US20080132964A1 - Selective nerve fiber stimulation for treating heart conditions - Google Patents

Selective nerve fiber stimulation for treating heart conditions Download PDF

Info

Publication number
US20080132964A1
US20080132964A1 US11/981,369 US98136907A US2008132964A1 US 20080132964 A1 US20080132964 A1 US 20080132964A1 US 98136907 A US98136907 A US 98136907A US 2008132964 A1 US2008132964 A1 US 2008132964A1
Authority
US
United States
Prior art keywords
current
subject
control unit
heart
heart rate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US11/981,369
Inventor
Ehud Cohen
Shai Ayal
Tamir Ben-David
Omry Ben-Ezra
Yossi Gross
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
BioControl Medical BCM Ltd
Medtronic Inc
Original Assignee
BioControl Medical Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/IL2002/000068 external-priority patent/WO2003018113A1/en
Priority claimed from US10/205,475 external-priority patent/US7778703B2/en
Application filed by BioControl Medical Ltd filed Critical BioControl Medical Ltd
Priority to US11/981,369 priority Critical patent/US20080132964A1/en
Assigned to BIO CONTROL MEDICAL (B.C.M.) LTD. reassignment BIO CONTROL MEDICAL (B.C.M.) LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BIOCONTROL MEDICAL, LTD.
Publication of US20080132964A1 publication Critical patent/US20080132964A1/en
Assigned to BIOCONTROL MEDICAL LTD. reassignment BIOCONTROL MEDICAL LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GROSS, YOSSI, AYAL, SHAI, BEN-DAVID, TAMIR, BEN-EZRA, OMRY, COHEN, EHUD
Assigned to MEDTRONIC, INC. reassignment MEDTRONIC, INC. SECURITY AGREEMENT Assignors: BIO CONTROL MEDICAL (B.C.M.) LTD
Assigned to MEDTRONIC, INC. reassignment MEDTRONIC, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BIOCONTROL ,EDICAL (B.C.M.) LTD
Abandoned legal-status Critical Current

Links

Images

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Measuring for diagnostic purposes; Identification of persons
    • A61B5/41Detecting, measuring or recording for evaluating the immune or lymphatic systems
    • A61B5/412Detecting or monitoring sepsis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Measuring for diagnostic purposes; Identification of persons
    • A61B5/40Detecting, measuring or recording for evaluating the nervous system
    • A61B5/4029Detecting, measuring or recording for evaluating the nervous system for evaluating the peripheral nervous systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Measuring for diagnostic purposes; Identification of persons
    • A61B5/40Detecting, measuring or recording for evaluating the nervous system
    • A61B5/4029Detecting, measuring or recording for evaluating the nervous system for evaluating the peripheral nervous systems
    • A61B5/4041Evaluating nerves condition
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00Electrotherapy; Circuits therefor
    • A61N1/02Details
    • A61N1/04Electrodes
    • A61N1/05Electrodes for implantation or insertion into the body, e.g. heart electrode
    • A61N1/0551Spinal or peripheral nerve electrodes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00Electrotherapy; Circuits therefor
    • A61N1/18Applying electric currents by contact electrodes
    • A61N1/32Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/3605Implantable neurostimulators for stimulating central or peripheral nerve system
    • A61N1/3606Implantable neurostimulators for stimulating central or peripheral nerve system adapted for a particular treatment
    • A61N1/36114Cardiac control, e.g. by vagal stimulation
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Measuring for diagnostic purposes; Identification of persons
    • A61B5/02Detecting, measuring or recording pulse, heart rate, blood pressure or blood flow; Combined pulse/heart-rate/blood pressure determination; Evaluating a cardiovascular condition not otherwise provided for, e.g. using combinations of techniques provided for in this group with electrocardiography or electroauscultation; Heart catheters for measuring blood pressure
    • A61B5/024Detecting, measuring or recording pulse rate or heart rate
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Measuring for diagnostic purposes; Identification of persons
    • A61B5/72Signal processing specially adapted for physiological signals or for diagnostic purposes
    • A61B5/7203Signal processing specially adapted for physiological signals or for diagnostic purposes for noise prevention, reduction or removal
    • A61B5/7217Signal processing specially adapted for physiological signals or for diagnostic purposes for noise prevention, reduction or removal of noise originating from a therapeutic or surgical apparatus, e.g. from a pacemaker
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00Electrotherapy; Circuits therefor
    • A61N1/02Details
    • A61N1/04Electrodes
    • A61N1/05Electrodes for implantation or insertion into the body, e.g. heart electrode
    • A61N1/0551Spinal or peripheral nerve electrodes
    • A61N1/0556Cuff electrodes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00Electrotherapy; Circuits therefor
    • A61N1/18Applying electric currents by contact electrodes
    • A61N1/32Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/362Heart stimulators
    • A61N1/3621Heart stimulators for treating or preventing abnormally high heart rate
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00Electrotherapy; Circuits therefor
    • A61N1/18Applying electric currents by contact electrodes
    • A61N1/32Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/362Heart stimulators
    • A61N1/3627Heart stimulators for treating a mechanical deficiency of the heart, e.g. congestive heart failure or cardiomyopathy

