Selective nerve fiber stimulation for heart treatment

SELECTIVE NERVE FIBER STIMULATION FOR TREATING HEART CONDITIONS

CROSS-REFERENCES TO RELATED APPLICATIONS

The'present patent application claims priority from: (1) US Patent Application 10/719,659, filed November 20, 2003, entitled, Selective nerve fiber .stimulation for treating heart conditions, and (2) PCT Patent Application PCT / IL03 / 00431, filed May 23,2003, entitled, Selective nerve fiber stimulation for treating heart conditions..

US Patent Application 10/719,659 is a continuation-in-part of PCT Patent Application PCT / IL03 / 00431, which:

(a) is a continuation-in-part of US Patent Application 10/205,475, filed July 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 January 23, 2002, entitled, Treatment of disorders by unidirectional nerve stimulation, which is a continuation-in-part of US Patent Application 09/944,913 (now US Patent 6,684,105), filed August 31, 2001, entitled, Treatment of disorders by unidirectional nerve stimulation, and (b) claims the benefit of US 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 INV ENTION

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 heartrate-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, July₅.1968, 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 2 *׳ 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 5 the heart rate by vagal tuning, coupled with increased contractility ofthe heart induced the inotropic effect of Isuprel, appeared.to increase the efficiency of cardiac performance'' (p.79). . , _; .

US Patent 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 10 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 2QQ3/0Q40774 to. Terry et al., which is 15 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 ; 1 ' /׳ ־ ' ו U . 1. ־־־ '. > ^; . י l ־ 1. 1 > :: ; י * ''-־* ׳!

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 20 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 varythe 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,

5 the neurostimulator rate increases the patient's heart rate above the normal resting rate.

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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

0 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:Hl 102Hl 110 (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 MN et al., in Parasympathetic Control of the Heart, Nervous Control of Vascular Function, Randall WC ed., Oxford University Press (1984)

..!. . -.1 .. .. . ' ,1^; . _; . .

Levy MN et al. ed., Vagal Control of the Heart: Experimental Basis and Clinical • «/-<.. . . - ’ ' I . . ,

Implications (The Bakken Research Center Series Volume 7), Future Publishing Company, Inc., Armonk, NY (1993)

Randall WC ed., Neural Regulation of the Heart, Oxford University Press (1977), particularly pages 100 - 106.

Armour JA et al. eds., Neurocardiology. Oxford University Press (1994)

Perez MG et al., Effect of stimulating non-myelinated vagal axon on atrioventricular conduction and left ventricular function in anaesthetized rabbits, Auton Neurosco 86 (2001)

Jones, JFX 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 DW et al., Effects of ouabain and vagal stimulation on heart rate in the dog, Cardiovasc. Res., 18(2):75-9 (1984)

Martin PJ et al., Phasic effects of repetitive vagal stimulation on atrial contraction, Circ. Res. 52(6):657-63 (1983)

Wallick DW 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 LE et .al., ACC/AHA/ESC Practice ׳Guidelines-Executive Summary, J Am Coll Cardiol 38(4):1231-65 (2001)

Fuster V and Ryden LE et al.׳, ACC/AHAZESC Practice Guidelines-Full Text, J

Am Coll Cardiol 3 8(4) :12661-12661xx (2001) ׳ . > ' .,.:.

Morady F et al., Effects of resting vagal tone on accessory atrioventricular connections/'Circulation 81(1):86-90 (1990). .

Waninger MS et al., Electrophysiological control of ventricular rate during atrial 10 fibrillation, PACE 23:1239-1244 (2000) .־, < .:u.

• Wijffels MC et al., Electrical. remodeling diie 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 MC et aL, Atrial fibrillation, begets, atrial fibrillation, Circulation

. ־ . . (1995) 92:1954-196815 • Goldberger AL 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 GS, Experimental models י of atrial fibrillation/flutter, J

Pharmacological and Toxicological Methods 43:117-123 (2000)

Hayashi H et al., Different effects of class Ic and HI antiarrhythmic drugs on vagotonic atrial fibrillation in the canine heart, Journal of Cardiovascular Pharmacology 31:101-107(1998)

5 Morillo CA 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 SJ 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 Π) (1998)

Kwan H et al., Cardiovascular adverse drug reactions during initiation of ai-iti arrhythmic therapy for atrial fibrillation, Can J Hosp Phann 54:10-14 (2001)

