode, configured to generate an electrical impulse including a burst of pulses and transmit the electrical impulse through the outer skin surface to a target nerve; wherein each burst of the pulses includes a burst period and a constant period, the electrical impulse includes 2 to 20 pulses within each burst period, each of the pulses has a duration of 50 microseconds to 1000 microseconds, each constant period has zero pulses throughout the constant period such that the amplitude of the electrical impulse is zero throughout each constant period; the apparatus.

2. The apparatus according to claim 1, wherein each burst period has a duration of 800 microseconds to 2000 microseconds.

3. The apparatus according to claim 1, wherein each of the pulses has a duration of 100 microseconds to 400 microseconds.

4. The apparatus according to claim 3, wherein each burst period has a duration of 200 microseconds to 8000 microseconds.

5. The apparatus according to claim 1, wherein the burst period has a duration of 400 microseconds to 4000 microseconds.

6. The apparatus according to claim 1, wherein the energy source applies a voltage to the electrode such that an electric field is generated at or near the target nerve.

7. The apparatus according to claim 6, wherein the energy source varies the voltage such that the charge of the electric field generated during each burst period alternates between positive and negative and the magnitude of the electric field generated during each constant period becomes zero.

8. The apparatus according to claim 1, wherein each burst period has a frequency of 15 Hz to 50 Hz.

9. An apparatus for treating a patient's medical condition, comprising: a housing having an energy source and an electrode for contacting the outer surface of the patient's skin within the housing; a signal generator coupled to the energy source and the electrode, configured to generate an electrical impulse including a burst of pulses and transmit the electrical impulse through the outer skin surface to a target nerve; wherein Each burst of the pulses includes a burst period and a fixed period. In the pulses, the charges of the electric field emitted during each burst period alternate between positive and negative, and each fixed period has zero pulses throughout the fixed period so that the amplitude of the electrical impulse becomes zero throughout each fixed period. Each burst period includes 2 to 20 pulses. Device.

10. The device according to claim 9, wherein each burst period includes 4 to 40 pulses instead of 2 to 20 pulses.

11. The device according to claim 9, wherein each pulse has a duration of 50 microseconds to 1000 microseconds.

12. The device according to claim 9, wherein each of the pulses has a duration of 100 microseconds to 400 microseconds.

13. The device according to claim 9, wherein each burst period has a frequency of 15 Hz to 50 Hz.

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