Definitions

  • the present invention relates generally to treating patients by application of electrical signals to a selected nerve or nerve bundle, and specifically to methods and apparatus for stimulating the vagus nerve for treating heart conditions.
  • vagus nerve the tenth cranial nerve, and part of the parasympathetic nervous system
  • vagus nerve is composed of somatic and visceral afferents (inward conducting nerve fibers, which convey impulses toward the brain) and efferents (outward conducting nerve fibers, which convey impulses to an effector to regulate activity such as muscle contraction or glandular secretion).
  • the rate of the heart is restrained in part by parasympathetic stimulation from the right and left vagus nerves.
  • Low vagal nerve activity is considered to be related to various arrhythmias, including tachycardia, ventricular accelerated rhythm, and rapid atrial fibrillation.
  • By artificially stimulating the vagus nerves it is possible to slow the heart, allowing the heart to more completely relax and the ventricles to experience increased filling.
  • the heart may beat more efficiently because it may expend less energy to overcome the myocardial viscosity and elastic forces of the heart with each beat.
  • Heart failure is a cardiac condition characterized by a deficiency in the ability of the heart to pump blood throughout the body and/or to prevent blood from backing up in the lungs.
  • Customary treatment of heart failure includes medication and lifestyle changes. It is often desirable to lower the heart rates of patients suffering from faster than normal heart rates.
  • beta blockers in treating heart disease is attributed in part to their heart-rate-lowering effect.
  • Bilgutay et al. in “Vagal tuning: a new concept in the treatment of supraventricular arrhythmias, angina pectoris, and heart failure,” J. Thoracic Cardiovas. Surg. 56(1):71-82, July, 1968, which is incorporated herein by reference, studied the use of a permanently-implanted device with electrodes to stimulate the right vagus nerve for treatment of supraventricular arrhythmias, angina pectoris, and heart failure. Experiments were conducted to determine amplitudes, frequencies, wave shapes and pulse lengths of the stimulating current to achieve slowing of the heart rate. The authors additionally studied an external device, triggered by the R-wave of the electrocardiogram (ECG) of the subject to provide stimulation only upon an achievement of a certain heart rate.
  • ECG electrocardiogram
  • U.S. Pat. No. 6,473,644 to Terry, Jr. et al. which is incorporated herein by reference, describes a method for treating patients suffering from heart failure to increase cardiac output, by stimulating or modulating the vagus nerve with a sequence of substantially equally-spaced pulses by an implanted neurostimulator.
  • the frequency of the stimulating pulses is adjusted until the patient's heart rate reaches a target rate within a relatively stable target rate range below the low end of the patient's customary resting heart rate.
  • the device includes an implantable neurostimulator for stimulating the patient's vagus nerve at or above the cardiac branch with an electrical pulse waveform at a stimulating rate sufficient to maintain the patient's heart beat at a rate well below the patient's normal resting heart rate, thereby allowing rest and recovery of the heart muscle, to increase in coronary blood flow, and/or growth of coronary capillaries.
  • a metabolic need sensor detects the patient's current physical state and concomitantly supplies a control signal to the neurostimulator to vary the stimulating rate. If the detection indicates a state of rest, the neurostimulator rate reduces the patient's heart rate below the patient's normal resting rate. If the detection indicates physical exertion, the neurostimulator rate increases the patient's heart rate above the normal resting rate.
  • US Patent Publication 2003/0045909 to Gross et al. which is assigned to the assignee of the present patent application and is incorporated herein by reference, describes apparatus for treating a heart condition of a subject, including an electrode device, which is adapted to be coupled to a vagus nerve of the subject.
  • a control unit is adapted to drive the electrode device to apply to the vagus nerve a stimulating current, which is capable of inducing action potentials in a therapeutic direction in a first set and a second set of nerve fibers of the vagus nerve.
  • the control unit is also adapted to drive the electrode device to apply to the vagus nerve an inhibiting current, which is capable of inhibiting the induced action potentials traveling in the therapeutic direction in the second set of nerve fibers, the nerve fibers in the second set having generally larger diameters than the nerve fibers in the first set.
  • vagal stimulation has been studied in animals.
  • Zhang Y et al. in “Optimal ventricular rate slowing during atrial fibrillation by feedback AV nodal-selective vagal stimulation,” Am J Physiol Heart Circ Physiol 282:H1102-H1110 (2002), describe the application of selective vagal stimulation by varying the nerve stimulation intensity, in order to achieve graded slowing of heart rate. This article is incorporated herein by reference.
  • Vanoli E et al. “Vagal stimulation and prevention of sudden death in conscious dogs with a healed myocardial infarction,” Circ Res 68(5):1471-81 (1991)
  • Heart rate variability is considered an important determinant of cardiac function. Heart rate normally fluctuates within a normal range in order to accommodate constantly changing physiological needs. For example, heart rate increases during waking hours, exertion, and inspiration, and decreases during sleeping, relaxation, and expiration. Two representations of heart rate variability are commonly used: (a) the standard deviation of beat-to-beat RR interval differences within a certain time window (i.e., variability in the time domain), and (b) the magnitude of variability as a function of frequency (i.e., variability in the frequency domain).
  • Short-term (beat-to-beat) variability in heart rate represents fast, high-frequency (HF) changes in heart rate.
  • the changes in heart rate associated with breathing are characterized by a frequency of between about 0.15 and about 0.4 Hz (corresponding to a time constant between about 2.5 and 7 seconds).
  • Low-frequency (LF) changes in heart rate (for example, blood pressure variations) are characterized by a frequency of between about 0.04 and about 0.15 Hz (corresponding to a time constant between about 7 and 25 seconds).
  • Very-low-frequency (VLF) changes in heart rate are characterized by a frequency of between about 0.003 and about 0.04 Hz (0.5 to 5 minutes).
  • Ultra-low-frequency (ULF) changes in heart rate are characterized by a frequency of between about 0.0001 and about 0.003 Hz (5 minutes to 2.75 hours).
  • a commonly used indicator of heart rate variability is the ratio of HF power to LF power.
  • High heart rate variability (especially in the high frequency range, as described hereinabove) is generally correlated with a good prognosis in conditions such as ischemic heart disease and heart failure.
  • increased heart rate variability in an even higher frequency range can cause a reduction in cardiac efficiency by producing beats that arrive too quickly (when the ventricle is not optimally filled) and beats that arrive too late (when the ventricle is fully filled and the pressure is too high).
  • a number of patents describe techniques for treating arrhythmias and/or ischemia by, at least in part, stimulating the vagus nerve.
  • Arrhythmias in which the heart rate is too fast include fibrillation, flutter and tachycardia.
  • Arrhythmia in which the heart rate is too slow is known as bradyarrhythmia.
  • U.S. Pat. No. 5,700,282 to Zabara which is incorporated herein by reference, describes techniques for stabilizing the heart rhythm of a patient by detecting arrhythmias and then electronically stimulating the vagus and cardiac sympathetic nerves of the patient. The stimulation of vagus efferents directly causes the heart rate to slow down, while the stimulation of cardiac sympathetic nerve efferents causes the heart rate to quicken.
  • U.S. Pat. No. 5,330,507 to Schwartz which is incorporated herein by reference, describes a cardiac pacemaker for preventing or interrupting tachyarrhythmias and for applying pacing therapies to maintain the heart rhythm of a patient within acceptable limits.
  • the device automatically stimulates the right or left vagus nerves as well as the cardiac tissue in a concerted fashion dependent upon need. Continuous and/or phasic electrical pulses are applied. Phasic pulses are applied in a specific relationship with the R-wave of the ECG of the patient.
  • European Patent Application EP 0 688 577 to Holmstrom et al. which is incorporated herein by reference, describes a device to treat atrial tachyarrhythmia by detecting arrhythmia and stimulating a parasympathetic nerve that innervates the heart, such as the vagus nerve.
  • the apparatus stimulates the left vagus nerve, and automatically and continuously adjusts the vagal stimulation frequency as a function of the difference between actual and desired ventricular excitation rates.
  • the apparatus automatically adjusts the vagal stimulation frequency as a function of the difference between ventricular excitation rate and arterial pulse rate in order to eliminate or minimize pulse deficit.
  • U.S. Pat. No. 5,203,326 to Collins which is incorporated herein by reference, describes a pacemaker which detects a cardiac abnormality and responds with electrical stimulation of the heart combined with vagus nerve stimulation.
  • the vagal stimulation frequency is progressively increased in one-minute intervals, and, for the pulse delivery rate selected, the heart rate is described as being slowed to a desired, stable level by increasing the pulse current.
  • U.S. Pat. No. 6,511,500 to Rahme which is incorporated herein by reference, describes various aspects of the effects of autonomic nervous system tone on atrial arrhythmias, and its interaction with class III antiarrhythmic drug effects.
  • the significance of sympathetic and parasympathetic activation are described as being evaluated by determining the effects of autonomic nervous system using vagal and stellar ganglions stimulation, and by using autonomic nervous system neurotransmitters infusion (norepinephrine, acetylcholine).
  • U.S. Pat. Nos. 5,334,221 to Bardy and 5,356,425 to Bardy et al. which are incorporated herein by reference, describe a stimulator for applying stimulus pulses to the AV nodal fat pad in response to the heart rate exceeding a predetermined rate, in order to reduce the ventricular rate.
  • the device also includes a cardiac pacemaker which serves to pace the ventricle in the event that the ventricular rate is lowered below a pacing rate, and provides for feedback control of the stimulus parameters applied to the AV nodal fat pad, as a function of the determined effect of the stimulus pulses on the heart rate.
  • US Patent Application Publication 2002/0120304 to Mest which is incorporated herein by reference, describes a method for regulating the heart rate of a patient by inserting into a blood vessel of the patient a catheter having an electrode at its distal end, and directing the catheter to an intravascular location so that the electrode is adjacent to a selected cardiac sympathetic or parasympathetic nerve.
  • PCT Publication WO 02/085448 to Foreman et al. which is incorporated herein by reference, describes a method for protecting cardiac function and reducing the impact of ischemia on the heart, by electrically stimulating a neural structure capable of carrying the predetermined electrical signal from the neural structure to the “intrinsic cardiac nervous system,” which is defined and described therein.
  • U.S. Pat. No. 5,658,318 to Stroetmann et al. which is incorporated herein by reference, describes a device for detecting a state of imminent cardiac arrhythmia in response to activity in nerve signals conveying information from the autonomic nerve system to the heart.
  • the device comprises a sensor adapted to be placed in an extracardiac position and to detect activity in at least one of the sympathetic and vagus nerves.
  • U.S. Pat. No. 6,292,695 to Webster, Jr. et al. which is incorporated herein by reference, describes a method for controlling cardiac fibrillation, tachycardia, or cardiac arrhythmia by the use of a catheter comprising a stimulating electrode, which is placed at an intravascular location.
  • the electrode is connected to a stimulating means, and stimulation is applied across the wall of the vessel, transvascularly, to a sympathetic or parasympathetic nerve that innervates the heart at a strength sufficient to depolarize the nerve and effect the control of the heart.
  • U.S. Pat. No. 6,134,470 to Hartlaub which is incorporated herein by reference, describes an implantable anti-arrhythmia system which includes a spinal cord stimulator coupled to an implantable heart rhythm monitor.
  • the monitor is adapted to detect the occurrence of tachyarrhythmias or of precursors thereto and, in response, trigger the operation of the spinal cord stimulator in order to prevent occurrences of tachyarrhythmias and/or as a stand-alone therapy for termination of tachyarrhythmias and/or to reduce the level of aggressiveness required of an additional therapy such as antitachycardia pacing, cardioversion or defibrillation.
  • an additional therapy such as antitachycardia pacing, cardioversion or defibrillation.
  • a cathode is adapted to be placed in a vicinity of a cathodic longitudinal site of the nerve and to apply a cathodic current to the nerve.
  • a primary inhibiting anode is adapted to be placed in a vicinity of a primary anodal longitudinal site of the nerve and to apply a primary anodal current to the nerve.
  • a secondary inhibiting anode is adapted to be placed in a vicinity of a secondary anodal longitudinal site of the nerve and to apply a secondary anodal current to the nerve, the secondary anodal longitudinal site being closer to the primary anodal longitudinal site than to the cathodic longitudinal site.
  • PCT Patent Publication WO 01/10375 to Felsen et al. which is incorporated herein by reference, describes apparatus for modifying the electrical behavior of nervous tissue. Electrical energy is applied with an electrode to a nerve in order to selectively inhibit propagation of an action potential.
  • Mushahwar V K et al. “Muscle recruitment through electrical stimulation of the lumbo-sacral spinal cord,” IEEE Trans Rehabil Eng, 8(1):22-9 (2000)
  • nerve fibers are recruited in the order of increasing size, from smaller-diameter fibers to progressively larger-diameter fibers.
  • artificial electrical stimulation of nerves using standard techniques recruits fibers in a larger- to smaller-diameter order, because larger-diameter fibers have a lower excitation threshold.
  • This unnatural recruitment order causes muscle fatigue and poor force gradation. Techniques have been explored to mimic the natural order of recruitment when performing artificial stimulation of nerves to stimulate muscles.
  • Fitzpatrick et al. in “A nerve cuff design for the selective activation and blocking of myelinated nerve fibers,” Ann. Conf. of the IEEE Eng. in Medicine and Biology Soc, 13(2), 906 (1991), which is incorporated herein by reference, describe a tripolar electrode used for muscle control.
  • the electrode includes a central cathode flanked on its opposite sides by two anodes.
  • the central cathode generates action potentials in the motor nerve fiber by cathodic stimulation.
  • One of the anodes produces a complete anodal block in one direction so that the action potential produced by the cathode is unidirectional.
  • the other anode produces a selective anodal block to permit passage of the action potential in the opposite direction through selected motor nerve fibers to produce the desired muscle stimulation or suppression.
  • the activation function is the second spatial derivative of the electric potential along an axon. In the region where the activation function is positive, the axon depolarizes, and in the region where the activation function is negative, the axon hyperpolarizes. If the activation function is sufficiently positive, then the depolarization will cause the axon to generate an action potential; similarly, if the activation function is sufficiently negative, then local blocking of action potentials transmission occurs.
  • the activation function depends on the current applied, as well as the geometry of the electrodes and of the axon.
  • U is the potential
  • is the conductance tensor specifying the conductance of the various materials (electrode housing, axon, intracellular fluid, etc.)
  • j is a scalar function representing the current source density specifying the locations of current injection.
  • apparatus for treating a heart condition comprises a multipolar electrode device that is applied to a portion of a vagus nerve that innervates the heart of a patient.
  • the system is configured to treat heart failure and/or heart arrhythmia, such as atrial fibrillation or tachycardia.
  • a control unit typically drives the electrode device to (i) apply signals to induce the propagation of efferent action potentials towards the heart, and (ii) suppress artificially-induced afferent and efferent action potentials, in order to minimize any unintended side effect of the signal application.
  • the control unit typically suppresses afferent action potentials induced by the cathodic current by inhibiting essentially all or a large fraction of fibers using anodal current (“afferent anodal current”) from a second set of one or more anodes (the “afferent anode set”).
  • afferent anode set is typically placed between the central cathode and the edge of the electrode device closer to the brain (the “afferent edge”), to block a large fraction of fibers from conveying signals in the direction of the brain during application of the afferent anodal current.
  • the cathodic current is applied with an amplitude sufficient to induce action potentials in large- and medium-diameter fibers (e.g., A- and B-fibers), but insufficient to induce action potentials in small-diameter fibers (e.g., C-fibers).
  • a small anodal current is applied in order to inhibit action potentials induced by the cathodic current in the large-diameter fibers (e.g., A-fibers).
  • This combination of cathodic and anodal current generally results in the stimulation of medium-diameter fibers (e.g., B-fibers) only.
  • the efferent anode set comprises a plurality of anodes.
  • Application of the efferent anodal current in appropriate ratios from the plurality of anodes in these embodiments generally minimizes the “virtual cathode effect,” whereby application of too large an anodal current creates a virtual cathode, which stimulates rather than blocks fibers.
  • the virtual cathode effect generally hinders blocking of smaller-diameter fibers, because a relatively large anodal current is typically necessary to block such fibers, and this same large anodal current induces the virtual cathode effect.
  • the afferent anode set typically comprises a plurality of anodes in order to minimize the virtual cathode effect in the direction of the brain.
  • the efferent and afferent anode sets each comprise exactly one electrode, which are directly electrically coupled to each other.
  • the cathodic current is applied with an amplitude sufficient to induce action potentials in large- and medium-diameter fibers (e.g., A- and B-fibers), but insufficient to induce action potentials in small-diameter fibers (e.g., C-fibers).
  • an anodal current is applied in order to inhibit action potentials induced by the cathodic current in the large-diameter fibers (e.g., A-fibers), but not in the small- and medium-diameter fibers (e.g., B- and C-fibers).
  • This combination of cathodic and anodal current generally results in the stimulation of medium-diameter fibers (e.g., B-fibers) only.
  • parasympathetic stimulation of the vagus nerve is applied responsive to one or more sensed physiological parameters or other parameters, such as heart rate, electrocardiogram (ECG), blood pressure, indicators of cardiac contractility, cardiac output, norepinephrine concentration, baroreflex sensitivity, or motion of the patient.
  • stimulation is applied in a closed-loop system in order to achieve and maintain a desired heart rate responsive to one or more such sensed parameters.
  • vagal stimulation is applied in a burst (i.e., a series of pulses).
  • the application of the burst in each cardiac cycle typically commences after a variable delay after a detected R-wave, P-wave, or other feature of an ECG.
  • the delay is typically calculated in real time using a function, the inputs of which include one or more pre-programmed but updateable constants and one or more sensed parameters, such as the R-R interval between cardiac cycles and/or the P-R interval.
  • a lookup table of delays is used to determine in real time the appropriate delay for each application of pulses, based on the one or more sensed parameters.
  • control unit is configured to drive the electrode device to stimulate the vagus nerve so as to reduce the heart rate of the subject towards a target heart rate.
  • Parameters of stimulation are varied in real time in order to vary the heart-rate-lowering effects of the stimulation.
  • parameters of such pulse series typically include, but are not limited to: (a) timing of the stimulation within the cardiac cycle, (b) pulse duration (width), (c) pulse repetition interval, (d) pulse period, (e) number of pulses per burst, also referred to herein as “pulses per trigger” (PPT), (f) amplitude, (g) duty cycle, (h) choice of vagus nerve, and (i) “on”/“off” ratio and timing (i.e., during intermittent operation).
  • the control unit is configured to drive the electrode device to stimulate the vagus nerve so as to modify heart rate variability of the subject.
  • the control unit is configured to apply stimulation with parameters that tend to or that are selected to reduce heart rate variability, while for other applications parameters are used that tend to or that are selected to increase variability.
  • the parameters of the stimulation are selected to both reduce the heart rate of the subject and heart rate variability of the subject.
  • the parameters are selected to reduce heart rate variability while substantially not reducing the heart rate of the subject.
  • the control unit is configured to drive the electrode device to stimulate the vagus nerve so as to modify heart rate variability in order to treat a condition of the subject.
  • the techniques described herein generally enable relatively fine control of the level of stimulation of the vagus nerve, by imitating the natural physiological smaller-to-larger diameter recruitment order of nerve fibers.
  • This recruitment order allows improved and more natural control over the heart rate.
  • Such fine control is particularly advantageous when applied in a closed-loop system, wherein such control results in smaller changes in heart rate and lower latencies in the control loop, which generally contribute to greater loop stability and reduced loop stabilization time.
  • Vagus nerve and derivatives thereof, as used in the specification and the claims, is to be understood to include portions of the left vagus nerve, the right vagus nerve, and branches of the vagus nerve such as the superior cardiac nerve, superior cardiac branch, and inferior cardiac branch.
  • stimulation of the vagus nerve is described herein by way of illustration and not limitation, and it is to be understood that stimulation of other autonomic nerves, including nerves in the epicardial fat pads, for treatment of heart conditions or other conditions, is also included within the scope of the present invention.
  • Heart failure as used in the specification and the claims, is to be understood to include all forms of heart failure, including ischemic heart failure, non-ischemic heart failure, and diastolic heart failure.
  • apparatus for treating a heart condition of a subject including:
  • an electrode device adapted to be coupled to a vagus nerve of the subject
  • control unit adapted to:
  • a stimulating current which is capable of inducing action potentials in a therapeutic direction in a first set and a second set of nerve fibers of the vagus nerve
  • the electrode device to apply to the vagus nerve an inhibiting current, which is capable of inhibiting the induced action potentials traveling in the therapeutic direction in the second set of nerve fibers, the nerve fibers in the second set having generally larger diameters than the nerve fibers in the first set.
  • the therapeutic direction is an efferent therapeutic direction towards a heart of the subject.
  • the therapeutic direction is an afferent therapeutic direction towards a brain of the subject.
  • control unit increases a number of action potentials traveling in the therapeutic direction by decreasing an amplitude of the applied inhibiting current, and/or decreases a number of action potentials traveling in the therapeutic direction by increasing an amplitude of the applied inhibiting current.
  • the heart condition includes heart failure and/or cardiac arrhythmia
  • the apparatus is adapted to treat the heart condition.
  • the apparatus includes an override, adapted to be used by the subject so as to influence the application by the electrode device of the stimulating and inhibiting currents.
  • the apparatus includes a pacemaker, and the control unit is adapted to drive the pacemaker to apply pacing pulses to a heart of the subject.
  • the apparatus includes an implantable cardioverter defibrillator (ICD), and the control unit is adapted to drive the ICD to apply energy to a heart of the subject.
  • ICD implantable cardioverter defibrillator
  • control unit is adapted to drive the electrode device to apply the stimulating current and/or the inhibiting current in a series of pulses.
  • control unit receives an electrical signal from the electrode device, and drives the electrode device to regulate the stimulating and/or inhibiting current responsive to the electrical signal.
  • the electrode device includes a cathode, adapted to apply the stimulating current, and a primary set of anodes, which applies the inhibiting current.
  • the primary set of anodes includes a primary anode and a secondary anode, disposed so that the primary anode is located between the secondary anode and the cathode, and the secondary anode applies a current with an amplitude less than about one half an amplitude of a current applied by the primary anode.
  • control unit is adapted to drive the electrode device to apply the stimulating current so as to regulate a heart rate of the subject.
  • the control unit is adapted to drive the electrode device to regulate an amplitude of the stimulating current so as to regulate the heart rate of the subject.
  • control unit drives the electrode device to apply the inhibiting current so as to regulate a heart rate of the subject.
  • control unit typically drives the electrode device to regulate an amplitude of the inhibiting current so as to regulate the heart rate of the subject.
  • control unit is adapted to drive the electrode device to apply the stimulating and inhibiting currents in a series of pulses.
  • the control unit is adapted to drive the electrode device to apply the stimulating and inhibiting currents in a series of pulses.
  • control unit :
  • the control unit drives the electrode device to apply the stimulating and inhibiting currents in the series of pulses so as to regulate a heart rate of the subject.
  • the control unit regulates the number of pulses in the series of pulses so as to regulate the heart rate of the subject.
  • the control unit regulates a duration of each pulse so as to regulate the heart rate of the subject.
  • the control unit varies a length of a period of application of the series of pulses so as to regulate the heart rate of the subject.
  • control unit drives the electrode device to apply to the vagus nerve a second inhibiting current, which is capable of inhibiting device-induced action potentials traveling in a non-therapeutic direction opposite the therapeutic direction in the first and second sets of nerve fibers.
  • control unit drives the electrode device to apply the second inhibiting current to the vagus nerve at a primary and a secondary location, the primary location located between the secondary location and an application location of the stimulating current, and to apply at the secondary location a current with an amplitude less than about one half an amplitude of a current applied at the primary location.
  • the apparatus includes a sensor unit, and the control unit is adapted to receive at least one sensed parameter from the sensor unit, and to drive the electrode device to apply the stimulating and inhibiting currents responsive to the at least one sensed parameter.
  • control unit is programmed with a predetermined target heart rate, or is adapted to determine a target heart rate of the subject responsive to the at least one sensed parameter, and the control unit is adapted to drive the electrode device to apply the stimulating and inhibiting currents so as to adjust a heart rate of the subject towards the target heart rate.
  • the sensor unit may include one or more of the following sensors, in which case the control unit receives the at least one sensed parameter from the following one or more sensors:
  • the at least one sensed parameter includes an indicator of decreased cardiac contractility, an indicator of cardiac output, and/or an indicator of a time derivative of a LVP, and the control unit receives the indicator.
  • the sensor unit includes an electrocardiogram (ECG) monitor
  • the at least one sensed parameter includes an ECG value
  • the control unit receives the at least one sensed parameter from the ECG monitor.
  • ECG electrocardiogram
  • the at least one sensed parameter includes an ECG reading indicative of a presence of arrhythmia
  • the control unit is adapted to receive the at least one sensed parameter from the ECG monitor.
  • the at least one sensed parameter includes an indication of a heart rate of the subject, and the control unit is adapted to receive the indication of the heart rate.
  • the at least one sensed parameter includes indications of a plurality of heart rates of the subject at a respective plurality of points in time, and the control unit is adapted to receive the at least one sensed parameter and to determine a measure of variability of heart rate responsive thereto.
  • the sensor unit is adapted to sense an initiation physiological parameter and a termination physiological parameter of the subject
  • the control unit is adapted to drive the electrode device to apply the stimulating and inhibiting currents to the vagus nerve after a delay, to initiate the delay responsive to the sensing of the initiation physiological parameter, and to set a length of the delay responsive to the termination physiological parameter.
  • control unit is adapted to determine a target heart rate of the subject responsive to the at least one sensed parameter, and the control unit is adapted to set the delay so as to adjust the heart rate towards the target heart rate.
  • the termination physiological parameter includes an atrioventricular (AV) delay of the subject
  • the control unit is adapted to set the length of the delay responsive to the AV delay.
  • AV atrioventricular
  • the sensor unit includes an electrocardiogram (ECG) monitor
  • the initiation physiological parameter includes a P-wave or R-wave of a cardiac cycle of the subject
  • the control unit is adapted to initiate the delay responsive to the sensing of the P-wave or R-wave, as the case may be.
  • the termination physiological parameter includes a difference in time between two features of an ECG signal recorded by the ECG monitor, such as an R-R interval between a sensing of an R-wave of a first cardiac cycle of the subject and a sensing of an R-wave of a next cardiac cycle of the subject, or a P-R interval between a sensing of a P-wave of a cardiac cycle of the subject and a sensing of an R-wave of the cardiac cycle, and the control unit sets the length of the delay and/or the magnitude of the stimulation responsive to the termination physiological parameter.
  • apparatus for treating a heart condition of a subject including:
  • a cathode adapted to apply to a vagus nerve of the subject a stimulating current which is capable of inducing action potentials in the vagus nerve;
  • a primary and a secondary anode adapted to be disposed so that the primary anode is located between the secondary anode and the cathode, and adapted to apply to the vagus nerve respective primary and secondary inhibiting currents which are capable of inhibiting action potentials in the vagus nerve.
  • the primary and secondary anodes are adapted to be placed between about 0.5 and about 2.0 millimeters apart from one another.
  • the secondary anode is typically adapted to apply the secondary inhibiting current with an amplitude equal to between about 2 and about 5 milliamps.
  • the secondary anode is typically adapted to apply the secondary inhibiting current with an amplitude less than about one half an amplitude of the primary inhibiting current applied by the primary anode.
  • the primary anode, the secondary anode, and/or the cathode includes a ring electrode adapted to apply a generally uniform current around a circumference of the vagus nerve.
  • the primary anode, the secondary anode, and/or the cathode includes a plurality of discrete primary anodes, adapted to be disposed at respective positions around an axis of the vagus nerve.
  • the apparatus includes a tertiary anode, adapted to be disposed such that the secondary anode is between the tertiary anode and the primary anode.
  • the electrode device includes an efferent edge, and the cathode is adapted to be disposed closer than the anodes to the efferent edge of the electrode device.
  • the cathode and/or the anodes are adapted to apply the stimulating current so as to regulate a heart rate of the subject.
  • the cathode includes a plurality of discrete cathodes, adapted to be disposed at respective positions around an axis of the vagus nerve, so as to selectively stimulate nerve fibers of the vagus nerve responsive to the positions of the nerve fibers in the vagus nerve.
  • the apparatus includes a set of one or more blocking anodes, adapted to be disposed such that the cathode is between the set of blocking anodes and the primary anode, and adapted to apply to the vagus nerve a current which is capable of inhibiting action potentials propagating in the vagus nerve in a direction from the cathode towards the set of blocking anodes.
  • the set of blocking anodes includes a first anode and a second anode, adapted to be disposed such that the first anode is located between the second anode and the cathode, and wherein the second anode is adapted to apply a current with an amplitude less than about one half an amplitude of a current applied by the first anode.
  • the electrode device includes an afferent edge, wherein the cathode is adapted to be disposed closer than the anodes to the afferent edge of the electrode device.
  • the apparatus includes a cuff, and an electrically-insulating element coupled to an inner portion of the cuff, and the primary anode and the cathode are adapted to be mounted in the cuff and separated from one another by the insulating element.
  • the primary and secondary anodes and the cathode are recessed in the cuff so as not to be in direct contact with the vagus nerve.
  • the apparatus includes a control unit, adapted to drive the cathode and the anodes to apply the respective currents to the vagus nerve, so as to treat the subject.
  • the cathode is adapted to apply the stimulating current and the anodes are adapted to apply the inhibiting current so as to regulate a heart rate of the subject.
  • the cathode is adapted to vary an amplitude of the applied stimulating current and the anodes are adapted to vary an amplitude of the applied inhibiting current so as to regulate a heart rate of the subject.
  • control unit is adapted to:
  • a stimulating current which is capable of inducing action potentials in a therapeutic direction in a first set and a second set of nerve fibers of the vagus nerve
  • the electrode device to apply to the vagus nerve an inhibiting current, which is capable of inhibiting the induced action potentials traveling in the therapeutic direction in the second set of nerve fibers, the nerve fibers in the second set having generally larger diameters than the nerve fibers in the first set.
  • the termination physiological parameter includes a blood pressure of the subject, and wherein the control unit is adapted to set the length of the delay responsive to the blood pressure.
  • the sensor unit is adapted to sense a rate-setting parameter of the subject, wherein the rate-setting parameter includes a blood pressure of the subject, and wherein the control unit is adapted to receive the rate-setting parameter from the sensor unit and to drive the electrode device to apply the current responsive to the rate-setting parameter.
  • the rate-setting parameter includes the initiation physiological parameter and/or the termination physiological parameter
  • the control unit is adapted to drive the electrode device to apply the current responsive to the initiation physiological parameter so as to regulate the heart rate of the subject.
  • control unit is adapted to set the length of the delay so as to adjust the heart rate towards the target heart rate.
  • control unit is adapted to access a lookup table of delays, and to set the length of the delay using the lookup table and responsive to the initiation and termination physiological parameters.
  • the initiation physiological parameter includes a P-wave, R-wave, Q-wave, S-wave, or T-wave of a cardiac cycle of the subject, and wherein the control unit is adapted to initiate the delay responsive to the sensing of the cardiac wave.
  • the termination physiological parameter includes a difference in time between two features of an ECG signal recorded by the ECG monitor, and the control unit is adapted to set the length of the delay responsive to the difference in time between the two features.
  • the termination physiological parameter may include an R-R interval between a sensing of an R-wave of a first cardiac cycle of the subject and a sensing of an R-wave of a next cardiac cycle of the subject, and wherein the control unit is adapted to set the length of the delay responsive to the R-R interval.
  • the termination physiological parameter includes an average of R-R intervals sensed for a number of cardiac cycles, and wherein the control unit is adapted to set the length of the delay responsive to the average of the R-R intervals.
  • the termination physiological parameter includes a P-R interval between a sensing of a P-wave of a cardiac cycle of the subject and a sensing of an R-wave of the cardiac cycle, and wherein the control unit is adapted to set the length of the delay responsive to the P-R interval.
  • the termination physiological parameter includes an average of P-R intervals sensed for a number of cardiac cycles, and wherein the control unit is adapted to set the length of the delay responsive to the average of the P-R intervals.
  • apparatus for treating a condition of a subject including:
  • an electrode device adapted to be coupled to an autonomic nerve of the subject
  • control unit adapted to:
  • a stimulating current which is capable of inducing action potentials in a therapeutic direction in a first set and a second set of nerve fibers of the nerve
  • the electrode device to apply to the nerve an inhibiting current, which is capable of inhibiting the induced action potentials traveling in the therapeutic direction in the second set of nerve fibers, the nerve fibers in the second set having generally larger diameters than the nerve fibers in the first set.
  • the autonomic nerve includes the vagus nerve
  • the control unit is adapted to drive the electrode device to apply the stimulating and inhibiting currents to the nerve.
  • control unit is adapted to drive the electrode device to apply the stimulating and inhibiting currents to the nerve so as to affect behavior of one of the following, so as to treat the condition:
  • apparatus for treating a condition of a subject including:
  • a cathode adapted to apply to an autonomic nerve of the subject a stimulating current which is capable of inducing action potentials in the nerve;
  • a primary and a secondary anode adapted to be disposed so that the primary anode is located between the secondary anode and the cathode, and adapted to apply to the nerve respective primary and secondary inhibiting currents which are capable of inhibiting action potentials in the nerve.
  • a method for treating a heart condition of a subject including:
  • a stimulating current which is capable of inducing action potentials in a therapeutic direction in a first set and a second set of nerve fibers of the vagus nerve;
  • an inhibiting current which is capable of inhibiting the induced action potentials traveling in the therapeutic direction in the second set of nerve fibers, the nerve fibers in the second set having generally larger diameters than the nerve fibers in the first set.
  • a method for treating a heart condition of a subject including:
  • a stimulating current which is capable of inducing action potentials in the vagus nerve, so as to treat the subject
  • an inhibiting current which is capable of inhibiting action potentials in the vagus nerve.
  • a method for treating a condition of a subject including:
  • a stimulating current which is capable of inducing action potentials in a therapeutic direction in a first set and a second set of nerve fibers of the nerve;
  • an inhibiting current which is capable of inhibiting the induced action potentials traveling in the therapeutic direction in the second set of nerve fibers, the nerve fibers in the second set having generally larger diameters than the nerve fibers in the first set.
  • a method for treating a condition of a subject including:
  • an inhibiting current which is capable of inhibiting action potentials in the nerve.
  • apparatus for treating a subject including:
  • an electrode device adapted to be coupled to a vagus nerve of the subject
  • a heart rate sensor configured to detect a heart rate of the subject, and to generate a heart rate signal responsive thereto;
  • control unit adapted to:
  • a threshold value which threshold value is greater than a normal heart rate
  • drive the electrode device responsive to determining that the heart rate is greater than a threshold value, which threshold value is greater than a normal heart rate, drive the electrode device to apply a current to the vagus nerve, and configure the current so as to reduce the heart rate of the subject.
  • control unit is adapted to configure the current to include a stimulating current, which is capable of inducing action potentials in a first set and a second set of nerve fibers of the vagus nerve, and an inhibiting current, which is capable of inhibiting the induced action potentials traveling in the second set of nerve fibers, the nerve fibers in the second set having generally larger diameters than the nerve fibers in the first set, and the control unit is adapted to drive the electrode device to apply the stimulating current and the inhibiting current to the vagus nerve.
  • the current includes a stimulating current, which is capable of inducing action potentials in the vagus nerve, and an inhibiting current, which is capable of inhibiting device-induced action potentials traveling in the vagus nerve in an afferent direction toward a brain of the subject, and the control unit is adapted to drive the electrode device to apply the stimulating current and the inhibiting current to the vagus nerve.
  • the vagus nerve includes small-, medium-, and large-diameter fibers
  • the electrode device includes:
  • a cathode adapted to be disposed at a cathodic site of the vagus nerve, and to apply a cathodic current to the vagus nerve which is capable of inducing action potentials in the vagus nerve;
  • an anode adapted to be disposed at an anodal site of the vagus nerve, and to apply to the vagus nerve an anodal current which is capable of inhibiting action potentials in the vagus nerve, and
  • control unit is adapted to:
  • the cathodic current having a cathodic amplitude sufficient to induce action potentials in the medium- and large-diameter fibers, but generally insufficient to induce action potentials in the small-diameter fibers, and
  • anode to apply to the vagus nerve the anodal current having an anodal amplitude sufficient to inhibit action potentials in the large-diameter fibers, but generally insufficient to inhibit action potentials in the medium-diameter fibers.
  • control unit is adapted to utilize a value of at least 100 beats per minute as the threshold value.
  • control unit is adapted to withhold driving the electrode device upon determining that the heart rate is less than a value associated with bradycardia.
  • control unit is adapted to configure the current so as to reduce the heart rate towards a target heart rate.
  • the normal heart rate includes a normal heart rate of the subject.
  • the normal heart rate includes a normal heart rate of a typical human.
  • control unit is adapted to drive the electrode device to apply the current with an amplitude of between about 2 and about 10 milliamps.
  • control unit is adapted to drive the electrode device to apply the current in intermittent ones of a plurality of cardiac cycles of the subject.
  • the apparatus includes an electrode selected from the list consisting of: an electrode for pacing the heart, and an electrode for defibrillating the heart, and the control unit is adapted to withhold driving the electrode device to apply the current to the vagus nerve if the control unit is driving the electrode selected from the list.
  • control unit is adapted to drive the electrode device to apply the current in respective pulse bursts in each of a plurality of cardiac cycles of the subject.
  • the control unit may be adapted to configure each pulse of each of the bursts to have a pulse duration of between about 0.2 and about 4 milliseconds.
  • the control unit may be adapted to configure each of the bursts to have a pulse repetition interval of greater than about 3 milliseconds.
  • the control unit is adapted to configure at least one of the bursts to have between about 0 and about 8 pulses.
  • the apparatus includes an electrocardiogram (ECG) monitor, adapted to generate an ECG signal, and the control unit is adapted to receive the ECG signal, and to initiate the applying of each burst after a delay following detection of a feature of the ECG.
  • ECG electrocardiogram
  • apparatus for applying current to a vagus nerve including:
  • a cathode adapted to be disposed at a cathodic site of the vagus nerve and to apply a cathodic current to the vagus nerve so as to stimulate the vagus nerve;
  • a first anode adapted to be disposed at a first anodal site of the vagus nerve
  • a second anode directly electrically connected to the first anode, and adapted to be disposed at a second anodal site of the vagus nerve, such that the cathodic site is between the first anodal site and the second anodal site.
  • the cathode and anodes are disposed such that the cathodic site is disposed closer to the first anodal site than to the second anodal site.
  • the nerve includes small-, medium-, and large-diameter fibers
  • the apparatus includes a control unit, adapted to:
  • the cathodic current having a cathodic amplitude sufficient to induce action potentials in the medium- and large-diameter fibers, but generally insufficient to induce action potentials in the small-diameter fibers, and
  • the apparatus includes:
  • an electrode selected from the list consisting of: an electrode for pacing the heart, and an electrode for defibrillating the heart,
  • control unit is adapted to drive current through the cathode and the first and second anodes, and the control unit is adapted to withhold driving current through the cathode and the first and second anodes if the control unit is driving current through the electrode selected from the list.
  • the apparatus includes a control unit, adapted to:
  • the cathodic current to induce action potentials in a first set and a second set of nerve fibers of the vagus nerve, the nerve fibers in the second set having generally larger diameters than the nerve fibers in the first set,
  • the first and second anodes are configured such that a level of impedance between the first anode and the cathode is lower than a level of impedance between the second anode and the cathode
  • the control unit is adapted to configure the anodal current driven to the first and second anodes such that the first anodal current inhibits the induced action potentials traveling in the first set of nerve fibers
  • the control unit is adapted to configure the anodal current driven to the first and second anodes to be such that the second anodal current is generally insufficient to inhibit the induced action potentials traveling in the first set of nerve fibers.
  • apparatus for treating a subject including:
  • an electrode device adapted to be coupled to a vagus nerve of the subject
  • a sensor configured to detect a heart rate of the subject, and to generate a heart rate signal responsive thereto;
  • control unit including an integral feedback controller that has inputs including the detected heart rate and a target heart rate, the control unit adapted to:
  • control unit is adapted to configure the current to include a stimulating current, which is capable of inducing action potentials in a first set and a second set of nerve fibers of the vagus nerve, and an inhibiting current, which is capable of inhibiting the induced action potentials traveling in the second set of nerve fibers, the nerve fibers in the second set having generally larger diameters than the nerve fibers in the first set, and the control unit is adapted to drive the electrode device to apply the stimulating current and the inhibiting current to the vagus nerve.
  • the current includes a stimulating current, which is capable of inducing action potentials in the vagus nerve, and an inhibiting current, which is capable of inhibiting device-induced action potentials traveling in the vagus nerve in an afferent direction toward a brain of the subject, and the control unit is adapted to drive the electrode device to apply the stimulating current and the inhibiting current to the vagus nerve.
  • the vagus nerve includes small-, medium-, and large-diameter fibers
  • the electrode device includes:
  • a cathode adapted to be disposed at a cathodic site of the vagus nerve, and to apply a cathodic current to the vagus nerve which is capable of inducing action potentials in the vagus nerve;
  • an anode adapted to be disposed at an anodal site of the vagus nerve, and to apply to the vagus nerve an anodal current which is capable of inhibiting action potentials in the vagus nerve, and
  • control unit is adapted to:
  • the cathodic current having a cathodic amplitude sufficient to induce action potentials in the medium- and large-diameter fibers, but generally insufficient to induce action potentials in the small-diameter fibers, and
  • anode to apply to the vagus nerve the anodal current having an anodal amplitude sufficient to inhibit action potentials in the large-diameter fibers, but generally insufficient to inhibit action potentials in the medium-diameter fibers.
  • control unit is adapted to change the parameter by:
  • control unit is adapted to withhold driving the electrode device upon determining that the heart rate is less than a value associated with bradycardia.
  • control unit is adapted to drive the electrode device to apply the current with an amplitude of between about 2 and about 10 milliamps.
  • control unit is adapted to drive the electrode device to apply the current in intermittent ones of a plurality of cardiac cycles of the subject.
  • the apparatus includes an electrode selected from the list consisting of: an electrode for pacing the heart, and an electrode for defibrillating the heart, and the control unit is adapted to withhold driving the electrode device to apply the current to the vagus nerve when the control unit drives the electrode selected from the list.
  • the integral feedback controller is adapted to calculate a difference between the target heart rate and the detected heart rate, and the control unit is adapted to set a level of a stimulation parameter of the current responsive to a summation over time of the difference.
  • control unit is adapted to set a level of a stimulation parameter of the current by selecting the level from fewer than 16 discrete values.
  • control unit is adapted to set the level of the stimulation parameter of the current by selecting the level from fewer than 10 discrete values.
  • the level of the stimulation parameter of the current includes a number of pulses to apply during a cardiac cycle, and the control unit is adapted to set the number to be a number between 0 and 16.
  • the control unit when a value of the level of the stimulation parameter suitable to achieve the target heart rate is between two of the discrete values, the control unit is adapted to vary the level, in turns, between the two of the discrete values. For some applications, when the suitable value of the level is between the two discrete values, the control unit is adapted to vary the level from a first one of the two discrete values, to a second one of the two discrete values, and back to the first one of the two discrete values, in a time period lasting fewer than 20 heartbeats.
  • control unit when the suitable value of the level is between the two discrete values, the control unit is adapted to vary the level from a first one of the two discrete values, to a second one of the two discrete values, and back to the first one of the two discrete values, in a time period lasting fewer than 10 heartbeats.
  • the control unit is adapted to drive the electrode device to apply the current in respective pulse bursts in each of a plurality of cardiac cycles of the subject.
  • the at least one parameter may include a number of pulses per burst, and the control unit is adapted to change the at least one parameter by changing the number of pulses per burst no more than once in any given approximately 15-second period during operation of the apparatus.
  • the at least one parameter includes a number of pulses per burst, and the control unit is adapted to change the at least one parameter by changing, during any given approximately 15-second period during operation of the apparatus, the number of pulses per burst by no more than one pulse.
  • control unit is adapted to configure each pulse of each of the bursts to have a pulse duration of between about 0.2 and about 4 milliseconds. In an embodiment, the control unit is adapted to configure each of the bursts to have a pulse repetition interval of greater than about 3 milliseconds.
  • control unit is adapted to configure at least one of the bursts to have between about 0 and about 8 pulses.
  • the apparatus includes an electrocardiogram (ECG) monitor, adapted to measure an ECG signal, the control unit is adapted to receive the ECG signal, and to initiate the applying of each burst after a delay following detection of a feature of the ECG.
  • ECG electrocardiogram
  • control unit is adapted to set a control parameter of a feedback algorithm governing the current application to be a number of pulses per burst.
  • the at least one parameter includes a number of pulses per burst
  • the control unit is adapted to change the at least one parameter by changing, over the period, the number of pulses per burst by less than about three pulses.
  • the control unit is adapted to change the at least one parameter by changing, over the period, the number of pulses per burst by exactly one pulse.
  • the control unit is adapted to change the at least one parameter by changing, during each of two consecutive periods, the number of pulses per burst by less than about three pulses, each of the two consecutive periods having a duration of at least about 15 seconds.
  • the control unit may be adapted to change the at least one parameter by changing, during each of the two consecutive periods, the number of pulses per burst by exactly one pulse.
  • control unit is adapted to change the at least one parameter at a rate of change, the rate of change determined at least in part responsive to a heart rate variable selected from: an R-R interval of the subject and a time derivative of the heart rate of the subject.
  • control unit is adapted to increase the rate of change as the heart rate approaches a threshold limit greater than a normal heart rate of the subject.
  • control unit is adapted to increase the rate of change as the heart rate approaches a threshold limit less than a normal heart rate of the subject.
  • the control unit is adapted to decrease the rate of change as the heart rate increases, and to increase the rate of change as the heart rate decreases.
  • control unit is adapted to use a time derivative of an R-R interval of the subject as an input to a feedback algorithm governing the current application.
  • control unit is adapted to correct for an absence of an expected heartbeat.
  • control unit is adapted to sense an R-R interval and: (a) store the sensed R-R interval, if the sensed R-R interval is less than a threshold value, and (b) store the threshold value, if the sensed R-R interval is greater than the threshold value.
  • control unit is adapted to cycle between “on” periods, during which the control unit drives the electrode device to apply the current, and “off” periods, during which the control unit withholds driving the electrode device.
  • control unit is adapted to determine a desired level of stimulation applied by the electrode device, and to configure the cycling between the “on” and “off” periods responsive to the desired level of stimulation.
  • control unit is adapted to set each of the “on” periods to have a duration of less than about 300 seconds.
  • control unit is adapted to set each of the “off” periods to have a duration of between about 0 and about 300 seconds.
  • control unit is adapted to set the parameter at a beginning of one of the “on” periods equal to a value of the parameter at an end of an immediately preceding one of the “on” periods. In an embodiment, the control unit is adapted to configure the current using an algorithm that disregards between about one and about five heart beats at a beginning of each of the “on” periods.
  • control unit is adapted to set the target heart rate during at least one of the “on” periods at least in part responsive to a historic heart rate sensed during a preceding one of the “off” periods.
  • the control unit may be adapted to set the target heart rate during the at least one of the “on” periods at least in part responsive to a historic heart rate sensed during an immediately preceding one of the “off” periods.
  • apparatus for treating a heart condition of a subject including:
  • an electrode device adapted to be coupled to a vagus nerve of the subject
  • control unit adapted to cycle between “on” periods, during which the control unit drives the electrode device to apply a current to the vagus nerve, and “off” periods, during which the control unit withholds driving the electrode device, so as to treat the heart condition.
  • control unit is adapted to withhold driving the electrode device upon determining that the heart rate is less than a value associated with bradycardia. In an embodiment, the control unit is adapted to drive the electrode device to apply the current with an amplitude of between about 2 and about 10 milliamps. In an embodiment, the control unit is adapted to drive the electrode device to apply the current in intermittent ones of a plurality of cardiac cycles of the subject.
  • the apparatus includes an electrode selected from the list consisting of: an electrode for pacing the heart, and an electrode for defibrillating the heart, and the control unit is adapted to withhold driving the electrode device to apply the current to the vagus nerve during an “on” period if the control unit is driving the electrode selected from the list.
  • control unit is adapted to drive the electrode device to apply the current in respective pulse bursts in each of a plurality of cardiac cycles of the subject.
  • control unit is adapted to configure each pulse of each of the bursts to have a pulse duration of between about 0.2 and about 4 milliseconds.
  • control unit is adapted to configure each of the bursts to have a pulse repetition interval of greater than about 3 milliseconds.
  • control unit is adapted to configure at least one of the bursts to have between about 0 and about 8 pulses.
  • the apparatus includes an electrocardiogram (ECG) monitor, adapted to measure an ECG signal, the control unit is adapted to receive the ECG signal, and to initiate the applying of each burst after a delay following detection of a feature of the ECG.
  • ECG electrocardiogram
  • control unit is adapted to configure the current to include a stimulating current, which is capable of inducing action potentials in a first set and a second set of nerve fibers of the vagus nerve, and an inhibiting current, which is capable of inhibiting the induced action potentials traveling in the second set of nerve fibers, the nerve fibers in the second set having generally larger diameters than the nerve fibers in the first set, and the control unit is adapted to drive the electrode device to apply the stimulating current and the inhibiting current to the vagus nerve.
  • the current includes a stimulating current, which is capable of inducing action potentials in the vagus nerve, and an inhibiting current, which is capable of inhibiting device-induced action potentials traveling in the vagus nerve in an afferent direction toward a brain of the subject, and the control unit is adapted to drive the electrode device to apply the stimulating current and the inhibiting current to the vagus nerve.
  • the vagus nerve includes small-, medium-, and large-diameter fibers
  • the electrode device includes:
  • a cathode adapted to be disposed at a cathodic site of the vagus nerve, and to apply a cathodic current to the vagus nerve which is capable of inducing action potentials in the vagus nerve;
  • an anode adapted to be disposed at an anodal site of the vagus nerve, and to apply to the vagus nerve an anodal current which is capable of inhibiting action potentials in the vagus nerve, and
  • control unit is adapted to:
  • the cathodic current having a cathodic amplitude sufficient to induce action potentials in the medium- and large-diameter fibers, but generally insufficient to induce action potentials in the small-diameter fibers, and
  • anode to apply to the vagus nerve the anodal current having an anodal amplitude sufficient to inhibit action potentials in the large-diameter fibers, but generally insufficient to inhibit action potentials in the medium-diameter fibers.
  • apparatus for treating a subject including:
  • an electrode device adapted to be coupled to a vagus nerve of the subject
  • a sensor configured to detect a heart rate of the subject, and to generate a heart rate signal responsive thereto;
  • control unit adapted to:
  • control unit is adapted to configure the current to include a stimulating current, which is capable of inducing action potentials in a first set and a second set of nerve fibers of the vagus nerve, and an inhibiting current, which is capable of inhibiting the induced action potentials traveling in the second set of nerve fibers, the nerve fibers in the second set having generally larger diameters than the nerve fibers in the first set, and the control unit is adapted to drive the electrode device to apply the stimulating current and the inhibiting current to the vagus nerve.
  • the current includes a stimulating current, which is capable of inducing action potentials in the vagus nerve, and an inhibiting current, which is capable of inhibiting device-induced action potentials traveling in the vagus nerve in an afferent direction toward a brain of the subject, and the control unit is adapted to drive the electrode device to apply the stimulating current and the inhibiting current to the vagus nerve.
  • the vagus nerve includes small-, medium-, and large-diameter fibers
  • the electrode device includes:
  • a cathode adapted to be disposed at a cathodic site of the vagus nerve, and to apply a cathodic current to the vagus nerve which is capable of inducing action potentials in the vagus nerve;
  • an anode adapted to be disposed at an anodal site of the vagus nerve, and to apply to the vagus nerve an anodal current which is capable of inhibiting action potentials in the vagus nerve, and
  • control unit is adapted to:
  • the cathodic current having a cathodic amplitude sufficient to induce action potentials in the medium- and large-diameter fibers, but generally insufficient to induce action potentials in the small-diameter fibers, and
  • anode to apply to the vagus nerve the anodal current having an anodal amplitude sufficient to inhibit action potentials in the large-diameter fibers, but generally insufficient to inhibit action potentials in the medium-diameter fibers.
  • control unit is adapted to configure the current to increase the variability of the heart rate above a target heart rate variability.
  • the senor includes an electrocardiogram (ECG) monitor.
  • ECG electrocardiogram
  • control unit is adapted to withhold driving the electrode device upon determining that the heart rate is less than a value associated with bradycardia.
  • control unit is adapted to drive the electrode device to apply the current with an amplitude of between about 2 and about 10 milliamps. In an embodiment, the control unit is adapted to drive the electrode device to apply the current in intermittent ones of a plurality of cardiac cycles of the subject.
  • the apparatus includes an electrode selected from the list consisting of: an electrode for pacing the heart, and an electrode for defibrillating the heart, and the control unit is adapted to withhold driving the electrode device to apply the current to the vagus nerve if the control unit is driving the electrode selected from the list.
  • control unit is adapted to drive the electrode device to apply the current in respective pulse bursts in each of a plurality of cardiac cycles of the subject.
  • control unit is adapted to configure each pulse of each of the bursts to have a pulse duration of between about 0.2 and about 4 milliseconds.
  • control unit is adapted to configure each of the bursts to have a pulse repetition interval of greater than about 3 milliseconds.
  • control unit is adapted to configure at least one of the bursts to have between about 0 and about 8 pulses.
  • the apparatus includes an electrocardiogram (ECG) monitor, adapted to measure an ECG signal, the control unit is adapted to receive the ECG signal, and to initiate the applying of each burst after a delay following detection of a feature of the ECG.
  • ECG electrocardiogram
  • control unit is adapted to configure the current using a feedback algorithm.
  • a method for treating a subject including:
  • a threshold value which threshold value is greater than a normal heart rate
  • applying a current to a vagus nerve of the subject and configuring the current so as to reduce the heart rate of the subject.
  • a method for applying current to a vagus nerve including:
  • anodal current at a first anodal site of the vagus nerve and at a second anodal site of the vagus nerve; and applying a cathodic current to the vagus nerve at a cathodic site of the vagus nerve, so as to stimulate the vagus nerve, the cathodic site disposed between the first anodal site and the second anodal site.
  • a method for treating a subject including:
  • a method for treating a heart condition of a subject including:
  • a method for treating a subject including:
  • apparatus for treating a subject suffering from a heart condition including:
  • an electrode device adapted to be coupled to a vagus nerve of the subject
  • control unit adapted to drive the electrode device to apply a current to the vagus nerve, and to configure the current to suppress an adrenergic system of the subject, so as to treat the subject.
  • the heart condition includes heart failure
  • the control unit is adapted to configure the current to treat the heart failure
  • apparatus for treating a subject suffering from a heart condition including:
  • an electrode device adapted to be coupled to a vagus nerve of the subject
  • control unit adapted to drive the electrode device to apply a current to the vagus nerve, and to configure the current to modulate contractility of at least a portion of a heart of the subject, so as to treat the subject.
  • control unit is adapted to configure the current to reduce atrial and ventricular contractility.
  • the heart condition includes hypertrophic cardiopathy
  • the control unit is adapted to configure the current so as to treat the hypertrophic cardiopathy.
  • apparatus for treating a subject suffering from a heart condition including:
  • an electrode device adapted to be coupled to a vagus nerve of the subject; and a control unit, adapted to drive the electrode device to apply a current to the vagus nerve, and to configure the current to increase coronary blood flow, so as to treat the subject.
  • the heart condition is selected from the list consisting of: myocardial ischemia, ischemic heart disease, heart failure, and variant angina
  • the control unit is adapted to configure the current to increase the coronary blood flow so as to treat the selected heart condition.
  • a treatment method including:
  • a treatment method including:
  • configuring the current to modulate contractility of at least a portion of a heart of the subject, so as to treat the subject.
  • a treatment method including:
  • apparatus including:
  • an electrode device adapted to be coupled to a vagus nerve of a subject
  • control unit adapted to drive the electrode device to apply to the vagus nerve a current that reduces heart rate variability of the subject.
  • control unit is adapted to configure the current to substantially not reduce a heart rate of the subject.
  • control unit is adapted to configure the current to reduce the heart rate variability by at least 5% below a baseline thereof during a time period in which a heart rate of the subject is not reduced responsive to the current by more than 10% below a baseline thereof.
  • control unit is adapted to configure the current to effect a reduction of a heart rate of the subject while reducing the heart rate variability of the subject.
  • control unit is adapted to drive the electrode device during exertion by the subject.
  • control unit is adapted to withhold driving the electrode device when the subject is not experiencing exertion.
  • control unit is adapted to configure the current to reduce a heart rate variability of the subject having a characteristic frequency between about 0.15 and about 0.4 Hz.
  • control unit is adapted to configure the current to reduce a heart rate variability of the subject having a characteristic frequency between about 0.04 and about 0.15 Hz.
  • control unit is adapted to drive the electrode device to apply the current with an amplitude of between about 2 and about 10 milliamps.
  • control unit is adapted to drive the electrode device to apply the current in intermittent ones of a plurality of cardiac cycles of the subject.
  • control unit is adapted to drive the electrode device to apply the current unsynchronized with a cardiac cycle of the subject.
  • control unit is adapted to drive the electrode device responsive to a circadian rhythm of the subject.
  • control unit is adapted to drive the electrode device when the subject is awake.
  • control unit is adapted to withhold driving the electrode device when the subject is sleeping.
  • control unit is adapted to drive the electrode device to apply the current in a manner that reduces the heart rate variability by at least 10%.
  • control unit is adapted to drive the electrode device to apply the current in a manner that reduces the heart rate variability by at least 50%.
  • control unit is adapted to drive the electrode device to apply the current in a manner that reduces a standard deviation of a heart rate of the subject within a time window, e.g., a time window that is longer than 10 seconds.
  • a time window e.g., a time window that is longer than 10 seconds.
  • the standard deviation of the heart rate is reduced by at least about 10% or at least about 50% within the time window that is longer than 10 seconds.
  • control unit is adapted to drive the electrode device to apply the current in respective pulse bursts in each of a plurality of cardiac cycles of the subject.
  • control unit is adapted to configure each pulse of each of the bursts to have a pulse duration of between about 0.1 and about 4 milliseconds.
  • control unit is adapted to configure each pulse of each of the bursts to have a pulse duration of between about 0.5 and about 2 milliseconds.
  • control unit is adapted to configure each of the bursts to have a pulse repetition interval of between about 2 and about 10 milliseconds.
  • control unit is adapted to configure each of the bursts to have a pulse repetition interval of between about 2 and about 6 milliseconds.
  • the apparatus includes a cardiac monitor, adapted to generate a cardiac signal, and the control unit is adapted to receive the cardiac signal, and to initiate the applying of each burst after a delay following detection of a feature of the cardiac signal.
  • the control unit is adapted to initiate the applying of each burst after a delay of about 30 to about 200 milliseconds following an R-wave of the cardiac signal.
  • the control unit is adapted to initiate the applying of each burst after a delay of about 50 to about 150 milliseconds following an R-wave of the cardiac signal.
  • control unit is adapted to configure at least one of the bursts to have between about 0 and about 20 pulses.
  • the control unit is adapted to configure the bursts to have between about 1 and about 8 pulses during steady state operation.
  • the apparatus includes a heart sensor, configured to detect heart activity of the subject, and to generate a heart signal responsive thereto, and the control unit is adapted to receive the heart signal, and, responsive to receiving the heart signal, drive the electrode device to apply the current to the vagus nerve.
  • control unit is adapted to, responsive to receiving the heart signal, drive the electrode device to apply to the vagus nerve the current synchronized with a cardiac cycle of the subject.
  • control unit is adapted to, responsive to receiving the heart signal, drive the electrode device to apply to the vagus nerve the current unsynchronized with a cardiac cycle of the subject.
  • control unit is adapted to configure the current to reduce a heart rate of the subject.
  • the apparatus includes a sensor, configured to detect the heart rate of the subject, and to generate a heart rate signal responsive thereto
  • the control unit includes an integral feedback controller that has inputs including the detected heart rate and a target heart rate, and the control unit is adapted to configure the current responsive to an output of the integral feedback controller, so as to reduce the heart rate of the subject toward the target heart rate.
  • the target heart rate includes a target normal heart rate within a range of normal heart rates of the subject, and the control unit is adapted to configure the current so as to reduce the heart rate of the subject toward the target normal heart rate.
  • control unit is adapted to configure the current to reduce the heart rate variability so as to treat a condition of the subject.
  • the condition includes heart failure of the subject, and the control unit is adapted to configure the current to reduce the heart rate variability by at least about 10% so as to treat the heart failure.
  • the condition includes an occurrence of arrhythmia of the subject, and the control unit is adapted to configure the current to reduce the heart rate variability by at least about 10% so as to treat the occurrence of arrhythmia.
  • the condition includes atrial fibrillation of the subject, and the control unit is adapted to configure the current to reduce the heart rate variability so as to treat the atrial fibrillation.
  • a method including applying to a vagus nerve of a subject a current that reduces heart rate variability of the subject.
  • FIG. 1 is a block diagram that schematically illustrates a vagal stimulation system applied to a vagus nerve of a patient, in accordance with an embodiment of the present invention
  • FIG. 2A is a simplified cross-sectional illustration of a multipolar electrode device applied to a vagus nerve, in accordance with an embodiment of the present invention
  • FIG. 2B is a simplified cross-sectional illustration of a generally-cylindrical electrode device applied to a vagus nerve, in accordance with an embodiment of the present invention
  • FIG. 2C is a simplified perspective illustration of the electrode device of FIG. 2A , in accordance with an embodiment of the present invention.
  • FIG. 3 is a simplified perspective illustration of a multipolar point electrode device applied to a vagus nerve, in accordance with an embodiment of the present invention
  • FIG. 4 is a conceptual illustration, of the application of current to a vagus nerve, in accordance with an embodiment of the present invention
  • FIG. 5 is a simplified illustration of an electrocardiogram (ECG) recording and of example timelines showing the timing of the application of a series of stimulation pulses, in accordance with an embodiment of the present invention.
  • ECG electrocardiogram
  • FIG. 6 is a graph showing in vivo experimental results, measured in accordance with an embodiment of the present invention.
  • FIG. 1 is a block diagram that schematically illustrates a vagal stimulation system 18 comprising a multipolar electrode device 40 , in accordance with an embodiment of the present invention.
  • Electrode device 40 is applied to a portion of a vagus nerve 36 (either a left vagus nerve 37 or a right vagus nerve 39 ), which innervates a heart 30 of a patient 31 .
  • system 18 is utilized for treating a heart condition such as heart failure and/or cardiac arrhythmia.
  • Vagal stimulation system 18 further comprises an implanted or external control unit 20 , which typically communicates with electrode device 40 over a set of leads 42 .
  • Control unit 20 drives electrode device 40 to (i) apply signals to induce the propagation of efferent nerve impulses towards heart 30 , and (ii) suppress artificially-induced afferent nerve impulses towards a brain 34 of the patient, in order to minimize unintended side effects of the signal application.
  • the efferent nerve pulses in vagus nerve 36 are induced by electrode device 40 in order to regulate the heart rate of the patient.
  • control unit 20 is adapted to receive feedback from one or more of the electrodes in electrode device 40 , and to regulate the signals applied to the electrode device responsive thereto.
  • Control unit 20 is typically adapted to receive and analyze one or more sensed physiological parameters or other parameters of the patient, such as heart rate, electrocardiogram (ECG), blood pressure, indicators of decreased cardiac contractility, cardiac output, norepinephrine concentration, or motion of the patient.
  • control unit 20 may comprise, for example, an ECG monitor 24 , connected to a site on the patient's body such as heart 30 , for example using one or more subcutaneous sensors or ventricular and/or atrial intracardiac sensors.
  • the control unit may also comprise an accelerometer 22 for detecting motion of the patient.
  • ECG monitor 24 and/or accelerometer 22 comprise separate implanted devices placed external to control unit 20 , and, optionally, external to the patient's body.
  • control unit 20 receives signals from one or more physiological sensors 26 , such as blood pressure sensors. Sensors 26 are typically implanted in the patient, for example in a left ventricle 32 of heart 30 .
  • control unit 20 comprises or is coupled to an implanted device 25 for monitoring and correcting the heart rate, such as an implantable cardioverter defibrillator (ICD) or a pacemaker (e.g., a bi-ventricular or standard pacemaker).
  • ICD implantable cardioverter defibrillator
  • pacemaker e.g., a bi-ventricular or standard pacemaker
  • implanted device 25 may be incorporated into a control loop executed by control unit 20 , in order to increase the heart rate when the heart rate for any reason is too low.
  • FIG. 2A is a simplified cross-sectional illustration of a generally-cylindrical electrode device 40 applied to vagus nerve 36 , in accordance with an embodiment of the present invention.
  • Electrode device 40 comprises a central cathode 46 for applying a negative current (“cathodic current”) in order to stimulate vagus nerve 36 , as described below.
  • Electrode device 40 additionally comprises a set of one or more anodes 44 ( 44 a , 44 b , herein: “efferent anode set 44 ”), placed between cathode 46 and the edge of electrode device 40 closer to heart 30 (the “efferent edge”).
  • Efferent anode set 44 applies a positive current (“efferent anodal current”) to vagus nerve 36 , for blocking action potential conduction in vagus nerve 36 induced by the cathodic current, as described below.
  • electrode device 40 comprises an additional set of one or more anodes 45 ( 45 a , 45 b , herein: “afferent anode set 45 ”), placed between cathode 46 and the edge of electrode device 40 closer to brain 34 .
  • Afferent anode set 45 applies a positive current (“afferent anodal current”) to vagus nerve 36 , in order to block propagation of action potentials in the direction of the brain during application of the cathodic current.
  • the one or more anodes of efferent anode set 44 are directly electrically coupled to the one or more anodes of afferent anode set 45 , such as by a common wire or shorted wires providing current to both anode sets substantially without any intermediary elements.
  • coatings on the anodes, shapes of the anodes, positions of the anodes, sizes of the anodes and/or distances of the various anodes from the nerve are regulated so as to produce desired ratios of currents and/or desired activation functions delivered through or caused by the various anodes.
  • the relative impedance between the respective anodes and central cathode 46 is regulated, whereupon more anodal current is driven through the one or more anodes having lower relative impedance.
  • central cathode 46 is typically placed closer to one of the anode sets than to the other, for example, so as to induce asymmetric stimulation (i.e., not necessarily unidirectional in all fibers) between the two sides of the electrode device. The closer anode set typically induces a stronger blockade of the cathodic stimulation.
  • Electrode device 240 comprises exactly one efferent anode 244 and exactly one afferent anode 245 , which are electrically coupled to each other, such as by a common wire 250 or shorted wires providing current to both anodes 244 and 245 , substantially without any intermediary elements.
  • the cathodic current is applied by a cathode 246 with an amplitude sufficient to induce action potentials in large- and medium-diameter fibers (e.g., A- and B-fibers), but insufficient to induce action potentials in small-diameter fibers (e.g., C-fibers).
  • large- and medium-diameter fibers e.g., A- and B-fibers
  • small-diameter fibers e.g., C-fibers
  • Electrodes 46 and anode sets 44 and 45 are typically mounted in an electrically-insulating cuff 48 and separated from one another by insulating elements such as protrusions 49 of the cuff.
  • the width of the electrodes is between about 0.5 and about 2 millimeters, or is equal to approximately one-half the radius of the vagus nerve.
  • the electrodes are typically recessed so as not to come in direct contact with vagus nerve 36 . For some applications, such recessing enables the electrodes to achieve generally uniform field distributions of the generated currents and/or generally uniform values of the activation function defined by the electric potential field in the vicinity of vagus nerve 24 .
  • protrusions 49 allow vagus nerve 24 to swell into the canals defined by the protrusions, while still holding the vagus nerve centered within cuff 48 and maintaining a rigid electrode geometry.
  • cuff 48 comprises additional recesses separated by protrusions, which recesses do not contain active electrodes. Such additional recesses accommodate swelling of vagus nerve 24 without increasing the contact area between the vagus nerve and the electrodes.
  • the distance between the electrodes and the axis of the vagus nerve is between about 1 and about 4 millimeters, and is greater than the closest distance from the ends of the protrusions to the axis of the vagus nerve.
  • protrusions 49 are relatively short (as shown).
  • the distance between the ends of protrusions 49 and the center of the vagus nerve is between about 1 and 3 millimeters. (Generally, the diameter of the vagus nerve is between about 2 and 3 millimeters.)
  • protrusions 49 are longer and/or the electrodes are placed closer to the vagus nerve in order to reduce the energy consumption of electrode device 40 .
  • efferent anode set 44 comprises a plurality of anodes 44 , typically two anodes 44 a and 44 b , spaced approximately 0.5 to 2.0 millimeters apart.
  • Application of the efferent anodal current in appropriate ratios from a plurality of anodes generally minimizes the “virtual cathode effect,” whereby application of too large an anodal current stimulates rather than blocks fibers.
  • anode 44 a applies a current with an amplitude equal to about 0.5 to about 5 milliamps (typically one-third of the amplitude of the current applied by anode 44 b ).
  • the virtual cathode effect generally hinders blocking of smaller-diameter fibers, as described below, because a relatively large anodal current is generally necessary to block such fibers.
  • Anode 44 a is typically positioned in cuff 48 to apply current at the location on vagus nerve 36 where the virtual cathode effect is maximally generated by anode 44 b .
  • efferent anode set 44 typically comprises a plurality of virtual-cathode-inhibiting anodes 44 a , one or more of which is activated at any time based on the expected magnitude and location of the virtual cathode effect.
  • afferent anode set 45 typically comprises a plurality of anodes 45 , typically two anodes 45 a and 45 b , in order to minimize the virtual cathode effect in the direction of the brain.
  • cathode 46 comprises a plurality of cathodes in order to minimize the “virtual anode effect,” which is analogous to the virtual cathode effect.
  • FIG. 2C is a simplified perspective illustration of electrode device 40 ( FIG. 2A ), in accordance with an embodiment of the present invention.
  • electrode device 40 When applied to vagus nerve 36 , electrode device 40 typically encompasses the nerve.
  • control unit 20 typically drives electrode device 40 to (i) apply signals to vagus nerve 36 in order to induce the propagation of efferent action potentials towards heart 30 , and (ii) suppress artificially-induced afferent action potentials towards brain 34 .
  • the electrodes typically comprise ring electrodes adapted to apply a generally uniform current around the circumference of the nerve, as best shown in FIG. 2C .
  • FIG. 3 is a simplified perspective illustration of a multipolar point electrode device 140 applied to vagus nerve 36 , in accordance with an embodiment of the present invention.
  • anodes 144 a and 144 b and a cathode 146 typically comprise point electrodes (typically 2 to 100), fixed inside an insulating cuff 148 and arranged around vagus nerve 36 so as to selectively stimulate nerve fibers according to their positions inside the nerve.
  • point electrodes typically have a surface area between about 0.01 mm 2 and 1 mm 2 .
  • the point electrodes are in contact with vagus nerve 36 , as shown, while in other applications the point electrodes are recessed in cuff 148 , so as not to come in direct contact with vagus nerve 36 , similar to the recessed ring electrode arrangement described above with reference to FIG. 2A .
  • one or more of the electrodes such as cathode 146 or anode 144 a , comprise a ring electrode, as described with reference to FIG. 2C , such that electrode device 140 comprises both ring electrode(s) and point electrodes (configuration not shown).
  • electrode device 40 optionally comprises an afferent anode set (positioned like anodes 45 a and 45 b in FIG. 2A ), the anodes of which comprise point electrodes and/or ring electrodes.
  • ordinary, non-cuff electrodes are used, such as when the electrodes are placed on the epicardial fat pads instead of on the vagus nerve.
  • FIG. 4 is a conceptual illustration of the application of current to vagus nerve 36 in order to achieve smaller-to-larger diameter fiber recruitment, in accordance with an embodiment of the present invention.
  • control unit 20 drives electrode device 40 to selectively recruit nerve fibers beginning with smaller-diameter fibers and to progressively recruit larger-diameter fibers as the desired stimulation level increases. This smaller-to-larger diameter recruitment order mimics the body's natural order of recruitment.
  • the control unit stimulates myelinated fibers essentially of all diameters using cathodic current from cathode 46 , while simultaneously inhibiting fibers in a larger-to-smaller diameter order using efferent anodal current from efferent anode set 44 .
  • FIG. 4 illustrates the recruitment of a single, smallest nerve fiber 56 , without the recruitment of any larger fibers 50 , 52 and 54 .
  • the depolarizations generated by cathode 46 stimulate all of the nerve fibers shown, producing action potentials in both directions along all the nerve fibers.
  • Efferent anode set 44 generates a hyperpolarization effect sufficiently strong to block only the three largest nerve fibers 50 , 52 and 54 , but not fiber 56 .
  • This blocking order of larger-to-smaller diameter fibers is achieved because larger nerve fibers are inhibited by weaker anodal currents than are smaller nerve fibers. Stronger anodal currents inhibit progressively smaller nerve fibers.
  • the action potentials induced by cathode 46 in larger fibers 50 , 52 and 54 reach the hyperpolarized region in the larger fibers adjacent to efferent anode set 44 , these action potentials are blocked.
  • the action potentials induced by cathode 46 in smallest fiber 56 are not blocked, and continue traveling unimpeded toward heart 30 .
  • Anode pole 44 a is shown generating less current than anode pole 44 b in order to minimize the virtual cathode effect in the direction of the heart, as described above.
  • the number of fibers not blocked is progressively increased by decreasing the amplitude of the current applied by efferent anode set 44 .
  • the action potentials induced by cathode 46 in the fibers now not blocked travel unimpeded towards the heart.
  • the parasympathetic stimulation delivered to the heart is progressively increased in a smaller-to-larger diameter fiber order, mimicking the body's natural method of increasing stimulation.
  • the amplitudes of the currents applied by cathode 46 and efferent anode set 44 are both increased (thereby increasing both the number of fibers stimulated and blocked).
  • the amount of stimulation delivered to the heart can be increased by increasing the PPT, frequency, and/or pulse width of the current applied to vagus nerve 36 .
  • control unit 20 In order to suppress artificially-induced afferent action potentials from traveling towards the brain in response to the cathodic stimulation, control unit 20 typically drives electrode device 40 to inhibit fibers 50 , 52 , 54 and 56 using afferent anodal current from afferent anode set 45 .
  • afferent-directed action potentials induced by cathode 46 in all of the fibers reach the hyperpolarized region in all of the fibers adjacent to afferent anode set 45 , the action potentials are blocked. Blocking these afferent action potentials generally minimizes any unintended side effects, such as undesired or counterproductive feedback to the brain, that might be caused by these action potentials.
  • Anode 45 b is shown generating less current than anode 45 a in order to minimize the virtual cathode effect in the direction of the brain, as described above.
  • the amplitude of the cathodic current applied in the vicinity of the vagus nerve is between about 2 milliamps and about 10 milliamps.
  • Such a current is typically used in embodiments that employ techniques for achieving generally uniform stimulation of the vagus nerve, i.e., stimulation in which the stimulation applied to fibers on or near the surface of the vagus nerve is generally no more than about 400% greater than stimulation applied to fibers situated more deeply in the nerve.
  • stimulation in which the value of the activation function at fibers on or near the surface of the vagus nerve is generally no more than about four times greater than the value of the activation function at fibers situated more deeply in the nerve.
  • the electrodes may be recessed so as not to come in direct contact with vagus nerve 24 , in order to achieve generally uniform values of the activation function.
  • embodiments using approximately 5 mA of cathodic current have the various electrodes disposed approximately 0.5 to 2.5 mm from the axis of the vagus nerve.
  • larger cathodic currents e.g., 10-30 mA
  • electrode distances from the axis of the vagus nerve of greater than 2.5 mm e.g., 2.5-4.0 mm
  • the cathodic current is applied by cathode 46 with an amplitude sufficient to induce action potentials in large- and medium-diameter fibers 50 , 52 , and 54 (e.g., A- and B-fibers), but insufficient to induce action potentials in small-diameter fibers 56 (e.g., C-fibers).
  • an anodal current is applied by anode 44 b in order to inhibit action potentials induced by the cathodic current in the large-diameter fibers (e.g., A-fibers).
  • This combination of cathodic and anodal current generally results in the stimulation of medium-diameter fibers (e.g., B-fibers) only.
  • medium-diameter fibers e.g., B-fibers
  • a portion of the afferent action potentials induced by the cathodic current are blocked by anode 45 a , as described above.
  • the afferent anodal current is configured to not fully block afferent action potentials, or is simply not applied. In these cases, artificial afferent action potentials are nevertheless generally not generated in C-fibers, because the applied cathodic current is not strong enough to generate action potentials in these fibers.
  • the amplitude of the cathodic current applied by cathode 46 may be between about 3 and about 10 milliamps, and the amplitude of the anodal current applied by anode 44 b may be between about 1 and about 7 milliamps. (Current applied at a different site and/or a different time is used to achieve a net current injection of zero.)
  • Control unit 20 is typically configured to commence or halt stimulation, or to vary the amount and/or timing of stimulation in order to achieve a desired target heart rate, typically based on configuration values and on parameters including one or more of the following:
  • control unit can be configured to drive electrode device 40 to stimulate the vagus nerve based on baroreflex sensitivity.
  • control unit 20 is configured to drive electrode device 40 to stimulate the vagus nerve so as to reduce the heart rate of the subject towards a target heart rate.
  • the target heart rate is typically (a) programmable or configurable, (b) determined responsive to one or more sensed physiological values, such as those described hereinabove (e.g., motion, blood pressure, etc.), and/or (c) determined responsive to a time of day or circadian cycle of the subject.
  • Parameters of stimulation are varied in real time in order to vary the heart-rate-lowering effects of the stimulation. For example, such parameters may include the amplitude of the applied current.
  • the stimulation is applied in a series of pulses that are synchronized or are not synchronized with the cardiac cycle of the subject, such as described hereinbelow with reference to FIG. 5 .
  • Parameters of such pulse series typically include, but are not limited to:
  • values of the “on”/“off” parameter are determined in real time, responsive to one or more inputs, such as sensed physiological values.
  • inputs typically include motion or activity of the subject (e.g., detected using an accelerometer), the average heart rate of the subject when the device is in “off” mode, and/or the time of day.
  • the device may operate in continuous “on” mode when the subject is exercising and therefore has a high heart rate, and the device may alternate between “on” and “off” when the subject is at rest.
  • the heart-rate-lowering effect is concentrated during periods of high heart rate, and the nerve is allowed to rest when the heart rate is generally naturally lower.
  • heart rate regulation is achieved by setting two or more parameters in combination. For example, if it is desired to apply 5.2 pulses of stimulation, the control unit may apply 5 pulses of 1 ms duration each, followed by a single pulse of 0.2 ms duration. For other applications, the control unit switches between two values of PPT, so that the desired PPT is achieved by averaging the applied PPTs. For example, a sequence of PPTs may be 5, 5, 5, 5, 6, 5, 5, 5, 5, 6, . . . , in order to achieve an effective PPT of 5.2.
  • control unit 20 uses a slow-reacting heart rate regulation algorithm to modify heart-rate-controlling parameters of the stimulation, i.e., the algorithm varies stimulation parameters slowly in reaction to changes in heart rate. For example, in response to a sudden increase in heart rate, e.g., an increase from a target heart rate of 60 beats per minute (BPM) to 100 BPM over a period of only a few seconds, the algorithm slowly increases the stimulation level over a period of minutes. If the heart rate naturally returns to the target rate over this period, the stimulation levels generally do not change substantially before returning to baseline levels.
  • a slow-reacting heart rate regulation algorithm to modify heart-rate-controlling parameters of the stimulation, i.e., the algorithm varies stimulation parameters slowly in reaction to changes in heart rate. For example, in response to a sudden increase in heart rate, e.g., an increase from a target heart rate of 60 beats per minute (BPM) to 100 BPM over a period of only a few seconds, the algorithm slowly increases the stimulation level over a
  • the heart of a subject is regulated while the subject is inactive, such as while sitting.
  • the subject suddenly increases his activity level, such as by standing up or climbing stairs, the subject's heart rate increases suddenly.
  • the control unit adjusts the stimulation parameters slowly to reduce the subject's heart rate.
  • Such a gradual modification of stimulation parameters allows the subject to engage in relatively stressful activities for a short period of time before his heart rate is substantially regulated, generally resulting in an improved quality of life.
  • control unit 20 is adapted to detect bradycardia (i.e., that an average detected R-R interval exceeds a preset bradycardia limit), and to terminate heart rate regulation substantially immediately upon such detection, such as by ceasing vagal stimulation.
  • the control unit uses an algorithm that reacts quickly to regulate heart rate when the heart rate crosses limits that are predefined (e.g., a low limit of 40 beats per minute (BPM) and a high limit of 140 BPM), or determined in real time, such as responsive to sensed physiological values.
  • BPM beats per minute
  • control unit 20 is configured to operate intermittently. Typically, upon each resumption of operation, control unit 20 sets the stimulation parameters to those in effect immediately prior to the most recent cessation of operation. For some applications, such parameters applied upon resumption of operation are maintained without adjustment for a certain number of heartbeats (e.g., between about one and about ten), in order to allow the heart rate to stabilize after resumption of operation.
  • a certain number of heartbeats e.g., between about one and about ten
  • control unit 20 is configured to operate intermittently with gradual changes in stimulation.
  • the control unit may operate according to the following “on”/“off” pattern: (a) “off” mode for 30 minutes, (b) a two-minute “on” period characterized by a gradual increase in stimulation so as to achieve a target heart rate, (c) a six-minute “on” period of feedback-controlled stimulation to maintain the target heart rate, and (d) a two-minute “on” period characterized by a gradual decrease in stimulation to return the heart rate to baseline.
  • the control unit then repeats the cycle, beginning with another 30-minute “off” period.
  • control unit 20 is configured to operate in an adaptive intermittent mode.
  • the control unit sets the target heart rate for the “on” period equal to a fixed or configurable fraction of the average heart rate during the previous “off” period, typically bounded by a preset minimum. For example, assume that for a certain subject the average heart rates during sleep and during exercise are 70 and 150 BPM, respectively. Further assume that the target heart rate for the “on” period is set at 70% of the average heart rate during the previous “off” period, with a minimum of 60 BPM.
  • a heart rate regulation algorithm used by control unit 20 has as an input a time derivative of the sensed heart rate.
  • the algorithm typically directs the control unit to respond slowly to increases in heart rate and quickly to decreases in heart rate.
  • the heart rate regulation algorithm utilizes sensed physiological parameters for feedback.
  • the feedback is updated periodically by inputting the current heart rate.
  • such updating occurs at equally-spaced intervals.
  • the feedback is updated by inputting the current heart rate upon each detection of a feature of the ECG, such as an R-wave.
  • the algorithm adds the square of each R-R interval, thus taking into account the non-uniformity of the update interval, e.g., in order to properly analyze feedback stability using standard tools and methods developed for canonical feedback.
  • control unit 20 implements a detection blanking period, during which the control unit does not detect heart beats. In some instances, such non-detection may reduce false detections of heart beats.
  • detection blanking period during which the control unit does not detect heart beats.
  • the heart rate regulation algorithm is implemented using only integer arithmetic.
  • division is implemented as integer division by a power of two, and multiplication is always of two 8-bit numbers.
  • time is measured in units of 1/128 of a second.
  • control unit 20 implements an integral feedback controller, which can most generally be described by:
  • K represents the strength of the feedback
  • K I is a coefficient
  • ⁇ e dt represents the cumulative error
  • heart rate is typically expressed as an R-R interval (the inverse of heart rate).
  • Parameters of the integral controller typically include TargetRR (the target R-R interval) and TimeCoeff (which determines the overall feedback reaction time).
  • the previous R-R interval is calculated and assigned to a variable (LastRR).
  • e i.e., the difference between the target R-R interval and the last measured R-R interval
  • e is typically limited by control unit 20 to a certain range, such as between ⁇ 0.25 and +0.25 seconds, by reducing values outside the range to the endpoint values of the range.
  • LastRR is typically limited, such as to 255/128 seconds. The error is then calculated by multiplying LastRR by e:
  • a cumulative error (representing the integral in the above generalized equation) is then calculated by dividing the error by TimeCoeff and adding the result to the cumulative error, as follows:
  • the integral is limited to positive values less than, e.g., 36,863.
  • the number of pulses applied in the next series of pulses (pulses per trigger, or PPT) is equal to the integral/4096.
  • the following table illustrates example calculations using a heart rate regulation algorithm that implements an integral controller, in accordance with an embodiment of the present invention.
  • the parameter TargetRR (the target heart rate) is set to 1 second (128/128 seconds), and the parameter TimeCoeff is set to 0.
  • the initial value of Integral is 0.
  • the number of pulses per trigger (PPT) increases from 0 during the first heart beat, to 2 during the fourth heart beat of the example.
  • the heart rate regulation algorithm corrects for missed heart beats (either of physiological origin or because of a failure to detect a beat).
  • any R-R interval which is about twice as long as the immediately preceding R-R interval is interpreted as two R-R intervals, each having a length equal to half the measured interval.
  • the R-R interval sequence (measured in seconds) 1, 1, 1, 2.2 is interpreted by the algorithm as the sequence 1, 1, 1, 1.1, 1.1.
  • the algorithm corrects for premature beats, typically by adjusting the timing of beats that do not occur approximately halfway between the preceding and following beats.
  • the R-R interval sequence (measured in seconds) 1, 1, 0.5, 1.5 is interpreted as 1, 1, 1, 1, 1, 1, using the assumption that the third beat was premature.
  • control unit 20 is configured to operate in one of the following modes:
  • the amplitude of the applied stimulation current is calibrated by fixing a number of pulses in the series of pulses (per cardiac cycle), and then increasing the applied current until a desired pre-determined heart rate reduction is achieved.
  • the current is calibrated by fixing the number of pulses per series of pulses, and then increasing the current to achieve a substantial reduction in heart rate, e.g., 40%.
  • control unit 20 In embodiments of the present invention in which vagal stimulation system 18 comprises implanted device 25 for monitoring and correcting the heart rate, control unit 20 typically uses measured parameters received from device 25 as additional inputs for determining the level and/or type of stimulation to apply. Control unit 20 typically coordinates its behavior with the behavior of device 25 . Control unit 20 and device 25 typically share sensors 26 in order to avoid redundancy in the combined system.
  • vagal stimulation system 18 comprises a patient override, such as a switch that can be activated by the patient using an external magnet.
  • the override typically can be used by the patient to activate vagal stimulation, for example in the event of arrhythmia apparently undetected by the system, or to deactivate vagal stimulation, for example in the event of apparently undetected physical exertion.
  • FIG. 5 is a simplified illustration of an ECG recording 70 and example timelines 72 and 76 showing the timing of the application of a burst of stimulation pulses 74 , in accordance with an embodiment of the present invention.
  • Stimulation is typically applied to vagus nerve 36 in a closed-loop system in order to achieve and maintain the desired target heart rate, determined as described above.
  • Precise graded slowing of the heart beat is typically achieved by varying the number of nerve fibers stimulated, in a smaller-to-larger diameter order, and/or the intensity of vagus nerve stimulation, such as by changing the stimulation amplitude, pulse width, PPT, and/or delay.
  • Stimulation with blocking is typically applied during each cardiac cycle in burst of pulses 74 , typically containing between about 1 and about 20 pulses, each of about 1-3 milliseconds duration, over a period of about 1-200 milliseconds.
  • pulses 74 typically containing between about 1 and about 20 pulses, each of about 1-3 milliseconds duration, over a period of about 1-200 milliseconds.
  • such short pulse durations generally do not substantially block or interfere with the natural efferent or afferent action potentials traveling along the vagus nerve.
  • the number of pulses and/or their duration is sometimes varied in order to facilitate achievement of precise graded slowing of the heart beat.
  • the target heart rate is expressed as a ventricular R-R interval (shown as the interval between R 1 and R 2 in FIG. 5 ).
  • the actual R-R interval is measured in real time and compared with the target R-R interval. The difference between the two intervals is defined as a control error.
  • Control unit 20 calculates the change in stimulation necessary to move the actual R-R towards the target R-R, and drives electrode device 40 to apply the new calculated stimulation. Intermittently, e.g., every 1, 10, or 100 beats, measured R-R intervals or average R-R intervals are evaluated, and stimulation of the vagus nerve is modified accordingly.
  • vagal stimulation system 18 is further configured to apply stimulation responsive to pre-set time parameters, such as intermittently, constantly, or based on the time of day.
  • one or more of the techniques of smaller-to-larger diameter fiber recruitment, selective fiber population stimulation and blocking, and varying the intensity of vagus nerve stimulation by changing the stimulation amplitude, pulse width, PPT, and/or delay are applied in conjunction with methods and apparatus described in one or more of the patents, patent applications, articles and books cited herein.
  • control unit 20 is configured to stimulate vagus nerve 36 so as to suppress the adrenergic system, in order to treat a subject suffering from a heart condition.
  • vagal stimulation may be applied for treating a subject suffering from heart failure.
  • hyper-activation of the adrenergic system damages the heart. This damage causes further activation of the adrenergic system, resulting in a vicious cycle.
  • High adrenergic tone is harmful because it often results in excessive release of angiotensin and epinephrine, which increase vascular resistance (blood pressure), reduce heart rest time (accelerated heart rate), and cause direct toxic damage to myocardial muscles through oxygen free radicals and DNA damage.
  • control unit 20 is configured to stimulate vagus nerve 36 so as to modulate atrial and ventricular contractility, in order to treat a subject suffering from a heart condition.
  • Vagal stimulation generally reduces both atrial and ventricular contractility (see, for example, the above-cited article by Levy M N et al., entitled “Parasympathetic Control of the Heart”).
  • Vagal stimulation using the techniques described herein, typically (a) reduces the contractility of the atria, thereby reducing the pressure in the venous system, and (b) reduces the ventricular contractile force of the atria, which may reduce oxygen consumption, such as in cases of ischemia.
  • vagal stimulation, as described herein is applied in order to reduce the contractile force of the ventricles in cases of hypertrophic cardiopathy.
  • the vagal stimulation is typically applied with a current of at least about 4 mA.
  • control unit 20 is configured to stimulate vagus nerve 36 so as to improve coronary blood flow, in order to treat a subject suffering from a heart condition. Improving coronary blood flow by administering acetylcholine is a well known technique. For example, during Percutaneous Transluminal Coronary Angioplasty (PTCA), when maximal coronary dilation is needed, direct infusion of acetylcholine is often used to dilate the coronary arteries (see, for example, the above-cited article by Feliciano L et al.).
  • PTCA Percutaneous Transluminal Coronary Angioplasty
  • vagal stimulation techniques described herein are used to improve coronary blood flow in subjects suffering from myocardial ischemia, ischemic heart disease, heart failure, and/or variant angina (spastic coronary arteries). It is hypothesized that such vagal stimulation simulates the effect of acetylcholine administration.
  • control unit 20 is configured to drive electrode device 40 to stimulate vagus nerve 36 so as to modify heart rate variability of the subject.
  • control unit 20 is configured to apply the stimulation having a duty cycle, which typically produces heart rate variability at the corresponding frequency.
  • duty cycles may be in the range of once per every several heartbeats.
  • control unit 20 is configured to apply generally continuous stimulation (e.g., in a manner that produces a prolonged reduced level of heart rate variability).
  • control unit 20 synchronizes the stimulation with the cardiac cycle of the subject, while for other applications, the control unit does not synchronize the stimulation with the cardiac cycle.
  • the stimulation may be applied in a series of pulses that are not synchronized with the cardiac cycle of the subject.
  • the stimulation may be applied in a series of pulses that are synchronized with the cardiac cycle of the subject, such as described hereinabove with reference to FIG. 5 .
  • control unit 20 is configured to apply stimulation with parameters selected to reduce heart rate variability, while for other applications parameters are selected that increase variability.
  • parameters selected to reduce heart rate variability may include one or more of the following:
  • the parameters of the stimulation are selected to both reduce the heart rate of the subject and heart rate variability of the subject.
  • the parameters are selected to reduce heart rate variability while substantially not reducing the average heart rate of the subject.
  • a non-substantial heart rate reduction may be less than about 10%.
  • stimulation is applied using the feedback techniques described hereinabove, with a target heart rate greater than the normal average heart rate of the subject. Such stimulation typically does not substantially change the average heart rate, yet reduces heart rate variability (however, the instantaneous (but not average) heart rate may sometimes be reduced).
  • stimulation is applied using a target heart rate lower than the normal average heart rate of the subject.
  • the magnitude of the change in average heart rate as well as the percentage of time during which reduced heart rate variability occurs in these applications are controlled by varying the difference between the target heart rate and the normal average heart rate.
  • control unit 20 is configured to apply stimulation only when the subject is awake. Reducing heart variability when the subject is awake offsets natural increases in heart rate variability during this phase of the circadian cycle.
  • control unit 20 is configured to apply or apply greater stimulation at times of exertion by the subject, in order to offset the increase in heart rate variability typically caused by exertion.
  • control unit 20 may determine that the subject is experiencing exertion responsive to an increase in heart rate, or responsive to a signal generated by an accelerometer.
  • the control unit uses other techniques known in the art for detecting exertion.
  • control unit 20 is configured to drive electrode device 40 to stimulate vagus nerve 36 so as to modify heart rate variability in order to treat a condition of the subject.
  • control unit is configured to additionally modify heart rate to treat the condition, while for other applications, the control unit is configured to modify heart rate variability while substantially not modifying average heart rate.
  • Therapeutic effects of reduction in heart rate variability include, but are not limited to:
  • FIG. 6 is a graph showing in vivo experimental results, measured in accordance with an embodiment of the present invention.
  • a dog was anesthetized, and cuff electrodes, similar to those described hereinabove with reference to FIG. 2B , were implanted in the right cervical vagus nerve. After a recovery period of two weeks, experimental vagal stimulation was applied to the dog while the dog was awake and allowed to move freely within its cage.
  • control unit 20 was programmed to apply vagal stimulation in a series of pulses, having the following parameters:
  • the control unit applied stimulation to the vagus nerve.
  • Heart rate variability was substantially reduced, while an average heart rate of 80 beats per minute was maintained. (Baseline heart rate, without stimulation, was approximately 95 beats per minute.)
  • stimulation was discontinued, and, as a result, heart rate variability increased substantially, returning to normal values. Average heart rate during these non-stimulation periods increased to approximately 95 beats per minute (approximately baseline value).
  • the scope of the present invention generally includes utilizing the techniques described herein to controllably stimulate the vagus nerve to facilitate treatments of, for example, heart failure, atrial fibrillation, and ischemic heart diseases.
  • the techniques described herein may be performed in combination with other techniques, which are well known in the art or which are described in the references cited herein, that stimulate the vagus nerve in order to achieve a desired therapeutic end.
  • controlled stimulation is used to one or more of the following: the lacrimal nerve, the salivary nerve, the vagus nerve, the pelvic splancnic nerve, or one or more sympathetic or parasympathetic autonomic nerves.
  • Such controlled stimulation may be used, for example, to regulate or treat a condition of the lung, heart, stomach, pancreas, small intestine, liver, spleen, kidney, bladder, rectum, large intestine, reproductive organs, or adrenal gland.