Jideus L, Atrial fibrillation after coronary artery bypass surgery: A study of 15 causes and risk factors, Acta Universitatis Upsaliensis, Uppsala, Sweden (2001)

Borovikova LV 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 GM, 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. 3 0 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 conmonly used: (a) the standard deviation of beat-to-beat RR interval differences within a certain time window (i.e., variability in the 5 time domain), and (b) the magnitude of variability as a function of frequency (i.c., variability in the frequency domain): ' ׳ . . q. < .־ ׳. ,

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 10 (corresponding to a time constant between about 2.5’ahd 7 seconds), Low-frecjuency (LF) changes in heart fate (for example, blood pressure‘³ variations) are characterized by a frequency of between¹ about 0.04 and about O.l'^Hz (corresponding to a time constant between about 7 and 25 seconds). Very-low-frequericy (VLF) changes in heart rate are characterized by a frequency ^!of between' about i)’.003^f arid about'0.04 Hz^i;(0'5 to 5 15 minutes). Uifra-lbw-frequency (ULF) changes³ in heart rate are characterized by a frequency of between about 0.0001 and about .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 20 heart disease and heart failure. In other conditions, such as atrial fibrillation^ increased heart fate variability in an even higher fiequericy 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).

5 Kafnath et al., in Effect of vagal nerve electrostimulation on the power spectrum of heart rate variability in man, Pacing Clin Electrbphysiol 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

0 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 RE 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. US Patent 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.

US Patent 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.

US Patents 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. ' . .

US Patent 5,203,326 to-Collins, which is incorporated herein by reference, describes a pacemaker which detects a cardiac abnormality and responds with electrical 5 stimulation of the heart combined with vagus nerve stimulation. Hie 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. ־. ;_!נ

US Patent 6,511,500 to. Rahme, which is incorporated herein by reference, 10 describes various aspects of the effects of autonomic nervous system tone on atrial arrhythmias, and its interactioii. 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 15 (norepinephrine, acetylcholine). ,

US Patent 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 20 myocardium.

US Patents 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

5 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 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

0 then stimulating afferent nerves to prevent the arrhythmia.

US Patent 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.

US Patents 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 oh 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.

US Patent 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.

US Patent 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.

US Patent 6,292,695 to Webster, Jr. et al., which is incorporated herein by reference, describes a method fof 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.

US Patent 6jl34,470 to Hartlaub, which is incorporated herein by reference, describes an implantable anti-arrhythmia system which includes a spinal cord stimulator 5 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 10 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 15 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. 20 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.

US Patents 4,608,985 to Crish et al. and 4,649,936 to Ungar et al., which are 25 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 Pubheation WO 01/10375 to Felsen et al., which is incorporated herein by reference, describes apparatus for modifying the electrical behavior of nervous 3 0 tissue. Electrical energy is applied with an electrode to a nerve in order to selectively inhibit propagation of an action potential.

US Patent 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 U et al., Generation of unidirectionally propagating action potentials using a monopolar electrode cuff, Annals of Biomedical Engineering, 14:437-450 (1986)

Sweeney ID 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 ID et al., A nerve cuff technique for selective excitation of peripheral nerve trunk regions, IEEE Transactions on Biomedical Engineering, 37(7) (1990)

Naples GG 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 NJ 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 VK et al., Muscle recruitment through electrical stimulation of the lumbo-sacral spinal cord, IEEE Trans Rehabil Eng, 8(1):22-9 (2000)

Deurloo KE et al., Transverse tripolar stimulation of peripheral nerve: a modelling study of spatial selectivity, Med Biol Eng Comput, 36(1):66-74 (1998)

Tarver WB et al., Clinical experience , with a helical bipolar stimulating lead, Pace, Vol. 15, October, Part H (1992) י ./. . .

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.

.׳ ־ י י^:’ '־׳׳ i ’ .1 . ’ . ׳ .?7 ז-. ׳ י י

Fitzpatrick et al., in A nerve cuff design for the selective activation and blocking ^: ז J < ז-, ן־י ’ . י י . ־ . ־ r . * . . 1 ' י . < . 1 ן .׳׳ ί Η 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 ‘ -i. .: ‘ 1 . ־ .׳ . f־. .