Abstract

Apparatus is provided that includes an electrode device, adapted to be coupled to a vagus nerve of a subject, and a control unit, adapted to drive the electrode device to apply to the vagus nerve a current that reduces heart rate variability of the subject. Also provided is a method comprising applying to a vagus nerve of a subject a current that reduces heart rate variability of the subject.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • The present patent application is a continuation-in-part of PCT Patent Application PCT/IL03/00431, filed May 23, 2003, entitled, “Selective nerve fiber stimulation for treating heart conditions,” which:
  • (a) is a continuation-in-part of U.S. patent application Ser. No. 10/205,475, filed Jul. 24, 2002, entitled, “Selective nerve fiber stimulation for treating heart conditions,” which is a continuation-in-part of PCT Patent Application PCT/IL02/00068, filed Jan. 23, 2002, entitled, “Treatment of disorders by unidirectional nerve stimulation,” which is a continuation-in-part of U.S. patent application Ser. No. 09/944,913, filed Aug. 31, 2001, entitled, “Treatment of disorders by unidirectional nerve stimulation,” and
  • (b) claims the benefit of U.S. Provisional Patent Application 60/383,157 to Ayal et al., filed May 23, 2002, entitled, “Inverse recruitment for autonomic nerve systems.”
  • Each of the above-referenced applications is assigned to the assignee of the present patent application and incorporated herein by reference.
  • FIELD OF THE INVENTION
  • The present invention relates generally to treating patients by application of electrical signals to a selected nerve or nerve bundle, and specifically to methods and apparatus for stimulating the vagus nerve for treating heart conditions.
  • BACKGROUND OF THE INVENTION
  • The use of nerve stimulation for treating and controlling a variety of medical, psychiatric, and neurological disorders has seen significant growth over the last several decades. In particular, stimulation of the vagus nerve (the tenth cranial nerve, and part of the parasympathetic nervous system) has been the subject of considerable research. The vagus nerve is composed of somatic and visceral afferents (inward conducting nerve fibers, which convey impulses toward the brain) and efferents (outward conducting nerve fibers, which convey impulses to an effector to regulate activity such as muscle contraction or glandular secretion).
  • The rate of the heart is restrained in part by parasympathetic stimulation from the right and left vagus nerves. Low vagal nerve activity is considered to be related to various arrhythmias, including tachycardia, ventricular accelerated rhythm, and rapid atrial fibrillation. By artificially stimulating the vagus nerves, it is possible to slow the heart, allowing the heart to more completely relax and the ventricles to experience increased filling. With larger diastolic volumes, the heart may beat more efficiently because it may expend less energy to overcome the myocardial viscosity and elastic forces of the heart with each beat.
  • Stimulation of the vagus nerve has been proposed as a method for treating various heart conditions, including heart failure and atrial fibrillation. Heart failure is a cardiac condition characterized by a deficiency in the ability of the heart to pump blood throughout the body and/or to prevent blood from backing up in the lungs. Customary treatment of heart failure includes medication and lifestyle changes. It is often desirable to lower the heart rates of patients suffering from faster than normal heart rates. The effectiveness of beta blockers in treating heart disease is attributed in part to their heart-rate-lowering effect.
  • Bilgutay et al., in “Vagal tuning: a new concept in the treatment of supraventricular arrhythmias, angina pectoris, and heart failure,” J. Thoracic Cardiovas. Surg. 56(1):71-82, July, 1968, which is incorporated herein by reference, studied the use of a permanently-implanted device with electrodes to stimulate the right vagus nerve for treatment of supraventricular arrhythmias, angina pectoris, and heart failure. Experiments were conducted to determine amplitudes, frequencies, wave shapes and pulse lengths of the stimulating current to achieve slowing of the heart rate. The authors additionally studied an external device, triggered by the R-wave of the electrocardiogram (ECG) of the subject to provide stimulation only upon an achievement of a certain heart rate. They found that when a pulsatile current with a frequency of ten pulses per second and 0.2 milliseconds pulse duration was applied to the vagus nerve, the heart rate could be decreased to half the resting rate while still preserving sinus rhythm. Low amplitude vagal stimulation was employed to control induced tachycardias and ectopic beats. The authors further studied the use of the implanted device in conjunction with the administration of Isuprel, a sympathomimetic drug. They found that Isuprel retained its inotropic effect of increasing contractility, while its chronotropic effect was controlled by the vagal stimulation: “An increased end diastolic volume brought about by slowing of the heart rate by vagal tuning, coupled with increased contractility of the heart induced by the inotropic effect of Isuprel, appeared to increase the efficiency of cardiac performance” (p. 79).
  • U.S. Pat. No. 6,473,644 to Terry, Jr. et al., which is incorporated herein by reference, describes a method for treating patients suffering from heart failure to increase cardiac output, by stimulating or modulating the vagus nerve with a sequence of substantially equally-spaced pulses by an implanted neurostimulator. The frequency of the stimulating pulses is adjusted until the patient's heart rate reaches a target rate within a relatively stable target rate range below the low end of the patient's customary resting heart rate.
  • US Patent Application Publication 2003/0040774 to Terry et al., which is incorporated herein by reference, describes a device for treating patients suffering from congestive heart failure. The device includes an implantable neurostimulator for stimulating the patient's vagus nerve at or above the cardiac branch with an electrical pulse waveform at a stimulating rate sufficient to maintain the patient's heart beat at a rate well below the patient's normal resting heart rate, thereby allowing rest and recovery of the heart muscle, to increase in coronary blood flow, and/or growth of coronary capillaries. A metabolic need sensor detects the patient's current physical state and concomitantly supplies a control signal to the neurostimulator to vary the stimulating rate. If the detection indicates a state of rest, the neurostimulator rate reduces the patient's heart rate below the patient's normal resting rate. If the detection indicates physical exertion, the neurostimulator rate increases the patient's heart rate above the normal resting rate.
  • US Patent Publication 2003/0045909 to Gross et al., which is assigned to the assignee of the present patent application and is incorporated herein by reference, describes apparatus for treating a heart condition of a subject, including an electrode device, which is adapted to be coupled to a vagus nerve of the subject. A control unit is adapted to drive the electrode device to apply to the vagus nerve a stimulating current, which is capable of inducing action potentials in a therapeutic direction in a first set and a second set of nerve fibers of the vagus nerve. The control unit is also adapted to drive the electrode device to apply to the vagus nerve an inhibiting current, which is capable of inhibiting the induced action potentials traveling in the therapeutic direction in the second set of nerve fibers, the nerve fibers in the second set having generally larger diameters than the nerve fibers in the first set.
  • The effect of vagal stimulation on heart rate and other aspects of heart function, including the relationship between the timing of vagal stimulation within the cardiac cycle and the induced effect on heart rate, has been studied in animals. For example, Zhang Y et al., in “Optimal ventricular rate slowing during atrial fibrillation by feedback AV nodal-selective vagal stimulation,” Am J Physiol Heart Circ Physiol 282:H1102-H1110 (2002), describe the application of selective vagal stimulation by varying the nerve stimulation intensity, in order to achieve graded slowing of heart rate. This article is incorporated herein by reference.
  • The following articles and book, which are incorporated herein by reference, may be of interest:
  • Levy M N et al., in “Parasympathetic Control of the Heart,” Nervous Control of Vascular Function, Randall W C ed., Oxford University Press (1984) Levy M N et al. ed., Vagal Control of the Heart: Experimental Basis and Clinical Implications (The Bakken Research Center Series Volume 7), Futura Publishing Company, Inc., Armonk, N.Y. (1993)
  • Randall W C ed., Neural Regulation of the Heart, Oxford University Press (1977), particularly pages 100-106.
  • Armour J A et al. eds., Neurocardiology, Oxford University Press (1994)
  • Perez M G et al., “Effect of stimulating non-myelinated vagal axon on atrio-ventricular conduction and left ventricular function in anaesthetized rabbits,” Auton Neurosco 86 (2001)
  • Jones, J F X et al., “Heart rate responses to selective stimulation of cardiac vagal C fibres in anaesthetized cats, rats and rabbits,” J Physiol 489 (Pt 1):203-14 (1995)
  • Wallick D W et al., “Effects of ouabain and vagal stimulation on heart rate in the dog,” Cardiovasc. Res., 18(2):75-9 (1984)
  • Martin P J et al., “Phasic effects of repetitive vagal stimulation on atrial contraction,” Circ. Res. 52(6):657-63 (1983)
  • Wallick D W et al., “Effects of repetitive bursts of vagal activity on atrioventricular junctional rate in dogs,” Am J Physiol 237(3):H275-81 (1979)
  • Fuster V and Ryden L E et al., “ACC/AHA/ESC Practice Guidelines—Executive Summary,” J Am Coll Cardiol 38(4):1231-65 (2001)
  • Fuster V and Ryden L E et al., “ACC/AHA/ESC Practice Guidelines—Full Text,” J Am Coll Cardiol 38(4):1266i-12661xx (2001)
  • Morady F et al., “Effects of resting vagal tone on accessory atrioventricular connections,” Circulation 81(1):86-90 (1990)
  • Waninger M S et al., “Electrophysiological control of ventricular rate during atrial fibrillation,” PACE 23:1239-1244 (2000)
  • Wijffels M C et al., “Electrical remodeling due to atrial fibrillation in chronically instrumented conscious goats: roles of neurohumoral changes, ischemia, atrial stretch, and high rate of electrical activation,” Circulation 96(10):3710-20 (1997)
  • Wijffels M C et al., “Atrial fibrillation begets atrial fibrillation,” Circulation 92:1954-1968 (1995)
  • Goldberger A L et al., “Vagally-mediated atrial fibrillation in dogs: conversion with bretylium tosylate,” Int J Cardiol 13(1):47-55 (1986)
  • Takei M et al., “Vagal stimulation prior to atrial rapid pacing protects the atrium from electrical remodeling in anesthetized dogs,” Jpn Circ J 65(12):1077-81 (2001)
  • Friedrichs G S, “Experimental models of atrial fibrillation/flutter,” J Pharmacological and Toxicological Methods 43:117-123 (2000)
  • Hayashi H et al., “Different effects of class Ic and III antiarrhythmic drugs on vagotonic atrial fibrillation in the canine heart,” Journal of Cardiovascular Pharmacology 31:101-107 (1998)
  • Morillo C A et al., “Chronic rapid atrial pacing. Structural, functional, and electrophysiological characteristics of a new model of sustained atrial fibrillation,” Circulation 91:1588-1595 (1995)
  • Lew S J et al., “Stroke prevention in elderly patients with atrial fibrillation,” Singapore Med J 43(4):198-201 (2002)
  • Higgins CB, “Parasympathetic control of the heart,” Pharmacol. Rev. 25:120-155 (1973)
  • Hunt R, “Experiments on the relations of the inhibitory to the accelerator nerves of the heart,” J. Exptl. Med. 2:151-179 (1897)
  • Billette J et al., “Roles of the AV junction in determining the ventricular response to atrial fibrillation,” Can J Physiol Pharamacol 53(4)575-85 (1975)
  • Stramba-Badiale M et al., “Sympathetic-Parasympathetic Interaction and Accentuated Antagonism in Conscious Dogs,” American Journal of Physiology 260 (2Pt 2):H335-340 (1991)
  • Garrigue S et al., “Post-ganglionic vagal stimulation of the atrioventricular node reduces ventricular rate during atrial fibrillation,” PACE 21(4), 878 (Part II) (1998)
  • Kwan H et al., “Cardiovascular adverse drug reactions during initiation of antiarrhythmic therapy for atrial fibrillation,” Can J Hosp Pharm 54:10-14 (2001)
  • Jidéus L, “Atrial fibrillation after coronary artery bypass surgery: A study of causes and risk factors,” Acta Universitatis Upsaliensis, Uppsala, Sweden (2001)
  • Borovikova L V et al., “Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin,” Nature 405(6785):458-62 (2000)
  • Wang H et al., “Nicotinic acetylcholine receptor alpha-7 subunit is an essential regulator of inflammation,” Nature 421:384-388 (2003)
  • Vanoli E et al., “Vagal stimulation and prevention of sudden death in conscious dogs with a healed myocardial infarction,” Circ Res 68(5):1471-81 (1991)
  • De Ferrari G M, “Vagal reflexes and survival during acute myocardial ischemia in conscious dogs with healed myocardial infarction,” Am J Physiol 261(1 Pt 2):H63-9 (1991)
  • Li D et al., “Promotion of Atrial Fibrillation by Heart Failure in Dogs: Atrial Remodeling of a Different Sort,” Circulation 100(1):87-95 (1999)
  • Feliciano L et al., “Vagal nerve stimulation during muscarinic and beta-adrenergic blockade causes significant coronary artery dilation,” Cardiovasc Res 40(1):45-55 (1998)
  • Heart rate variability is considered an important determinant of cardiac function. Heart rate normally fluctuates within a normal range in order to accommodate constantly changing physiological needs. For example, heart rate increases during waking hours, exertion, and inspiration, and decreases during sleeping, relaxation, and expiration. Two representations of heart rate variability are commonly used: (a) the standard deviation of beat-to-beat RR interval differences within a certain time window (i.e., variability in the time domain), and (b) the magnitude of variability as a function of frequency (i.e., variability in the frequency domain).
  • Short-term (beat-to-beat) variability in heart rate represents fast, high-frequency (HF) changes in heart rate. For example, the changes in heart rate associated with breathing are characterized by a frequency of between about 0.15 and about 0.4 Hz (corresponding to a time constant between about 2.5 and 7 seconds). Low-frequency (LF) changes in heart rate (for example, blood pressure variations) are characterized by a frequency of between about 0.04 and about 0.15 Hz (corresponding to a time constant between about 7 and 25 seconds). Very-low-frequency (VLF) changes in heart rate are characterized by a frequency of between about 0.003 and about 0.04 Hz (0.5 to 5 minutes). Ultra-low-frequency (ULF) changes in heart rate are characterized by a frequency of between about 0.0001 and about 0.003 Hz (5 minutes to 2.75 hours). A commonly used indicator of heart rate variability is the ratio of HF power to LF power.
  • High heart rate variability (especially in the high frequency range, as described hereinabove) is generally correlated with a good prognosis in conditions such as ischemic heart disease and heart failure. In other conditions, such as atrial fibrillation, increased heart rate variability in an even higher frequency range can cause a reduction in cardiac efficiency by producing beats that arrive too quickly (when the ventricle is not optimally filled) and beats that arrive too late (when the ventricle is fully filled and the pressure is too high).
  • Kamath et al., in “Effect of vagal nerve electrostimulation on the power spectrum of heart rate variability in man,” Pacing Clin Electrophysiol 15:235-43 (1992), describe an increase in the ratio of low frequency to high frequency components of the peak power spectrum of heart rate variability during a period without vagal stimulation, compared to periods with vagal stimulation. Iwao et al., in “Effect of constant and intermittent vagal stimulation on the heart rate and heart rate variability in rabbits,” Jpn J Physiol 50:33-9 (2000), describe no change in heart rate variability caused by respiration in all modes of stimulation with respect to baseline data. Each of these articles is incorporated herein by reference.
  • The following articles, which are incorporated herein by reference, may be of interest:
  • Kleiger R E et al., “Decreased heart rate variability and its association with increased mortality after myocardial infarction,” Am J Cardiol 59: 256-262 (1987)
  • Akselrod S et al., “Power spectrum analysis of heart rate fluctuation: a quantitative probe of beat-to-beat cardiovascular control,” Science 213: 220-222 (1981)
  • A number of patents describe techniques for treating arrhythmias and/or ischemia by, at least in part, stimulating the vagus nerve. Arrhythmias in which the heart rate is too fast include fibrillation, flutter and tachycardia. Arrhythmia in which the heart rate is too slow is known as bradyarrhythmia. U.S. Pat. No. 5,700,282 to Zabara, which is incorporated herein by reference, describes techniques for stabilizing the heart rhythm of a patient by detecting arrhythmias and then electronically stimulating the vagus and cardiac sympathetic nerves of the patient. The stimulation of vagus efferents directly causes the heart rate to slow down, while the stimulation of cardiac sympathetic nerve efferents causes the heart rate to quicken.
  • U.S. Pat. No. 5,330,507 to Schwartz, which is incorporated herein by reference, describes a cardiac pacemaker for preventing or interrupting tachyarrhythmias and for applying pacing therapies to maintain the heart rhythm of a patient within acceptable limits. The device automatically stimulates the right or left vagus nerves as well as the cardiac tissue in a concerted fashion dependent upon need. Continuous and/or phasic electrical pulses are applied. Phasic pulses are applied in a specific relationship with the R-wave of the ECG of the patient.
  • European Patent Application EP 0 688 577 to Holmstrom et al., which is incorporated herein by reference, describes a device to treat atrial tachyarrhythmia by detecting arrhythmia and stimulating a parasympathetic nerve that innervates the heart, such as the vagus nerve.
  • U.S. Pat. Nos. 5,690,681 and 5,916,239 to Geddes et al., which are incorporated herein by reference, describe closed-loop, variable-frequency, vagal-stimulation apparatus for control of ventricular rate during atrial fibrillation. The apparatus stimulates the left vagus nerve, and automatically and continuously adjusts the vagal stimulation frequency as a function of the difference between actual and desired ventricular excitation rates. In an alternative embodiment, the apparatus automatically adjusts the vagal stimulation frequency as a function of the difference between ventricular excitation rate and arterial pulse rate in order to eliminate or minimize pulse deficit.
  • U.S. Pat. No. 5,203,326 to Collins, which is incorporated herein by reference, describes a pacemaker which detects a cardiac abnormality and responds with electrical stimulation of the heart combined with vagus nerve stimulation. The vagal stimulation frequency is progressively increased in one-minute intervals, and, for the pulse delivery rate selected, the heart rate is described as being slowed to a desired, stable level by increasing the pulse current.
  • U.S. Pat. No. 6,511,500 to Rahme, which is incorporated herein by reference, describes various aspects of the effects of autonomic nervous system tone on atrial arrhythmias, and its interaction with class III antiarrhythmic drug effects. The significance of sympathetic and parasympathetic activation are described as being evaluated by determining the effects of autonomic nervous system using vagal and stellar ganglions stimulation, and by using autonomic nervous system neurotransmitters infusion (norepinephrine, acetylcholine).
  • U.S. Pat. No. 5,199,428 to Obel et al., which is incorporated herein by reference, describes a cardiac pacemaker for detecting and treating myocardial ischemia. The device automatically stimulates the vagal nervous system as well as the cardiac tissue in a concerted fashion in order to decrease cardiac workload and thereby protect the myocardium.
  • U.S. Pat. Nos. 5,334,221 to Bardy and 5,356,425 to Bardy et al., which are incorporated herein by reference, describe a stimulator for applying stimulus pulses to the AV nodal fat pad in response to the heart rate exceeding a predetermined rate, in order to reduce the ventricular rate. The device also includes a cardiac pacemaker which serves to pace the ventricle in the event that the ventricular rate is lowered below a pacing rate, and provides for feedback control of the stimulus parameters applied to the AV nodal fat pad, as a function of the determined effect of the stimulus pulses on the heart rate.
  • U.S. Pat. No. 5,522,854 to Ideker et al., which is incorporated herein by reference, describes techniques for preventing arrhythmia by detecting a high risk of arrhythmia and then stimulating afferent nerves to prevent the arrhythmia.
  • U.S. Pat. No. 6,434,424 to Igel et al., which is incorporated herein by reference, describes a pacing system with a mode switching feature and ventricular rate regularization function adapted to stabilize or regularize ventricular heart rate during chronic or paroxysmal atrial tachyarrhythmia.
  • US Patent Application Publication 2002/0120304 to Mest, which is incorporated herein by reference, describes a method for regulating the heart rate of a patient by inserting into a blood vessel of the patient a catheter having an electrode at its distal end, and directing the catheter to an intravascular location so that the electrode is adjacent to a selected cardiac sympathetic or parasympathetic nerve.
  • U.S. Pat. Nos. 6,006,134 and 6,266,564 to Hill et al., which are incorporated herein by reference, describe an electro-stimulation device including a pair of electrodes for connection to at least one location in the body that affects or regulates the heartbeat.
  • PCT Publication WO 02/085448 to Foreman et al., which is incorporated herein by reference, describes a method for protecting cardiac function and reducing the impact of ischemia on the heart, by electrically stimulating a neural structure capable of carrying the predetermined electrical signal from the neural structure to the “intrinsic cardiac nervous system,” which is defined and described therein.
  • U.S. Pat. No. 5,243,980 to Mehra, which is incorporated herein by reference, describes techniques for discrimination between ventricular and supraventricular tachycardia. In response to the detection of the occurrence of a tachycardia, stimulus pulses are delivered to one or both of the SA and AV nodal fat pads. The response of the heart rhythm to these stimulus pulses is monitored. Depending upon the change or lack of change in the heart rhythm, a diagnosis is made as to the origin of the tachycardia.
  • U.S. Pat. No. 5,658,318 to Stroetmann et al., which is incorporated herein by reference, describes a device for detecting a state of imminent cardiac arrhythmia in response to activity in nerve signals conveying information from the autonomic nerve system to the heart. The device comprises a sensor adapted to be placed in an extracardiac position and to detect activity in at least one of the sympathetic and vagus nerves.
  • U.S. Pat. No. 6,292,695 to Webster, Jr. et al., which is incorporated herein by reference, describes a method for controlling cardiac fibrillation, tachycardia, or cardiac arrhythmia by the use of a catheter comprising a stimulating electrode, which is placed at an intravascular location. The electrode is connected to a stimulating means, and stimulation is applied across the wall of the vessel, transvascularly, to a sympathetic or parasympathetic nerve that innervates the heart at a strength sufficient to depolarize the nerve and effect the control of the heart.
  • U.S. Pat. No. 6,134,470 to Hartlaub, which is incorporated herein by reference, describes an implantable anti-arrhythmia system which includes a spinal cord stimulator coupled to an implantable heart rhythm monitor. The monitor is adapted to detect the occurrence of tachyarrhythmias or of precursors thereto and, in response, trigger the operation of the spinal cord stimulator in order to prevent occurrences of tachyarrhythmias and/or as a stand-alone therapy for termination of tachyarrhythmias and/or to reduce the level of aggressiveness required of an additional therapy such as antitachycardia pacing, cardioversion or defibrillation.
  • A number of patents and articles describe other methods and devices for stimulating nerves to achieve a desired effect. Often these techniques include a design for an electrode or electrode cuff.
  • US Patent Publication 2003/0050677 to Gross et al., which is assigned to the assignee of the present patent application and is incorporated herein by reference, describes apparatus for applying current to a nerve. A cathode is adapted to be placed in a vicinity of a cathodic longitudinal site of the nerve and to apply a cathodic current to the nerve. A primary inhibiting anode is adapted to be placed in a vicinity of a primary anodal longitudinal site of the nerve and to apply a primary anodal current to the nerve. A secondary inhibiting anode is adapted to be placed in a vicinity of a secondary anodal longitudinal site of the nerve and to apply a secondary anodal current to the nerve, the secondary anodal longitudinal site being closer to the primary anodal longitudinal site than to the cathodic longitudinal site.
  • U.S. Pat. Nos. 4,608,985 to Crish et al. and 4,649,936 to Ungar et al., which are incorporated herein by reference, describe electrode cuffs for selectively blocking orthodromic action potentials passing along a nerve trunk, in a manner intended to avoid causing nerve damage.
  • PCT Patent Publication WO 01/10375 to Felsen et al., which is incorporated herein by reference, describes apparatus for modifying the electrical behavior of nervous tissue. Electrical energy is applied with an electrode to a nerve in order to selectively inhibit propagation of an action potential.
  • U.S. Pat. No. 5,755,750 to Petruska et al., which is incorporated herein by reference, describes techniques for selectively blocking different size fibers of a nerve by applying direct electric current between an anode and a cathode that is larger than the anode. The current applied to the electrodes blocks nerve transmission, but, as described, does not activate the nerve fibers in either direction.
  • The following articles, which are incorporated herein by reference, may be of interest:
  • Ungar I J et al., “Generation of unidirectionally propagating action potentials using a monopolar electrode cuff,” Annals of Biomedical Engineering, 14:437-450 (1986)
  • Sweeney J D et al., “An asymmetric two electrode cuff for generation of unidirectionally propagated action potentials,” IEEE Transactions on Biomedical Engineering, vol. BME-33(6) (1986)
  • Sweeney J D et al., “A nerve cuff technique for selective excitation of peripheral nerve trunk regions,” IEEE Transactions on Biomedical Engineering, 37(7) (1990)
  • Naples G G et al., “A spiral nerve cuff electrode for peripheral nerve stimulation,” by IEEE Transactions on Biomedical Engineering, 35(11) (1988)
  • van den Honert C et al., “Generation of unidirectionally propagated action potentials in a peripheral nerve by brief stimuli,” Science, 206:1311-1312 (1979)
  • van den Honert C et al., “A technique for collision block of peripheral nerve: Single stimulus analysis,” MP-11, IEEE Trans. Biomed. Eng. 28:373-378 (1981)
  • van den Honert C et al., “A technique for collision block of peripheral nerve: Frequency dependence,” MP-12, IEEE Trans. Biomed. Eng. 28:379-382 (1981)
  • Rijkhoff N J et al., “Acute animal studies on the use of anodal block to reduce urethral resistance in sacral root stimulation,” IEEE Transactions on Rehabilitation Engineering, 2(2):92 (1994)
  • Mushahwar V K et al., “Muscle recruitment through electrical stimulation of the lumbo-sacral spinal cord,” IEEE Trans Rehabil Eng, 8(1):22-9 (2000)
  • Deurloo K E et al., “Transverse tripolar stimulation of peripheral nerve: a modelling study of spatial selectivity,” Med Biol Eng Comput, 36(1):66-74 (1998)
  • Tarver W B et al., “Clinical experience with a helical bipolar stimulating lead,” Pace, Vol. 15, October, Part II (1992)
  • Manfredi M, “Differential block of conduction of larger fibers in peripheral nerve by direct current,” Arch. Ital. Biol., 108:52-71 (1970)
  • In physiological muscle contraction, nerve fibers are recruited in the order of increasing size, from smaller-diameter fibers to progressively larger-diameter fibers. In contrast, artificial electrical stimulation of nerves using standard techniques recruits fibers in a larger- to smaller-diameter order, because larger-diameter fibers have a lower excitation threshold. This unnatural recruitment order causes muscle fatigue and poor force gradation. Techniques have been explored to mimic the natural order of recruitment when performing artificial stimulation of nerves to stimulate muscles.
  • Fitzpatrick et al., in “A nerve cuff design for the selective activation and blocking of myelinated nerve fibers,” Ann. Conf. of the IEEE Eng. in Medicine and Biology Soc, 13(2), 906 (1991), which is incorporated herein by reference, describe a tripolar electrode used for muscle control. The electrode includes a central cathode flanked on its opposite sides by two anodes. The central cathode generates action potentials in the motor nerve fiber by cathodic stimulation. One of the anodes produces a complete anodal block in one direction so that the action potential produced by the cathode is unidirectional. The other anode produces a selective anodal block to permit passage of the action potential in the opposite direction through selected motor nerve fibers to produce the desired muscle stimulation or suppression.
  • The following articles, which are incorporated herein by reference, may be of interest:
  • Rijkhoff N J et al., “Orderly recruitment of motoneurons in an acute rabbit model,” Ann. Conf. of the IEEE Eng., Medicine and Biology Soc., 20(5):2564 (1998)
  • Rijkhoff N J et al., “Selective stimulation of small diameter nerve fibers in a mixed bundle,” Proceedings of the Annual Project Meeting Sensations/Neuros and Mid-Term Review Meeting on the TMR-Network Neuros, Apr. 21-23, 1999, pp. 20-21 (1999)
  • Baratta R et al., “Orderly stimulation of skeletal muscle motor units with tripolar nerve cuff electrode,” IEEE Transactions on Biomedical Engineering, 36(8):836-43 (1989)
  • Levy M N, Blattberg B., “Effect of vagal stimulation on the overflow of norepinephrine into the coronary sinus during sympathetic nerve stimulation in the dog,” Circ Res 1976 February; 38(2):81-4
  • Lavallee et al. “Muscarinic inhibition of endogenous myocardial catecholamine liberation in the dog,” Can J Physiol Pharmacol 1978 August; 56(4):642-9
  • Mann D L, Kent R L, Parsons B, Cooper G, “Adrenergic effects on the biology of the adult mammalian cardiocyte,” Circulation 1992 February; 85(2):790-804
  • Mann D L, “Basic mechanisms of disease progression in the failing heart: role of excessive adrenergic drive,” Prog Cardiovasc Dis 1998 July-August; 41(1suppl 1):1-8
  • Barzilai A, Daily D, Zilkha-Falb R, Ziv I, Offen D, Melamed E, Sirv A, “The molecular mechanisms of dopamine toxicity,” Adv Neurol 2003; 91:73-82
  • The following articles, which are incorporated herein by reference, describe techniques using point electrodes to selectively excite peripheral nerve fibers:
  • Grill W M et al., “Inversion of the current-distance relationship by transient depolarization,” IEEE Trans Biomed Eng, 44(1):1-9 (1997)
  • Goodall E V et al., “Position-selective activation of peripheral nerve fibers with a cuff electrode,” IEEE Trans Biomed Eng, 43(8):851-6 (1996)
  • Veraart C et al., “Selective control of muscle activation with a multipolar nerve cuff electrode,” IEEE Trans Biomed Eng, 40(7):640-53 (1993)
  • As defined by Rattay, in the article, “Analysis of models for extracellular fiber stimulation,” IEEE Transactions on Biomedical Engineering, Vol. 36, no. 2, p. 676, 1989, which is incorporated herein by reference, the activation function (AF) is the second spatial derivative of the electric potential along an axon. In the region where the activation function is positive, the axon depolarizes, and in the region where the activation function is negative, the axon hyperpolarizes. If the activation function is sufficiently positive, then the depolarization will cause the axon to generate an action potential; similarly, if the activation function is sufficiently negative, then local blocking of action potentials transmission occurs. The activation function depends on the current applied, as well as the geometry of the electrodes and of the axon.
  • For a given electrode geometry, the equation governing the electrical potential is:

  • ∇(σ∇U)=4πj,
  • where U is the potential, σ is the conductance tensor specifying the conductance of the various materials (electrode housing, axon, intracellular fluid, etc.), and j is a scalar function representing the current source density specifying the locations of current injection.
  • SUMMARY OF THE INVENTION
  • In embodiments of the present invention, apparatus for treating a heart condition comprises a multipolar electrode device that is applied to a portion of a vagus nerve that innervates the heart of a patient. Typically, the system is configured to treat heart failure and/or heart arrhythmia, such as atrial fibrillation or tachycardia. A control unit typically drives the electrode device to (i) apply signals to induce the propagation of efferent action potentials towards the heart, and (ii) suppress artificially-induced afferent and efferent action potentials, in order to minimize any unintended side effect of the signal application.
  • The control unit typically suppresses afferent action potentials induced by the cathodic current by inhibiting essentially all or a large fraction of fibers using anodal current (“afferent anodal current”) from a second set of one or more anodes (the “afferent anode set”). The afferent anode set is typically placed between the central cathode and the edge of the electrode device closer to the brain (the “afferent edge”), to block a large fraction of fibers from conveying signals in the direction of the brain during application of the afferent anodal current.
  • In some embodiments of the present invention, the cathodic current is applied with an amplitude sufficient to induce action potentials in large- and medium-diameter fibers (e.g., A- and B-fibers), but insufficient to induce action potentials in small-diameter fibers (e.g., C-fibers). Simultaneously, a small anodal current is applied in order to inhibit action potentials induced by the cathodic current in the large-diameter fibers (e.g., A-fibers). This combination of cathodic and anodal current generally results in the stimulation of medium-diameter fibers (e.g., B-fibers) only. At the same time, a portion of the afferent action potentials induced by the cathodic current are blocked, as described above. By not stimulating large-diameter fibers, such stimulation generally avoids adverse effects sometimes associated with recruitment of such large fibers, such as dyspnea and hoarseness. Stimulation of small-diameter fibers is avoided because these fibers transmit pain sensations and are important for regulation of reflexes such as respiratory reflexes.
  • In some embodiments of the present invention, the efferent anode set comprises a plurality of anodes. Application of the efferent anodal current in appropriate ratios from the plurality of anodes in these embodiments generally minimizes the “virtual cathode effect,” whereby application of too large an anodal current creates a virtual cathode, which stimulates rather than blocks fibers. When such techniques are not used, the virtual cathode effect generally hinders blocking of smaller-diameter fibers, because a relatively large anodal current is typically necessary to block such fibers, and this same large anodal current induces the virtual cathode effect. Likewise, the afferent anode set typically comprises a plurality of anodes in order to minimize the virtual cathode effect in the direction of the brain.
  • In some embodiments of the present invention, the efferent and afferent anode sets each comprise exactly one electrode, which are directly electrically coupled to each other. The cathodic current is applied with an amplitude sufficient to induce action potentials in large- and medium-diameter fibers (e.g., A- and B-fibers), but insufficient to induce action potentials in small-diameter fibers (e.g., C-fibers). Simultaneously, an anodal current is applied in order to inhibit action potentials induced by the cathodic current in the large-diameter fibers (e.g., A-fibers), but not in the small- and medium-diameter fibers (e.g., B- and C-fibers). This combination of cathodic and anodal current generally results in the stimulation of medium-diameter fibers (e.g., B-fibers) only.
  • Typically, parasympathetic stimulation of the vagus nerve is applied responsive to one or more sensed physiological parameters or other parameters, such as heart rate, electrocardiogram (ECG), blood pressure, indicators of cardiac contractility, cardiac output, norepinephrine concentration, baroreflex sensitivity, or motion of the patient. Typically, stimulation is applied in a closed-loop system in order to achieve and maintain a desired heart rate responsive to one or more such sensed parameters.
  • In some embodiments of the present invention, vagal stimulation is applied in a burst (i.e., a series of pulses). The application of the burst in each cardiac cycle typically commences after a variable delay after a detected R-wave, P-wave, or other feature of an ECG. The delay is typically calculated in real time using a function, the inputs of which include one or more pre-programmed but updateable constants and one or more sensed parameters, such as the R-R interval between cardiac cycles and/or the P-R interval. Alternatively or additionally, a lookup table of delays is used to determine in real time the appropriate delay for each application of pulses, based on the one or more sensed parameters.
  • In some embodiments of the present invention, the control unit is configured to drive the electrode device to stimulate the vagus nerve so as to reduce the heart rate of the subject towards a target heart rate. Parameters of stimulation are varied in real time in order to vary the heart-rate-lowering effects of the stimulation. In embodiments of the present invention in which the stimulation is applied in a series of pulses that are synchronized with the cardiac cycle of the subject, such as described hereinabove, parameters of such pulse series typically include, but are not limited to: (a) timing of the stimulation within the cardiac cycle, (b) pulse duration (width), (c) pulse repetition interval, (d) pulse period, (e) number of pulses per burst, also referred to herein as “pulses per trigger” (PPT), (f) amplitude, (g) duty cycle, (h) choice of vagus nerve, and (i) “on”/“off” ratio and timing (i.e., during intermittent operation).
  • In some embodiments of the present invention, the control unit is configured to drive the electrode device to stimulate the vagus nerve so as to modify heart rate variability of the subject. For some applications, the control unit is configured to apply stimulation with parameters that tend to or that are selected to reduce heart rate variability, while for other applications parameters are used that tend to or that are selected to increase variability. For some applications, the parameters of the stimulation are selected to both reduce the heart rate of the subject and heart rate variability of the subject. For other applications, the parameters are selected to reduce heart rate variability while substantially not reducing the heart rate of the subject. For some applications, the control unit is configured to drive the electrode device to stimulate the vagus nerve so as to modify heart rate variability in order to treat a condition of the subject.
  • Advantageously, the techniques described herein generally enable relatively fine control of the level of stimulation of the vagus nerve, by imitating the natural physiological smaller-to-larger diameter recruitment order of nerve fibers. This recruitment order allows improved and more natural control over the heart rate. Such fine control is particularly advantageous when applied in a closed-loop system, wherein such control results in smaller changes in heart rate and lower latencies in the control loop, which generally contribute to greater loop stability and reduced loop stabilization time.
  • “Vagus nerve,” and derivatives thereof, as used in the specification and the claims, is to be understood to include portions of the left vagus nerve, the right vagus nerve, and branches of the vagus nerve such as the superior cardiac nerve, superior cardiac branch, and inferior cardiac branch. Similarly, stimulation of the vagus nerve is described herein by way of illustration and not limitation, and it is to be understood that stimulation of other autonomic nerves, including nerves in the epicardial fat pads, for treatment of heart conditions or other conditions, is also included within the scope of the present invention.
  • “Heart failure,” as used in the specification and the claims, is to be understood to include all forms of heart failure, including ischemic heart failure, non-ischemic heart failure, and diastolic heart failure.
  • There is therefore provided, in accordance with an embodiment of the present invention, apparatus for treating a heart condition of a subject, including:
  • an electrode device, adapted to be coupled to a vagus nerve of the subject; and
  • a control unit, adapted to:
  • drive the electrode device to apply to the vagus nerve a stimulating current, which is capable of inducing action potentials in a therapeutic direction in a first set and a second set of nerve fibers of the vagus nerve, and
  • drive the electrode device to apply to the vagus nerve an inhibiting current, which is capable of inhibiting the induced action potentials traveling in the therapeutic direction in the second set of nerve fibers, the nerve fibers in the second set having generally larger diameters than the nerve fibers in the first set.
  • Typically, the therapeutic direction is an efferent therapeutic direction towards a heart of the subject. Alternatively or additionally, the therapeutic direction is an afferent therapeutic direction towards a brain of the subject.
  • In an embodiment, the control unit increases a number of action potentials traveling in the therapeutic direction by decreasing an amplitude of the applied inhibiting current, and/or decreases a number of action potentials traveling in the therapeutic direction by increasing an amplitude of the applied inhibiting current.
  • In an embodiment, the heart condition includes heart failure and/or cardiac arrhythmia, and the apparatus is adapted to treat the heart condition.
  • Optionally, the apparatus includes an override, adapted to be used by the subject so as to influence the application by the electrode device of the stimulating and inhibiting currents.
  • In an embodiment, the apparatus includes a pacemaker, and the control unit is adapted to drive the pacemaker to apply pacing pulses to a heart of the subject. Alternatively, the apparatus includes an implantable cardioverter defibrillator (ICD), and the control unit is adapted to drive the ICD to apply energy to a heart of the subject.
  • Typically, the control unit is adapted to drive the electrode device to apply the stimulating current and/or the inhibiting current in a series of pulses.
  • In an embodiment, the control unit receives an electrical signal from the electrode device, and drives the electrode device to regulate the stimulating and/or inhibiting current responsive to the electrical signal.
  • Typically, the electrode device includes a cathode, adapted to apply the stimulating current, and a primary set of anodes, which applies the inhibiting current. For some applications, the primary set of anodes includes a primary anode and a secondary anode, disposed so that the primary anode is located between the secondary anode and the cathode, and the secondary anode applies a current with an amplitude less than about one half an amplitude of a current applied by the primary anode.
  • Typically, the control unit is adapted to drive the electrode device to apply the stimulating current so as to regulate a heart rate of the subject. For some applications, the control unit is adapted to drive the electrode device to regulate an amplitude of the stimulating current so as to regulate the heart rate of the subject.
  • Alternatively or additionally, the control unit drives the electrode device to apply the inhibiting current so as to regulate a heart rate of the subject. In this case, the control unit typically drives the electrode device to regulate an amplitude of the inhibiting current so as to regulate the heart rate of the subject.
  • Typically, the control unit is adapted to drive the electrode device to apply the stimulating and inhibiting currents in a series of pulses. For some applications, the control unit:
      • drives the electrode device to apply the stimulating and inhibiting currents in a series of about one to 20 pulses,
      • configures the pulses to have a duration of between about one and three milliseconds, and/or
      • drives the electrode device to apply the stimulating and inhibiting currents in the series of pulses over a period of between about one and about 200 milliseconds.
  • Typically, the control unit drives the electrode device to apply the stimulating and inhibiting currents in the series of pulses so as to regulate a heart rate of the subject. For some applications, the control unit regulates the number of pulses in the series of pulses so as to regulate the heart rate of the subject. Optionally, the control unit regulates a duration of each pulse so as to regulate the heart rate of the subject. Optionally, the control unit varies a length of a period of application of the series of pulses so as to regulate the heart rate of the subject.
  • In an embodiment, the control unit drives the electrode device to apply to the vagus nerve a second inhibiting current, which is capable of inhibiting device-induced action potentials traveling in a non-therapeutic direction opposite the therapeutic direction in the first and second sets of nerve fibers.
  • Typically, the control unit drives the electrode device to apply the second inhibiting current to the vagus nerve at a primary and a secondary location, the primary location located between the secondary location and an application location of the stimulating current, and to apply at the secondary location a current with an amplitude less than about one half an amplitude of a current applied at the primary location.
  • In an embodiment, the apparatus includes a sensor unit, and the control unit is adapted to receive at least one sensed parameter from the sensor unit, and to drive the electrode device to apply the stimulating and inhibiting currents responsive to the at least one sensed parameter.
  • Typically, the control unit is programmed with a predetermined target heart rate, or is adapted to determine a target heart rate of the subject responsive to the at least one sensed parameter, and the control unit is adapted to drive the electrode device to apply the stimulating and inhibiting currents so as to adjust a heart rate of the subject towards the target heart rate.
  • The sensor unit may include one or more of the following sensors, in which case the control unit receives the at least one sensed parameter from the following one or more sensors:
      • a blood pressure sensor,
      • a left ventricular pressure (LVP) sensor,
      • an accelerometer (in which case, the at least one sensed parameter includes motion of the subject),
      • a detector of norepinephrine concentration in the subject,
      • an ECG sensor,
      • a respiration sensor, and/or an impedance cardiography sensor.
  • Alternatively or additionally, the at least one sensed parameter includes an indicator of decreased cardiac contractility, an indicator of cardiac output, and/or an indicator of a time derivative of a LVP, and the control unit receives the indicator.
  • In an embodiment, the sensor unit includes an electrocardiogram (ECG) monitor, the at least one sensed parameter includes an ECG value, and the control unit receives the at least one sensed parameter from the ECG monitor.
  • Typically, the at least one sensed parameter includes an ECG reading indicative of a presence of arrhythmia, and the control unit is adapted to receive the at least one sensed parameter from the ECG monitor. Optionally, the at least one sensed parameter includes an indication of a heart rate of the subject, and the control unit is adapted to receive the indication of the heart rate. Further optionally, the at least one sensed parameter includes indications of a plurality of heart rates of the subject at a respective plurality of points in time, and the control unit is adapted to receive the at least one sensed parameter and to determine a measure of variability of heart rate responsive thereto.
  • In an embodiment, the sensor unit is adapted to sense an initiation physiological parameter and a termination physiological parameter of the subject, and the control unit is adapted to drive the electrode device to apply the stimulating and inhibiting currents to the vagus nerve after a delay, to initiate the delay responsive to the sensing of the initiation physiological parameter, and to set a length of the delay responsive to the termination physiological parameter.
  • Typically, the control unit is adapted to determine a target heart rate of the subject responsive to the at least one sensed parameter, and the control unit is adapted to set the delay so as to adjust the heart rate towards the target heart rate.
  • Optionally, the termination physiological parameter includes an atrioventricular (AV) delay of the subject, and the control unit is adapted to set the length of the delay responsive to the AV delay.
  • Typically, the sensor unit includes an electrocardiogram (ECG) monitor, and the initiation physiological parameter includes a P-wave or R-wave of a cardiac cycle of the subject, and wherein the control unit is adapted to initiate the delay responsive to the sensing of the P-wave or R-wave, as the case may be. Typically, the termination physiological parameter includes a difference in time between two features of an ECG signal recorded by the ECG monitor, such as an R-R interval between a sensing of an R-wave of a first cardiac cycle of the subject and a sensing of an R-wave of a next cardiac cycle of the subject, or a P-R interval between a sensing of a P-wave of a cardiac cycle of the subject and a sensing of an R-wave of the cardiac cycle, and the control unit sets the length of the delay and/or the magnitude of the stimulation responsive to the termination physiological parameter.
  • There is further provided, in accordance with an embodiment of the present invention, apparatus for treating a heart condition of a subject, including:
  • a cathode, adapted to apply to a vagus nerve of the subject a stimulating current which is capable of inducing action potentials in the vagus nerve; and
  • a primary and a secondary anode, adapted to be disposed so that the primary anode is located between the secondary anode and the cathode, and adapted to apply to the vagus nerve respective primary and secondary inhibiting currents which are capable of inhibiting action potentials in the vagus nerve.
  • Typically, the primary and secondary anodes are adapted to be placed between about 0.5 and about 2.0 millimeters apart from one another. The secondary anode is typically adapted to apply the secondary inhibiting current with an amplitude equal to between about 2 and about 5 milliamps. The secondary anode is typically adapted to apply the secondary inhibiting current with an amplitude less than about one half an amplitude of the primary inhibiting current applied by the primary anode.
  • In an embodiment, the primary anode, the secondary anode, and/or the cathode includes a ring electrode adapted to apply a generally uniform current around a circumference of the vagus nerve. Alternatively or additionally, the primary anode, the secondary anode, and/or the cathode includes a plurality of discrete primary anodes, adapted to be disposed at respective positions around an axis of the vagus nerve.
  • Optionally, the apparatus includes a tertiary anode, adapted to be disposed such that the secondary anode is between the tertiary anode and the primary anode.
  • Typically, the electrode device includes an efferent edge, and the cathode is adapted to be disposed closer than the anodes to the efferent edge of the electrode device.
  • Typically, the cathode and/or the anodes are adapted to apply the stimulating current so as to regulate a heart rate of the subject.
  • Optionally, the cathode includes a plurality of discrete cathodes, adapted to be disposed at respective positions around an axis of the vagus nerve, so as to selectively stimulate nerve fibers of the vagus nerve responsive to the positions of the nerve fibers in the vagus nerve.
  • Optionally, the apparatus includes a set of one or more blocking anodes, adapted to be disposed such that the cathode is between the set of blocking anodes and the primary anode, and adapted to apply to the vagus nerve a current which is capable of inhibiting action potentials propagating in the vagus nerve in a direction from the cathode towards the set of blocking anodes.
  • Typically, the set of blocking anodes includes a first anode and a second anode, adapted to be disposed such that the first anode is located between the second anode and the cathode, and wherein the second anode is adapted to apply a current with an amplitude less than about one half an amplitude of a current applied by the first anode.
  • Typically, the electrode device includes an afferent edge, wherein the cathode is adapted to be disposed closer than the anodes to the afferent edge of the electrode device.
  • Typically, the apparatus includes a cuff, and an electrically-insulating element coupled to an inner portion of the cuff, and the primary anode and the cathode are adapted to be mounted in the cuff and separated from one another by the insulating element. Typically, the primary and secondary anodes and the cathode are recessed in the cuff so as not to be in direct contact with the vagus nerve.
  • Typically, the apparatus includes a control unit, adapted to drive the cathode and the anodes to apply the respective currents to the vagus nerve, so as to treat the subject.
  • Typically, the cathode is adapted to apply the stimulating current and the anodes are adapted to apply the inhibiting current so as to regulate a heart rate of the subject. Optionally, the cathode is adapted to vary an amplitude of the applied stimulating current and the anodes are adapted to vary an amplitude of the applied inhibiting current so as to regulate a heart rate of the subject.
  • Typically, the control unit is adapted to:
  • drive the electrode device to apply to the vagus nerve a stimulating current, which is capable of inducing action potentials in a therapeutic direction in a first set and a second set of nerve fibers of the vagus nerve, and
  • drive the electrode device to apply to the vagus nerve an inhibiting current, which is capable of inhibiting the induced action potentials traveling in the therapeutic direction in the second set of nerve fibers, the nerve fibers in the second set having generally larger diameters than the nerve fibers in the first set.
  • Optionally, the termination physiological parameter includes a blood pressure of the subject, and wherein the control unit is adapted to set the length of the delay responsive to the blood pressure.
  • Typically, the sensor unit is adapted to sense a rate-setting parameter of the subject, wherein the rate-setting parameter includes a blood pressure of the subject, and wherein the control unit is adapted to receive the rate-setting parameter from the sensor unit and to drive the electrode device to apply the current responsive to the rate-setting parameter.
  • Optionally, the rate-setting parameter includes the initiation physiological parameter and/or the termination physiological parameter, and the control unit is adapted to drive the electrode device to apply the current responsive to the initiation physiological parameter so as to regulate the heart rate of the subject.
  • Typically, the control unit is adapted to set the length of the delay so as to adjust the heart rate towards the target heart rate. Optionally, the control unit is adapted to access a lookup table of delays, and to set the length of the delay using the lookup table and responsive to the initiation and termination physiological parameters.
  • Typically, the initiation physiological parameter includes a P-wave, R-wave, Q-wave, S-wave, or T-wave of a cardiac cycle of the subject, and wherein the control unit is adapted to initiate the delay responsive to the sensing of the cardiac wave.
  • Typically, the termination physiological parameter includes a difference in time between two features of an ECG signal recorded by the ECG monitor, and the control unit is adapted to set the length of the delay responsive to the difference in time between the two features. The termination physiological parameter may include an R-R interval between a sensing of an R-wave of a first cardiac cycle of the subject and a sensing of an R-wave of a next cardiac cycle of the subject, and wherein the control unit is adapted to set the length of the delay responsive to the R-R interval. Alternatively or additionally, the termination physiological parameter includes an average of R-R intervals sensed for a number of cardiac cycles, and wherein the control unit is adapted to set the length of the delay responsive to the average of the R-R intervals.
  • Alternatively, the termination physiological parameter includes a P-R interval between a sensing of a P-wave of a cardiac cycle of the subject and a sensing of an R-wave of the cardiac cycle, and wherein the control unit is adapted to set the length of the delay responsive to the P-R interval. Alternatively or additionally, the termination physiological parameter includes an average of P-R intervals sensed for a number of cardiac cycles, and wherein the control unit is adapted to set the length of the delay responsive to the average of the P-R intervals.
  • There is also provided, in accordance with an embodiment of the present invention, apparatus for treating a condition of a subject, including:
  • an electrode device, adapted to be coupled to an autonomic nerve of the subject; and
  • a control unit, adapted to:
  • drive the electrode device to apply to the nerve a stimulating current, which is capable of inducing action potentials in a therapeutic direction in a first set and a second set of nerve fibers of the nerve, and
  • drive the electrode device to apply to the nerve an inhibiting current, which is capable of inhibiting the induced action potentials traveling in the therapeutic direction in the second set of nerve fibers, the nerve fibers in the second set having generally larger diameters than the nerve fibers in the first set.
  • Typically, the autonomic nerve includes the vagus nerve, and the control unit is adapted to drive the electrode device to apply the stimulating and inhibiting currents to the nerve.
  • Typically, the control unit is adapted to drive the electrode device to apply the stimulating and inhibiting currents to the nerve so as to affect behavior of one of the following, so as to treat the condition:
      • a lung of the subject,
      • a heart of the subject,
      • an immune system of the subject, and/or
      • an adrenal gland of the subject.
  • There is additionally provided, in accordance with an embodiment of the present invention, apparatus for treating a condition of a subject, including:
  • a cathode, adapted to apply to an autonomic nerve of the subject a stimulating current which is capable of inducing action potentials in the nerve; and
  • a primary and a secondary anode, adapted to be disposed so that the primary anode is located between the secondary anode and the cathode, and adapted to apply to the nerve respective primary and secondary inhibiting currents which are capable of inhibiting action potentials in the nerve.
  • There is yet additionally provided, in accordance with an embodiment of the present invention, a method for treating a heart condition of a subject, including:
  • applying, to a vagus nerve of the subject, a stimulating current which is capable of inducing action potentials in a therapeutic direction in a first set and a second set of nerve fibers of the vagus nerve; and
  • applying to the vagus nerve an inhibiting current which is capable of inhibiting the induced action potentials traveling in the therapeutic direction in the second set of nerve fibers, the nerve fibers in the second set having generally larger diameters than the nerve fibers in the first set.
  • There is still additionally provided, in accordance with an embodiment of the present invention, a method for treating a heart condition of a subject, including:
  • applying, to a vagus nerve of the subject, at a stimulation location, a stimulating current which is capable of inducing action potentials in the vagus nerve, so as to treat the subject; and
  • applying to the vagus nerve at a primary and a secondary location, the primary location located between the secondary location and the stimulation location, an inhibiting current which is capable of inhibiting action potentials in the vagus nerve.
  • There is still further provided, in accordance with an embodiment of the present invention, a method for treating a condition of a subject, including:
  • applying, to an autonomic nerve of the subject, a stimulating current which is capable of inducing action potentials in a therapeutic direction in a first set and a second set of nerve fibers of the nerve; and
  • applying to the nerve an inhibiting current which is capable of inhibiting the induced action potentials traveling in the therapeutic direction in the second set of nerve fibers, the nerve fibers in the second set having generally larger diameters than the nerve fibers in the first set.
  • There is also provided, in accordance with an embodiment of the present invention, a method for treating a condition of a subject, including:
  • applying, to an autonomic nerve of the subject, at a stimulation location, a stimulating current which is capable of inducing action potentials in the nerve, so as to treat the subject; and
  • applying to the nerve at a primary and a secondary location, the primary location located between the secondary location and the stimulation location, an inhibiting current which is capable of inhibiting action potentials in the nerve.
  • There is further provided, in accordance with an embodiment of the present invention, apparatus for treating a subject, including:
  • an electrode device, adapted to be coupled to a vagus nerve of the subject;
  • a heart rate sensor, configured to detect a heart rate of the subject, and to generate a heart rate signal responsive thereto; and
  • a control unit, adapted to:
  • receive the heart rate signal, and
  • responsive to determining that the heart rate is greater than a threshold value, which threshold value is greater than a normal heart rate, drive the electrode device to apply a current to the vagus nerve, and configure the current so as to reduce the heart rate of the subject.
  • For some applications, the control unit is adapted to configure the current to include a stimulating current, which is capable of inducing action potentials in a first set and a second set of nerve fibers of the vagus nerve, and an inhibiting current, which is capable of inhibiting the induced action potentials traveling in the second set of nerve fibers, the nerve fibers in the second set having generally larger diameters than the nerve fibers in the first set, and the control unit is adapted to drive the electrode device to apply the stimulating current and the inhibiting current to the vagus nerve.
  • Alternatively or additionally, the current includes a stimulating current, which is capable of inducing action potentials in the vagus nerve, and an inhibiting current, which is capable of inhibiting device-induced action potentials traveling in the vagus nerve in an afferent direction toward a brain of the subject, and the control unit is adapted to drive the electrode device to apply the stimulating current and the inhibiting current to the vagus nerve.
  • For some applications, the vagus nerve includes small-, medium-, and large-diameter fibers, and the electrode device includes:
  • a cathode, adapted to be disposed at a cathodic site of the vagus nerve, and to apply a cathodic current to the vagus nerve which is capable of inducing action potentials in the vagus nerve; and
  • an anode, adapted to be disposed at an anodal site of the vagus nerve, and to apply to the vagus nerve an anodal current which is capable of inhibiting action potentials in the vagus nerve, and
  • the control unit is adapted to:
  • drive the cathode to apply to the vagus nerve the cathodic current having a cathodic amplitude sufficient to induce action potentials in the medium- and large-diameter fibers, but generally insufficient to induce action potentials in the small-diameter fibers, and
  • drive the anode to apply to the vagus nerve the anodal current having an anodal amplitude sufficient to inhibit action potentials in the large-diameter fibers, but generally insufficient to inhibit action potentials in the medium-diameter fibers.
  • In an embodiment, the control unit is adapted to utilize a value of at least 100 beats per minute as the threshold value.
  • In an embodiment, the control unit is adapted to withhold driving the electrode device upon determining that the heart rate is less than a value associated with bradycardia.
  • In an embodiment, the control unit is adapted to configure the current so as to reduce the heart rate towards a target heart rate.
  • For some applications, the normal heart rate includes a normal heart rate of the subject. Alternatively, the normal heart rate includes a normal heart rate of a typical human.
  • In an embodiment, the control unit is adapted to drive the electrode device to apply the current with an amplitude of between about 2 and about 10 milliamps.
  • In an embodiment, the control unit is adapted to drive the electrode device to apply the current in intermittent ones of a plurality of cardiac cycles of the subject.
  • In an embodiment, the apparatus includes an electrode selected from the list consisting of: an electrode for pacing the heart, and an electrode for defibrillating the heart, and the control unit is adapted to withhold driving the electrode device to apply the current to the vagus nerve if the control unit is driving the electrode selected from the list.
  • In an embodiment, the control unit is adapted to drive the electrode device to apply the current in respective pulse bursts in each of a plurality of cardiac cycles of the subject. The control unit may be adapted to configure each pulse of each of the bursts to have a pulse duration of between about 0.2 and about 4 milliseconds. The control unit may be adapted to configure each of the bursts to have a pulse repetition interval of greater than about 3 milliseconds. Alternatively or additionally, the control unit is adapted to configure at least one of the bursts to have between about 0 and about 8 pulses.
  • In an embodiment, the apparatus includes an electrocardiogram (ECG) monitor, adapted to generate an ECG signal, and the control unit is adapted to receive the ECG signal, and to initiate the applying of each burst after a delay following detection of a feature of the ECG.
  • There is still further provided, in accordance with an embodiment of the present invention, apparatus for applying current to a vagus nerve, including:
  • a cathode, adapted to be disposed at a cathodic site of the vagus nerve and to apply a cathodic current to the vagus nerve so as to stimulate the vagus nerve;
  • a first anode, adapted to be disposed at a first anodal site of the vagus nerve; and
  • a second anode, directly electrically connected to the first anode, and adapted to be disposed at a second anodal site of the vagus nerve, such that the cathodic site is between the first anodal site and the second anodal site.
  • In an embodiment, the cathode and anodes are disposed such that the cathodic site is disposed closer to the first anodal site than to the second anodal site.
  • In an embodiment, the nerve includes small-, medium-, and large-diameter fibers, and the apparatus includes a control unit, adapted to:
  • drive the cathode to apply to the vagus nerve the cathodic current having a cathodic amplitude sufficient to induce action potentials in the medium- and large-diameter fibers, but generally insufficient to induce action potentials in the small-diameter fibers, and
  • drive the first and second anodes to apply to the vagus nerve an anodal current having an anodal amplitude sufficient to inhibit action potentials in the large-diameter fibers, but generally insufficient to inhibit action potentials in the medium-diameter fibers.
  • In an embodiment, the apparatus includes:
  • a control unit; and
  • an electrode selected from the list consisting of: an electrode for pacing the heart, and an electrode for defibrillating the heart,
  • and the control unit is adapted to drive current through the cathode and the first and second anodes, and the control unit is adapted to withhold driving current through the cathode and the first and second anodes if the control unit is driving current through the electrode selected from the list.
  • In an embodiment, the apparatus includes a control unit, adapted to:
  • drive the cathode to apply the cathodic current,
  • configure the cathodic current to induce action potentials in a first set and a second set of nerve fibers of the vagus nerve, the nerve fibers in the second set having generally larger diameters than the nerve fibers in the first set,
  • drive an anodal current to the first and second anodes, whereby the first and second anodes apply current to the vagus nerve at levels corresponding to respective first and second anodal currents, and
  • configure the anodal current driven to the first and second anodes to inhibit the induced action potentials traveling in the second set of nerve fibers.
  • In an embodiment, the first and second anodes are configured such that a level of impedance between the first anode and the cathode is lower than a level of impedance between the second anode and the cathode, the control unit is adapted to configure the anodal current driven to the first and second anodes such that the first anodal current inhibits the induced action potentials traveling in the first set of nerve fibers, and the control unit is adapted to configure the anodal current driven to the first and second anodes to be such that the second anodal current is generally insufficient to inhibit the induced action potentials traveling in the first set of nerve fibers.
  • There is additionally provided, in accordance with an embodiment of the present invention, apparatus for treating a subject, including:
  • an electrode device, adapted to be coupled to a vagus nerve of the subject;
  • a sensor, configured to detect a heart rate of the subject, and to generate a heart rate signal responsive thereto; and
  • a control unit including an integral feedback controller that has inputs including the detected heart rate and a target heart rate, the control unit adapted to:
  • drive the electrode device to apply a current to the vagus nerve, and
  • configure the current responsive to an output of the integral feedback controller, so as to reduce the heart rate of the subject toward a target heart rate.
  • In an embodiment, the control unit is adapted to configure the current to include a stimulating current, which is capable of inducing action potentials in a first set and a second set of nerve fibers of the vagus nerve, and an inhibiting current, which is capable of inhibiting the induced action potentials traveling in the second set of nerve fibers, the nerve fibers in the second set having generally larger diameters than the nerve fibers in the first set, and the control unit is adapted to drive the electrode device to apply the stimulating current and the inhibiting current to the vagus nerve.
  • In an embodiment, the current includes a stimulating current, which is capable of inducing action potentials in the vagus nerve, and an inhibiting current, which is capable of inhibiting device-induced action potentials traveling in the vagus nerve in an afferent direction toward a brain of the subject, and the control unit is adapted to drive the electrode device to apply the stimulating current and the inhibiting current to the vagus nerve.
  • In an embodiment, the vagus nerve includes small-, medium-, and large-diameter fibers, and the electrode device includes:
  • a cathode, adapted to be disposed at a cathodic site of the vagus nerve, and to apply a cathodic current to the vagus nerve which is capable of inducing action potentials in the vagus nerve; and
  • an anode, adapted to be disposed at an anodal site of the vagus nerve, and to apply to the vagus nerve an anodal current which is capable of inhibiting action potentials in the vagus nerve, and
  • the control unit is adapted to:
  • drive the cathode to apply to the vagus nerve the cathodic current having a cathodic amplitude sufficient to induce action potentials in the medium- and large-diameter fibers, but generally insufficient to induce action potentials in the small-diameter fibers, and
  • drive the anode to apply to the vagus nerve the anodal current having an anodal amplitude sufficient to inhibit action potentials in the large-diameter fibers, but generally insufficient to inhibit action potentials in the medium-diameter fibers.
  • In an embodiment, the control unit is adapted to change the parameter by:
  • determining a target value of the parameter, which target value is substantially appropriate for achieving the target heart rate,
  • determining an intermediate value for the parameter, the intermediate value between a current value of the parameter and the target value of the parameter, and
  • setting the parameter at the intermediate value.
  • In an embodiment, the control unit is adapted to withhold driving the electrode device upon determining that the heart rate is less than a value associated with bradycardia.
  • In an embodiment, the control unit is adapted to drive the electrode device to apply the current with an amplitude of between about 2 and about 10 milliamps.
  • In an embodiment, the control unit is adapted to drive the electrode device to apply the current in intermittent ones of a plurality of cardiac cycles of the subject.
  • In an embodiment, the apparatus includes an electrode selected from the list consisting of: an electrode for pacing the heart, and an electrode for defibrillating the heart, and the control unit is adapted to withhold driving the electrode device to apply the current to the vagus nerve when the control unit drives the electrode selected from the list.
  • In an embodiment, the integral feedback controller is adapted to calculate a difference between the target heart rate and the detected heart rate, and the control unit is adapted to set a level of a stimulation parameter of the current responsive to a summation over time of the difference.
  • In an embodiment, the control unit is adapted to set a level of a stimulation parameter of the current by selecting the level from fewer than 16 discrete values. For some applications, the control unit is adapted to set the level of the stimulation parameter of the current by selecting the level from fewer than 10 discrete values. For some applications, the level of the stimulation parameter of the current includes a number of pulses to apply during a cardiac cycle, and the control unit is adapted to set the number to be a number between 0 and 16.
  • For some applications, when a value of the level of the stimulation parameter suitable to achieve the target heart rate is between two of the discrete values, the control unit is adapted to vary the level, in turns, between the two of the discrete values. For some applications, when the suitable value of the level is between the two discrete values, the control unit is adapted to vary the level from a first one of the two discrete values, to a second one of the two discrete values, and back to the first one of the two discrete values, in a time period lasting fewer than 20 heartbeats. For some applications, when the suitable value of the level is between the two discrete values, the control unit is adapted to vary the level from a first one of the two discrete values, to a second one of the two discrete values, and back to the first one of the two discrete values, in a time period lasting fewer than 10 heartbeats.
  • In an embodiment, the control unit is adapted to drive the electrode device to apply the current in respective pulse bursts in each of a plurality of cardiac cycles of the subject. The at least one parameter may include a number of pulses per burst, and the control unit is adapted to change the at least one parameter by changing the number of pulses per burst no more than once in any given approximately 15-second period during operation of the apparatus. Alternatively or additionally, the at least one parameter includes a number of pulses per burst, and the control unit is adapted to change the at least one parameter by changing, during any given approximately 15-second period during operation of the apparatus, the number of pulses per burst by no more than one pulse.
  • In an embodiment, the control unit is adapted to configure each pulse of each of the bursts to have a pulse duration of between about 0.2 and about 4 milliseconds. In an embodiment, the control unit is adapted to configure each of the bursts to have a pulse repetition interval of greater than about 3 milliseconds.
  • In an embodiment, the control unit is adapted to configure at least one of the bursts to have between about 0 and about 8 pulses.
  • In an embodiment, the apparatus includes an electrocardiogram (ECG) monitor, adapted to measure an ECG signal, the control unit is adapted to receive the ECG signal, and to initiate the applying of each burst after a delay following detection of a feature of the ECG.
  • In an embodiment, the control unit is adapted to set a control parameter of a feedback algorithm governing the current application to be a number of pulses per burst.
  • In an embodiment, the at least one parameter includes a number of pulses per burst, and the control unit is adapted to change the at least one parameter by changing, over the period, the number of pulses per burst by less than about three pulses. For some applications, the control unit is adapted to change the at least one parameter by changing, over the period, the number of pulses per burst by exactly one pulse. Alternatively or additionally, the control unit is adapted to change the at least one parameter by changing, during each of two consecutive periods, the number of pulses per burst by less than about three pulses, each of the two consecutive periods having a duration of at least about 15 seconds. The control unit may be adapted to change the at least one parameter by changing, during each of the two consecutive periods, the number of pulses per burst by exactly one pulse.
  • In an embodiment, the control unit is adapted to change the at least one parameter at a rate of change, the rate of change determined at least in part responsive to a heart rate variable selected from: an R-R interval of the subject and a time derivative of the heart rate of the subject. For some applications, the control unit is adapted to increase the rate of change as the heart rate approaches a threshold limit greater than a normal heart rate of the subject. For other applications, the control unit is adapted to increase the rate of change as the heart rate approaches a threshold limit less than a normal heart rate of the subject. Alternatively or additionally, the control unit is adapted to decrease the rate of change as the heart rate increases, and to increase the rate of change as the heart rate decreases.
  • In an embodiment, the control unit is adapted to use a time derivative of an R-R interval of the subject as an input to a feedback algorithm governing the current application.
  • In an embodiment, the control unit is adapted to correct for an absence of an expected heartbeat.
  • For some applications, the control unit is adapted to sense an R-R interval and: (a) store the sensed R-R interval, if the sensed R-R interval is less than a threshold value, and (b) store the threshold value, if the sensed R-R interval is greater than the threshold value.
  • In an embodiment, the control unit is adapted to cycle between “on” periods, during which the control unit drives the electrode device to apply the current, and “off” periods, during which the control unit withholds driving the electrode device. For some applications, the control unit is adapted to determine a desired level of stimulation applied by the electrode device, and to configure the cycling between the “on” and “off” periods responsive to the desired level of stimulation. For some applications, the control unit is adapted to set each of the “on” periods to have a duration of less than about 300 seconds. For some applications, the control unit is adapted to set each of the “off” periods to have a duration of between about 0 and about 300 seconds.
  • In an embodiment, the control unit is adapted to set the parameter at a beginning of one of the “on” periods equal to a value of the parameter at an end of an immediately preceding one of the “on” periods. In an embodiment, the control unit is adapted to configure the current using an algorithm that disregards between about one and about five heart beats at a beginning of each of the “on” periods.
  • In an embodiment, the control unit is adapted to set the target heart rate during at least one of the “on” periods at least in part responsive to a historic heart rate sensed during a preceding one of the “off” periods. The control unit may be adapted to set the target heart rate during the at least one of the “on” periods at least in part responsive to a historic heart rate sensed during an immediately preceding one of the “off” periods.
  • There is yet additionally provided, in accordance with an embodiment of the present invention, apparatus for treating a heart condition of a subject, including:
  • an electrode device, adapted to be coupled to a vagus nerve of the subject; and
  • a control unit, adapted to cycle between “on” periods, during which the control unit drives the electrode device to apply a current to the vagus nerve, and “off” periods, during which the control unit withholds driving the electrode device, so as to treat the heart condition.
  • In an embodiment, the control unit is adapted to withhold driving the electrode device upon determining that the heart rate is less than a value associated with bradycardia. In an embodiment, the control unit is adapted to drive the electrode device to apply the current with an amplitude of between about 2 and about 10 milliamps. In an embodiment, the control unit is adapted to drive the electrode device to apply the current in intermittent ones of a plurality of cardiac cycles of the subject.
  • In an embodiment, the apparatus includes an electrode selected from the list consisting of: an electrode for pacing the heart, and an electrode for defibrillating the heart, and the control unit is adapted to withhold driving the electrode device to apply the current to the vagus nerve during an “on” period if the control unit is driving the electrode selected from the list.
  • In an embodiment, the control unit is adapted to drive the electrode device to apply the current in respective pulse bursts in each of a plurality of cardiac cycles of the subject. For some applications, the control unit is adapted to configure each pulse of each of the bursts to have a pulse duration of between about 0.2 and about 4 milliseconds. For some applications, the control unit is adapted to configure each of the bursts to have a pulse repetition interval of greater than about 3 milliseconds. For some applications, the control unit is adapted to configure at least one of the bursts to have between about 0 and about 8 pulses. In an embodiment, the apparatus includes an electrocardiogram (ECG) monitor, adapted to measure an ECG signal, the control unit is adapted to receive the ECG signal, and to initiate the applying of each burst after a delay following detection of a feature of the ECG.
  • In an embodiment, the control unit is adapted to configure the current to include a stimulating current, which is capable of inducing action potentials in a first set and a second set of nerve fibers of the vagus nerve, and an inhibiting current, which is capable of inhibiting the induced action potentials traveling in the second set of nerve fibers, the nerve fibers in the second set having generally larger diameters than the nerve fibers in the first set, and the control unit is adapted to drive the electrode device to apply the stimulating current and the inhibiting current to the vagus nerve.
  • In an embodiment, the current includes a stimulating current, which is capable of inducing action potentials in the vagus nerve, and an inhibiting current, which is capable of inhibiting device-induced action potentials traveling in the vagus nerve in an afferent direction toward a brain of the subject, and the control unit is adapted to drive the electrode device to apply the stimulating current and the inhibiting current to the vagus nerve.
  • In an embodiment, the vagus nerve includes small-, medium-, and large-diameter fibers, and the electrode device includes:
  • a cathode, adapted to be disposed at a cathodic site of the vagus nerve, and to apply a cathodic current to the vagus nerve which is capable of inducing action potentials in the vagus nerve; and
  • an anode, adapted to be disposed at an anodal site of the vagus nerve, and to apply to the vagus nerve an anodal current which is capable of inhibiting action potentials in the vagus nerve, and
  • the control unit is adapted to:
  • drive the cathode to apply to the vagus nerve the cathodic current having a cathodic amplitude sufficient to induce action potentials in the medium- and large-diameter fibers, but generally insufficient to induce action potentials in the small-diameter fibers, and
  • drive the anode to apply to the vagus nerve the anodal current having an anodal amplitude sufficient to inhibit action potentials in the large-diameter fibers, but generally insufficient to inhibit action potentials in the medium-diameter fibers.
  • There is also provided, in accordance with an embodiment of the present invention, apparatus for treating a subject, including:
  • an electrode device, adapted to be coupled to a vagus nerve of the subject;
  • a sensor, configured to detect a heart rate of the subject, and to generate a heart rate signal responsive thereto; and
  • a control unit, adapted to:
  • receive the heart rate signal, drive the electrode device to apply a current to the vagus nerve, and
  • configure the current to increase a variability of the heart rate.
  • In an embodiment, the control unit is adapted to configure the current to include a stimulating current, which is capable of inducing action potentials in a first set and a second set of nerve fibers of the vagus nerve, and an inhibiting current, which is capable of inhibiting the induced action potentials traveling in the second set of nerve fibers, the nerve fibers in the second set having generally larger diameters than the nerve fibers in the first set, and the control unit is adapted to drive the electrode device to apply the stimulating current and the inhibiting current to the vagus nerve.
  • In an embodiment, the current includes a stimulating current, which is capable of inducing action potentials in the vagus nerve, and an inhibiting current, which is capable of inhibiting device-induced action potentials traveling in the vagus nerve in an afferent direction toward a brain of the subject, and the control unit is adapted to drive the electrode device to apply the stimulating current and the inhibiting current to the vagus nerve.
  • In an embodiment, the vagus nerve includes small-, medium-, and large-diameter fibers, and the electrode device includes:
  • a cathode, adapted to be disposed at a cathodic site of the vagus nerve, and to apply a cathodic current to the vagus nerve which is capable of inducing action potentials in the vagus nerve; and
  • an anode, adapted to be disposed at an anodal site of the vagus nerve, and to apply to the vagus nerve an anodal current which is capable of inhibiting action potentials in the vagus nerve, and
  • the control unit is adapted to:
  • drive the cathode to apply to the vagus nerve the cathodic current having a cathodic amplitude sufficient to induce action potentials in the medium- and large-diameter fibers, but generally insufficient to induce action potentials in the small-diameter fibers, and
  • drive the anode to apply to the vagus nerve the anodal current having an anodal amplitude sufficient to inhibit action potentials in the large-diameter fibers, but generally insufficient to inhibit action potentials in the medium-diameter fibers.
  • For some applications, the control unit is adapted to configure the current to increase the variability of the heart rate above a target heart rate variability.
  • For some applications, the sensor includes an electrocardiogram (ECG) monitor.
  • For some applications, the control unit is adapted to withhold driving the electrode device upon determining that the heart rate is less than a value associated with bradycardia.
  • In an embodiment, the control unit is adapted to drive the electrode device to apply the current with an amplitude of between about 2 and about 10 milliamps. In an embodiment, the control unit is adapted to drive the electrode device to apply the current in intermittent ones of a plurality of cardiac cycles of the subject.
  • In an embodiment, the apparatus includes an electrode selected from the list consisting of: an electrode for pacing the heart, and an electrode for defibrillating the heart, and the control unit is adapted to withhold driving the electrode device to apply the current to the vagus nerve if the control unit is driving the electrode selected from the list.
  • In an embodiment, the control unit is adapted to drive the electrode device to apply the current in respective pulse bursts in each of a plurality of cardiac cycles of the subject. For some applications, the control unit is adapted to configure each pulse of each of the bursts to have a pulse duration of between about 0.2 and about 4 milliseconds. For some applications, the control unit is adapted to configure each of the bursts to have a pulse repetition interval of greater than about 3 milliseconds. For some applications, the control unit is adapted to configure at least one of the bursts to have between about 0 and about 8 pulses. In an embodiment, the apparatus includes an electrocardiogram (ECG) monitor, adapted to measure an ECG signal, the control unit is adapted to receive the ECG signal, and to initiate the applying of each burst after a delay following detection of a feature of the ECG.
  • In an embodiment, the control unit is adapted to configure the current using a feedback algorithm.
  • There is further provided, in accordance with an embodiment of the present invention, a method for treating a subject, including:
  • detecting a heart rate of the subject; and
  • responsive to determining that the heart rate is greater than a threshold value, which threshold value is greater than a normal heart rate, applying a current to a vagus nerve of the subject, and configuring the current so as to reduce the heart rate of the subject.
  • There is still further provided, in accordance with an embodiment of the present invention, a method for applying current to a vagus nerve, including:
  • applying to the vagus nerve, through a common conductor, an anodal current at a first anodal site of the vagus nerve and at a second anodal site of the vagus nerve; and applying a cathodic current to the vagus nerve at a cathodic site of the vagus nerve, so as to stimulate the vagus nerve, the cathodic site disposed between the first anodal site and the second anodal site.
  • There is additionally provided, in accordance with an embodiment of the present invention, a method for treating a subject, including:
  • detecting a heart rate of the subject;
  • applying a current to a vagus nerve of the subject; and
  • configuring the current so as to reduce the heart rate toward a target heart rate, responsive to an output of an integral feedback controller whose inputs include the detected heart rate and a target heart rate.
  • There is yet additionally provided, in accordance with an embodiment of the present invention, a method for treating a heart condition of a subject, including:
  • cycling between “on” and “off” periods;
  • during the “on” periods, applying a current to a vagus nerve of the subject; and
  • during the “off” periods, withholding applying the current, so as to treat the heart condition.
  • There is also provided, in accordance with an embodiment of the present invention, a method for treating a subject, including:
  • detecting a heart rate of the subject;
  • applying a current to a vagus nerve of the subject; and
  • configuring the current to increase a variability of the heart rate.
  • There is further provided, in accordance with an embodiment of the present invention, apparatus for treating a subject suffering from a heart condition, including:
  • an electrode device, adapted to be coupled to a vagus nerve of the subject; and
  • a control unit, adapted to drive the electrode device to apply a current to the vagus nerve, and to configure the current to suppress an adrenergic system of the subject, so as to treat the subject.
  • In an embodiment, the heart condition includes heart failure, and the control unit is adapted to configure the current to treat the heart failure.
  • There is still further provided, in accordance with an embodiment of the present invention, apparatus for treating a subject suffering from a heart condition, including:
  • an electrode device, adapted to be coupled to a vagus nerve of the subject; and
  • a control unit, adapted to drive the electrode device to apply a current to the vagus nerve, and to configure the current to modulate contractility of at least a portion of a heart of the subject, so as to treat the subject.
  • In an embodiment, the control unit is adapted to configure the current to reduce atrial and ventricular contractility.
  • In an embodiment, the heart condition includes hypertrophic cardiopathy, and the control unit is adapted to configure the current so as to treat the hypertrophic cardiopathy.
  • There is additionally provided, in accordance with an embodiment of the present invention, apparatus for treating a subject suffering from a heart condition, including:
  • an electrode device, adapted to be coupled to a vagus nerve of the subject; and a control unit, adapted to drive the electrode device to apply a current to the vagus nerve, and to configure the current to increase coronary blood flow, so as to treat the subject.
  • In an embodiment, the heart condition is selected from the list consisting of: myocardial ischemia, ischemic heart disease, heart failure, and variant angina, and the control unit is adapted to configure the current to increase the coronary blood flow so as to treat the selected heart condition.
  • There is yet additionally provided, in accordance with an embodiment of the present invention, a treatment method, including:
  • identifying a subject suffering from a heart condition;
  • applying a current to a vagus nerve of the subject; and
  • configuring the current to suppress an adrenergic system of the subject, so as to treat the subject.
  • There is also provided, in accordance with an embodiment of the present invention, a treatment method, including:
  • identifying a subject suffering from a heart condition;
  • applying a current to a vagus nerve of the subject; and
  • configuring the current to modulate contractility of at least a portion of a heart of the subject, so as to treat the subject.
  • There is further provided, in accordance with an embodiment of the present invention, a treatment method, including:
  • identifying a subject suffering from a heart condition;
  • applying a current to a vagus nerve of the subject; and
  • configuring the current to increase coronary blood flow, so as to treat the subject.
  • There is still further provided, in accordance with an embodiment of the present invention, apparatus including:
  • an electrode device, adapted to be coupled to a vagus nerve of a subject; and
  • a control unit, adapted to drive the electrode device to apply to the vagus nerve a current that reduces heart rate variability of the subject.
  • In an embodiment, the control unit is adapted to configure the current to substantially not reduce a heart rate of the subject.
  • In an embodiment, the control unit is adapted to configure the current to reduce the heart rate variability by at least 5% below a baseline thereof during a time period in which a heart rate of the subject is not reduced responsive to the current by more than 10% below a baseline thereof.
  • In an embodiment, the control unit is adapted to configure the current to effect a reduction of a heart rate of the subject while reducing the heart rate variability of the subject.
  • For some applications, the control unit is adapted to drive the electrode device during exertion by the subject. Alternatively, the control unit is adapted to withhold driving the electrode device when the subject is not experiencing exertion.
  • For some applications, the control unit is adapted to configure the current to reduce a heart rate variability of the subject having a characteristic frequency between about 0.15 and about 0.4 Hz. Alternatively or additionally, the control unit is adapted to configure the current to reduce a heart rate variability of the subject having a characteristic frequency between about 0.04 and about 0.15 Hz.
  • For some applications, the control unit is adapted to drive the electrode device to apply the current with an amplitude of between about 2 and about 10 milliamps.
  • For some applications, the control unit is adapted to drive the electrode device to apply the current in intermittent ones of a plurality of cardiac cycles of the subject. For some applications, the control unit is adapted to drive the electrode device to apply the current unsynchronized with a cardiac cycle of the subject.
  • In an embodiment, the control unit is adapted to drive the electrode device responsive to a circadian rhythm of the subject. For some applications, the control unit is adapted to drive the electrode device when the subject is awake. For some applications, the control unit is adapted to withhold driving the electrode device when the subject is sleeping.
  • For some applications, the control unit is adapted to drive the electrode device to apply the current in a manner that reduces the heart rate variability by at least 10%. For some applications, the control unit is adapted to drive the electrode device to apply the current in a manner that reduces the heart rate variability by at least 50%.
  • In an embodiment, the control unit is adapted to drive the electrode device to apply the current in a manner that reduces a standard deviation of a heart rate of the subject within a time window, e.g., a time window that is longer than 10 seconds. For some applications, the standard deviation of the heart rate is reduced by at least about 10% or at least about 50% within the time window that is longer than 10 seconds.
  • In an embodiment, the control unit is adapted to drive the electrode device to apply the current in respective pulse bursts in each of a plurality of cardiac cycles of the subject.
  • For some applications, the control unit is adapted to configure each pulse of each of the bursts to have a pulse duration of between about 0.1 and about 4 milliseconds. For some applications, the control unit is adapted to configure each pulse of each of the bursts to have a pulse duration of between about 0.5 and about 2 milliseconds. For some applications, the control unit is adapted to configure each of the bursts to have a pulse repetition interval of between about 2 and about 10 milliseconds. For some applications, the control unit is adapted to configure each of the bursts to have a pulse repetition interval of between about 2 and about 6 milliseconds.
  • In an embodiment, the apparatus includes a cardiac monitor, adapted to generate a cardiac signal, and the control unit is adapted to receive the cardiac signal, and to initiate the applying of each burst after a delay following detection of a feature of the cardiac signal. For some applications, the control unit is adapted to initiate the applying of each burst after a delay of about 30 to about 200 milliseconds following an R-wave of the cardiac signal. For some applications, the control unit is adapted to initiate the applying of each burst after a delay of about 50 to about 150 milliseconds following an R-wave of the cardiac signal.
  • For some applications, the control unit is adapted to configure at least one of the bursts to have between about 0 and about 20 pulses. For some applications, the control unit is adapted to configure the bursts to have between about 1 and about 8 pulses during steady state operation.
  • In an embodiment, the apparatus includes a heart sensor, configured to detect heart activity of the subject, and to generate a heart signal responsive thereto, and the control unit is adapted to receive the heart signal, and, responsive to receiving the heart signal, drive the electrode device to apply the current to the vagus nerve.
  • For some applications, the control unit is adapted to, responsive to receiving the heart signal, drive the electrode device to apply to the vagus nerve the current synchronized with a cardiac cycle of the subject. For some applications, the control unit is adapted to, responsive to receiving the heart signal, drive the electrode device to apply to the vagus nerve the current unsynchronized with a cardiac cycle of the subject.
  • In an embodiment, the control unit is adapted to configure the current to reduce a heart rate of the subject.
  • In an embodiment, the apparatus includes a sensor, configured to detect the heart rate of the subject, and to generate a heart rate signal responsive thereto, and the control unit includes an integral feedback controller that has inputs including the detected heart rate and a target heart rate, and the control unit is adapted to configure the current responsive to an output of the integral feedback controller, so as to reduce the heart rate of the subject toward the target heart rate. For some applications, the target heart rate includes a target normal heart rate within a range of normal heart rates of the subject, and the control unit is adapted to configure the current so as to reduce the heart rate of the subject toward the target normal heart rate.
  • In an embodiment, the control unit is adapted to configure the current to reduce the heart rate variability so as to treat a condition of the subject. For some applications, the condition includes heart failure of the subject, and the control unit is adapted to configure the current to reduce the heart rate variability by at least about 10% so as to treat the heart failure. For some applications, the condition includes an occurrence of arrhythmia of the subject, and the control unit is adapted to configure the current to reduce the heart rate variability by at least about 10% so as to treat the occurrence of arrhythmia. For some applications, the condition includes atrial fibrillation of the subject, and the control unit is adapted to configure the current to reduce the heart rate variability so as to treat the atrial fibrillation.
  • There is additionally provided, in accordance with an embodiment of the present invention, a method including applying to a vagus nerve of a subject a current that reduces heart rate variability of the subject.
  • The present invention will be more fully understood from the following detailed description of an embodiments thereof, taken together with the drawings, in which:
  • BRIEF DESCRIPTION OF THE DRAWINGS
  • FIG. 1 is a block diagram that schematically illustrates a vagal stimulation system applied to a vagus nerve of a patient, in accordance with an embodiment of the present invention;
  • FIG. 2A is a simplified cross-sectional illustration of a multipolar electrode device applied to a vagus nerve, in accordance with an embodiment of the present invention;
  • FIG. 2B is a simplified cross-sectional illustration of a generally-cylindrical electrode device applied to a vagus nerve, in accordance with an embodiment of the present invention;
  • FIG. 2C is a simplified perspective illustration of the electrode device of FIG. 2A, in accordance with an embodiment of the present invention;
  • FIG. 3 is a simplified perspective illustration of a multipolar point electrode device applied to a vagus nerve, in accordance with an embodiment of the present invention;
  • FIG. 4 is a conceptual illustration, of the application of current to a vagus nerve, in accordance with an embodiment of the present invention;
  • FIG. 5 is a simplified illustration of an electrocardiogram (ECG) recording and of example timelines showing the timing of the application of a series of stimulation pulses, in accordance with an embodiment of the present invention; and
  • FIG. 6 is a graph showing in vivo experimental results, measured in accordance with an embodiment of the present invention.
  • DETAILED DESCRIPTION OF EMBODIMENTS
  • FIG. 1 is a block diagram that schematically illustrates a vagal stimulation system 18 comprising a multipolar electrode device 40, in accordance with an embodiment of the present invention. Electrode device 40 is applied to a portion of a vagus nerve 36 (either a left vagus nerve 37 or a right vagus nerve 39), which innervates a heart 30 of a patient 31. Typically, system 18 is utilized for treating a heart condition such as heart failure and/or cardiac arrhythmia. Vagal stimulation system 18 further comprises an implanted or external control unit 20, which typically communicates with electrode device 40 over a set of leads 42. Control unit 20 drives electrode device 40 to (i) apply signals to induce the propagation of efferent nerve impulses towards heart 30, and (ii) suppress artificially-induced afferent nerve impulses towards a brain 34 of the patient, in order to minimize unintended side effects of the signal application. The efferent nerve pulses in vagus nerve 36 are induced by electrode device 40 in order to regulate the heart rate of the patient.
  • For some applications, control unit 20 is adapted to receive feedback from one or more of the electrodes in electrode device 40, and to regulate the signals applied to the electrode device responsive thereto.
  • Control unit 20 is typically adapted to receive and analyze one or more sensed physiological parameters or other parameters of the patient, such as heart rate, electrocardiogram (ECG), blood pressure, indicators of decreased cardiac contractility, cardiac output, norepinephrine concentration, or motion of the patient. In order to receive these sensed parameters, control unit 20 may comprise, for example, an ECG monitor 24, connected to a site on the patient's body such as heart 30, for example using one or more subcutaneous sensors or ventricular and/or atrial intracardiac sensors. The control unit may also comprise an accelerometer 22 for detecting motion of the patient. Alternatively, ECG monitor 24 and/or accelerometer 22 comprise separate implanted devices placed external to control unit 20, and, optionally, external to the patient's body. Alternatively or additionally, control unit 20 receives signals from one or more physiological sensors 26, such as blood pressure sensors. Sensors 26 are typically implanted in the patient, for example in a left ventricle 32 of heart 30. In an embodiment, control unit 20 comprises or is coupled to an implanted device 25 for monitoring and correcting the heart rate, such as an implantable cardioverter defibrillator (ICD) or a pacemaker (e.g., a bi-ventricular or standard pacemaker). For example, implanted device 25 may be incorporated into a control loop executed by control unit 20, in order to increase the heart rate when the heart rate for any reason is too low.
  • FIG. 2A is a simplified cross-sectional illustration of a generally-cylindrical electrode device 40 applied to vagus nerve 36, in accordance with an embodiment of the present invention. Electrode device 40 comprises a central cathode 46 for applying a negative current (“cathodic current”) in order to stimulate vagus nerve 36, as described below. Electrode device 40 additionally comprises a set of one or more anodes 44 (44 a, 44 b, herein: “efferent anode set 44”), placed between cathode 46 and the edge of electrode device 40 closer to heart 30 (the “efferent edge”). Efferent anode set 44 applies a positive current (“efferent anodal current”) to vagus nerve 36, for blocking action potential conduction in vagus nerve 36 induced by the cathodic current, as described below. Typically, electrode device 40 comprises an additional set of one or more anodes 45 (45 a, 45 b, herein: “afferent anode set 45”), placed between cathode 46 and the edge of electrode device 40 closer to brain 34. Afferent anode set 45 applies a positive current (“afferent anodal current”) to vagus nerve 36, in order to block propagation of action potentials in the direction of the brain during application of the cathodic current.
  • For some applications, the one or more anodes of efferent anode set 44 are directly electrically coupled to the one or more anodes of afferent anode set 45, such as by a common wire or shorted wires providing current to both anode sets substantially without any intermediary elements. Typically, coatings on the anodes, shapes of the anodes, positions of the anodes, sizes of the anodes and/or distances of the various anodes from the nerve are regulated so as to produce desired ratios of currents and/or desired activation functions delivered through or caused by the various anodes. For example, by varying one or more of these characteristics, the relative impedance between the respective anodes and central cathode 46 is regulated, whereupon more anodal current is driven through the one or more anodes having lower relative impedance. In these applications, central cathode 46 is typically placed closer to one of the anode sets than to the other, for example, so as to induce asymmetric stimulation (i.e., not necessarily unidirectional in all fibers) between the two sides of the electrode device. The closer anode set typically induces a stronger blockade of the cathodic stimulation.
  • Reference is now made to FIG. 2B, which is a simplified cross-sectional illustration of a generally-cylindrical electrode device 240 applied to vagus nerve 36, in accordance with an embodiment of the present invention. Electrode device 240 comprises exactly one efferent anode 244 and exactly one afferent anode 245, which are electrically coupled to each other, such as by a common wire 250 or shorted wires providing current to both anodes 244 and 245, substantially without any intermediary elements. The cathodic current is applied by a cathode 246 with an amplitude sufficient to induce action potentials in large- and medium-diameter fibers (e.g., A- and B-fibers), but insufficient to induce action potentials in small-diameter fibers (e.g., C-fibers).
  • Reference is again made to FIG. 2A. Cathodes 46 and anode sets 44 and 45 (collectively, “electrodes”) are typically mounted in an electrically-insulating cuff 48 and separated from one another by insulating elements such as protrusions 49 of the cuff. Typically, the width of the electrodes is between about 0.5 and about 2 millimeters, or is equal to approximately one-half the radius of the vagus nerve. The electrodes are typically recessed so as not to come in direct contact with vagus nerve 36. For some applications, such recessing enables the electrodes to achieve generally uniform field distributions of the generated currents and/or generally uniform values of the activation function defined by the electric potential field in the vicinity of vagus nerve 24. Alternatively or additionally, protrusions 49 allow vagus nerve 24 to swell into the canals defined by the protrusions, while still holding the vagus nerve centered within cuff 48 and maintaining a rigid electrode geometry. For some applications, cuff 48 comprises additional recesses separated by protrusions, which recesses do not contain active electrodes. Such additional recesses accommodate swelling of vagus nerve 24 without increasing the contact area between the vagus nerve and the electrodes. For some applications, the distance between the electrodes and the axis of the vagus nerve is between about 1 and about 4 millimeters, and is greater than the closest distance from the ends of the protrusions to the axis of the vagus nerve. Typically, protrusions 49 are relatively short (as shown). For some applications, the distance between the ends of protrusions 49 and the center of the vagus nerve is between about 1 and 3 millimeters. (Generally, the diameter of the vagus nerve is between about 2 and 3 millimeters.) Alternatively, for some applications, protrusions 49 are longer and/or the electrodes are placed closer to the vagus nerve in order to reduce the energy consumption of electrode device 40.
  • In an embodiment of the present invention, efferent anode set 44 comprises a plurality of anodes 44, typically two anodes 44 a and 44 b, spaced approximately 0.5 to 2.0 millimeters apart. Application of the efferent anodal current in appropriate ratios from a plurality of anodes generally minimizes the “virtual cathode effect,” whereby application of too large an anodal current stimulates rather than blocks fibers. In an embodiment, anode 44 a applies a current with an amplitude equal to about 0.5 to about 5 milliamps (typically one-third of the amplitude of the current applied by anode 44 b). When such techniques are not used, the virtual cathode effect generally hinders blocking of smaller-diameter fibers, as described below, because a relatively large anodal current is generally necessary to block such fibers.
  • Anode 44 a is typically positioned in cuff 48 to apply current at the location on vagus nerve 36 where the virtual cathode effect is maximally generated by anode 44 b. For applications in which the blocking current through anode 44 b is expected to vary substantially, efferent anode set 44 typically comprises a plurality of virtual-cathode-inhibiting anodes 44 a, one or more of which is activated at any time based on the expected magnitude and location of the virtual cathode effect.
  • Likewise, afferent anode set 45 typically comprises a plurality of anodes 45, typically two anodes 45 a and 45 b, in order to minimize the virtual cathode effect in the direction of the brain. In certain electrode configurations, cathode 46 comprises a plurality of cathodes in order to minimize the “virtual anode effect,” which is analogous to the virtual cathode effect.
  • As appropriate, techniques described herein are practiced in conjunction with methods and apparatus described in U.S. patent application Ser. No. 10/205,474 to Gross et al., filed Jul. 24, 2002, entitled, “Electrode assembly for nerve control,” which published as US Patent Publication 2003/0050677, is assigned to the assignee of the present patent application, and is incorporated herein by reference. Alternatively or additionally, techniques described herein are practiced in conjunction with methods and apparatus described in U.S. patent application Ser. No. 10/205,475 to Gross et al., filed Jul. 24, 2002, entitled, “Selective nerve fiber stimulation for treating heart conditions,” which published as US Patent Publication 2003/0045909, is assigned to the assignee of the present patent application, and is incorporated herein by reference. Further alternatively or additionally, techniques described herein are practiced in conjunction with methods and apparatus described in U.S. Provisional Patent Application 60/383,157 to Ayal et al., filed May 23, 2002, entitled, “Inverse recruitment for autonomic nerve systems,” which is assigned to the assignee of the present patent application and is incorporated herein by reference.
  • FIG. 2C is a simplified perspective illustration of electrode device 40 (FIG. 2A), in accordance with an embodiment of the present invention. When applied to vagus nerve 36, electrode device 40 typically encompasses the nerve. As described, control unit 20 typically drives electrode device 40 to (i) apply signals to vagus nerve 36 in order to induce the propagation of efferent action potentials towards heart 30, and (ii) suppress artificially-induced afferent action potentials towards brain 34. The electrodes typically comprise ring electrodes adapted to apply a generally uniform current around the circumference of the nerve, as best shown in FIG. 2C.
  • FIG. 3 is a simplified perspective illustration of a multipolar point electrode device 140 applied to vagus nerve 36, in accordance with an embodiment of the present invention. In this embodiment, anodes 144 a and 144 b and a cathode 146 typically comprise point electrodes (typically 2 to 100), fixed inside an insulating cuff 148 and arranged around vagus nerve 36 so as to selectively stimulate nerve fibers according to their positions inside the nerve. In this case, techniques described in the above-cited articles by Grill et al., Goodall et al., and/or Veraart et al. are typically used. The point electrodes typically have a surface area between about 0.01 mm2 and 1 mm2. In some applications, the point electrodes are in contact with vagus nerve 36, as shown, while in other applications the point electrodes are recessed in cuff 148, so as not to come in direct contact with vagus nerve 36, similar to the recessed ring electrode arrangement described above with reference to FIG. 2A. For some applications, one or more of the electrodes, such as cathode 146 or anode 144 a, comprise a ring electrode, as described with reference to FIG. 2C, such that electrode device 140 comprises both ring electrode(s) and point electrodes (configuration not shown). Additionally, electrode device 40 optionally comprises an afferent anode set (positioned like anodes 45 a and 45 b in FIG. 2A), the anodes of which comprise point electrodes and/or ring electrodes.
  • Alternatively, ordinary, non-cuff electrodes are used, such as when the electrodes are placed on the epicardial fat pads instead of on the vagus nerve.
  • FIG. 4 is a conceptual illustration of the application of current to vagus nerve 36 in order to achieve smaller-to-larger diameter fiber recruitment, in accordance with an embodiment of the present invention. When inducing efferent action potentials towards heart 30, control unit 20 drives electrode device 40 to selectively recruit nerve fibers beginning with smaller-diameter fibers and to progressively recruit larger-diameter fibers as the desired stimulation level increases. This smaller-to-larger diameter recruitment order mimics the body's natural order of recruitment.
  • Typically, in order to achieve this recruitment order, the control unit stimulates myelinated fibers essentially of all diameters using cathodic current from cathode 46, while simultaneously inhibiting fibers in a larger-to-smaller diameter order using efferent anodal current from efferent anode set 44. For example, FIG. 4 illustrates the recruitment of a single, smallest nerve fiber 56, without the recruitment of any larger fibers 50, 52 and 54. The depolarizations generated by cathode 46 stimulate all of the nerve fibers shown, producing action potentials in both directions along all the nerve fibers. Efferent anode set 44 generates a hyperpolarization effect sufficiently strong to block only the three largest nerve fibers 50, 52 and 54, but not fiber 56. This blocking order of larger-to-smaller diameter fibers is achieved because larger nerve fibers are inhibited by weaker anodal currents than are smaller nerve fibers. Stronger anodal currents inhibit progressively smaller nerve fibers. When the action potentials induced by cathode 46 in larger fibers 50, 52 and 54 reach the hyperpolarized region in the larger fibers adjacent to efferent anode set 44, these action potentials are blocked. On the other hand, the action potentials induced by cathode 46 in smallest fiber 56 are not blocked, and continue traveling unimpeded toward heart 30. Anode pole 44 a is shown generating less current than anode pole 44 b in order to minimize the virtual cathode effect in the direction of the heart, as described above.
  • When desired, in order to increase the parasympathetic stimulation delivered to the heart, the number of fibers not blocked is progressively increased by decreasing the amplitude of the current applied by efferent anode set 44. The action potentials induced by cathode 46 in the fibers now not blocked travel unimpeded towards the heart. As a result, the parasympathetic stimulation delivered to the heart is progressively increased in a smaller-to-larger diameter fiber order, mimicking the body's natural method of increasing stimulation. Alternatively or additionally, in order to increase the number of fibers stimulated, while simultaneously decreasing the average diameter of fibers stimulated, the amplitudes of the currents applied by cathode 46 and efferent anode set 44 are both increased (thereby increasing both the number of fibers stimulated and blocked). In addition, for any given number of fibers stimulated (and not blocked), the amount of stimulation delivered to the heart can be increased by increasing the PPT, frequency, and/or pulse width of the current applied to vagus nerve 36.
  • In order to suppress artificially-induced afferent action potentials from traveling towards the brain in response to the cathodic stimulation, control unit 20 typically drives electrode device 40 to inhibit fibers 50, 52, 54 and 56 using afferent anodal current from afferent anode set 45. When the afferent-directed action potentials induced by cathode 46 in all of the fibers reach the hyperpolarized region in all of the fibers adjacent to afferent anode set 45, the action potentials are blocked. Blocking these afferent action potentials generally minimizes any unintended side effects, such as undesired or counterproductive feedback to the brain, that might be caused by these action potentials. Anode 45 b is shown generating less current than anode 45 a in order to minimize the virtual cathode effect in the direction of the brain, as described above.
  • In an embodiment of the present invention, the amplitude of the cathodic current applied in the vicinity of the vagus nerve is between about 2 milliamps and about 10 milliamps. Such a current is typically used in embodiments that employ techniques for achieving generally uniform stimulation of the vagus nerve, i.e., stimulation in which the stimulation applied to fibers on or near the surface of the vagus nerve is generally no more than about 400% greater than stimulation applied to fibers situated more deeply in the nerve. This corresponds to stimulation in which the value of the activation function at fibers on or near the surface of the vagus nerve is generally no more than about four times greater than the value of the activation function at fibers situated more deeply in the nerve. For example, as described hereinabove with reference to FIG. 2A, the electrodes may be recessed so as not to come in direct contact with vagus nerve 24, in order to achieve generally uniform values of the activation function. Typically, but not necessarily, embodiments using approximately 5 mA of cathodic current have the various electrodes disposed approximately 0.5 to 2.5 mm from the axis of the vagus nerve. Alternatively, larger cathodic currents (e.g., 10-30 mA) are used in combination with electrode distances from the axis of the vagus nerve of greater than 2.5 mm (e.g., 2.5-4.0 mm), so as to achieve an even greater level of uniformity of stimulation of fibers in the vagus nerve.
  • In an embodiment of the present invention, the cathodic current is applied by cathode 46 with an amplitude sufficient to induce action potentials in large- and medium- diameter fibers 50, 52, and 54 (e.g., A- and B-fibers), but insufficient to induce action potentials in small-diameter fibers 56 (e.g., C-fibers). Simultaneously, an anodal current is applied by anode 44 b in order to inhibit action potentials induced by the cathodic current in the large-diameter fibers (e.g., A-fibers). This combination of cathodic and anodal current generally results in the stimulation of medium-diameter fibers (e.g., B-fibers) only. At the same time, a portion of the afferent action potentials induced by the cathodic current are blocked by anode 45 a, as described above. Alternatively, the afferent anodal current is configured to not fully block afferent action potentials, or is simply not applied. In these cases, artificial afferent action potentials are nevertheless generally not generated in C-fibers, because the applied cathodic current is not strong enough to generate action potentials in these fibers.
  • These techniques for efferent stimulation of only B-fibers are typically used in combination with techniques described hereinabove for achieving generally uniform stimulation of the vagus nerve. Such generally uniform stimulation enables the use of a cathodic current sufficiently weak to avoid stimulation of C-fibers near the surface of the nerve, while still sufficiently strong to stimulate B-fibers, including B-fibers situated more deeply in the nerve, i.e., near the center of the nerve. For some applications, when employing such techniques for achieving generally uniform stimulation of the vagus nerve, the amplitude of the cathodic current applied by cathode 46 may be between about 3 and about 10 milliamps, and the amplitude of the anodal current applied by anode 44 b may be between about 1 and about 7 milliamps. (Current applied at a different site and/or a different time is used to achieve a net current injection of zero.)
  • In an embodiment of the present invention, stimulation of the vagus nerve is applied responsive to one or more sensed parameters. Control unit 20 is typically configured to commence or halt stimulation, or to vary the amount and/or timing of stimulation in order to achieve a desired target heart rate, typically based on configuration values and on parameters including one or more of the following:
      • Heart rate—the control unit can be configured to drive electrode device 40 to stimulate the vagus nerve only when the heart rate exceeds a certain value.
      • ECG readings—the control unit can be configured to drive electrode device 40 to stimulate the vagus nerve based on certain ECG readings, such as readings indicative of designated forms of arrhythmia. Additionally, ECG readings are typically used for achieving a desire heart rate, as described below with reference to FIG. 5.
      • Blood pressure—the control unit can be configured to regulate the current applied by electrode device 40 to the vagus nerve when blood pressure exceeds a certain threshold or falls below a certain threshold.
      • Indicators of decreased cardiac contractility
        • these indicators include left ventricular pressure (LVP). When LVP and/or d(LVP)/dt exceeds a certain threshold or falls below a certain threshold, control unit 20 can drive electrode device 40 to regulate the current applied by electrode device 40 to the vagus nerve.
      • Motion of the patient—the control unit can be configured to interpret motion of the patient as an indicator of increased exertion by the patient, and appropriately reduce parasympathetic stimulation of the heart in order to allow the heart to naturally increase its rate.
      • Heart rate variability—the control unit can be configured to drive electrode device 40 to stimulate the vagus nerve based on heart rate variability, which is typically calculated based on certain ECG readings.
      • Norepinephrine concentration—the control unit can be configured to drive electrode device 40 to stimulate the vagus nerve based on norepinephrine concentration.
      • Cardiac output—the control unit can be configured to drive electrode device 40 to stimulate the vagus nerve based on cardiac output, which is typically determined using impedance cardiography.
  • Baroreflex sensitivity—the control unit can be configured to drive electrode device 40 to stimulate the vagus nerve based on baroreflex sensitivity.
  • The parameters and behaviors included in this list are for illustrative purposes only, and other possible parameters and/or behaviors will readily present themselves to those skilled in the art, having read the disclosure of the present patent application.
  • In an embodiment of the present invention, control unit 20 is configured to drive electrode device 40 to stimulate the vagus nerve so as to reduce the heart rate of the subject towards a target heart rate. The target heart rate is typically (a) programmable or configurable, (b) determined responsive to one or more sensed physiological values, such as those described hereinabove (e.g., motion, blood pressure, etc.), and/or (c) determined responsive to a time of day or circadian cycle of the subject. Parameters of stimulation are varied in real time in order to vary the heart-rate-lowering effects of the stimulation. For example, such parameters may include the amplitude of the applied current. Alternatively or additionally, in an embodiment of the present invention, the stimulation is applied in a series of pulses that are synchronized or are not synchronized with the cardiac cycle of the subject, such as described hereinbelow with reference to FIG. 5. Parameters of such pulse series typically include, but are not limited to:
      • Timing of the stimulation within the cardiac cycle. Delivery of the series of pulses typically begins after a fixed or variable delay following an ECG feature, such as each R- or P-wave. For some applications, the delay is between about 20 ms and about 300 ms from the R-wave, or between about 100 and about 500 ms from the P-wave.
      • Pulse duration (width). Longer pulse durations typically result in a greater heart-rate-lowering effect. For some applications, the pulse duration is between about 0.2 and about 4 ms.
      • Pulse repetition interval. Maintaining a pulse repetition interval (the time from the initiation of a pulse to the initiation of the following pulse) greater than about 3 ms generally results in maximal stimulation effectiveness for multiple pulses within a burst.
      • Pulses per trigger (PPT). A greater PPT (the number of pulses in each series of pulses after a trigger such as an R-wave) typically results in a greater heart-rate-lowering effect. For some applications, PPT is between about 0 and about 8.
      • Amplitude. A greater amplitude of the signal applied typically results in a greater heart-rate-lowering effect. The amplitude is typically less than about 10 milliamps, e.g., between about 2 and about 10 milliamps. For some applications, the amplitude is between about 2 and about 6 milliamps.
      • Duty cycle. Application of stimulation every heartbeat typically results in a greater heart-rate-lowering effect. For less heart rate reduction, stimulation is applied only once every several heartbeats.
      • Choice of vagus nerve. Stimulation of the right vagus nerve typically results in greater heart rate reduction than stimulation of the left vagus nerve.
      • “On”/“off” ratio and timing. For some applications, the device operates intermittently, alternating between “on” and “off” states, the length of each state typically between 0 and about 300 seconds (with a O-length “off” state equivalent to always “on”). Greater heart rate reduction is typically achieved if the device is “on” a greater portion of the time.
  • For some applications, values of the “on”/“off” parameter are determined in real time, responsive to one or more inputs, such as sensed physiological values. Such inputs typically include motion or activity of the subject (e.g., detected using an accelerometer), the average heart rate of the subject when the device is in “off” mode, and/or the time of day. For example, the device may operate in continuous “on” mode when the subject is exercising and therefore has a high heart rate, and the device may alternate between “on” and “off” when the subject is at rest. As a result, the heart-rate-lowering effect is concentrated during periods of high heart rate, and the nerve is allowed to rest when the heart rate is generally naturally lower.
  • For some applications, heart rate regulation is achieved by setting two or more parameters in combination. For example, if it is desired to apply 5.2 pulses of stimulation, the control unit may apply 5 pulses of 1 ms duration each, followed by a single pulse of 0.2 ms duration. For other applications, the control unit switches between two values of PPT, so that the desired PPT is achieved by averaging the applied PPTs. For example, a sequence of PPTs may be 5, 5, 5, 5, 6, 5, 5, 5, 5, 6, . . . , in order to achieve an effective PPT of 5.2.
  • In an embodiment of the present invention, control unit 20 uses a slow-reacting heart rate regulation algorithm to modify heart-rate-controlling parameters of the stimulation, i.e., the algorithm varies stimulation parameters slowly in reaction to changes in heart rate. For example, in response to a sudden increase in heart rate, e.g., an increase from a target heart rate of 60 beats per minute (BPM) to 100 BPM over a period of only a few seconds, the algorithm slowly increases the stimulation level over a period of minutes. If the heart rate naturally returns to the target rate over this period, the stimulation levels generally do not change substantially before returning to baseline levels.
  • For example, the heart of a subject is regulated while the subject is inactive, such as while sitting. When the subject suddenly increases his activity level, such as by standing up or climbing stairs, the subject's heart rate increases suddenly. In response, the control unit adjusts the stimulation parameters slowly to reduce the subject's heart rate. Such a gradual modification of stimulation parameters allows the subject to engage in relatively stressful activities for a short period of time before his heart rate is substantially regulated, generally resulting in an improved quality of life.
  • In an embodiment of the present invention, control unit 20 is adapted to detect bradycardia (i.e., that an average detected R-R interval exceeds a preset bradycardia limit), and to terminate heart rate regulation substantially immediately upon such detection, such as by ceasing vagal stimulation. Alternatively or additionally, the control unit uses an algorithm that reacts quickly to regulate heart rate when the heart rate crosses limits that are predefined (e.g., a low limit of 40 beats per minute (BPM) and a high limit of 140 BPM), or determined in real time, such as responsive to sensed physiological values.
  • In an embodiment of the present invention, control unit 20 is configured to operate intermittently. Typically, upon each resumption of operation, control unit 20 sets the stimulation parameters to those in effect immediately prior to the most recent cessation of operation. For some applications, such parameters applied upon resumption of operation are maintained without adjustment for a certain number of heartbeats (e.g., between about one and about ten), in order to allow the heart rate to stabilize after resumption of operation.
  • For some applications, control unit 20 is configured to operate intermittently with gradual changes in stimulation. For example, the control unit may operate according to the following “on”/“off” pattern: (a) “off” mode for 30 minutes, (b) a two-minute “on” period characterized by a gradual increase in stimulation so as to achieve a target heart rate, (c) a six-minute “on” period of feedback-controlled stimulation to maintain the target heart rate, and (d) a two-minute “on” period characterized by a gradual decrease in stimulation to return the heart rate to baseline. The control unit then repeats the cycle, beginning with another 30-minute “off” period.
  • In an embodiment of the present invention, control unit 20 is configured to operate in an adaptive intermittent mode. The control unit sets the target heart rate for the “on” period equal to a fixed or configurable fraction of the average heart rate during the previous “off” period, typically bounded by a preset minimum. For example, assume that for a certain subject the average heart rates during sleep and during exercise are 70 and 150 BPM, respectively. Further assume that the target heart rate for the “on” period is set at 70% of the average heart rate during the previous “off” period, with a minimum of 60 BPM. During sleep, stimulation is applied so as to produce a heart rate of MAX(60 BPM, 70% of 70 BPM)=60 BPM, and is thus applied with parameters similar to those that would be used in the simple intermittent mode described hereinabove. Correspondingly, during exercise, stimulation is applied so as to produce a heart rate of MAX(60 BPM, 70% of 150 BPM)=105 BPM.
  • In an embodiment of the present invention, a heart rate regulation algorithm used by control unit 20 has as an input a time derivative of the sensed heart rate. The algorithm typically directs the control unit to respond slowly to increases in heart rate and quickly to decreases in heart rate.
  • In an embodiment of the present invention, the heart rate regulation algorithm utilizes sensed physiological parameters for feedback. For some applications, the feedback is updated periodically by inputting the current heart rate. For some applications, such updating occurs at equally-spaced intervals. Alternatively, the feedback is updated by inputting the current heart rate upon each detection of a feature of the ECG, such as an R-wave. In order to convert non-fixed R-R intervals into a form similar to canonical fixed intervals, the algorithm adds the square of each R-R interval, thus taking into account the non-uniformity of the update interval, e.g., in order to properly analyze feedback stability using standard tools and methods developed for canonical feedback.
  • In an embodiment of the present invention, control unit 20 implements a detection blanking period, during which the control unit does not detect heart beats. In some instances, such non-detection may reduce false detections of heart beats. One or both of the following techniques are typically implemented:
      • Absolute blanking. An expected maximal heart rate is used to determine a minimum interval between expected heart beats. During this interval, the control unit does not detect heart beats, thereby generally reducing false detections. For example, the expected maximal heart rate may be 200 BPM, resulting in a minimal detection interval of 300 milliseconds. After detection of a beat, the control unit disregards any signals indicative of a beat during the next 300 milliseconds.
      • Stimulation blanking. During application of a stimulation burst, and for an interval thereafter, the control unit does not detect heart beats, thereby generally reducing false detections of stimulation artifacts as beats. For example, assume stimulation is applied with the following parameters: a PPT of 5 pulses, a pulse width of 1 ms, and a pulse repetition interval of 5 ms. The control unit disregards any signals indicative of a beat during the entire 25 ms duration of the burst and for an additional interval thereafter, e.g., 50 ms, resulting in a total blanking period of 75 ms beginning with the start of the burst.
  • In an embodiment of the present invention, the heart rate regulation algorithm is implemented using only integer arithmetic. For example, division is implemented as integer division by a power of two, and multiplication is always of two 8-bit numbers. For some applications, time is measured in units of 1/128 of a second.
  • In an embodiment of the present invention, control unit 20 implements an integral feedback controller, which can most generally be described by:

  • K=K I *∫e dt
  • in which K represents the strength of the feedback, KI is a coefficient, and ∫e dt represents the cumulative error. It is to be understood that such an integral feedback controller can be implemented in hardware, or in software running in control unit 20.
  • In an embodiment of such an integral controller, heart rate is typically expressed as an R-R interval (the inverse of heart rate). Parameters of the integral controller typically include TargetRR (the target R-R interval) and TimeCoeff (which determines the overall feedback reaction time).
  • Typically, following the detection of each R-wave, the previous R-R interval is calculated and assigned to a variable (LastRR). e (i.e., the difference between the target R-R interval and the last measured R-R interval) is then calculated as:

  • e=TargetRR−LastRR
  • e is typically limited by control unit 20 to a certain range, such as between −0.25 and +0.25 seconds, by reducing values outside the range to the endpoint values of the range. Similarly, LastRR is typically limited, such as to 255/128 seconds. The error is then calculated by multiplying LastRR by e:

  • Error=e*LastRR
  • A cumulative error (representing the integral in the above generalized equation) is then calculated by dividing the error by TimeCoeff and adding the result to the cumulative error, as follows:

  • Integral=Integral+Error/2TimeCoeff
  • The integral is limited to positive values less than, e.g., 36,863. The number of pulses applied in the next series of pulses (pulses per trigger, or PPT) is equal to the integral/4096.
  • The following table illustrates example calculations using a heart rate regulation algorithm that implements an integral controller, in accordance with an embodiment of the present invention. In this example, the parameter TargetRR (the target heart rate) is set to 1 second (128/128 seconds), and the parameter TimeCoeff is set to 0. The initial value of Integral is 0. As can be seen in the table, the number of pulses per trigger (PPT) increases from 0 during the first heart beat, to 2 during the fourth heart beat of the example.
  • Heart Beat Number
    1 2 3 4
    Heart rate (BPM) 100 98 96 102
    R-R interval (ms) 600 610 620 590
    R-R ( 1/128 sec) 76 78 79 75
    e ( 1/128 sec) 52 50 49 53
    Limited e 32 32 32 32
    Error 2432 2496 2528 2400
    Integral 2432 4928 7456 9856
    PPT 0 1 1 2
  • In an embodiment of the present invention, the heart rate regulation algorithm corrects for missed heart beats (either of physiological origin or because of a failure to detect a beat). Typically, to perform this correction, any R-R interval which is about twice as long as the immediately preceding R-R interval is interpreted as two R-R intervals, each having a length equal to half the measured interval. For example, the R-R interval sequence (measured in seconds) 1, 1, 1, 2.2 is interpreted by the algorithm as the sequence 1, 1, 1, 1.1, 1.1. Alternatively or additionally, the algorithm corrects for premature beats, typically by adjusting the timing of beats that do not occur approximately halfway between the preceding and following beats. For example, the R-R interval sequence (measured in seconds) 1, 1, 0.5, 1.5 is interpreted as 1, 1, 1, 1, using the assumption that the third beat was premature.
  • In an embodiment of the present invention, control unit 20 is configured to operate in one of the following modes:
      • vagal stimulation is not applied when the heart rate of the subject is lower than the low end of the normal range of a heart rate of the subject and/or of a typical human subject;
      • vagal stimulation is not applied when the heart rate of the subject is lower than a threshold value equal to the current low end of the range of the heart rate of the subject, i.e., the threshold value is variable over time as the low end generally decreases as a result of chronic vagal stimulation treatment;
      • vagal stimulation is applied only when the heart rate of the subject is within the normal of range of a heart rate of the subject and/or of a typical human subjects;
      • vagal stimulation is applied only when the heart rate of the subject is greater than a programmable threshold value, such as a rate higher than a normal rate of the subject and/or a normal rate of a typical human subject. This mode generally removes peaks in heart rate; or
      • vagal stimulation is applied using fixed programmable parameters, i.e., not in response to any feedback, target heart rate, or target heart rate range. These parameters may be externally updated from time to time, for example by a physician.
  • In an embodiment of the present invention, the amplitude of the applied stimulation current is calibrated by fixing a number of pulses in the series of pulses (per cardiac cycle), and then increasing the applied current until a desired pre-determined heart rate reduction is achieved. Alternatively, the current is calibrated by fixing the number of pulses per series of pulses, and then increasing the current to achieve a substantial reduction in heart rate, e.g., 40%.
  • In embodiments of the present invention in which vagal stimulation system 18 comprises implanted device 25 for monitoring and correcting the heart rate, control unit 20 typically uses measured parameters received from device 25 as additional inputs for determining the level and/or type of stimulation to apply. Control unit 20 typically coordinates its behavior with the behavior of device 25. Control unit 20 and device 25 typically share sensors 26 in order to avoid redundancy in the combined system.
  • Optionally, vagal stimulation system 18 comprises a patient override, such as a switch that can be activated by the patient using an external magnet. The override typically can be used by the patient to activate vagal stimulation, for example in the event of arrhythmia apparently undetected by the system, or to deactivate vagal stimulation, for example in the event of apparently undetected physical exertion.
  • FIG. 5 is a simplified illustration of an ECG recording 70 and example timelines 72 and 76 showing the timing of the application of a burst of stimulation pulses 74, in accordance with an embodiment of the present invention. Stimulation is typically applied to vagus nerve 36 in a closed-loop system in order to achieve and maintain the desired target heart rate, determined as described above. Precise graded slowing of the heart beat is typically achieved by varying the number of nerve fibers stimulated, in a smaller-to-larger diameter order, and/or the intensity of vagus nerve stimulation, such as by changing the stimulation amplitude, pulse width, PPT, and/or delay. Stimulation with blocking, as described herein, is typically applied during each cardiac cycle in burst of pulses 74, typically containing between about 1 and about 20 pulses, each of about 1-3 milliseconds duration, over a period of about 1-200 milliseconds. Advantageously, such short pulse durations generally do not substantially block or interfere with the natural efferent or afferent action potentials traveling along the vagus nerve. Additionally, the number of pulses and/or their duration is sometimes varied in order to facilitate achievement of precise graded slowing of the heart beat.
  • In an embodiment of the present invention (e.g., when the heart rate regulation algorithm described hereinabove is not implemented), to apply the closed-loop system, the target heart rate is expressed as a ventricular R-R interval (shown as the interval between R1 and R2 in FIG. 5). The actual R-R interval is measured in real time and compared with the target R-R interval. The difference between the two intervals is defined as a control error. Control unit 20 calculates the change in stimulation necessary to move the actual R-R towards the target R-R, and drives electrode device 40 to apply the new calculated stimulation. Intermittently, e.g., every 1, 10, or 100 beats, measured R-R intervals or average R-R intervals are evaluated, and stimulation of the vagus nerve is modified accordingly.
  • In an embodiment, vagal stimulation system 18 is further configured to apply stimulation responsive to pre-set time parameters, such as intermittently, constantly, or based on the time of day.
  • Alternatively or additionally, one or more of the techniques of smaller-to-larger diameter fiber recruitment, selective fiber population stimulation and blocking, and varying the intensity of vagus nerve stimulation by changing the stimulation amplitude, pulse width, PPT, and/or delay, are applied in conjunction with methods and apparatus described in one or more of the patents, patent applications, articles and books cited herein.
  • In an embodiment of the present invention, control unit 20 is configured to stimulate vagus nerve 36 so as to suppress the adrenergic system, in order to treat a subject suffering from a heart condition. For example, such vagal stimulation may be applied for treating a subject suffering from heart failure. In heart failure, hyper-activation of the adrenergic system damages the heart. This damage causes further activation of the adrenergic system, resulting in a vicious cycle. High adrenergic tone is harmful because it often results in excessive release of angiotensin and epinephrine, which increase vascular resistance (blood pressure), reduce heart rest time (accelerated heart rate), and cause direct toxic damage to myocardial muscles through oxygen free radicals and DNA damage. Artificial stimulation of the vagus nerve causes a down regulation of the adrenergic system, with reduced release of catecholamines. The natural effects of vagal stimulation, applied using the techniques described herein, typically reduces the release of catecholamines in the heart, thereby lowering the adrenergic tone at its source.
  • In an embodiment of the present invention, control unit 20 is configured to stimulate vagus nerve 36 so as to modulate atrial and ventricular contractility, in order to treat a subject suffering from a heart condition. Vagal stimulation generally reduces both atrial and ventricular contractility (see, for example, the above-cited article by Levy M N et al., entitled “Parasympathetic Control of the Heart”). Vagal stimulation, using the techniques described herein, typically (a) reduces the contractility of the atria, thereby reducing the pressure in the venous system, and (b) reduces the ventricular contractile force of the atria, which may reduce oxygen consumption, such as in cases of ischemia. For some applications, vagal stimulation, as described herein, is applied in order to reduce the contractile force of the ventricles in cases of hypertrophic cardiopathy. The vagal stimulation is typically applied with a current of at least about 4 mA.
  • In an embodiment of the present invention, control unit 20 is configured to stimulate vagus nerve 36 so as to improve coronary blood flow, in order to treat a subject suffering from a heart condition. Improving coronary blood flow by administering acetylcholine is a well known technique. For example, during Percutaneous Transluminal Coronary Angioplasty (PTCA), when maximal coronary dilation is needed, direct infusion of acetylcholine is often used to dilate the coronary arteries (see, for example, the above-cited article by Feliciano L et al.). For some applications, the vagal stimulation techniques described herein are used to improve coronary blood flow in subjects suffering from myocardial ischemia, ischemic heart disease, heart failure, and/or variant angina (spastic coronary arteries). It is hypothesized that such vagal stimulation simulates the effect of acetylcholine administration.
  • In an embodiment of the present invention, control unit 20 is configured to drive electrode device 40 to stimulate vagus nerve 36 so as to modify heart rate variability of the subject. For some applications, control unit 20 is configured to apply the stimulation having a duty cycle, which typically produces heart rate variability at the corresponding frequency. For example, such duty cycles may be in the range of once per every several heartbeats. For other applications, control unit 20 is configured to apply generally continuous stimulation (e.g., in a manner that produces a prolonged reduced level of heart rate variability).
  • For some applications, control unit 20 synchronizes the stimulation with the cardiac cycle of the subject, while for other applications, the control unit does not synchronize the stimulation with the cardiac cycle. For example, the stimulation may be applied in a series of pulses that are not synchronized with the cardiac cycle of the subject. Alternatively, the stimulation may be applied in a series of pulses that are synchronized with the cardiac cycle of the subject, such as described hereinabove with reference to FIG. 5.
  • For some applications, control unit 20 is configured to apply stimulation with parameters selected to reduce heart rate variability, while for other applications parameters are selected that increase variability. For example, when the stimulation is applied as a series of pulses, values of parameters that reduce heart variability may include one or more of the following:
      • Timing of the stimulation within the cardiac cycle: a delay of between about 50 ms and about 150 ms from the R-wave, or between about 100 and about 500 ms from the P-wave.
      • Pulse duration (width) of between about 0.5 and about 1.5 ms.
      • Pulse repetition interval (the time from the initiation of a pulse to the initiation of the following pulse) of between about 2 and about 8 ms.
      • Pulses per trigger (PPT), e.g., pulses per cardiac cycle, of between about 0 and about 8.
      • Amplitude of between about 5 and about 10 milliamps.
  • For some applications, the parameters of the stimulation are selected to both reduce the heart rate of the subject and heart rate variability of the subject. For other applications, the parameters are selected to reduce heart rate variability while substantially not reducing the average heart rate of the subject. In this context, a non-substantial heart rate reduction may be less than about 10%. For some applications, to achieve such a reduction in variability without a reduction in average rate, stimulation is applied using the feedback techniques described hereinabove, with a target heart rate greater than the normal average heart rate of the subject. Such stimulation typically does not substantially change the average heart rate, yet reduces heart rate variability (however, the instantaneous (but not average) heart rate may sometimes be reduced).
  • For some applications, in order to additionally reduce the heart rate, stimulation is applied using a target heart rate lower than the normal average heart rate of the subject. The magnitude of the change in average heart rate as well as the percentage of time during which reduced heart rate variability occurs in these applications are controlled by varying the difference between the target heart rate and the normal average heart rate.
  • For some applications, control unit 20 is configured to apply stimulation only when the subject is awake. Reducing heart variability when the subject is awake offsets natural increases in heart rate variability during this phase of the circadian cycle. Alternatively or additionally, control unit 20 is configured to apply or apply greater stimulation at times of exertion by the subject, in order to offset the increase in heart rate variability typically caused by exertion. For example, control unit 20 may determine that the subject is experiencing exertion responsive to an increase in heart rate, or responsive to a signal generated by an accelerometer. Alternatively, the control unit uses other techniques known in the art for detecting exertion.
  • In an embodiment of the present invention, control unit 20 is configured to drive electrode device 40 to stimulate vagus nerve 36 so as to modify heart rate variability in order to treat a condition of the subject. For some applications, the control unit is configured to additionally modify heart rate to treat the condition, while for other applications, the control unit is configured to modify heart rate variability while substantially not modifying average heart rate.
  • Therapeutic effects of reduction in heart rate variability include, but are not limited to:
      • Narrowing of the heart rate range, thereby eliminating very slow heart rates and very fast heart rates, both of which are inefficient for a subject suffering from heart failure. For this therapeutic application, control unit 20 is typically configured to reduce low-frequency heart rate variability, and to adjust the level of stimulation applied based on the circadian and activity cycles of the subject.
      • Stabilizing the heart rate, thereby reducing the occurrence of arrhythmia. For this therapeutic application, control unit 20 is typically configured to reduce heart rate variability at all frequencies.
      • Maximizing the mechanical efficiency of the heart by maintaining relatively constant ventricular filling times and pressures. For example, this therapeutic effect may be beneficial for subjects suffering from atrial fibrillation, in which fluctuations in heart filling times and pressure reduce cardiac efficiency.
      • Eliminating the normal cardiac response to changes in the breathing cycle (i.e., respiratory sinus arrhythmia). Although generally beneficial in young and efficient hearts, respiratory sinus arrhythmia may be harmful to subjects suffering from heart failure, because respiratory sinus arrhythmia causes unwanted accelerations and decelerations in the heart rate. For this therapeutic application, control unit 20 is typically configured to reduce heart rate variability at high frequencies.
  • Reference is now made to FIG. 6, which is a graph showing in vivo experimental results, measured in accordance with an embodiment of the present invention. A dog was anesthetized, and cuff electrodes, similar to those described hereinabove with reference to FIG. 2B, were implanted in the right cervical vagus nerve. After a recovery period of two weeks, experimental vagal stimulation was applied to the dog while the dog was awake and allowed to move freely within its cage.
  • A control unit, similar to control unit 20, was programmed to apply vagal stimulation in a series of pulses, having the following parameters:
      • Stimulation synchronized with the intracardiac R-wave signal, with a delay from the R-wave of 60 ms;
      • Stimulation amplitude of 8 mA;
      • Stimulation pulse duration of 1 ms; and
      • Time between pulses within a burst of 5 ms.
        The control unit implemented an integral feedback controller, similar to the integral feedback controller described hereinabove, in order to vary the number of pulses within a burst. The integral feedback controller used a target heart rate of 80 beats per minute. After 2 minutes of stimulation, the number of pulses within each burst was typically between about 1 and about 8.
  • During a first period and a third period from 0 to 18 minutes and 54 to 74 minutes, respectively, the control unit applied stimulation to the vagus nerve. Heart rate variability was substantially reduced, while an average heart rate of 80 beats per minute was maintained. (Baseline heart rate, without stimulation, was approximately 95 beats per minute.) During a second period and a fourth period from 18 to 54 minutes and 74 to 90 minutes, respectively, stimulation was discontinued, and, as a result, heart rate variability increased substantially, returning to normal values. Average heart rate during these non-stimulation periods increased to approximately 95 beats per minute (approximately baseline value). Thus, these experimental results demonstrate that the application of vagal stimulation using some of the techniques described herein results in a substantial reduction in heart rate variability.
  • Although embodiments of the present invention are described herein, in some cases, with respect to treating specific heart conditions, it is to be understood that the scope of the present invention generally includes utilizing the techniques described herein to controllably stimulate the vagus nerve to facilitate treatments of, for example, heart failure, atrial fibrillation, and ischemic heart diseases. In particular, the techniques described herein may be performed in combination with other techniques, which are well known in the art or which are described in the references cited herein, that stimulate the vagus nerve in order to achieve a desired therapeutic end.
  • For some applications, techniques described herein are used to apply controlled stimulation to one or more of the following: the lacrimal nerve, the salivary nerve, the vagus nerve, the pelvic splancnic nerve, or one or more sympathetic or parasympathetic autonomic nerves. Such controlled stimulation may be used, for example, to regulate or treat a condition of the lung, heart, stomach, pancreas, small intestine, liver, spleen, kidney, bladder, rectum, large intestine, reproductive organs, or adrenal gland.
  • It will be appreciated by persons skilled in the art that the present invention is not limited to what has been particularly shown and described hereinabove. Rather, the scope of the present invention includes both combinations and subcombinations of the various features described hereinabove, as well as variations and modifications thereof that are not in the prior art, which would occur to persons skilled in the art upon reading the foregoing description.

Claims (16)

1-80. (canceled)
81. A method for treating a subject, comprising:
identifying that the subject suffers from a condition selected from the group consisting of: atrial arrhythmia, and atrial arrhythmia combined with heart failure; and
treating the condition by:
driving, by a control unit, application of a current to a site of the subject selected from the group consisting of: a vagus nerve and an epicardial fat pad,
configuring the current so as to treat the condition, and
driving an implantable cardioverter defibrillator (ICD) to apply energy to a heart of the subject, the ICD being in communication with the control unit that drives the application of the current.
82. A method for treating a subject, comprising:
identifying that the subject suffers from atrial arrhythmia; and
treating the atrial arrhythmia by:
applying a current to a site of the subject selected from the group consisting of: a vagus nerve and an epicardial fat pad, and
configuring the current to control a heart rate during atrial arrhythmia.
83. The method according to claim 82, wherein applying the current comprises synchronizing the application of the current with a cardiac cycle of the subject.
84. The method according to claim 82, comprising driving an implantable cardioverter defibrillator (ICD) to apply energy to a heart of the subject, the ICD being in communication with a control unit that drives the application of the current.
85. The method according to claim 82, comprising driving an implantable pacemaker to apply energy to a heart of the subject, the pacemaker being in communication with a control unit that drives the application of the current.
86. The method according to claim 82, wherein identifying comprises identifying that the subject suffers from the atrial arrhythmia combined with heart failure, and wherein treating comprises treating the atrial arrhythmia combined with the heart failure.
87. A treatment method, comprising:
identifying that a subject suffers from a heart condition; and
treating the heart condition by:
applying a current to a vagus nerve of the subject, and
configuring the current to increase coronary blood flow.
88. The method according to claim 87, wherein the heart condition includes variant angina, and wherein identifying comprises identifying that the subject suffers from the variant angina.
89. The method according to claim 87, wherein applying the current comprises receiving an override signal generated by the subject, and applying the current responsively to the override signal.
90. Apparatus comprising:
an electrode device, configured to be coupled to a vagus nerve of the subject; and
a control unit, configured to:
receive a subject-generated override signal indicative of variant angina, and
responsively to the override signal, apply a current to the vagus nerve, and to configure the current to treat the variant angina.
91. The apparatus according to claim 90, and comprising an external magnet, wherein the control unit is configured to receive the subject-generated override signal generated using the external magnet.
92. The apparatus according to claim 90, wherein the control unit is configured to configure the current to increase coronary blood flow, so as to treat the variant angina.
93. A treatment method comprising:
identifying that a subject suffers from a variant angina; and
treating the variant angina by applying a current to a vagus nerve of the subject responsively to receiving an override signal from the subject.
94. The method according to claim 93, wherein treating the variant angina comprises configuring the current to increase coronary blood flow.
95. The method according to claim 93, wherein receiving the override signal comprises receiving the override signal generated by the subject using an external magnet.
US11/981,369 2002-01-23 2007-10-30 Selective nerve fiber stimulation for treating heart conditions Abandoned US20080132964A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US11/981,369 US20080132964A1 (en) 2002-01-23 2007-10-30 Selective nerve fiber stimulation for treating heart conditions

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
PCT/IL2002/000068 WO2003018113A1 (en) 2001-08-31 2002-01-23 Treatment of disorders by unidirectional nerve stimulation
US38315702P 2002-05-23 2002-05-23
US10/205,475 US7778703B2 (en) 2001-08-31 2002-07-24 Selective nerve fiber stimulation for treating heart conditions
PCT/IL2003/000431 WO2003099377A1 (en) 2002-05-23 2003-05-23 Selective nerve fiber stimulation for treating heart conditions
US10/719,659 US7778711B2 (en) 2001-08-31 2003-11-20 Reduction of heart rate variability by parasympathetic stimulation
US11/981,369 US20080132964A1 (en) 2002-01-23 2007-10-30 Selective nerve fiber stimulation for treating heart conditions

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US10/719,659 Continuation US7778711B2 (en) 2001-08-31 2003-11-20 Reduction of heart rate variability by parasympathetic stimulation

Publications (1)

Publication Number Publication Date
US20080132964A1 true US20080132964A1 (en) 2008-06-05

Family

ID=33477801

Family Applications (5)

Application Number Title Priority Date Filing Date
US10/719,659 Expired - Fee Related US7778711B2 (en) 2001-08-31 2003-11-20 Reduction of heart rate variability by parasympathetic stimulation
US11/062,324 Expired - Fee Related US7634317B2 (en) 2001-08-31 2005-02-18 Techniques for applying, calibrating, and controlling nerve fiber stimulation
US11/070,842 Active 2025-10-18 US8386056B2 (en) 2001-08-31 2005-02-24 Parasympathetic stimulation for treating atrial arrhythmia and heart failure
US11/978,440 Abandoned US20080125827A1 (en) 2002-07-24 2007-10-29 Selective nerve fiber stimulation for treating heart conditions
US11/981,369 Abandoned US20080132964A1 (en) 2002-01-23 2007-10-30 Selective nerve fiber stimulation for treating heart conditions

Family Applications Before (4)

Application Number Title Priority Date Filing Date
US10/719,659 Expired - Fee Related US7778711B2 (en) 2001-08-31 2003-11-20 Reduction of heart rate variability by parasympathetic stimulation
US11/062,324 Expired - Fee Related US7634317B2 (en) 2001-08-31 2005-02-18 Techniques for applying, calibrating, and controlling nerve fiber stimulation
US11/070,842 Active 2025-10-18 US8386056B2 (en) 2001-08-31 2005-02-24 Parasympathetic stimulation for treating atrial arrhythmia and heart failure
US11/978,440 Abandoned US20080125827A1 (en) 2002-07-24 2007-10-29 Selective nerve fiber stimulation for treating heart conditions

Country Status (3)

Country Link
US (5) US7778711B2 (en)
EP (1) EP1638645A4 (en)
WO (1) WO2004103455A2 (en)

Cited By (88)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012155186A1 (en) * 2011-05-13 2012-11-22 National Ict Australia Ltd Method and apparatus for controlling a neural stimulus - h
US20130131746A1 (en) * 2009-03-20 2013-05-23 ElectroCore, LLC. Non-invasive vagus nerve stimulation devices and methods to treat or avert atrial fibrillation
US8565896B2 (en) 2010-11-22 2013-10-22 Bio Control Medical (B.C.M.) Ltd. Electrode cuff with recesses
US8571653B2 (en) 2001-08-31 2013-10-29 Bio Control Medical (B.C.M.) Ltd. Nerve stimulation techniques
US20140296940A1 (en) * 2013-03-29 2014-10-02 Rainbow Medical Ltd. Independently-controlled bidirectional nerve stimulation
US8948873B2 (en) 2006-02-10 2015-02-03 ElectroCore, LLC Electrical stimulation treatment of hypotension
US8972004B2 (en) 2005-11-10 2015-03-03 ElectroCore, LLC Magnetic stimulation devices and methods of therapy
US8983628B2 (en) 2009-03-20 2015-03-17 ElectroCore, LLC Non-invasive vagal nerve stimulation to treat disorders
US8983629B2 (en) 2009-03-20 2015-03-17 ElectroCore, LLC Non-invasive vagal nerve stimulation to treat disorders
US9014823B2 (en) 2005-11-10 2015-04-21 ElectroCore, LLC Methods and devices for treating primary headache
US9067054B2 (en) 2011-03-10 2015-06-30 ElectroCore, LLC Devices and methods for non-invasive capacitive electrical stimulation and their use for vagus nerve stimulation on the neck of a patient
US9174049B2 (en) 2013-01-27 2015-11-03 ElectroCore, LLC Systems and methods for electrical stimulation of sphenopalatine ganglion and other branches of cranial nerves
US9205258B2 (en) 2013-11-04 2015-12-08 ElectroCore, LLC Nerve stimulator system
US9248286B2 (en) 2009-03-20 2016-02-02 ElectroCore, LLC Medical self-treatment using non-invasive vagus nerve stimulation
US9254383B2 (en) 2009-03-20 2016-02-09 ElectroCore, LLC Devices and methods for monitoring non-invasive vagus nerve stimulation
US9283390B2 (en) 2006-02-10 2016-03-15 ElectroCore, LLC Methods and apparatus for treating anaphylaxis using electrical modulation
US9327118B2 (en) 2010-08-19 2016-05-03 ElectroCore, LLC Non-invasive treatment of bronchial constriction
US9333347B2 (en) 2010-08-19 2016-05-10 ElectroCore, LLC Devices and methods for non-invasive electrical stimulation and their use for vagal nerve stimulation on the neck of a patient
US9370654B2 (en) 2009-01-27 2016-06-21 Medtronic, Inc. High frequency stimulation to block laryngeal stimulation during vagal nerve stimulation
US9375571B2 (en) 2013-01-15 2016-06-28 ElectroCore, LLC Mobile phone using non-invasive nerve stimulation
US9399134B2 (en) 2011-03-10 2016-07-26 ElectroCore, LLC Non-invasive vagal nerve stimulation to treat disorders
US9566426B2 (en) 2011-08-31 2017-02-14 ElectroCore, LLC Systems and methods for vagal nerve stimulation
US9597521B2 (en) 2015-01-21 2017-03-21 Bluewind Medical Ltd. Transmitting coils for neurostimulation
US9643022B2 (en) 2013-06-17 2017-05-09 Nyxoah SA Flexible control housing for disposable patch
US9713707B2 (en) 2015-11-12 2017-07-25 Bluewind Medical Ltd. Inhibition of implant migration
US9764146B2 (en) 2015-01-21 2017-09-19 Bluewind Medical Ltd. Extracorporeal implant controllers
WO2017173331A1 (en) * 2016-04-01 2017-10-05 Cyberonics, Inc. Vagus nerve stimulation patient selection
US9782589B2 (en) 2015-06-10 2017-10-10 Bluewind Medical Ltd. Implantable electrostimulator for improving blood flow
US9821164B2 (en) 2005-11-10 2017-11-21 ElectroCore, LLC Electrical treatment of bronchial constriction
US9849289B2 (en) 2009-10-20 2017-12-26 Nyxoah SA Device and method for snoring detection and control
US9855032B2 (en) 2012-07-26 2018-01-02 Nyxoah SA Transcutaneous power conveyance device
US9861812B2 (en) 2012-12-06 2018-01-09 Blue Wind Medical Ltd. Delivery of implantable neurostimulators
US9878150B2 (en) 2005-09-12 2018-01-30 The Cleveland Clinic Foundation Methods and systems for increasing heart contractility by neuromodulation
US9943686B2 (en) 2009-10-20 2018-04-17 Nyxoah SA Method and device for treating sleep apnea based on tongue movement
US10004896B2 (en) 2015-01-21 2018-06-26 Bluewind Medical Ltd. Anchors and implant devices
US10052097B2 (en) 2012-07-26 2018-08-21 Nyxoah SA Implant unit delivery tool
US10105540B2 (en) 2015-11-09 2018-10-23 Bluewind Medical Ltd. Optimization of application of current
US10124178B2 (en) 2016-11-23 2018-11-13 Bluewind Medical Ltd. Implant and delivery tool therefor
US10172549B2 (en) 2016-03-09 2019-01-08 CARDIONOMIC, Inc. Methods of facilitating positioning of electrodes
US10173048B2 (en) 2011-03-10 2019-01-08 Electrocore, Inc. Electrical and magnetic stimulators used to treat migraine/sinus headache, rhinitis, sinusitis, rhinosinusitis, and comorbid disorders
US10207106B2 (en) 2009-03-20 2019-02-19 ElectroCore, LLC Non-invasive magnetic or electrical nerve stimulation to treat gastroparesis, functional dyspepsia, and other functional gastrointestinal disorders
US10220207B2 (en) 2009-03-20 2019-03-05 Electrocore, Inc. Nerve stimulation methods for averting imminent onset or episode of a disease
US10232174B2 (en) 2009-03-20 2019-03-19 Electrocore, Inc. Non-invasive electrical and magnetic nerve stimulators used to treat overactive bladder and urinary incontinence
US10252074B2 (en) 2009-03-20 2019-04-09 ElectroCore, LLC Nerve stimulation methods for averting imminent onset or episode of a disease
US10265523B2 (en) 2009-03-20 2019-04-23 Electrocore, Inc. Non-invasive treatment of neurodegenerative diseases
US10286212B2 (en) 2009-03-20 2019-05-14 Electrocore, Inc. Nerve stimulation methods for averting imminent onset or episode of a disease
US10293160B2 (en) 2013-01-15 2019-05-21 Electrocore, Inc. Mobile phone for treating a patient with dementia
US10350411B2 (en) 2013-04-28 2019-07-16 Electrocore, Inc. Devices and methods for treating medical disorders with evoked potentials and vagus nerve stimulation
US10376696B2 (en) 2009-03-20 2019-08-13 Electrocore, Inc. Medical self-treatment using non-invasive vagus nerve stimulation
US10384059B2 (en) 2011-03-10 2019-08-20 Electrocore, Inc. Non-invasive vagal nerve stimulation to treat disorders
US10441780B2 (en) 2005-11-10 2019-10-15 Electrocore, Inc. Systems and methods for vagal nerve stimulation
US10493278B2 (en) 2015-01-05 2019-12-03 CARDIONOMIC, Inc. Cardiac modulation facilitation methods and systems
US10507325B2 (en) 2009-03-20 2019-12-17 Electrocore, Inc. Devices and methods for non-invasive capacitive electrical stimulation and their use for vagus nerve stimulation on the neck of a patient
US10512769B2 (en) 2009-03-20 2019-12-24 Electrocore, Inc. Non-invasive magnetic or electrical nerve stimulation to treat or prevent autism spectrum disorders and other disorders of psychological development
US10537728B2 (en) 2005-11-10 2020-01-21 ElectroCore, LLC Vagal nerve stimulation to avert or treat stroke or transient ischemic attack
US10576273B2 (en) 2014-05-22 2020-03-03 CARDIONOMIC, Inc. Catheter and catheter system for electrical neuromodulation
US10653888B2 (en) 2012-01-26 2020-05-19 Bluewind Medical Ltd Wireless neurostimulators
US10722716B2 (en) 2014-09-08 2020-07-28 Cardionomia Inc. Methods for electrical neuromodulation of the heart
US10751537B2 (en) 2009-10-20 2020-08-25 Nyxoah SA Arced implant unit for modulation of nerves
US10814137B2 (en) 2012-07-26 2020-10-27 Nyxoah SA Transcutaneous power conveyance device
US10894160B2 (en) 2014-09-08 2021-01-19 CARDIONOMIC, Inc. Catheter and electrode systems for electrical neuromodulation
US11077298B2 (en) 2018-08-13 2021-08-03 CARDIONOMIC, Inc. Partially woven expandable members
US11110270B2 (en) 2015-05-31 2021-09-07 Closed Loop Medical Pty Ltd Brain neurostimulator electrode fitting
US11172864B2 (en) 2013-11-15 2021-11-16 Closed Loop Medical Pty Ltd Monitoring brain neural potentials
US11179091B2 (en) 2016-06-24 2021-11-23 Saluda Medical Pty Ltd Neural stimulation for reduced artefact
US11191966B2 (en) 2016-04-05 2021-12-07 Saluda Medical Pty Ltd Feedback control of neuromodulation
US11191953B2 (en) 2010-08-19 2021-12-07 Electrocore, Inc. Systems and methods for vagal nerve stimulation
US11213685B2 (en) 2017-06-13 2022-01-04 Bluewind Medical Ltd. Antenna configuration
US11219766B2 (en) 2014-12-11 2022-01-11 Saluda Medical Pty Ltd Method and device for feedback control of neural stimulation
US11229790B2 (en) 2013-01-15 2022-01-25 Electrocore, Inc. Mobile phone for treating a patient with seizures
US11253712B2 (en) 2012-07-26 2022-02-22 Nyxoah SA Sleep disordered breathing treatment apparatus
US11297445B2 (en) 2005-11-10 2022-04-05 Electrocore, Inc. Methods and devices for treating primary headache
US11324427B2 (en) 2011-05-13 2022-05-10 Saluda Medical Pty Ltd Method and apparatus for measurement of neural response
US11337658B2 (en) 2013-11-22 2022-05-24 Saluda Medical Pty Ltd Method and device for detecting a neural response in a neural measurement
US11351363B2 (en) 2005-11-10 2022-06-07 Electrocore, Inc. Nerve stimulation devices and methods for treating cardiac arrhythmias
US11389098B2 (en) 2012-11-06 2022-07-19 Saluda Medical Pty Ltd Method and system for controlling electrical conditions of tissue
US11400288B2 (en) 2010-08-19 2022-08-02 Electrocore, Inc Devices and methods for electrical stimulation and their use for vagus nerve stimulation on the neck of a patient
US11400299B1 (en) 2021-09-14 2022-08-02 Rainbow Medical Ltd. Flexible antenna for stimulator
US11413460B2 (en) 2011-05-13 2022-08-16 Saluda Medical Pty Ltd Method and apparatus for application of a neural stimulus
US11432760B2 (en) 2011-01-12 2022-09-06 Electrocore, Inc. Devices and methods for remote therapy and patient monitoring
US11439818B2 (en) 2011-03-10 2022-09-13 Electrocore, Inc. Electrical nerve stimulation to treat gastroparesis, functional dyspepsia, and other functional gastrointestinal disorders
US11445958B2 (en) 2011-05-13 2022-09-20 Saluda Medical Pty Ltd Method and apparatus for estimating neural recruitment
US11457849B2 (en) 2014-05-05 2022-10-04 Saluda Medical Pty Ltd Neural measurement
US11458297B2 (en) 2011-03-10 2022-10-04 Electrocore, Inc Electrical and magnetic stimulators used to treat migraine/sinus headache, rhinitis, sinusitis, rhinosinusitis, and comorbid disorders
US11559687B2 (en) 2017-09-13 2023-01-24 CARDIONOMIC, Inc. Methods for detecting catheter movement
US11607176B2 (en) 2019-05-06 2023-03-21 CARDIONOMIC, Inc. Systems and methods for denoising physiological signals during electrical neuromodulation
US11819332B2 (en) 2011-05-13 2023-11-21 Saluda Medical Pty Ltd Method and apparatus for measurement of neural response
US11865329B2 (en) 2010-08-19 2024-01-09 Electrocore, Inc. Vagal nerve stimulation for treating post-traumatic stress disorder

Families Citing this family (289)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7799337B2 (en) 1997-07-21 2010-09-21 Levin Bruce H Method for directed intranasal administration of a composition
US8914114B2 (en) 2000-05-23 2014-12-16 The Feinstein Institute For Medical Research Inhibition of inflammatory cytokine production by cholinergic agonists and vagus nerve stimulation
US7840271B2 (en) 2000-09-27 2010-11-23 Cvrx, Inc. Stimulus regimens for cardiovascular reflex control
US8086314B1 (en) 2000-09-27 2011-12-27 Cvrx, Inc. Devices and methods for cardiovascular reflex control
US20070185542A1 (en) * 2002-03-27 2007-08-09 Cvrx, Inc. Baroreflex therapy for disordered breathing
US7623926B2 (en) * 2000-09-27 2009-11-24 Cvrx, Inc. Stimulus regimens for cardiovascular reflex control
US7616997B2 (en) 2000-09-27 2009-11-10 Kieval Robert S Devices and methods for cardiovascular reflex control via coupled electrodes
US7499742B2 (en) 2001-09-26 2009-03-03 Cvrx, Inc. Electrode structures and methods for their use in cardiovascular reflex control
US6907295B2 (en) 2001-08-31 2005-06-14 Biocontrol Medical Ltd. Electrode assembly for nerve control
US8615294B2 (en) 2008-08-13 2013-12-24 Bio Control Medical (B.C.M.) Ltd. Electrode devices for nerve stimulation and cardiac sensing
US7885709B2 (en) 2001-08-31 2011-02-08 Bio Control Medical (B.C.M.) Ltd. Nerve stimulation for treating disorders
US20090005845A1 (en) * 2007-06-26 2009-01-01 Tamir Ben David Intra-Atrial parasympathetic stimulation
US7778711B2 (en) * 2001-08-31 2010-08-17 Bio Control Medical (B.C.M.) Ltd. Reduction of heart rate variability by parasympathetic stimulation
US20080119898A1 (en) * 2005-09-22 2008-05-22 Biocontrol Medical Ltd. Nitric oxide synthase-affecting parasympathetic stimulation
US7904176B2 (en) 2006-09-07 2011-03-08 Bio Control Medical (B.C.M.) Ltd. Techniques for reducing pain associated with nerve stimulation
DE10151089A1 (en) * 2001-10-13 2003-04-17 Biotronik Mess & Therapieg Device for predicting tachyarrhythmias
US20080077192A1 (en) 2002-05-03 2008-03-27 Afferent Corporation System and method for neuro-stimulation
US7837719B2 (en) 2002-05-09 2010-11-23 Daemen College Electrical stimulation unit and waterbath system
US8204591B2 (en) 2002-05-23 2012-06-19 Bio Control Medical (B.C.M.) Ltd. Techniques for prevention of atrial fibrillation
US7885711B2 (en) * 2003-06-13 2011-02-08 Bio Control Medical (B.C.M.) Ltd. Vagal stimulation for anti-embolic therapy
US7321793B2 (en) * 2003-06-13 2008-01-22 Biocontrol Medical Ltd. Vagal stimulation for atrial fibrillation therapy
US7904151B2 (en) 2002-07-24 2011-03-08 Bio Control Medical (B.C.M.) Ltd. Parasympathetic stimulation for treating ventricular arrhythmia
US7189204B2 (en) 2002-12-04 2007-03-13 Cardiac Pacemakers, Inc. Sleep detection using an adjustable threshold
US7627384B2 (en) 2004-11-15 2009-12-01 Bio Control Medical (B.C.M.) Ltd. Techniques for nerve stimulation
US8880192B2 (en) 2012-04-02 2014-11-04 Bio Control Medical (B.C.M.) Ltd. Electrode cuffs
US11439815B2 (en) 2003-03-10 2022-09-13 Impulse Dynamics Nv Protein activity modification
US8718791B2 (en) 2003-05-23 2014-05-06 Bio Control Medical (B.C.M.) Ltd. Electrode cuffs
US7887493B2 (en) * 2003-09-18 2011-02-15 Cardiac Pacemakers, Inc. Implantable device employing movement sensing for detecting sleep-related disorders
EP1670547B1 (en) 2003-08-18 2008-11-12 Cardiac Pacemakers, Inc. Patient monitoring system
US8606356B2 (en) 2003-09-18 2013-12-10 Cardiac Pacemakers, Inc. Autonomic arousal detection system and method
US8002553B2 (en) 2003-08-18 2011-08-23 Cardiac Pacemakers, Inc. Sleep quality data collection and evaluation
US7657312B2 (en) * 2003-11-03 2010-02-02 Cardiac Pacemakers, Inc. Multi-site ventricular pacing therapy with parasympathetic stimulation
US7783353B2 (en) 2003-12-24 2010-08-24 Cardiac Pacemakers, Inc. Automatic neural stimulation modulation based on activity and circadian rhythm
US8200331B2 (en) 2004-11-04 2012-06-12 Cardiac Pacemakers, Inc. System and method for filtering neural stimulation
US8024050B2 (en) 2003-12-24 2011-09-20 Cardiac Pacemakers, Inc. Lead for stimulating the baroreceptors in the pulmonary artery
US7643875B2 (en) * 2003-12-24 2010-01-05 Cardiac Pacemakers, Inc. Baroreflex stimulation system to reduce hypertension
US20050149132A1 (en) 2003-12-24 2005-07-07 Imad Libbus Automatic baroreflex modulation based on cardiac activity
US9020595B2 (en) * 2003-12-24 2015-04-28 Cardiac Pacemakers, Inc. Baroreflex activation therapy with conditional shut off
US7460906B2 (en) 2003-12-24 2008-12-02 Cardiac Pacemakers, Inc. Baroreflex stimulation to treat acute myocardial infarction
US8126560B2 (en) 2003-12-24 2012-02-28 Cardiac Pacemakers, Inc. Stimulation lead for stimulating the baroreceptors in the pulmonary artery
US7486991B2 (en) 2003-12-24 2009-02-03 Cardiac Pacemakers, Inc. Baroreflex modulation to gradually decrease blood pressure
US7706884B2 (en) 2003-12-24 2010-04-27 Cardiac Pacemakers, Inc. Baroreflex stimulation synchronized to circadian rhythm
US7873413B2 (en) * 2006-07-24 2011-01-18 Cardiac Pacemakers, Inc. Closed loop neural stimulation synchronized to cardiac cycles
US7647114B2 (en) 2003-12-24 2010-01-12 Cardiac Pacemakers, Inc. Baroreflex modulation based on monitored cardiovascular parameter
US7769450B2 (en) * 2004-11-18 2010-08-03 Cardiac Pacemakers, Inc. Cardiac rhythm management device with neural sensor
US7869881B2 (en) 2003-12-24 2011-01-11 Cardiac Pacemakers, Inc. Baroreflex stimulator with integrated pressure sensor
US7509166B2 (en) 2003-12-24 2009-03-24 Cardiac Pacemakers, Inc. Automatic baroreflex modulation responsive to adverse event
US11779768B2 (en) 2004-03-10 2023-10-10 Impulse Dynamics Nv Protein activity modification
AU2005225458B2 (en) 2004-03-25 2008-12-04 The Feinstein Institutes For Medical Research Neural tourniquet
US10912712B2 (en) 2004-03-25 2021-02-09 The Feinstein Institutes For Medical Research Treatment of bleeding by non-invasive stimulation
US7260431B2 (en) * 2004-05-20 2007-08-21 Cardiac Pacemakers, Inc. Combined remodeling control therapy and anti-remodeling therapy by implantable cardiac device
US7747323B2 (en) 2004-06-08 2010-06-29 Cardiac Pacemakers, Inc. Adaptive baroreflex stimulation therapy for disordered breathing
US7751891B2 (en) * 2004-07-28 2010-07-06 Cyberonics, Inc. Power supply monitoring for an implantable device
EP1804902A4 (en) * 2004-09-10 2008-04-16 Cleveland Clinic Foundation Intraluminal electrode assembly
US8175705B2 (en) * 2004-10-12 2012-05-08 Cardiac Pacemakers, Inc. System and method for sustained baroreflex stimulation
US7613520B2 (en) * 2004-10-21 2009-11-03 Advanced Neuromodulation Systems, Inc. Spinal cord stimulation to treat auditory dysfunction
US7613519B2 (en) * 2004-10-21 2009-11-03 Advanced Neuromodulation Systems, Inc. Peripheral nerve stimulation to treat auditory dysfunction
US11207518B2 (en) 2004-12-27 2021-12-28 The Feinstein Institutes For Medical Research Treating inflammatory disorders by stimulation of the cholinergic anti-inflammatory pathway
AU2005323463B2 (en) 2004-12-27 2009-11-19 The Feinstein Institutes For Medical Research Treating inflammatory disorders by electrical vagus nerve stimulation
US8565867B2 (en) 2005-01-28 2013-10-22 Cyberonics, Inc. Changeable electrode polarity stimulation by an implantable medical device
US9314633B2 (en) 2008-01-25 2016-04-19 Cyberonics, Inc. Contingent cardio-protection for epilepsy patients
US8224444B2 (en) * 2005-02-18 2012-07-17 Bio Control Medical (B.C.M.) Ltd. Intermittent electrical stimulation
US10154792B2 (en) 2005-03-01 2018-12-18 Checkpoint Surgical, Inc. Stimulation device adapter
US20060200219A1 (en) * 2005-03-01 2006-09-07 Ndi Medical, Llc Systems and methods for differentiating and/or identifying tissue regions innervated by targeted nerves for diagnostic and/or therapeutic purposes
US7769446B2 (en) * 2005-03-11 2010-08-03 Cardiac Pacemakers, Inc. Neural stimulation system for cardiac fat pads
US7840266B2 (en) * 2005-03-11 2010-11-23 Cardiac Pacemakers, Inc. Integrated lead for applying cardiac resynchronization therapy and neural stimulation therapy
US7587238B2 (en) 2005-03-11 2009-09-08 Cardiac Pacemakers, Inc. Combined neural stimulation and cardiac resynchronization therapy
US7920915B2 (en) * 2005-11-16 2011-04-05 Boston Scientific Neuromodulation Corporation Implantable stimulator
US7660628B2 (en) 2005-03-23 2010-02-09 Cardiac Pacemakers, Inc. System to provide myocardial and neural stimulation
US8423108B2 (en) * 2005-03-24 2013-04-16 Intelomed, Inc. Device and system that identifies cardiovascular insufficiency
US7678057B2 (en) * 2005-03-24 2010-03-16 Intelomed, Inc. Device and system that identifies cardiovascular insufficiency
US7542800B2 (en) 2005-04-05 2009-06-02 Cardiac Pacemakers, Inc. Method and apparatus for synchronizing neural stimulation to cardiac cycles
US7493161B2 (en) 2005-05-10 2009-02-17 Cardiac Pacemakers, Inc. System and method to deliver therapy in presence of another therapy
US7555341B2 (en) 2005-04-05 2009-06-30 Cardiac Pacemakers, Inc. System to treat AV-conducted ventricular tachyarrhythmia
US8473049B2 (en) 2005-05-25 2013-06-25 Cardiac Pacemakers, Inc. Implantable neural stimulator with mode switching
US8406876B2 (en) 2005-04-05 2013-03-26 Cardiac Pacemakers, Inc. Closed loop neural stimulation synchronized to cardiac cycles
US7499748B2 (en) * 2005-04-11 2009-03-03 Cardiac Pacemakers, Inc. Transvascular neural stimulation device
US7881782B2 (en) * 2005-04-20 2011-02-01 Cardiac Pacemakers, Inc. Neural stimulation system to prevent simultaneous energy discharges
US9555252B2 (en) * 2005-04-25 2017-01-31 Cardiac Pacemakers, Inc. Systems for providing neural markers for sensed autonomic nervous system activity
US8055340B2 (en) * 2005-05-05 2011-11-08 Cardiac Pacemakers, Inc. Method and device for comprehensive anti-tachyarrhythmia therapy
US7617003B2 (en) * 2005-05-16 2009-11-10 Cardiac Pacemakers, Inc. System for selective activation of a nerve trunk using a transvascular reshaping lead
US9861836B2 (en) * 2005-06-16 2018-01-09 Biosense Webster, Inc. Less invasive methods for ablation of fat pads
US20070021786A1 (en) * 2005-07-25 2007-01-25 Cyberonics, Inc. Selective nerve stimulation for the treatment of angina pectoris
US7706874B2 (en) * 2005-07-28 2010-04-27 Cyberonics, Inc. Stimulating cranial nerve to treat disorders associated with the thyroid gland
US7860566B2 (en) * 2005-10-06 2010-12-28 The Cleveland Clinic Foundation System and method for achieving regular slow ventricular rhythm in response to atrial fibrillation
US7616990B2 (en) 2005-10-24 2009-11-10 Cardiac Pacemakers, Inc. Implantable and rechargeable neural stimulator
US7957796B2 (en) 2005-10-28 2011-06-07 Cyberonics, Inc. Using physiological sensor data with an implantable medical device
US8109879B2 (en) 2006-01-10 2012-02-07 Cardiac Pacemakers, Inc. Assessing autonomic activity using baroreflex analysis
US7801601B2 (en) 2006-01-27 2010-09-21 Cyberonics, Inc. Controlling neuromodulation using stimulus modalities
EP1981584B1 (en) 2006-02-03 2015-05-13 Interventional Autonomics Corporation Intravascular device for neuromodulation
EP2026874B1 (en) 2006-03-29 2015-05-20 Dignity Health Vagus nerve stimulation system
US20080183237A1 (en) * 2006-04-18 2008-07-31 Electrocore, Inc. Methods And Apparatus For Treating Ileus Condition Using Electrical Signals
US7869885B2 (en) 2006-04-28 2011-01-11 Cyberonics, Inc Threshold optimization for tissue stimulation therapy
US7689286B2 (en) * 2006-05-02 2010-03-30 Cardiac Pacemakers, Inc. Myocardium conditioning using myocardial and parasympathetic stimulation
US8255049B2 (en) * 2006-05-08 2012-08-28 Cardiac Pacemakers, Inc. Method and device for providing anti-tachyarrhythmia therapy
WO2007139861A2 (en) * 2006-05-22 2007-12-06 The Trustees Of The University Of Pennsylvania Method and device for the recording, localization and stimulation-based mapping of epileptic seizures and brain function utilizing the intracranial and extracranial cerebral vasulature and/or central and/or peripheral nervous system
US20070282376A1 (en) 2006-06-06 2007-12-06 Shuros Allan C Method and apparatus for neural stimulation via the lymphatic system
US8170668B2 (en) 2006-07-14 2012-05-01 Cardiac Pacemakers, Inc. Baroreflex sensitivity monitoring and trending for tachyarrhythmia detection and therapy
US7899531B1 (en) * 2006-08-22 2011-03-01 Pacesetter, Inc. Neural sensing for atrial fibrillation
US8103341B2 (en) 2006-08-25 2012-01-24 Cardiac Pacemakers, Inc. System for abating neural stimulation side effects
US8983598B2 (en) * 2006-10-04 2015-03-17 Cardiac Pacemakers, Inc. System for neurally-mediated anti-arrhythmic therapy
US20080086180A1 (en) * 2006-10-05 2008-04-10 Omry Ben-Ezra Techniques for gall bladder stimulation
US7869867B2 (en) 2006-10-27 2011-01-11 Cyberonics, Inc. Implantable neurostimulator with refractory stimulation
US20100217347A1 (en) * 2006-12-16 2010-08-26 Greatbatch, Inc. Neurostimulation for the treatment of pulmonary disorders
US7826899B1 (en) 2006-12-22 2010-11-02 Pacesetter, Inc. Neurostimulation and neurosensing techniques to optimize atrial anti-tachycardia pacing for termination of atrial tachyarrhythmias
US7715915B1 (en) 2006-12-22 2010-05-11 Pacesetter, Inc. Neurostimulation and neurosensing techniques to optimize atrial anti-tachycardia pacing for prevention of atrial tachyarrhythmias
US20080183186A1 (en) * 2007-01-30 2008-07-31 Cardiac Pacemakers, Inc. Method and apparatus for delivering a transvascular lead
US7949409B2 (en) 2007-01-30 2011-05-24 Cardiac Pacemakers, Inc. Dual spiral lead configurations
US8244378B2 (en) * 2007-01-30 2012-08-14 Cardiac Pacemakers, Inc. Spiral configurations for intravascular lead stability
US20080183265A1 (en) * 2007-01-30 2008-07-31 Cardiac Pacemakers, Inc. Transvascular lead with proximal force relief
US7917230B2 (en) * 2007-01-30 2011-03-29 Cardiac Pacemakers, Inc. Neurostimulating lead having a stent-like anchor
US20080183187A1 (en) * 2007-01-30 2008-07-31 Cardiac Pacemakers, Inc. Direct delivery system for transvascular lead
US7937147B2 (en) * 2007-02-28 2011-05-03 Cardiac Pacemakers, Inc. High frequency stimulation for treatment of atrial fibrillation
WO2008112915A1 (en) * 2007-03-13 2008-09-18 The Feinstein Institute For Medical Research Treatment of inflammation by non-invasive stimulation
US8406877B2 (en) * 2007-03-19 2013-03-26 Cardiac Pacemakers, Inc. Selective nerve stimulation with optionally closed-loop capabilities
US8364273B2 (en) * 2007-04-24 2013-01-29 Dirk De Ridder Combination of tonic and burst stimulations to treat neurological disorders
US7974701B2 (en) 2007-04-27 2011-07-05 Cyberonics, Inc. Dosing limitation for an implantable medical device
US20080281365A1 (en) * 2007-05-09 2008-11-13 Tweden Katherine S Neural signal duty cycle
US8594794B2 (en) 2007-07-24 2013-11-26 Cvrx, Inc. Baroreflex activation therapy with incrementally changing intensity
US8135464B1 (en) 2007-07-30 2012-03-13 Pacesetter, Inc. Painless ventricular rate control during supraventricular tachycardia
WO2009029614A1 (en) 2007-08-27 2009-03-05 The Feinstein Institute For Medical Research Devices and methods for inhibiting granulocyte activation by neural stimulation
WO2009027755A1 (en) * 2007-08-28 2009-03-05 Institut National De La Recherche Agronomique (Inra) Device and method for reducing weight
WO2009035515A1 (en) 2007-09-13 2009-03-19 Cardiac Pacemakers, Inc. Systems for avoiding neural stimulation habituation
US8352033B2 (en) 2007-10-15 2013-01-08 Mark Kroll Apparatus and methods for measuring defibrillation lead impedance via a high magnitude, short duration current pulse
US20090112962A1 (en) * 2007-10-31 2009-04-30 Research In Motion Limited Modular squaring in binary field arithmetic
US9089707B2 (en) 2008-07-02 2015-07-28 The Board Of Regents, The University Of Texas System Systems, methods and devices for paired plasticity
US8457757B2 (en) 2007-11-26 2013-06-04 Micro Transponder, Inc. Implantable transponder systems and methods
US8180447B2 (en) * 2007-12-05 2012-05-15 The Invention Science Fund I, Llc Method for reversible chemical modulation of neural activity
US8874223B2 (en) * 2008-02-01 2014-10-28 Prev Biotech Inc. Mitigation of pressure ulcers using electrical stimulation
US7925352B2 (en) 2008-03-27 2011-04-12 Synecor Llc System and method for transvascularly stimulating contents of the carotid sheath
US9662490B2 (en) 2008-03-31 2017-05-30 The Feinstein Institute For Medical Research Methods and systems for reducing inflammation by neuromodulation and administration of an anti-inflammatory drug
US9211409B2 (en) 2008-03-31 2015-12-15 The Feinstein Institute For Medical Research Methods and systems for reducing inflammation by neuromodulation of T-cell activity
US8204603B2 (en) * 2008-04-25 2012-06-19 Cyberonics, Inc. Blocking exogenous action potentials by an implantable medical device
US8473062B2 (en) 2008-05-01 2013-06-25 Autonomic Technologies, Inc. Method and device for the treatment of headache
JP5427233B2 (en) 2008-07-08 2014-02-26 カーディアック ペースメイカーズ, インコーポレイテッド Medical system delivering vagus nerve stimulation
US8244350B2 (en) * 2008-08-05 2012-08-14 Cardiac Pacemakers, Inc. Neural stimulation for arrhythmia recognition and therapy
US8768469B2 (en) 2008-08-08 2014-07-01 Enteromedics Inc. Systems for regulation of blood pressure and heart rate
US8457747B2 (en) 2008-10-20 2013-06-04 Cyberonics, Inc. Neurostimulation with signal duration determined by a cardiac cycle
US20100114227A1 (en) * 2008-10-30 2010-05-06 Pacesetter, Inc. Systems and Methds for Use by an Implantable Medical Device for Controlling Vagus Nerve Stimulation Based on Heart Rate Reduction Curves and Thresholds to Mitigate Heart Failure
US8452394B2 (en) * 2008-10-31 2013-05-28 Medtronic, Inc. Implantable medical device crosstalk evaluation and mitigation
US8611996B2 (en) * 2008-10-31 2013-12-17 Medtronic, Inc. Implantable medical device crosstalk evaluation and mitigation
US8249708B2 (en) * 2008-10-31 2012-08-21 Medtronic, Inc. Implantable medical device crosstalk evaluation and mitigation
US8260412B2 (en) * 2008-10-31 2012-09-04 Medtronic, Inc. Implantable medical device crosstalk evaluation and mitigation
US8532779B2 (en) * 2008-10-31 2013-09-10 Medtronic, Inc. Implantable medical device crosstalk evaluation and mitigation
US20100114209A1 (en) * 2008-10-31 2010-05-06 Medtronic, Inc. Communication between implantable medical devices
US9775987B2 (en) * 2008-10-31 2017-10-03 Medtronic, Inc. Implantable medical device crosstalk evaluation and mitigation
US9597505B2 (en) * 2008-10-31 2017-03-21 Medtronic, Inc. Implantable medical device crosstalk evaluation and mitigation
US8688210B2 (en) * 2008-10-31 2014-04-01 Medtronic, Inc. Implantable medical device crosstalk evaluation and mitigation
US8774918B2 (en) * 2008-10-31 2014-07-08 Medtronic, Inc. Implantable medical device crosstalk evaluation and mitigation
US8301263B2 (en) * 2008-10-31 2012-10-30 Medtronic, Inc. Therapy module crosstalk mitigation
US8005539B2 (en) * 2008-10-31 2011-08-23 Medtronic, Inc. Implantable medical device crosstalk evaluation and mitigation
US8255057B2 (en) 2009-01-29 2012-08-28 Nevro Corporation Systems and methods for producing asynchronous neural responses to treat pain and/or other patient conditions
US9327121B2 (en) 2011-09-08 2016-05-03 Nevro Corporation Selective high frequency spinal cord modulation for inhibiting pain, including cephalic and/or total body pain with reduced side effects, and associated systems and methods
WO2010059617A2 (en) 2008-11-18 2010-05-27 Setpoint Medical Corporation Devices and methods for optimizing electrode placement for anti-inflamatory stimulation
US8412336B2 (en) 2008-12-29 2013-04-02 Autonomic Technologies, Inc. Integrated delivery and visualization tool for a neuromodulation system
US8494641B2 (en) 2009-04-22 2013-07-23 Autonomic Technologies, Inc. Implantable neurostimulator with integral hermetic electronic enclosure, circuit substrate, monolithic feed-through, lead assembly and anchoring mechanism
US9320908B2 (en) 2009-01-15 2016-04-26 Autonomic Technologies, Inc. Approval per use implanted neurostimulator
US20100191304A1 (en) 2009-01-23 2010-07-29 Scott Timothy L Implantable Medical Device for Providing Chronic Condition Therapy and Acute Condition Therapy Using Vagus Nerve Stimulation
WO2010088539A1 (en) 2009-01-30 2010-08-05 Medtronic, Inc. Detecting and treating electromechanical dissociation of the heart
ES2624748T3 (en) 2009-04-22 2017-07-17 Nevro Corporation Selective high frequency modulation of the spinal cord for pain inhibition with reduced side effects, and associated systems and methods
EP4257178A3 (en) 2009-04-22 2023-10-25 Nevro Corporation Spinal cord modulation systems for inducing paresthetic and anesthetic effects
US8996116B2 (en) 2009-10-30 2015-03-31 Setpoint Medical Corporation Modulation of the cholinergic anti-inflammatory pathway to treat pain or addiction
US8788034B2 (en) 2011-05-09 2014-07-22 Setpoint Medical Corporation Single-pulse activation of the cholinergic anti-inflammatory pathway to treat chronic inflammation
US9211410B2 (en) 2009-05-01 2015-12-15 Setpoint Medical Corporation Extremely low duty-cycle activation of the cholinergic anti-inflammatory pathway to treat chronic inflammation
WO2010144578A2 (en) 2009-06-09 2010-12-16 Setpoint Medical Corporation Nerve cuff with pocket for leadless stimulator
US20100331926A1 (en) 2009-06-24 2010-12-30 Boston Scientific Neuromodulation Corporation Reversing recruitment order by anode intensification
JP5613234B2 (en) 2009-07-15 2014-10-22 カーディアック ペースメイカーズ, インコーポレイテッド Remote pace detection in implantable medical devices
US8285373B2 (en) * 2009-07-15 2012-10-09 Cardiac Pacemakers, Inc. Remote sensing in an implantable medical device
US8588906B2 (en) * 2009-07-15 2013-11-19 Cardiac Pacemakers, Inc. Physiological vibration detection in an implanted medical device
US8498710B2 (en) 2009-07-28 2013-07-30 Nevro Corporation Linked area parameter adjustment for spinal cord stimulation and associated systems and methods
US9697336B2 (en) 2009-07-28 2017-07-04 Gearbox, Llc Electronically initiating an administration of a neuromodulation treatment regimen chosen in response to contactlessly acquired information
US8825158B2 (en) 2009-08-25 2014-09-02 Lamda Nu, Llc Method and apparatus for detection of lead conductor anomalies using dynamic electrical parameters
JP2011103981A (en) * 2009-11-13 2011-06-02 Olympus Corp Nerve stimulation device
US11051744B2 (en) 2009-11-17 2021-07-06 Setpoint Medical Corporation Closed-loop vagus nerve stimulation
US9833621B2 (en) 2011-09-23 2017-12-05 Setpoint Medical Corporation Modulation of sirtuins by vagus nerve stimulation
US8548585B2 (en) 2009-12-08 2013-10-01 Cardiac Pacemakers, Inc. Concurrent therapy detection in implantable medical devices
CN105126248B (en) 2009-12-23 2018-06-12 赛博恩特医疗器械公司 For treating the nerve stimulation apparatus of chronic inflammation and system
US8818508B2 (en) * 2010-03-12 2014-08-26 Medtronic, Inc. Dosing vagal nerve stimulation therapy in synchronization with transient effects
EP2374503B1 (en) * 2010-04-08 2012-07-11 Sorin CRM SAS Active implantable medical device for vagal stimulation with optimised ventricular filling
US8639327B2 (en) 2010-04-29 2014-01-28 Medtronic, Inc. Nerve signal differentiation in cardiac therapy
US8406868B2 (en) 2010-04-29 2013-03-26 Medtronic, Inc. Therapy using perturbation and effect of physiological systems
US9002440B2 (en) 2010-07-08 2015-04-07 Intelomed, Inc. System and method for characterizing circulatory blood flow
CA2804788C (en) 2010-07-08 2020-08-25 Intelomed, Inc. System and method for characterizing circulatory blood flow
WO2012149511A2 (en) 2011-04-28 2012-11-01 Synecor Llc Neuromodulation systems and methods for treating acute heart failure syndromes
US9821159B2 (en) 2010-11-16 2017-11-21 The Board Of Trustees Of The Leland Stanford Junior University Stimulation devices and methods
CA2817589A1 (en) 2010-11-16 2012-05-24 The Board Of Trustees Of The Leland Stanford Junior University Systems and methods for treatment of dry eye
US8725259B2 (en) 2011-01-19 2014-05-13 Medtronic, Inc. Vagal stimulation
US8706223B2 (en) 2011-01-19 2014-04-22 Medtronic, Inc. Preventative vagal stimulation
US8718763B2 (en) 2011-01-19 2014-05-06 Medtronic, Inc. Vagal stimulation
US8781582B2 (en) * 2011-01-19 2014-07-15 Medtronic, Inc. Vagal stimulation
US20140236042A1 (en) 2011-05-13 2014-08-21 Saluda Medical Pty. Ltd. Method and apparatus for measurement of neural response
EP2766086A4 (en) 2011-07-11 2015-09-30 Interventional Autonomics Corp System and method for neuromodulation
US20130072995A1 (en) 2011-07-11 2013-03-21 Terrance Ransbury Catheter system for acute neuromodulation
US9446240B2 (en) 2011-07-11 2016-09-20 Interventional Autonomics Corporation System and method for neuromodulation
US8630709B2 (en) 2011-12-07 2014-01-14 Cyberonics, Inc. Computer-implemented system and method for selecting therapy profiles of electrical stimulation of cervical vagus nerves for treatment of chronic cardiac dysfunction
US10188856B1 (en) 2011-12-07 2019-01-29 Cyberonics, Inc. Implantable device for providing electrical stimulation of cervical vagus nerves for treatment of chronic cardiac dysfunction
US8918190B2 (en) 2011-12-07 2014-12-23 Cyberonics, Inc. Implantable device for evaluating autonomic cardiovascular drive in a patient suffering from chronic cardiac dysfunction
US8577458B1 (en) 2011-12-07 2013-11-05 Cyberonics, Inc. Implantable device for providing electrical stimulation of cervical vagus nerves for treatment of chronic cardiac dysfunction with leadless heart rate monitoring
US8600505B2 (en) 2011-12-07 2013-12-03 Cyberonics, Inc. Implantable device for facilitating control of electrical stimulation of cervical vagus nerves for treatment of chronic cardiac dysfunction
US8918191B2 (en) 2011-12-07 2014-12-23 Cyberonics, Inc. Implantable device for providing electrical stimulation of cervical vagus nerves for treatment of chronic cardiac dysfunction with bounded titration
US8571654B2 (en) 2012-01-17 2013-10-29 Cyberonics, Inc. Vagus nerve neurostimulator with multiple patient-selectable modes for treating chronic cardiac dysfunction
US8700150B2 (en) 2012-01-17 2014-04-15 Cyberonics, Inc. Implantable neurostimulator for providing electrical stimulation of cervical vagus nerves for treatment of chronic cardiac dysfunction with bounded titration
US9572983B2 (en) 2012-03-26 2017-02-21 Setpoint Medical Corporation Devices and methods for modulation of bone erosion
US8843209B2 (en) 2012-04-27 2014-09-23 Medtronic, Inc. Ramping parameter values for electrical stimulation therapy
US8812103B2 (en) 2012-06-01 2014-08-19 Lamda Nu, Llc Method for detecting and treating insulation lead-to-housing failures
US9272150B2 (en) 2012-06-01 2016-03-01 Lambda Nu Technology Llc Method for detecting and localizing insulation failures of implantable device leads
US9833614B1 (en) 2012-06-22 2017-12-05 Nevro Corp. Autonomic nervous system control via high frequency spinal cord modulation, and associated systems and methods
US8688212B2 (en) 2012-07-20 2014-04-01 Cyberonics, Inc. Implantable neurostimulator-implemented method for managing bradycardia through vagus nerve stimulation
US8923964B2 (en) 2012-11-09 2014-12-30 Cyberonics, Inc. Implantable neurostimulator-implemented method for enhancing heart failure patient awakening through vagus nerve stimulation
US9452290B2 (en) 2012-11-09 2016-09-27 Cyberonics, Inc. Implantable neurostimulator-implemented method for managing tachyarrhythmia through vagus nerve stimulation
US9643008B2 (en) 2012-11-09 2017-05-09 Cyberonics, Inc. Implantable neurostimulator-implemented method for enhancing post-exercise recovery through vagus nerve stimulation
US9675799B2 (en) 2012-12-05 2017-06-13 Lambda Nu Technology Llc Method and apparatus for implantable cardiac lead integrity analysis
US9265956B2 (en) 2013-03-08 2016-02-23 Oculeve, Inc. Devices and methods for treating dry eye in animals
EP2967817B1 (en) 2013-03-12 2021-03-10 Oculeve, Inc. Implant delivery devices and systems
US9643011B2 (en) 2013-03-14 2017-05-09 Cyberonics, Inc. Implantable neurostimulator-implemented method for managing tachyarrhythmic risk during sleep through vagus nerve stimulation
NZ745920A (en) 2013-04-19 2020-01-31 Oculeve Inc Nasal stimulation devices and methods
US10039919B2 (en) 2013-04-30 2018-08-07 Lambda Nu Technology Llc Methods and apparatus for detecting and localizing partial conductor failures of implantable device leads
US20140324129A1 (en) * 2013-04-30 2014-10-30 Case Western Reserve University Systems and methods for temporary, incomplete, bi-directional, adjustable electrical nerve block
EP3003135B1 (en) 2013-06-04 2019-07-24 Intelomed, Inc Hemodynamic risk severity based upon detection and quantification of cardiac dysrhythmia behavior using a pulse volume waveform
US9895539B1 (en) 2013-06-10 2018-02-20 Nevro Corp. Methods and systems for disease treatment using electrical stimulation
EP3007616A4 (en) 2013-06-11 2017-01-25 Intelomed, Inc Predicting hypovolemic hypotensive conditions using a pulse volume waveform
US9486624B2 (en) 2013-06-13 2016-11-08 Lambda Nu Technology Llc Detection of implantable lead failures by differential EGM analysis
US10118031B2 (en) 2013-06-28 2018-11-06 Lambda Nu Technology Llc Method and apparatus for implantable cardiac lead integrity analysis
EP2818199B1 (en) 2013-06-30 2022-09-07 Cyberonics, Inc. Implantable vagal neurostimulator with bounded autotitration
EP3033002A4 (en) 2013-08-12 2017-04-05 Intelomed, Inc Methods for monitoring and analyzing cardiovascular states
US9999773B2 (en) 2013-10-30 2018-06-19 Cyberonics, Inc. Implantable neurostimulator-implemented method utilizing multi-modal stimulation parameters
US10149978B1 (en) 2013-11-07 2018-12-11 Nevro Corp. Spinal cord modulation for inhibiting pain via short pulse width waveforms, and associated systems and methods
US9511228B2 (en) 2014-01-14 2016-12-06 Cyberonics, Inc. Implantable neurostimulator-implemented method for managing hypertension through renal denervation and vagus nerve stimulation
CN111298285A (en) 2014-02-25 2020-06-19 奥库利维公司 Polymer formulations for nasolacrimal stimulation
GB2526249B (en) * 2014-03-20 2016-06-29 Branton Jakes Device for the automated non-invasive dynamically adaptive electrical stimulation of the vagus nerve
US9636500B2 (en) 2014-03-25 2017-05-02 Lambda Nu Technology Llc Active surveillance of implanted medical leads for lead integrity
US9272143B2 (en) 2014-05-07 2016-03-01 Cyberonics, Inc. Responsive neurostimulation for the treatment of chronic cardiac dysfunction
US9409024B2 (en) 2014-03-25 2016-08-09 Cyberonics, Inc. Neurostimulation in a neural fulcrum zone for the treatment of chronic cardiac dysfunction
US9713719B2 (en) 2014-04-17 2017-07-25 Cyberonics, Inc. Fine resolution identification of a neural fulcrum for the treatment of chronic cardiac dysfunction
US9415224B2 (en) 2014-04-25 2016-08-16 Cyberonics, Inc. Neurostimulation and recording of physiological response for the treatment of chronic cardiac dysfunction
US9950169B2 (en) 2014-04-25 2018-04-24 Cyberonics, Inc. Dynamic stimulation adjustment for identification of a neural fulcrum
EP2946806B1 (en) 2014-05-19 2016-07-27 Sorin CRM SAS Active implantable medical device with automatic optimisation of the configuration of a multi-electrode stimulation probe, in particular a probe for selective stimulation of the vagus nerve
EP2977078B1 (en) * 2014-07-23 2017-10-25 Sorin CRM SAS Active implantable medical device for therapy by vagus nerve stimulation, with dynamically adjusting stimulation periods
EP3673952A1 (en) 2014-07-25 2020-07-01 Oculeve, Inc. Stimulation patterns for treating dry eye
AU2015292272B2 (en) 2014-07-25 2020-11-12 Saluda Medical Pty Ltd Neural stimulation dosing
US9533153B2 (en) 2014-08-12 2017-01-03 Cyberonics, Inc. Neurostimulation titration process
US9770599B2 (en) 2014-08-12 2017-09-26 Cyberonics, Inc. Vagus nerve stimulation and subcutaneous defibrillation system
US9737716B2 (en) 2014-08-12 2017-08-22 Cyberonics, Inc. Vagus nerve and carotid baroreceptor stimulation system
US9974959B2 (en) * 2014-10-07 2018-05-22 Boston Scientific Neuromodulation Corporation Systems, devices, and methods for electrical stimulation using feedback to adjust stimulation parameters
AU2015335776B2 (en) 2014-10-22 2020-09-03 Oculeve, Inc. Stimulation devices and methods for treating dry eye
AU2015335774B2 (en) 2014-10-22 2020-07-16 Oculeve, Inc. Implantable nasal stimulator systems and methods
WO2016065211A1 (en) 2014-10-22 2016-04-28 Oculeve, Inc. Contact lens for increasing tear production
US11311725B2 (en) 2014-10-24 2022-04-26 Setpoint Medical Corporation Systems and methods for stimulating and/or monitoring loci in the brain to treat inflammation and to enhance vagus nerve stimulation
US9504832B2 (en) 2014-11-12 2016-11-29 Cyberonics, Inc. Neurostimulation titration process via adaptive parametric modification
EP3215216A4 (en) 2014-11-17 2018-08-22 Saluda Medical Pty Ltd Method and device for detecting a neural response in neural measurements
WO2016090420A1 (en) 2014-12-11 2016-06-16 Saluda Medical Pty Ltd Implantable electrode positioning
EP3229893B1 (en) 2015-01-19 2020-06-17 Saluda Medical Pty Ltd Method and device for neural implant communication
WO2016126807A1 (en) 2015-02-03 2016-08-11 Setpoint Medical Corporation Apparatus and method for reminding, prompting, or alerting a patient with an implanted stimulator
US10765863B2 (en) 2015-02-24 2020-09-08 Elira, Inc. Systems and methods for using a transcutaneous electrical stimulation device to deliver titrated therapy
US9956393B2 (en) 2015-02-24 2018-05-01 Elira, Inc. Systems for increasing a delay in the gastric emptying time for a patient using a transcutaneous electro-dermal patch
US10864367B2 (en) 2015-02-24 2020-12-15 Elira, Inc. Methods for using an electrical dermal patch in a manner that reduces adverse patient reactions
US10335302B2 (en) 2015-02-24 2019-07-02 Elira, Inc. Systems and methods for using transcutaneous electrical stimulation to enable dietary interventions
WO2016138176A1 (en) 2015-02-24 2016-09-01 Elira Therapeutics Llc Systems and methods for enabling appetite modulation and/or improving dietary compliance using an electro-dermal patch
US10376145B2 (en) 2015-02-24 2019-08-13 Elira, Inc. Systems and methods for enabling a patient to achieve a weight loss objective using an electrical dermal patch
EP3280487B1 (en) 2015-04-09 2021-09-15 Saluda Medical Pty Limited Electrode to nerve distance estimation
EP3302258A4 (en) 2015-05-31 2018-11-21 Saluda Medical Pty Limited Monitoring brain neural activity
EP3261533A4 (en) 2015-06-01 2018-10-31 Saluda Medical Pty Ltd Motor fibre neuromodulation
AU2016335931B2 (en) 2015-10-06 2019-06-27 Case Western Reserve University High-charge capacity electrodes to deliver direct current nerve conduction block
US11318310B1 (en) 2015-10-26 2022-05-03 Nevro Corp. Neuromodulation for altering autonomic functions, and associated systems and methods
US10252069B1 (en) 2015-11-19 2019-04-09 Lambda Nu Technology Llc Micro-charge ICD lead testing method and apparatus
US10426958B2 (en) 2015-12-04 2019-10-01 Oculeve, Inc. Intranasal stimulation for enhanced release of ocular mucins and other tear proteins
US10596367B2 (en) 2016-01-13 2020-03-24 Setpoint Medical Corporation Systems and methods for establishing a nerve block
US10314501B2 (en) 2016-01-20 2019-06-11 Setpoint Medical Corporation Implantable microstimulators and inductive charging systems
US11471681B2 (en) 2016-01-20 2022-10-18 Setpoint Medical Corporation Batteryless implantable microstimulators
WO2017127756A1 (en) 2016-01-20 2017-07-27 Setpoint Medical Corporation Control of vagal stimulation
US10583304B2 (en) 2016-01-25 2020-03-10 Setpoint Medical Corporation Implantable neurostimulator having power control and thermal regulation and methods of use
AU2017211121B2 (en) 2016-01-25 2022-02-24 Nevro Corp. Treatment of congestive heart failure with electrical stimulation, and associated systems and methods
US10252048B2 (en) 2016-02-19 2019-04-09 Oculeve, Inc. Nasal stimulation for rhinitis, nasal congestion, and ocular allergies
US10918864B2 (en) 2016-05-02 2021-02-16 Oculeve, Inc. Intranasal stimulation for treatment of meibomian gland disease and blepharitis
US10504229B2 (en) * 2016-10-28 2019-12-10 Canon Medical Systems Corporation Medical image processing apparatus and medical image processing method
RU2019118600A (en) 2016-12-02 2021-01-11 Окулив, Инк. APPARATUS AND METHOD FOR MAKING DRY EYE SYNDROME PREDICTION AND TREATMENT RECOMMENDATIONS
US10543364B2 (en) 2017-04-07 2020-01-28 Lambda Nu Technology Llc Detection of lead electrode dislodgement using cavitary electrogram
US11173307B2 (en) 2017-08-14 2021-11-16 Setpoint Medical Corporation Vagus nerve stimulation pre-screening test
US11723579B2 (en) 2017-09-19 2023-08-15 Neuroenhancement Lab, LLC Method and apparatus for neuroenhancement
US11717686B2 (en) 2017-12-04 2023-08-08 Neuroenhancement Lab, LLC Method and apparatus for neuroenhancement to facilitate learning and performance
US11273283B2 (en) 2017-12-31 2022-03-15 Neuroenhancement Lab, LLC Method and apparatus for neuroenhancement to enhance emotional response
US11660443B2 (en) 2018-04-20 2023-05-30 The Feinstein Institutes For Medical Research Methods and apparatuses for reducing bleeding via electrical trigeminal nerve stimulation
US11364361B2 (en) 2018-04-20 2022-06-21 Neuroenhancement Lab, LLC System and method for inducing sleep by transplanting mental states
WO2020056418A1 (en) 2018-09-14 2020-03-19 Neuroenhancement Lab, LLC System and method of improving sleep
US11260229B2 (en) 2018-09-25 2022-03-01 The Feinstein Institutes For Medical Research Methods and apparatuses for reducing bleeding via coordinated trigeminal and vagal nerve stimulation
US11096692B2 (en) 2018-12-13 2021-08-24 Nxt Biomedical, Llc Blood oxygenation treatment methods and devices
US11590352B2 (en) 2019-01-29 2023-02-28 Nevro Corp. Ramped therapeutic signals for modulating inhibitory interneurons, and associated systems and methods
CN110152191B (en) * 2019-05-22 2023-06-16 创领心律管理医疗器械(上海)有限公司 Leadless pacemaker
EP4122378A1 (en) * 2021-07-20 2023-01-25 Circle Safe Monitoring diaphragmatic response to phrenic nerve stimulation

Citations (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5139020A (en) * 1991-03-08 1992-08-18 Telectronics Pacing Systems, Inc. Method and apparatus for controlling the hemodynamic state of a patient based on systolic time interval measurements detecting using doppler ultrasound techniques
US5203326A (en) * 1991-12-18 1993-04-20 Telectronics Pacing Systems, Inc. Antiarrhythmia pacer using antiarrhythmia pacing and autonomic nerve stimulation therapy
US5251621A (en) * 1991-12-18 1993-10-12 Telectronics Pacing Systems, Inc. Arrhythmia control pacer using skeletal muscle cardiac graft stimulation
US5578061A (en) * 1994-06-24 1996-11-26 Pacesetter Ab Method and apparatus for cardiac therapy by stimulation of a physiological representative of the parasympathetic nervous system
US5602301A (en) * 1993-11-16 1997-02-11 Indiana University Foundation Non-human mammal having a graft and methods of delivering protein to myocardial tissue
US5628777A (en) * 1993-07-14 1997-05-13 Pacesetter, Inc. Implantable leads incorporating cardiac wall acceleration sensors and method of fabrication
US5658318A (en) * 1994-06-24 1997-08-19 Pacesetter Ab Method and apparatus for detecting a state of imminent cardiac arrhythmia in response to a nerve signal from the autonomic nerve system to the heart, and for administrating anti-arrhythmia therapy in response thereto
US5749900A (en) * 1995-12-11 1998-05-12 Sulzer Intermedics Inc. Implantable medical device responsive to heart rate variability analysis
US5916239A (en) * 1996-03-29 1999-06-29 Purdue Research Foundation Method and apparatus using vagal stimulation for control of ventricular rate during atrial fibrillation
US6038476A (en) * 1998-06-12 2000-03-14 Pacesetter, Inc. System and method for analyzing the efficacy of cardiac stimulation therapy
US6134471A (en) * 1997-10-23 2000-10-17 Biotronik Mess- Und Therapiegerate Gmbh & Co. Ingenieurburo Berlin Rate adaptive pacemaker
US6134470A (en) * 1998-11-09 2000-10-17 Medtronic, Inc. Method and apparatus for treating a tachyarrhythmic patient
US6195584B1 (en) * 1999-04-30 2001-02-27 Medtronic, Inc. Method and apparatus for determining atrial lead dislocation
US20020029002A1 (en) * 1999-11-16 2002-03-07 Bardy Gust H. Automated collection and analysis patient care system for managing the pathophysiological outcomes of atrial fibrillation
US20030078623A1 (en) * 2001-10-22 2003-04-24 Weinberg Lisa P. Implantable lead and method for stimulating the vagus nerve
US6650943B1 (en) * 2000-04-07 2003-11-18 Advanced Bionics Corporation Fully implantable neurostimulator for cavernous nerve stimulation as a therapy for erectile dysfunction and other sexual dysfunction
US20040193231A1 (en) * 2001-08-31 2004-09-30 Biocontrol Medical Ltd. Selective nerve fiber stimulation for treating heart conditions
US20040254612A1 (en) * 2003-06-13 2004-12-16 Ezra Omry Ben Vagal stimulation for anti-embolic therapy
US20050065553A1 (en) * 2003-06-13 2005-03-24 Omry Ben Ezra Applications of vagal stimulation
US20050267542A1 (en) * 2001-08-31 2005-12-01 Biocontrol Medical Ltd. Techniques for applying, configuring, and coordinating nerve fiber stimulation
US20060241697A1 (en) * 2005-04-25 2006-10-26 Cardiac Pacemakers, Inc. System to provide neural markers for sensed neural activity
US7142917B2 (en) * 2002-12-04 2006-11-28 Terumo Kabushiki Kaisha Heart treatment equipment and method for preventing fatal arrhythmia
US20070179558A1 (en) * 2006-01-30 2007-08-02 Gliner Bradford E Systems and methods for varying electromagnetic and adjunctive neural therapies
US20070203527A1 (en) * 2003-05-23 2007-08-30 Tamir Ben-David Parasympathetic stimulation for termination of non-sinus atrial tachycardia
US20070239243A1 (en) * 2006-03-30 2007-10-11 Advanced Bionics Corporation Electrode contact configurations for cuff leads
US20080021504A1 (en) * 2006-07-24 2008-01-24 Mccabe Aaron Closed loop neural stimulation synchronized to cardiac cycles
US20080086185A1 (en) * 2006-10-06 2008-04-10 Cardiac Pacemakers, Inc. Distributed neuromodulation system for treatment of cardiovascular disease
US20080109045A1 (en) * 2001-08-31 2008-05-08 Yossi Gross Selective nerve fiber stimulation for treating conditions
US7403819B1 (en) * 2002-06-12 2008-07-22 Pacesetter, Inc. Parasympathetic nerve stimulation for control of AV conduction
US20080234780A1 (en) * 2007-03-19 2008-09-25 Cardiac Pacemakers Selective nerve stimulation with optionally closed-loop capabilities
US7460906B2 (en) * 2003-12-24 2008-12-02 Cardiac Pacemakers, Inc. Baroreflex stimulation to treat acute myocardial infarction
US7509166B2 (en) * 2003-12-24 2009-03-24 Cardiac Pacemakers, Inc. Automatic baroreflex modulation responsive to adverse event
US7765000B2 (en) * 2005-05-10 2010-07-27 Cardiac Pacemakers, Inc. Neural stimulation system with pulmonary artery lead
US7840266B2 (en) * 2005-03-11 2010-11-23 Cardiac Pacemakers, Inc. Integrated lead for applying cardiac resynchronization therapy and neural stimulation therapy

Family Cites Families (214)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US366813A (en) * 1887-07-19 Gripping implement
US3411507A (en) 1964-04-01 1968-11-19 Medtronic Inc Method of gastrointestinal stimulation with electrical pulses
GB1493353A (en) * 1973-11-21 1977-11-30 Devices Implants Ltd Device for terminating tachycardia
US4026300A (en) * 1975-03-14 1977-05-31 Liberty Mutual Method and apparatus for interfacing to nerves
US4019518A (en) 1975-08-11 1977-04-26 Medtronic, Inc. Electrical stimulation system
US4161952A (en) 1977-11-01 1979-07-24 Mieczyslaw Mirowski Wound wire catheter cardioverting electrode
JPS54119792A (en) 1978-03-03 1979-09-17 Iriyou Kougaku Kenkiyuushiyo K Electric stimulation device for removing pain
US4392496A (en) 1981-03-13 1983-07-12 Medtronic, Inc. Neuromuscular stimulator
US4535785A (en) 1982-09-23 1985-08-20 Minnesota Mining And Manufacturing Co. Method and apparatus for determining the viability and survival of sensori-neutral elements within the inner ear
US4465079A (en) * 1982-10-13 1984-08-14 Medtronic, Inc. Biomedical lead with fibrosis-inducing anchoring strand
US4663102A (en) 1982-12-22 1987-05-05 Biosonics, Inc. Method of making a body member for use in a genital stimulator
US5025807A (en) 1983-09-14 1991-06-25 Jacob Zabara Neurocybernetic prosthesis
US4867164A (en) 1983-09-14 1989-09-19 Jacob Zabara Neurocybernetic prosthesis
US4702254A (en) 1983-09-14 1987-10-27 Jacob Zabara Neurocybernetic prosthesis
US4559948A (en) 1984-01-09 1985-12-24 Pain Suppression Labs Cerebral palsy treatment apparatus and methodology
US4585005A (en) 1984-04-06 1986-04-29 Regents Of University Of California Method and pacemaker for stimulating penile erection
US4739764A (en) 1984-05-18 1988-04-26 The Regents Of The University Of California Method for stimulating pelvic floor muscles for regulating pelvic viscera
US4573481A (en) 1984-06-25 1986-03-04 Huntington Institute Of Applied Research Implantable electrode array
US4632116A (en) 1984-06-29 1986-12-30 Rosen Joseph M Microelectronic axon processor
US4628942A (en) 1984-10-11 1986-12-16 Case Western Reserve University Asymmetric shielded two electrode cuff
US4608985A (en) 1984-10-11 1986-09-02 Case Western Reserve University Antidromic pulse generating wave form for collision blocking
US4602624A (en) 1984-10-11 1986-07-29 Case Western Reserve University Implantable cuff, method of manufacture, and method of installation
US4649936A (en) 1984-10-11 1987-03-17 Case Western Reserve University Asymmetric single electrode cuff for generation of unidirectionally propagating action potentials for collision blocking
US5235715A (en) * 1987-09-21 1993-08-17 Donzis Byron A Impact asborbing composites and their production
US4926865A (en) 1987-10-01 1990-05-22 Oman Paul S Microcomputer-based nerve and muscle stimulator
JPH024310A (en) * 1988-06-16 1990-01-09 Kowa Co Method and device for ophthalmological diagnosis
US5178161A (en) 1988-09-02 1993-01-12 The Board Of Trustees Of The Leland Stanford Junior University Microelectronic interface
JPH0692914B2 (en) * 1989-04-14 1994-11-16 株式会社日立製作所 Equipment / facility condition diagnosis system
US4962751A (en) 1989-05-30 1990-10-16 Welch Allyn, Inc. Hydraulic muscle pump
DE58909118D1 (en) 1989-06-15 1995-04-20 Pacesetter Ab Method and device for detecting a sequence of abnormal events in an electrical signal, in particular the depolarization signal of a heart.
US5069680A (en) 1989-12-06 1991-12-03 Medtronic, Inc. Muscle stimulator with variable duty cycle
US5042497A (en) 1990-01-30 1991-08-27 Cardiac Pacemakers, Inc. Arrhythmia prediction and prevention for implanted devices
US5143067A (en) * 1990-06-07 1992-09-01 Medtronic, Inc. Tool for implantable neural electrode
US5095905A (en) 1990-06-07 1992-03-17 Medtronic, Inc. Implantable neural electrode
US5170802A (en) 1991-01-07 1992-12-15 Medtronic, Inc. Implantable electrode for location within a blood vessel
US5224491A (en) 1991-01-07 1993-07-06 Medtronic, Inc. Implantable electrode for location within a blood vessel
US5188104A (en) 1991-02-01 1993-02-23 Cyberonics, Inc. Treatment of eating disorders by nerve stimulation
US5263480A (en) 1991-02-01 1993-11-23 Cyberonics, Inc. Treatment of eating disorders by nerve stimulation
US5437285A (en) 1991-02-20 1995-08-01 Georgetown University Method and apparatus for prediction of sudden cardiac death by simultaneous assessment of autonomic function and cardiac electrical stability
US5199430A (en) 1991-03-11 1993-04-06 Case Western Reserve University Micturitional assist device
US5199428A (en) 1991-03-22 1993-04-06 Medtronic, Inc. Implantable electrical nerve stimulator/pacemaker with ischemia for decreasing cardiac workload
US5215086A (en) 1991-05-03 1993-06-01 Cyberonics, Inc. Therapeutic treatment of migraine symptoms by stimulation
US5299569A (en) 1991-05-03 1994-04-05 Cyberonics, Inc. Treatment of neuropsychiatric disorders by nerve stimulation
US5335657A (en) 1991-05-03 1994-08-09 Cyberonics, Inc. Therapeutic treatment of sleep disorder by nerve stimulation
US5205285A (en) 1991-06-14 1993-04-27 Cyberonics, Inc. Voice suppression of vagal stimulation
US5215089A (en) * 1991-10-21 1993-06-01 Cyberonics, Inc. Electrode assembly for nerve stimulation
IT1259358B (en) 1992-03-26 1996-03-12 Sorin Biomedica Spa IMPLANTABLE DEVICE FOR DETECTION AND CONTROL OF THE SYMPATHIC-VAGAL TONE
US5330507A (en) 1992-04-24 1994-07-19 Medtronic, Inc. Implantable electrical vagal stimulation for prevention or interruption of life threatening arrhythmias
IT1260485B (en) 1992-05-29 1996-04-09 PROCEDURE AND DEVICE FOR THE TREATMENT OF THE OBESITY OF A PATIENT
US5243980A (en) 1992-06-30 1993-09-14 Medtronic, Inc. Method and apparatus for discrimination of ventricular and supraventricular tachycardia
JPH07504597A (en) 1992-06-30 1995-05-25 メドトロニック インコーポレーテッド Electrical medical stimulators and electrical stimulation methods
WO1994000190A1 (en) 1992-06-30 1994-01-06 Medtronic, Inc. Method and apparatus for treatment of heart disorders
US5292344A (en) 1992-07-10 1994-03-08 Douglas Donald D Percutaneously placed electrical gastrointestinal pacemaker stimulatory system, sensing system, and pH monitoring system, with optional delivery port
US5439938A (en) 1993-04-07 1995-08-08 The Johns Hopkins University Treatments for male sexual dysfunction
US5344438A (en) * 1993-04-16 1994-09-06 Medtronic, Inc. Cuff electrode
US6167304A (en) 1993-05-28 2000-12-26 Loos; Hendricus G. Pulse variability in electric field manipulation of nervous systems
US5597381A (en) * 1993-06-03 1997-01-28 Massachusetts Eye And Ear Infirmary Methods for epi-retinal implantation
US5411531A (en) 1993-09-23 1995-05-02 Medtronic, Inc. Method and apparatus for control of A-V interval
US5400784A (en) * 1993-10-15 1995-03-28 Case Western Reserve University Slowly penetrating inter-fascicular nerve cuff electrode and method of using
US5454840A (en) 1994-04-05 1995-10-03 Krakovsky; Alexander A. Potency package
US5505201A (en) * 1994-04-20 1996-04-09 Case Western Reserve University Implantable helical spiral cuff electrode
SE9401578D0 (en) 1994-05-06 1994-05-06 Siemens Elema Ab Medical device
US5522854A (en) 1994-05-19 1996-06-04 Duke University Method and apparatus for the prevention of arrhythmia by nerve stimulation
US5562718A (en) 1994-06-03 1996-10-08 Palermo; Francis X. Electronic neuromuscular stimulation device
EP0688577A1 (en) 1994-06-24 1995-12-27 Pacesetter AB Device for treating atrial tachyarrhythmia
DE4433111A1 (en) * 1994-09-16 1996-03-21 Fraunhofer Ges Forschung Cuff electrode
US5540734A (en) 1994-09-28 1996-07-30 Zabara; Jacob Cranial nerve stimulation treatments using neurocybernetic prosthesis
US6086525A (en) 1994-11-28 2000-07-11 Neotonus, Inc. Magnetic nerve stimulator for exciting peripheral nerves
US5571150A (en) 1994-12-19 1996-11-05 Cyberonics, Inc. Treatment of patients in coma by nerve stimulation
US5487756A (en) 1994-12-23 1996-01-30 Simon Fraser University Implantable cuff having improved closure
US5817030A (en) 1995-04-07 1998-10-06 University Of Miami Method and apparatus for controlling a device based on spatial discrimination of skeletal myopotentials
US5562592A (en) 1995-04-21 1996-10-08 Curiel; Yoram Hazardous or toxic waste material storage apparatus and associated method
US5540730A (en) 1995-06-06 1996-07-30 Cyberonics, Inc. Treatment of motility disorders by nerve stimulation
US5725561A (en) 1995-06-09 1998-03-10 Medtronic, Inc. Method and apparatus for variable rate cardiac stimulation
US5707400A (en) 1995-09-19 1998-01-13 Cyberonics, Inc. Treating refractory hypertension by nerve stimulation
US5700282A (en) 1995-10-13 1997-12-23 Zabara; Jacob Heart rhythm stabilization using a neurocybernetic prosthesis
US5755750A (en) 1995-11-13 1998-05-26 University Of Florida Method and apparatus for selectively inhibiting activity in nerve fibers
US6073048A (en) 1995-11-17 2000-06-06 Medtronic, Inc. Baroreflex modulation with carotid sinus nerve stimulation for the treatment of heart failure
US6035233A (en) 1995-12-11 2000-03-07 Intermedics Inc. Implantable medical device responsive to heart rate variability analysis
US6066163A (en) 1996-02-02 2000-05-23 John; Michael Sasha Adaptive brain stimulation method and system
US6463328B1 (en) 1996-02-02 2002-10-08 Michael Sasha John Adaptive brain stimulation method and system
US5913876A (en) 1996-02-20 1999-06-22 Cardiothoracic Systems, Inc. Method and apparatus for using vagus nerve stimulation in surgery
DE19609471A1 (en) 1996-03-01 1997-11-13 Biotronik Mess & Therapieg Electrode arrangement
US5716377A (en) 1996-04-25 1998-02-10 Medtronic, Inc. Method of treating movement disorders by brain stimulation
US6094598A (en) 1996-04-25 2000-07-25 Medtronics, Inc. Method of treating movement disorders by brain stimulation and drug infusion
US7269457B2 (en) 1996-04-30 2007-09-11 Medtronic, Inc. Method and system for vagal nerve stimulation with multi-site cardiac pacing
US5711316A (en) 1996-04-30 1998-01-27 Medtronic, Inc. Method of treating movement disorders by brain infusion
USRE38705E1 (en) 1996-04-30 2005-02-22 Medtronic, Inc. Method and device for electronically controlling the beating of a heart using venous electrical stimulation of nerve fibers
US6006134A (en) 1998-04-30 1999-12-21 Medtronic, Inc. Method and device for electronically controlling the beating of a heart using venous electrical stimulation of nerve fibers
US6449507B1 (en) 1996-04-30 2002-09-10 Medtronic, Inc. Method and system for nerve stimulation prior to and during a medical procedure
US6628987B1 (en) 2000-09-26 2003-09-30 Medtronic, Inc. Method and system for sensing cardiac contractions during vagal stimulation-induced cardiopalegia
US5690691A (en) 1996-05-08 1997-11-25 The Center For Innovative Technology Gastro-intestinal pacemaker having phased multi-point stimulation
WO1997045160A1 (en) 1996-05-31 1997-12-04 Southern Illinois University Methods of modulating aspects of brain neural plasticity by vagus nerve stimulation
US6058328A (en) 1996-08-06 2000-05-02 Pacesetter, Inc. Implantable stimulation device having means for operating in a preemptive pacing mode to prevent tachyarrhythmias and method thereof
JPH1096577A (en) 1996-09-25 1998-04-14 Matsushita Refrig Co Ltd Refrigerator
US5716385A (en) 1996-11-12 1998-02-10 University Of Virginia Crural diaphragm pacemaker and method for treating esophageal reflux disease
US6026326A (en) 1997-01-13 2000-02-15 Medtronic, Inc. Apparatus and method for treating chronic constipation
US6432947B1 (en) * 1997-02-19 2002-08-13 Berlex Laboratories, Inc. N-heterocyclic derivatives as NOS inhibitors
US5938596A (en) * 1997-03-17 1999-08-17 Medtronic, Inc. Medical electrical lead
USH1905H (en) 1997-03-21 2000-10-03 Medtronic, Inc. Mechanism for adjusting the exposed surface area and position of an electrode along a lead body
JP3884821B2 (en) * 1997-03-27 2007-02-21 株式会社日立製作所 Distributed information integration method and apparatus
US5861014A (en) 1997-04-30 1999-01-19 Medtronic, Inc. Method and apparatus for sensing a stimulating gastrointestinal tract on-demand
US5836994A (en) 1997-04-30 1998-11-17 Medtronic, Inc. Method and apparatus for electrical stimulation of the gastrointestinal tract
US6119516A (en) 1997-05-23 2000-09-19 Advantedge Systems, Inc. Biofeedback system for monitoring the motion of body joint
JP3699807B2 (en) * 1997-06-30 2005-09-28 株式会社東芝 Correlation extractor
US6146335A (en) 1997-07-01 2000-11-14 Neurometrix, Inc. Apparatus for methods for the assessment of neuromuscular function of the lower extremity
JP3963534B2 (en) 1997-08-02 2007-08-22 株式会社リコー Image forming apparatus
US5824027A (en) 1997-08-14 1998-10-20 Simon Fraser University Nerve cuff having one or more isolated chambers
US5938584A (en) 1997-11-14 1999-08-17 Cybernetic Medical Systems Corporation Cavernous nerve stimulation device
US6104955A (en) 1997-12-15 2000-08-15 Medtronic, Inc. Method and apparatus for electrical stimulation of the gastrointestinal tract
US6212434B1 (en) * 1998-07-22 2001-04-03 Cardiac Pacemakers, Inc. Single pass lead system
US6058331A (en) 1998-04-27 2000-05-02 Medtronic, Inc. Apparatus and method for treating peripheral vascular disease and organ ischemia by electrical stimulation with closed loop feedback control
US6319241B1 (en) 1998-04-30 2001-11-20 Medtronic, Inc. Techniques for positioning therapy delivery elements within a spinal cord or a brain
AU3973599A (en) 1998-05-08 1999-11-29 Genetronics, Inc. Electrically induced vessel vasodilation
KR20010025043A (en) * 1998-05-18 2001-03-26 바누치 유진 지. Stripping compositions for semiconductor substrate
WO1999065561A1 (en) 1998-06-19 1999-12-23 Cordis Webster, Inc. Method and apparatus for transvascular treatment of tachycardia and fibrillation
US6104960A (en) 1998-07-13 2000-08-15 Medtronic, Inc. System and method for providing medical electrical stimulation to a portion of the nervous system
US6092977A (en) * 1998-07-22 2000-07-25 Japan Tobacco Inc. Rod-shaped article supplying apparatus
US7599736B2 (en) 2001-07-23 2009-10-06 Dilorenzo Biomedical, Llc Method and apparatus for neuromodulation and physiologic modulation for the treatment of metabolic and neuropsychiatric disease
US6366813B1 (en) 1998-08-05 2002-04-02 Dilorenzo Daniel J. Apparatus and method for closed-loop intracranical stimulation for optimal control of neurological disease
US20020142419A1 (en) 1998-09-16 2002-10-03 Genentech, Inc. Secreted and transmembrane polypeptides and nucleic acids encoding the same
DE19847446B4 (en) * 1998-10-08 2010-04-22 Biotronik Gmbh & Co. Kg Nerve electrode assembly
US6668191B1 (en) 1998-10-26 2003-12-23 Birinder R. Boveja Apparatus and method for electrical stimulation adjunct (add-on) therapy of atrial fibrillation, inappropriate sinus tachycardia, and refractory hypertension with an external stimulator
US7062330B1 (en) 1998-10-26 2006-06-13 Boveja Birinder R Electrical stimulation adjunct (Add-ON) therapy for urinary incontinence and urological disorders using implanted lead stimulus-receiver and an external pulse generator
US6205359B1 (en) 1998-10-26 2001-03-20 Birinder Bob Boveja Apparatus and method for adjunct (add-on) therapy of partial complex epilepsy, generalized epilepsy and involuntary movement disorders utilizing an external stimulator
US6097984A (en) 1998-11-25 2000-08-01 Medtronic, Inc. System and method of stimulation for treating gastro-esophageal reflux disease
US6434424B1 (en) 1998-12-28 2002-08-13 Medtronic, Inc. Regularization of ventricular rate during atrial tachyarrhythmia
EP1023917B1 (en) 1999-01-28 2004-07-14 SORIN BIOMEDICA CRM S.r.l. A device for cardiac stimulation with electrotonic inhibition
US6161029A (en) 1999-03-08 2000-12-12 Medtronic, Inc. Apparatus and method for fixing electrodes in a blood vessel
US6304786B1 (en) * 1999-03-29 2001-10-16 Cardiac Pacemakers, Inc. Implantable lead with dissolvable coating for improved fixation and extraction
US6178349B1 (en) * 1999-04-15 2001-01-23 Medtronic, Inc. Drug delivery neural stimulation device for treatment of cardiovascular disorders
US6169924B1 (en) 1999-04-27 2001-01-02 T. Stuart Meloy Spinal cord stimulation
US6341236B1 (en) 1999-04-30 2002-01-22 Ivan Osorio Vagal nerve stimulation techniques for treatment of epileptic seizures
US6356784B1 (en) 1999-04-30 2002-03-12 Medtronic, Inc. Method of treating movement disorders by electrical stimulation and/or drug infusion of the pendunulopontine nucleus
US6516227B1 (en) 1999-07-27 2003-02-04 Advanced Bionics Corporation Rechargeable spinal cord stimulator system
US6456866B1 (en) * 1999-09-28 2002-09-24 Dustin Tyler Flat interface nerve electrode and a method for use
US6272377B1 (en) 1999-10-01 2001-08-07 Cardiac Pacemakers, Inc. Cardiac rhythm management system with arrhythmia prediction and prevention
US6473644B1 (en) 1999-10-13 2002-10-29 Cyberonics, Inc. Method to enhance cardiac capillary growth in heart failure patients
US6477406B1 (en) 1999-11-10 2002-11-05 Pacesetter, Inc. Extravascular hemodynamic acoustic sensor
US6611713B2 (en) 1999-11-30 2003-08-26 Patrick Schauerte Implantable device for diagnosing and distinguishing supraventricular and ventricular tachycardias
TW490598B (en) * 1999-11-30 2002-06-11 Asm Lithography Bv Lithographic projection apparatus and method of manufacturing a device using a lithographic projection apparatus
EP1106206B1 (en) 1999-11-30 2007-06-27 BIOTRONIK GmbH & Co. KG Apparatus for controlling the rate and the pumping action of the heart
US6885888B2 (en) 2000-01-20 2005-04-26 The Cleveland Clinic Foundation Electrical stimulation of the sympathetic nerve chain
US6720477B2 (en) * 2000-04-07 2004-04-13 Basf Plant Science Gmbh Signal transduction stress-related proteins and methods of use in plants
EP1289415A4 (en) * 2000-05-18 2008-12-03 Nuvasive Inc Tissue discrimination and applications in medical procedures
US6610713B2 (en) 2000-05-23 2003-08-26 North Shore - Long Island Jewish Research Institute Inhibition of inflammatory cytokine production by cholinergic agonists and vagus nerve stimulation
US6511500B1 (en) 2000-06-06 2003-01-28 Marc Mounir Rahme Use of autonomic nervous system neurotransmitters inhibition and atrial parasympathetic fibers ablation for the treatment of atrial arrhythmias and to preserve drug effects
US6405079B1 (en) 2000-09-22 2002-06-11 Mehdi M. Ansarinia Stimulation method for the dural venous sinuses and adjacent dura for treatment of medical conditions
WO2002026140A1 (en) 2000-09-26 2002-04-04 Medtronic, Inc. Medical method and system for directing blood flow
US6985774B2 (en) 2000-09-27 2006-01-10 Cvrx, Inc. Stimulus regimens for cardiovascular reflex control
US7623926B2 (en) 2000-09-27 2009-11-24 Cvrx, Inc. Stimulus regimens for cardiovascular reflex control
US6522926B1 (en) 2000-09-27 2003-02-18 Cvrx, Inc. Devices and methods for cardiovascular reflex control
US20040024439A1 (en) * 2000-10-11 2004-02-05 Riso Ronald R. Nerve cuff electrode
US8417334B2 (en) 2000-10-26 2013-04-09 Medtronic, Inc. Method and apparatus for electrically stimulating the nervous system to improve ventricular dysfunction, heart failure, and other cardiac conditions
US7519421B2 (en) 2001-01-16 2009-04-14 Kenergy, Inc. Vagal nerve stimulation using vascular implanted devices for treatment of atrial fibrillation
US6600954B2 (en) * 2001-01-25 2003-07-29 Biocontrol Medical Bcm Ltd. Method and apparatus for selective control of nerve fibers
US20060064140A1 (en) 2001-01-30 2006-03-23 Whitehurst Todd K Methods and systems for stimulating a trigeminal nerve to treat a psychiatric disorder
US6564096B2 (en) 2001-02-28 2003-05-13 Robert A. Mest Method and system for treatment of tachycardia and fibrillation
US6907293B2 (en) * 2001-03-30 2005-06-14 Case Western Reserve University Systems and methods for selectively stimulating components in, on, or near the pudendal nerve or its branches to achieve selective physiologic responses
WO2002085448A2 (en) 2001-04-20 2002-10-31 The Board Of Regents Of The University Of Oklahoma Cardiac neuromodulation and methods of using same
US6684105B2 (en) 2001-08-31 2004-01-27 Biocontrol Medical, Ltd. Treatment of disorders by unidirectional nerve stimulation
US6907295B2 (en) * 2001-08-31 2005-06-14 Biocontrol Medical Ltd. Electrode assembly for nerve control
US6892098B2 (en) * 2001-04-26 2005-05-10 Biocontrol Medical Ltd. Nerve stimulation for treating spasticity, tremor, muscle weakness, and other motor disorders
US6928320B2 (en) 2001-05-17 2005-08-09 Medtronic, Inc. Apparatus for blocking activation of tissue or conduction of action potentials while other tissue is being therapeutically activated
US20060167498A1 (en) 2001-07-23 2006-07-27 Dilorenzo Daniel J Method, apparatus, and surgical technique for autonomic neuromodulation for the treatment of disease
US6600956B2 (en) 2001-08-21 2003-07-29 Cyberonics, Inc. Circumneural electrode assembly
US6622041B2 (en) 2001-08-21 2003-09-16 Cyberonics, Inc. Treatment of congestive heart failure and autonomic cardiovascular drive disorders
US8565896B2 (en) * 2010-11-22 2013-10-22 Bio Control Medical (B.C.M.) Ltd. Electrode cuff with recesses
US7734355B2 (en) 2001-08-31 2010-06-08 Bio Control Medical (B.C.M.) Ltd. Treatment of disorders by unidirectional nerve stimulation
WO2003031941A2 (en) * 2001-10-12 2003-04-17 Matsushita Electric Industrial Co., Ltd. Detection and characterization of pyschoactives using parallel multi-site assays in neuronal tissue
AU2003217747A1 (en) 2002-02-26 2003-09-09 North Shore-Long Island Jewish Research Insitute Inhibition of inflammatory cytokine production by stimulation of brain muscarinic receptors
US7076299B2 (en) 2002-03-28 2006-07-11 Tran Thong Method and apparatus for preventing heart tachyarrhythmia
US7162303B2 (en) 2002-04-08 2007-01-09 Ardian, Inc. Renal nerve stimulation method and apparatus for treatment of patients
US7844346B2 (en) * 2002-05-23 2010-11-30 Biocontrol Medical Ltd. Electrode assembly for nerve control
US7561922B2 (en) * 2004-12-22 2009-07-14 Biocontrol Medical Ltd. Construction of electrode assembly for nerve control
EP1521615A4 (en) 2002-06-11 2010-11-03 Jeffrey A Matos System for cardiac resuscitation
US7277761B2 (en) 2002-06-12 2007-10-02 Pacesetter, Inc. Vagal stimulation for improving cardiac function in heart failure or CHF patients
US7113816B2 (en) * 2002-06-18 2006-09-26 Nippon Cable System Inc. Ultra-miniature in-vivo electrode used for measuring bioelectrical neural activity
US7292890B2 (en) 2002-06-20 2007-11-06 Advanced Bionics Corporation Vagus nerve stimulation via unidirectional propagation of action potentials
US20040015205A1 (en) * 2002-06-20 2004-01-22 Whitehurst Todd K. Implantable microstimulators with programmable multielectrode configuration and uses thereof
EP2462983A1 (en) 2002-06-28 2012-06-13 Boston Scientific Neuromodulation Corporation Microstimulator having self-contained power source and bi-directional telemetry system
US6893424B2 (en) * 2002-07-04 2005-05-17 Semyon Shchervinsky Drain catheters
US6866657B2 (en) * 2002-07-04 2005-03-15 Semyon Shchervinsky Drain catheters
US7280867B2 (en) 2002-10-15 2007-10-09 Medtronic, Inc. Clustering of recorded patient neurological activity to determine length of a neurological event
WO2004034879A2 (en) 2002-10-15 2004-04-29 Medtronic Inc. Screening techniques for management of a nervous system disorder
US20030229380A1 (en) 2002-10-31 2003-12-11 Adams John M. Heart failure therapy device and method
US7627384B2 (en) * 2004-11-15 2009-12-01 Bio Control Medical (B.C.M.) Ltd. Techniques for nerve stimulation
JP4252830B2 (en) 2003-03-24 2009-04-08 テルモ株式会社 Heart treatment equipment
CA2519771C (en) * 2003-04-02 2011-11-29 Neurostream Technologies Inc. Implantable nerve signal sensing and stimulation device for treating foot drop and other neurological disorders
US20060074450A1 (en) 2003-05-11 2006-04-06 Boveja Birinder R System for providing electrical pulses to nerve and/or muscle using an implanted stimulator
US7136700B1 (en) 2003-06-02 2006-11-14 Pacesetter, Inc. System and method for delivering post-atrial arrhythmia therapy
US7738952B2 (en) * 2003-06-09 2010-06-15 Palo Alto Investors Treatment of conditions through modulation of the autonomic nervous system
US7149574B2 (en) 2003-06-09 2006-12-12 Palo Alto Investors Treatment of conditions through electrical modulation of the autonomic nervous system
US7797058B2 (en) * 2004-08-04 2010-09-14 Ndi Medical, Llc Devices, systems, and methods employing a molded nerve cuff electrode
US20050131467A1 (en) 2003-11-02 2005-06-16 Boveja Birinder R. Method and apparatus for electrical stimulation therapy for at least one of atrial fibrillation, congestive heart failure, inappropriate sinus tachycardia, and refractory hypertension
US8055347B2 (en) * 2005-08-19 2011-11-08 Brainsgate Ltd. Stimulation for treating brain events and other conditions
US7333858B2 (en) 2004-03-31 2008-02-19 Cochlear Limited Pulse burst electrical stimulation of nerve or tissue fibers
US7225016B1 (en) * 2004-06-16 2007-05-29 Pacesetter, Inc. Implantable medical device with nerve signal sensing
US7483747B2 (en) 2004-07-15 2009-01-27 Northstar Neuroscience, Inc. Systems and methods for enhancing or affecting neural stimulation efficiency and/or efficacy
US7711432B2 (en) 2004-07-26 2010-05-04 Advanced Neuromodulation Systems, Inc. Stimulation system and method for treating a neurological disorder
US8788044B2 (en) 2005-01-21 2014-07-22 Michael Sasha John Systems and methods for tissue stimulation in medical treatment
WO2006102370A2 (en) 2005-03-22 2006-09-28 University Of Massachusetts Functional brain mri mapping as a marker in cns diseases and disorders
ATE496652T1 (en) * 2005-06-09 2011-02-15 Medtronic Inc IMPLANTABLE MEDICAL LINE
US7584004B2 (en) * 2005-06-13 2009-09-01 Cardiac Pacemakers, Inc. Vascularly stabilized peripheral nerve cuff assembly
US20080004673A1 (en) * 2006-04-03 2008-01-03 Cvrx, Inc. Implantable extravascular electrostimulation system having a resilient cuff
CA2653864A1 (en) * 2006-06-02 2007-12-13 Victhom Human Bionics Inc. Nerve cuff, method and apparatus for manufacturing same
EP2056927A4 (en) * 2006-08-14 2010-07-07 Med El Elektro Medizinische Ge Implantable medical cuff with electrode array
EP2059377A4 (en) * 2006-08-29 2011-04-13 Neurostream Technologies General Partnership Nerve cuff injection mold and method of making a nerve cuff
WO2008048471A2 (en) * 2006-10-13 2008-04-24 Apnex Medical, Inc. Obstructive sleep apnea treatment devices, systems and methods
US7996092B2 (en) * 2007-01-16 2011-08-09 Ndi Medical, Inc. Devices, systems, and methods employing a molded nerve cuff electrode
US8155757B1 (en) * 2007-07-26 2012-04-10 Advanced Neuromodulation Systems, Inc. Cuff electrode having tubular body with controlled closing force
US20100198103A1 (en) * 2007-10-09 2010-08-05 Imthera Medical, Inc. System and method for neural stimulation
WO2009135142A1 (en) * 2008-05-02 2009-11-05 Medtronic, Inc. Electrode lead system
US8509920B2 (en) * 2009-06-19 2013-08-13 Medtronic, Inc. Electrode arrangements for medical lead

Patent Citations (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5139020A (en) * 1991-03-08 1992-08-18 Telectronics Pacing Systems, Inc. Method and apparatus for controlling the hemodynamic state of a patient based on systolic time interval measurements detecting using doppler ultrasound techniques
US5203326A (en) * 1991-12-18 1993-04-20 Telectronics Pacing Systems, Inc. Antiarrhythmia pacer using antiarrhythmia pacing and autonomic nerve stimulation therapy
US5251621A (en) * 1991-12-18 1993-10-12 Telectronics Pacing Systems, Inc. Arrhythmia control pacer using skeletal muscle cardiac graft stimulation
US5628777A (en) * 1993-07-14 1997-05-13 Pacesetter, Inc. Implantable leads incorporating cardiac wall acceleration sensors and method of fabrication
US5602301A (en) * 1993-11-16 1997-02-11 Indiana University Foundation Non-human mammal having a graft and methods of delivering protein to myocardial tissue
US5658318A (en) * 1994-06-24 1997-08-19 Pacesetter Ab Method and apparatus for detecting a state of imminent cardiac arrhythmia in response to a nerve signal from the autonomic nerve system to the heart, and for administrating anti-arrhythmia therapy in response thereto
US5578061A (en) * 1994-06-24 1996-11-26 Pacesetter Ab Method and apparatus for cardiac therapy by stimulation of a physiological representative of the parasympathetic nervous system
US5749900A (en) * 1995-12-11 1998-05-12 Sulzer Intermedics Inc. Implantable medical device responsive to heart rate variability analysis
US5916239A (en) * 1996-03-29 1999-06-29 Purdue Research Foundation Method and apparatus using vagal stimulation for control of ventricular rate during atrial fibrillation
US6134471A (en) * 1997-10-23 2000-10-17 Biotronik Mess- Und Therapiegerate Gmbh & Co. Ingenieurburo Berlin Rate adaptive pacemaker
US6038476A (en) * 1998-06-12 2000-03-14 Pacesetter, Inc. System and method for analyzing the efficacy of cardiac stimulation therapy
US6134470A (en) * 1998-11-09 2000-10-17 Medtronic, Inc. Method and apparatus for treating a tachyarrhythmic patient
US6195584B1 (en) * 1999-04-30 2001-02-27 Medtronic, Inc. Method and apparatus for determining atrial lead dislocation
US20020029002A1 (en) * 1999-11-16 2002-03-07 Bardy Gust H. Automated collection and analysis patient care system for managing the pathophysiological outcomes of atrial fibrillation
US6650943B1 (en) * 2000-04-07 2003-11-18 Advanced Bionics Corporation Fully implantable neurostimulator for cavernous nerve stimulation as a therapy for erectile dysfunction and other sexual dysfunction
US20040193231A1 (en) * 2001-08-31 2004-09-30 Biocontrol Medical Ltd. Selective nerve fiber stimulation for treating heart conditions
US20080109045A1 (en) * 2001-08-31 2008-05-08 Yossi Gross Selective nerve fiber stimulation for treating conditions
US20050267542A1 (en) * 2001-08-31 2005-12-01 Biocontrol Medical Ltd. Techniques for applying, configuring, and coordinating nerve fiber stimulation
US20050197675A1 (en) * 2001-08-31 2005-09-08 Biocontrol Medical Ltd. Techniques for applying, calibrating, and controlling nerve fiber stimulation
US20030078623A1 (en) * 2001-10-22 2003-04-24 Weinberg Lisa P. Implantable lead and method for stimulating the vagus nerve
US7403819B1 (en) * 2002-06-12 2008-07-22 Pacesetter, Inc. Parasympathetic nerve stimulation for control of AV conduction
US7142917B2 (en) * 2002-12-04 2006-11-28 Terumo Kabushiki Kaisha Heart treatment equipment and method for preventing fatal arrhythmia
US20070203527A1 (en) * 2003-05-23 2007-08-30 Tamir Ben-David Parasympathetic stimulation for termination of non-sinus atrial tachycardia
US20040254612A1 (en) * 2003-06-13 2004-12-16 Ezra Omry Ben Vagal stimulation for anti-embolic therapy
US20050065553A1 (en) * 2003-06-13 2005-03-24 Omry Ben Ezra Applications of vagal stimulation
US7460906B2 (en) * 2003-12-24 2008-12-02 Cardiac Pacemakers, Inc. Baroreflex stimulation to treat acute myocardial infarction
US7509166B2 (en) * 2003-12-24 2009-03-24 Cardiac Pacemakers, Inc. Automatic baroreflex modulation responsive to adverse event
US7840266B2 (en) * 2005-03-11 2010-11-23 Cardiac Pacemakers, Inc. Integrated lead for applying cardiac resynchronization therapy and neural stimulation therapy
US20060241697A1 (en) * 2005-04-25 2006-10-26 Cardiac Pacemakers, Inc. System to provide neural markers for sensed neural activity
US7765000B2 (en) * 2005-05-10 2010-07-27 Cardiac Pacemakers, Inc. Neural stimulation system with pulmonary artery lead
US20070179558A1 (en) * 2006-01-30 2007-08-02 Gliner Bradford E Systems and methods for varying electromagnetic and adjunctive neural therapies
US20070239243A1 (en) * 2006-03-30 2007-10-11 Advanced Bionics Corporation Electrode contact configurations for cuff leads
US20080021504A1 (en) * 2006-07-24 2008-01-24 Mccabe Aaron Closed loop neural stimulation synchronized to cardiac cycles
US20080086185A1 (en) * 2006-10-06 2008-04-10 Cardiac Pacemakers, Inc. Distributed neuromodulation system for treatment of cardiovascular disease
US20080234780A1 (en) * 2007-03-19 2008-09-25 Cardiac Pacemakers Selective nerve stimulation with optionally closed-loop capabilities

Cited By (183)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8571653B2 (en) 2001-08-31 2013-10-29 Bio Control Medical (B.C.M.) Ltd. Nerve stimulation techniques
US9878150B2 (en) 2005-09-12 2018-01-30 The Cleveland Clinic Foundation Methods and systems for increasing heart contractility by neuromodulation
US11623080B2 (en) 2005-11-10 2023-04-11 Electrocore, Inc Vagal nerve stimulation for treating dopamine-related conditions
US10213601B2 (en) 2005-11-10 2019-02-26 Electrocore, Inc. Non-invasive vagus nerve stimulation devices and methods to treat or avert atrial fibrillation
US11297445B2 (en) 2005-11-10 2022-04-05 Electrocore, Inc. Methods and devices for treating primary headache
US11179560B2 (en) 2005-11-10 2021-11-23 Electrocore, Inc. Non-invasive vagus nerve stimulation devices and methods to treat or avert atrial fibrillation
US8972004B2 (en) 2005-11-10 2015-03-03 ElectroCore, LLC Magnetic stimulation devices and methods of therapy
US11351363B2 (en) 2005-11-10 2022-06-07 Electrocore, Inc. Nerve stimulation devices and methods for treating cardiac arrhythmias
US10441780B2 (en) 2005-11-10 2019-10-15 Electrocore, Inc. Systems and methods for vagal nerve stimulation
US9014823B2 (en) 2005-11-10 2015-04-21 ElectroCore, LLC Methods and devices for treating primary headache
US9821164B2 (en) 2005-11-10 2017-11-21 ElectroCore, LLC Electrical treatment of bronchial constriction
US9043001B2 (en) 2005-11-10 2015-05-26 ElectroCore, LLC Methods and devices for treating primary headache
US11654277B2 (en) 2005-11-10 2023-05-23 Electrocore, Inc. Nerve stimulation devices and methods
US10537728B2 (en) 2005-11-10 2020-01-21 ElectroCore, LLC Vagal nerve stimulation to avert or treat stroke or transient ischemic attack
US9020598B2 (en) 2005-11-10 2015-04-28 ElectroCore, LLC Methods and devices for treating primary headache
US11623079B2 (en) 2005-11-10 2023-04-11 Electrocore, Inc Vagal nerve stimulation devices and methods for treating medical conditions
US9233258B2 (en) 2005-11-10 2016-01-12 ElectroCore, LLC Magnetic stimulation devices and methods of therapy
US9233246B2 (en) 2005-11-10 2016-01-12 ElectroCore, LLC Methods and devices for treating primary headache
US10384061B2 (en) 2005-11-10 2019-08-20 Electrocore, Inc. Methods and devices for treating primary headache
US9283390B2 (en) 2006-02-10 2016-03-15 ElectroCore, LLC Methods and apparatus for treating anaphylaxis using electrical modulation
US9339653B2 (en) 2006-02-10 2016-05-17 ElectroCore, LLC Electrical stimulation treatment of hypotension
US8948873B2 (en) 2006-02-10 2015-02-03 ElectroCore, LLC Electrical stimulation treatment of hypotension
US10905873B2 (en) 2006-12-06 2021-02-02 The Cleveland Clinic Foundation Methods and systems for treating acute heart failure by neuromodulation
US9370654B2 (en) 2009-01-27 2016-06-21 Medtronic, Inc. High frequency stimulation to block laryngeal stimulation during vagal nerve stimulation
US11197998B2 (en) 2009-03-20 2021-12-14 Electrocore, Inc. Medical self-treatment using non-invasive vagus nerve stimulation
US11534600B2 (en) 2009-03-20 2022-12-27 Electrocore, Inc. Non-invasive nerve stimulation to treat or prevent autism spectrum disorders and other disorders of psychological development
US20130131746A1 (en) * 2009-03-20 2013-05-23 ElectroCore, LLC. Non-invasive vagus nerve stimulation devices and methods to treat or avert atrial fibrillation
US10376696B2 (en) 2009-03-20 2019-08-13 Electrocore, Inc. Medical self-treatment using non-invasive vagus nerve stimulation
US9415219B2 (en) 2009-03-20 2016-08-16 ElectroCore, LLC Non-invasive vagal nerve stimulation to treat disorders
US10507325B2 (en) 2009-03-20 2019-12-17 Electrocore, Inc. Devices and methods for non-invasive capacitive electrical stimulation and their use for vagus nerve stimulation on the neck of a patient
US10335593B2 (en) 2009-03-20 2019-07-02 Electrocore, Inc. Devices and methods for monitoring non-invasive vagus nerve stimulation
US10512769B2 (en) 2009-03-20 2019-12-24 Electrocore, Inc. Non-invasive magnetic or electrical nerve stimulation to treat or prevent autism spectrum disorders and other disorders of psychological development
US9623240B2 (en) 2009-03-20 2017-04-18 ElectroCore, LLC Non-invasive vagal nerve stimulation to treat disorders
US11701515B2 (en) 2009-03-20 2023-07-18 Electrocore, Inc Non-invasive nerve stimulation with mobile device
US10286212B2 (en) 2009-03-20 2019-05-14 Electrocore, Inc. Nerve stimulation methods for averting imminent onset or episode of a disease
US9254383B2 (en) 2009-03-20 2016-02-09 ElectroCore, LLC Devices and methods for monitoring non-invasive vagus nerve stimulation
US11389103B2 (en) 2009-03-20 2022-07-19 Electrocore, Inc Devices and methods for monitoring non-invasive vagus nerve stimulation
US9248286B2 (en) 2009-03-20 2016-02-02 ElectroCore, LLC Medical self-treatment using non-invasive vagus nerve stimulation
US10265523B2 (en) 2009-03-20 2019-04-23 Electrocore, Inc. Non-invasive treatment of neurodegenerative diseases
US10252074B2 (en) 2009-03-20 2019-04-09 ElectroCore, LLC Nerve stimulation methods for averting imminent onset or episode of a disease
US10232174B2 (en) 2009-03-20 2019-03-19 Electrocore, Inc. Non-invasive electrical and magnetic nerve stimulators used to treat overactive bladder and urinary incontinence
US10220207B2 (en) 2009-03-20 2019-03-05 Electrocore, Inc. Nerve stimulation methods for averting imminent onset or episode of a disease
US9126050B2 (en) * 2009-03-20 2015-09-08 ElectroCore, LLC Non-invasive vagus nerve stimulation devices and methods to treat or avert atrial fibrillation
US10207106B2 (en) 2009-03-20 2019-02-19 ElectroCore, LLC Non-invasive magnetic or electrical nerve stimulation to treat gastroparesis, functional dyspepsia, and other functional gastrointestinal disorders
US8983629B2 (en) 2009-03-20 2015-03-17 ElectroCore, LLC Non-invasive vagal nerve stimulation to treat disorders
US8983628B2 (en) 2009-03-20 2015-03-17 ElectroCore, LLC Non-invasive vagal nerve stimulation to treat disorders
US11298535B2 (en) 2009-03-20 2022-04-12 Electrocore, Inc Non-invasive vagus nerve stimulation
US11273307B2 (en) 2009-10-20 2022-03-15 Nyxoah SA Method and device for treating sleep apnea
US11857791B2 (en) 2009-10-20 2024-01-02 Nyxoah SA Arced implant unit for modulation of nerves
US10898717B2 (en) 2009-10-20 2021-01-26 Nyxoah SA Device and method for snoring detection and control
US9950166B2 (en) 2009-10-20 2018-04-24 Nyxoah SA Acred implant unit for modulation of nerves
US9849289B2 (en) 2009-10-20 2017-12-26 Nyxoah SA Device and method for snoring detection and control
US10751537B2 (en) 2009-10-20 2020-08-25 Nyxoah SA Arced implant unit for modulation of nerves
US9943686B2 (en) 2009-10-20 2018-04-17 Nyxoah SA Method and device for treating sleep apnea based on tongue movement
US10716940B2 (en) 2009-10-20 2020-07-21 Nyxoah SA Implant unit for modulation of small diameter nerves
US11147961B2 (en) 2010-08-19 2021-10-19 Electrocore, Inc. Devices and methods for nerve stimulation
US11400288B2 (en) 2010-08-19 2022-08-02 Electrocore, Inc Devices and methods for electrical stimulation and their use for vagus nerve stimulation on the neck of a patient
US11865329B2 (en) 2010-08-19 2024-01-09 Electrocore, Inc. Vagal nerve stimulation for treating post-traumatic stress disorder
US11324943B2 (en) 2010-08-19 2022-05-10 Electrocore, Inc Devices and methods for vagal nerve stimulation
US10639490B2 (en) 2010-08-19 2020-05-05 Electrocore, Inc. Non-invasive treatment of bronchial construction
US10016615B2 (en) 2010-08-19 2018-07-10 ElectroCore, LLC Non-invasive treatment of bronchial constriction
US11389646B2 (en) 2010-08-19 2022-07-19 Electrocore, Inc Systems and methods for treating headache with vagal nerve stimulation
US11458325B2 (en) 2010-08-19 2022-10-04 Electrocore, Inc Non-invasive nerve stimulation to patients
US11779756B2 (en) 2010-08-19 2023-10-10 Electrocore, Inc. Systems and methods for vagal nerve stimulation
US11141582B2 (en) 2010-08-19 2021-10-12 Electrocore, Inc Devices and methods for nerve stimulation
US11623078B2 (en) 2010-08-19 2023-04-11 Electrocore, Inc Devices and methods for non-invasive vagal nerve stimulation
US9327118B2 (en) 2010-08-19 2016-05-03 ElectroCore, LLC Non-invasive treatment of bronchial constriction
US11191953B2 (en) 2010-08-19 2021-12-07 Electrocore, Inc. Systems and methods for vagal nerve stimulation
US9333347B2 (en) 2010-08-19 2016-05-10 ElectroCore, LLC Devices and methods for non-invasive electrical stimulation and their use for vagal nerve stimulation on the neck of a patient
US9555260B2 (en) 2010-08-19 2017-01-31 ElectroCore, LLC Non-invasive treatment of bronchial constriction
US11123545B2 (en) 2010-08-19 2021-09-21 Electrocore, Inc. Devices and methods for nerve stimulation
US10363415B2 (en) 2010-08-19 2019-07-30 Electrocore, Inc. Devices and methods for non-invasive electrical stimulation and their use for Vagal nerve stimulation
US8565896B2 (en) 2010-11-22 2013-10-22 Bio Control Medical (B.C.M.) Ltd. Electrode cuff with recesses
US11432760B2 (en) 2011-01-12 2022-09-06 Electrocore, Inc. Devices and methods for remote therapy and patient monitoring
US11850056B2 (en) 2011-01-12 2023-12-26 Electrocore, Inc. Devices and methods for remote therapy and patient monitoring
US9399134B2 (en) 2011-03-10 2016-07-26 ElectroCore, LLC Non-invasive vagal nerve stimulation to treat disorders
US11458297B2 (en) 2011-03-10 2022-10-04 Electrocore, Inc Electrical and magnetic stimulators used to treat migraine/sinus headache, rhinitis, sinusitis, rhinosinusitis, and comorbid disorders
US9067054B2 (en) 2011-03-10 2015-06-30 ElectroCore, LLC Devices and methods for non-invasive capacitive electrical stimulation and their use for vagus nerve stimulation on the neck of a patient
US9717904B2 (en) 2011-03-10 2017-08-01 ElectroCore, LLC Devices and methods for non-invasive capacitive electrical stimulation and their use for vagus nerve stimulation on the neck of a patient
US10384059B2 (en) 2011-03-10 2019-08-20 Electrocore, Inc. Non-invasive vagal nerve stimulation to treat disorders
US11517742B2 (en) 2011-03-10 2022-12-06 Electrocore, Inc Non-invasive vagal nerve stimulation to treat disorders
US11439818B2 (en) 2011-03-10 2022-09-13 Electrocore, Inc. Electrical nerve stimulation to treat gastroparesis, functional dyspepsia, and other functional gastrointestinal disorders
US11511109B2 (en) 2011-03-10 2022-11-29 Electrocore, Inc. Non-invasive magnetic or electrical nerve stimulation to treat gastroparesis, functional dyspepsia, and other functional gastrointestinal disorders
US10173048B2 (en) 2011-03-10 2019-01-08 Electrocore, Inc. Electrical and magnetic stimulators used to treat migraine/sinus headache, rhinitis, sinusitis, rhinosinusitis, and comorbid disorders
US10279163B2 (en) 2011-03-10 2019-05-07 Electrocore, Inc. Electrical and magnetic stimulators used to treat migraine/sinus headache, rhinitis, sinusitis, rhinosinusitis, and comorbid disorders
US11554265B2 (en) 2011-05-13 2023-01-17 Saluda Medical Pty Ltd Method and apparatus for application of a neural stimulus
US11491334B2 (en) 2011-05-13 2022-11-08 Saluda Medical Pty Ltd Method and apparatus for application of a neural stimulus
US11426587B2 (en) 2011-05-13 2022-08-30 Saluda Medical Pty Ltd Method and apparatus for application of a neural stimulus
US11445958B2 (en) 2011-05-13 2022-09-20 Saluda Medical Pty Ltd Method and apparatus for estimating neural recruitment
US11420064B2 (en) 2011-05-13 2022-08-23 Saluda Medical Pty Ltd Method and apparatus for application of a neural stimulus
US11464979B2 (en) 2011-05-13 2022-10-11 Saluda Medical Pty Ltd Method and apparatus for application of a neural stimulus
US11324427B2 (en) 2011-05-13 2022-05-10 Saluda Medical Pty Ltd Method and apparatus for measurement of neural response
US11413460B2 (en) 2011-05-13 2022-08-16 Saluda Medical Pty Ltd Method and apparatus for application of a neural stimulus
US11819332B2 (en) 2011-05-13 2023-11-21 Saluda Medical Pty Ltd Method and apparatus for measurement of neural response
US11439828B2 (en) 2011-05-13 2022-09-13 Saluda Medical Pty Ltd Method and apparatus for application of a neural stimulus
WO2012155186A1 (en) * 2011-05-13 2012-11-22 National Ict Australia Ltd Method and apparatus for controlling a neural stimulus - h
US10286211B2 (en) 2011-08-31 2019-05-14 Electrocore, Inc. Systems and methods for vagal nerve stimulation
US9566426B2 (en) 2011-08-31 2017-02-14 ElectroCore, LLC Systems and methods for vagal nerve stimulation
US10653888B2 (en) 2012-01-26 2020-05-19 Bluewind Medical Ltd Wireless neurostimulators
US11648410B2 (en) 2012-01-26 2023-05-16 Bluewind Medical Ltd. Wireless neurostimulators
US10052097B2 (en) 2012-07-26 2018-08-21 Nyxoah SA Implant unit delivery tool
US11253712B2 (en) 2012-07-26 2022-02-22 Nyxoah SA Sleep disordered breathing treatment apparatus
US9855032B2 (en) 2012-07-26 2018-01-02 Nyxoah SA Transcutaneous power conveyance device
US11730469B2 (en) 2012-07-26 2023-08-22 Nyxoah SA Implant unit delivery tool
US10918376B2 (en) 2012-07-26 2021-02-16 Nyxoah SA Therapy protocol activation triggered based on initial coupling
US10814137B2 (en) 2012-07-26 2020-10-27 Nyxoah SA Transcutaneous power conveyance device
US10716560B2 (en) 2012-07-26 2020-07-21 Nyxoah SA Implant unit delivery tool
US11389098B2 (en) 2012-11-06 2022-07-19 Saluda Medical Pty Ltd Method and system for controlling electrical conditions of tissue
US9861812B2 (en) 2012-12-06 2018-01-09 Blue Wind Medical Ltd. Delivery of implantable neurostimulators
US10238863B2 (en) 2012-12-06 2019-03-26 Bluewind Medical Ltd. Delivery of implantable neurostimulators
US11464966B2 (en) 2012-12-06 2022-10-11 Bluewind Medical Ltd. Delivery of implantable neurostimulators
US11278719B2 (en) 2012-12-06 2022-03-22 Bluewind Medical Ltd. Delivery of implantable neurostimulators
US9375571B2 (en) 2013-01-15 2016-06-28 ElectroCore, LLC Mobile phone using non-invasive nerve stimulation
US11260225B2 (en) 2013-01-15 2022-03-01 Electrocore, Inc Nerve stimulator for use with a mobile device
US11406825B2 (en) 2013-01-15 2022-08-09 Electrocore, Inc Mobile phone for treating a patient with dementia
US11065444B2 (en) 2013-01-15 2021-07-20 Electrocore, Inc. Mobile phone for stimulating the trigeminal nerve to treat disorders
US11766562B2 (en) 2013-01-15 2023-09-26 Electrocore, Inc. Nerve stimulator for use with a mobile device
US11679258B2 (en) 2013-01-15 2023-06-20 Electrocore, Inc. Stimulator for use with a mobile device
US11229790B2 (en) 2013-01-15 2022-01-25 Electrocore, Inc. Mobile phone for treating a patient with seizures
US11839764B2 (en) 2013-01-15 2023-12-12 Electrocore, Inc. Systems and methods for treating a medical condition with an electrical stimulation treatment regimen
US10376695B2 (en) 2013-01-15 2019-08-13 Electrocore, Inc. Mobile phone for stimulating the trigeminal nerve to treat disorders
US10293160B2 (en) 2013-01-15 2019-05-21 Electrocore, Inc. Mobile phone for treating a patient with dementia
US11020591B2 (en) 2013-01-15 2021-06-01 Electrocore, Inc. Nerve stimulator for use with a mobile device
US11097102B2 (en) 2013-01-15 2021-08-24 Electrocore, Inc. Mobile phone using non-invasive nerve stimulation
US11446491B2 (en) 2013-01-15 2022-09-20 Electrocore, Inc Stimulator for use with a mobile device
US10232177B2 (en) 2013-01-15 2019-03-19 ElectroCore, LLC Mobile phone using non-invasive nerve stimulation
US10874857B2 (en) 2013-01-15 2020-12-29 Electrocore, Inc Mobile phone using non-invasive nerve stimulation
US9174049B2 (en) 2013-01-27 2015-11-03 ElectroCore, LLC Systems and methods for electrical stimulation of sphenopalatine ganglion and other branches of cranial nerves
US20140296940A1 (en) * 2013-03-29 2014-10-02 Rainbow Medical Ltd. Independently-controlled bidirectional nerve stimulation
US9370660B2 (en) * 2013-03-29 2016-06-21 Rainbow Medical Ltd. Independently-controlled bidirectional nerve stimulation
US10350411B2 (en) 2013-04-28 2019-07-16 Electrocore, Inc. Devices and methods for treating medical disorders with evoked potentials and vagus nerve stimulation
US11027127B2 (en) 2013-04-28 2021-06-08 Electrocore, Inc Devices and methods for treating medical disorders with evoked potentials and vagus nerve stimulation
US11298549B2 (en) 2013-06-17 2022-04-12 Nyxoah SA Control housing for disposable patch
US11642534B2 (en) 2013-06-17 2023-05-09 Nyxoah SA Programmable external control unit
US10512782B2 (en) 2013-06-17 2019-12-24 Nyxoah SA Remote monitoring and updating of a medical device control unit
US9643022B2 (en) 2013-06-17 2017-05-09 Nyxoah SA Flexible control housing for disposable patch
US9656074B2 (en) 2013-11-04 2017-05-23 ElectroCore, LLC Nerve stimulator system
US9205258B2 (en) 2013-11-04 2015-12-08 ElectroCore, LLC Nerve stimulator system
US10363419B2 (en) 2013-11-04 2019-07-30 Electrocore, Inc. Nerve stimulator system
US11172864B2 (en) 2013-11-15 2021-11-16 Closed Loop Medical Pty Ltd Monitoring brain neural potentials
US11337658B2 (en) 2013-11-22 2022-05-24 Saluda Medical Pty Ltd Method and device for detecting a neural response in a neural measurement
US11890113B2 (en) 2013-11-22 2024-02-06 Saluda Medical Pty Ltd Method and device for detecting a neural response in a neural measurement
US11457849B2 (en) 2014-05-05 2022-10-04 Saluda Medical Pty Ltd Neural measurement
US10576273B2 (en) 2014-05-22 2020-03-03 CARDIONOMIC, Inc. Catheter and catheter system for electrical neuromodulation
US10722716B2 (en) 2014-09-08 2020-07-28 Cardionomia Inc. Methods for electrical neuromodulation of the heart
US10894160B2 (en) 2014-09-08 2021-01-19 CARDIONOMIC, Inc. Catheter and electrode systems for electrical neuromodulation
US11344729B1 (en) 2014-12-11 2022-05-31 Saluda Medical Pty Ltd Method and device for feedback control of neural stimulation
US11219766B2 (en) 2014-12-11 2022-01-11 Saluda Medical Pty Ltd Method and device for feedback control of neural stimulation
US11464980B2 (en) 2014-12-11 2022-10-11 Saluda Medical Pty Ltd Method and device for feedback control of neural stimulation
US10493278B2 (en) 2015-01-05 2019-12-03 CARDIONOMIC, Inc. Cardiac modulation facilitation methods and systems
US9597521B2 (en) 2015-01-21 2017-03-21 Bluewind Medical Ltd. Transmitting coils for neurostimulation
US9764146B2 (en) 2015-01-21 2017-09-19 Bluewind Medical Ltd. Extracorporeal implant controllers
US10004896B2 (en) 2015-01-21 2018-06-26 Bluewind Medical Ltd. Anchors and implant devices
US11110270B2 (en) 2015-05-31 2021-09-07 Closed Loop Medical Pty Ltd Brain neurostimulator electrode fitting
US10369366B2 (en) 2015-06-10 2019-08-06 Bluewind Medical Ltd. Implantable electrostimulator for improving blood flow
US9782589B2 (en) 2015-06-10 2017-10-10 Bluewind Medical Ltd. Implantable electrostimulator for improving blood flow
US10105540B2 (en) 2015-11-09 2018-10-23 Bluewind Medical Ltd. Optimization of application of current
US11612747B2 (en) 2015-11-09 2023-03-28 Bluewind Medical Ltd. Optimization of application of current
US11116975B2 (en) 2015-11-09 2021-09-14 Bluewind Medical Ltd. Optimization of application of current
US10449374B2 (en) 2015-11-12 2019-10-22 Bluewind Medical Ltd. Inhibition of implant migration
US9713707B2 (en) 2015-11-12 2017-07-25 Bluewind Medical Ltd. Inhibition of implant migration
US11806159B2 (en) 2016-03-09 2023-11-07 CARDIONOMIC, Inc. Differential on and off durations for neurostimulation devices and methods
US10172549B2 (en) 2016-03-09 2019-01-08 CARDIONOMIC, Inc. Methods of facilitating positioning of electrodes
US10952665B2 (en) 2016-03-09 2021-03-23 CARDIONOMIC, Inc. Methods of positioning neurostimulation devices
US11229398B2 (en) 2016-03-09 2022-01-25 CARDIONOMIC, Inc. Electrode assemblies for neurostimulation treatment
US10448884B2 (en) 2016-03-09 2019-10-22 CARDIONOMIC, Inc. Methods of reducing duty cycle during neurostimulation treatment
US10188343B2 (en) 2016-03-09 2019-01-29 CARDIONOMIC, Inc. Methods of monitoring effects of neurostimulation
IL262009A (en) * 2016-04-01 2018-10-31 Cyberonics Inc Vagus nerve stimulation patient selection
JP2022109942A (en) * 2016-04-01 2022-07-28 リヴァノヴァ ユーエスエイ インコーポレイテッド Vagus nerve stimulation patient selection
WO2017173331A1 (en) * 2016-04-01 2017-10-05 Cyberonics, Inc. Vagus nerve stimulation patient selection
US11612749B2 (en) 2016-04-01 2023-03-28 Livanova Usa, Inc. Vagus nerve stimulation patient selection
US11191966B2 (en) 2016-04-05 2021-12-07 Saluda Medical Pty Ltd Feedback control of neuromodulation
US11179091B2 (en) 2016-06-24 2021-11-23 Saluda Medical Pty Ltd Neural stimulation for reduced artefact
US11826156B2 (en) 2016-06-24 2023-11-28 Saluda Medical Pty Ltd Neural stimulation for reduced artefact
US11439833B2 (en) 2016-11-23 2022-09-13 Bluewind Medical Ltd. Implant-delivery tool
US10744331B2 (en) 2016-11-23 2020-08-18 Bluewind Medical Ltd. Implant and delivery tool therefor
US10124178B2 (en) 2016-11-23 2018-11-13 Bluewind Medical Ltd. Implant and delivery tool therefor
US11213685B2 (en) 2017-06-13 2022-01-04 Bluewind Medical Ltd. Antenna configuration
US11559687B2 (en) 2017-09-13 2023-01-24 CARDIONOMIC, Inc. Methods for detecting catheter movement
US11077298B2 (en) 2018-08-13 2021-08-03 CARDIONOMIC, Inc. Partially woven expandable members
US11648395B2 (en) 2018-08-13 2023-05-16 CARDIONOMIC, Inc. Electrode assemblies for neuromodulation
US11607176B2 (en) 2019-05-06 2023-03-21 CARDIONOMIC, Inc. Systems and methods for denoising physiological signals during electrical neuromodulation
US11400299B1 (en) 2021-09-14 2022-08-02 Rainbow Medical Ltd. Flexible antenna for stimulator

Also Published As

Publication number Publication date
WO2004103455A3 (en) 2005-01-06
US20040193231A1 (en) 2004-09-30
US20050187586A1 (en) 2005-08-25
WO2004103455A2 (en) 2004-12-02
US20080125827A1 (en) 2008-05-29
US20050197675A1 (en) 2005-09-08
US7634317B2 (en) 2009-12-15
US7778711B2 (en) 2010-08-17
US8386056B2 (en) 2013-02-26
EP1638645A4 (en) 2008-04-09
EP1638645A2 (en) 2006-03-29

Similar Documents

Publication Publication Date Title
US7778711B2 (en) Reduction of heart rate variability by parasympathetic stimulation
US7805203B2 (en) Method for surgically implanting an electrode device
US7904151B2 (en) Parasympathetic stimulation for treating ventricular arrhythmia
US8224444B2 (en) Intermittent electrical stimulation
US7885711B2 (en) Vagal stimulation for anti-embolic therapy
US7778703B2 (en) Selective nerve fiber stimulation for treating heart conditions
US8005545B2 (en) Parasympathetic stimulation for prevention and treatment of atrial fibrillation
US8204591B2 (en) Techniques for prevention of atrial fibrillation
US7904176B2 (en) Techniques for reducing pain associated with nerve stimulation
US7778702B2 (en) Combined parasympathetic stimulation and drug therapy
US7908008B2 (en) Treatment for disorders by parasympathetic stimulation
US20080091245A1 (en) Combined parasympathetic stimulation and cardiac pacing
IL172140A (en) Selective nerve fiber stimulation for heart treatment

Legal Events

Date Code Title Description
AS Assignment

Owner name: BIO CONTROL MEDICAL (B.C.M.) LTD., ISRAEL

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:BIOCONTROL MEDICAL, LTD.;REEL/FRAME:020783/0199

Effective date: 20080114

Owner name: BIO CONTROL MEDICAL (B.C.M.) LTD.,ISRAEL

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:BIOCONTROL MEDICAL, LTD.;REEL/FRAME:020783/0199

Effective date: 20080114

AS Assignment

Owner name: BIOCONTROL MEDICAL LTD.,ISRAEL

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:COHEN, EHUD;AYAL, SHAI;BEN-DAVID, TAMIR;AND OTHERS;SIGNING DATES FROM 20100223 TO 20100224;REEL/FRAME:024019/0125

AS Assignment

Owner name: MEDTRONIC, INC.,MINNESOTA

Free format text: SECURITY AGREEMENT;ASSIGNOR:BIO CONTROL MEDICAL (B.C.M.) LTD;REEL/FRAME:024411/0365

Effective date: 20100506

Owner name: MEDTRONIC, INC., MINNESOTA

Free format text: SECURITY AGREEMENT;ASSIGNOR:BIO CONTROL MEDICAL (B.C.M.) LTD;REEL/FRAME:024411/0365

Effective date: 20100506

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION

AS Assignment

Owner name: MEDTRONIC, INC., MINNESOTA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:BIOCONTROL ,EDICAL (B.C.M.) LTD;REEL/FRAME:046574/0208

Effective date: 20180628