0 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 NJ et al., Orderly recruitment of motoneurons in an acute rabbit model,

5 Ann. Conf, of the IEEE Eng., Medicine and Biology Soc., 20(5):2564 (1998)

Rijkhoff NJ 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, April 21-23, 1999, pp. 20-21 (1999)

Baratta R et al., Orderly stimulation of skeletal muscle motor units with tripolar

0 nerve cuff electrode, IEEE Transactions on Biomedical Engineering, 36(8):836-43 (1989)

Levy MN, 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 Feb; 38(2):81-4

Lavallee et al. Muscarinic inhibition of endogenous myocardial catecholamine liberation in the dog, Can J Physiol Pharmacol 1978 Aug; 56(4):642-9

Mann DL, Kent RL, Parsons B, Cooper G, Adrenergic effects on the biology of the adult mammalian cardiocyte, Circulation 1992 Feb; 85(2):79.0-804

Mann DL, Basic mechanisms of disease progression in the failing heart: role of excessive adrenergic drive, Prog Cardiovasc Dis 1998 Jul-Aug; 41(lsuppl 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 WM et al., Inversion of the current-distance relationship by transient depolarization, IEEE Trans Biomed Eng, 44(1): 1-9 (1997)

Goodall EV 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:

V(aVU) = 4?z/, 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

The present invention relates to an apparatus comprising:

an electrode device, configured to be coupled to a site of a subject selected from the group consisting of: a vagus nerve, and an epicardial fat pad;

a cardiac monitor, configured to detect a cardiac signal; and a control unit, configured to:

drive the electrode device to apply a current to the site in respective pulse bursts in each of a plurality of cardiac cycles of the subject, and configure the current to reduce heart rate variability of the subject below a baseline heart rate variability of the subject which corresponds to the subject's heart rate variability when the current is not applied, by initiating the applying of each burst after a delay of 30 to 200 milliseconds following an R-wave of the cardiac signal.

STATEMENT IN ACCORDANCE WITH COMMISSIONER’S CIRCULAR 23(P)

Inasmuch as the invention is defined in the appended claims, it will be apparent that the portions of the present specification, which fall outside the scope of the claims, do not relate directly to the claimed invention. This Notice is not meant to disclaim any legitimate rights to which the Patentee is legally entitled, especially any rights in accordance with Section 49 of the Israel Patent Law.

ADDITIONAL ASPECTS OF THE APPLICATION

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 smalldiameter 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

15a fibers transmit pain sensations and are important for regulation of reflexes such as respiratory reflexes.

Tn 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 5 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 10 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.

Tn 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. 15 The cathodic current is applied with an amplitude sufficient to induce action potentials in large- and mediurh-diainefer^; fibers (e.g. A- and B-fibers); blit 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

0 fibers (e.g., B- and C-fibers). This combination of cathodic and anodal cunent 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 25 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.

Tn 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

0 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. L. embodiments of the present invention in which the stimulation is applied in a series of pulses that are 10 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 dtiration (width), (c) pulse repetition interval, (d) pulse period, (e) number of pulses per burst, also referred to herein as pulses per trigger (PPT), (fj amplitude, (g) duty cycle, (h) choice of vagus nerve, and (i) 15 on/off” ratio and timing (i.e., during intermittent operation).

’^,'י- t .'^,)י';'. : .^,r. .. . . L-' ?L ; . ;7 . 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 20 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

5 control unit is configured to drive the electrode device to stimulate the vagus herve 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

0 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.

WO'2004/103455

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.

/.״ . -.־ :.<.*,.,. Ή.'־ .. ־ ; ן . \ . ׳ _v ; _־־ ).< . ־ j

Typically, the^r control unit is adapted to drive the electrode device to apply the stimulating current and/or.the inhibiting current in a series of pulses. . .10 ־ Tfi ah 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. .. .. ;_ג.. .. :f ' Typically, the electrode device includes? acathode, adapted to apply the stimulating current, and a primary set of anodes, which applies the inhibiting current. For 15 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 ofa current applied by the primary anode.. . :. . 1:.

Typically, the control unit is adapted , to drive the electrode device to apply the

0 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 tq 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 25 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 senes of pulses? For some applications, the control unit:

0 . 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.

Tn 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.

Tn 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, _r ,. ,. _v . ,, .,_|V . . aleft ventricular pressure (LVP) sensor, ’. ^{( !} ־ ׳ ' ' ' ׳ ־׳' ^; ׳ ־ - ־ . .. . _t 1 . ׳. ־ . .,J J^ri. J ' ‘ • an accelerometer (in which case', the at least one sensed parameter includes motion of the subject),׳־'׳''־ ל \ ־ '׳ ־ . ; ־'^iL; “ . :׳. ״ ־>(, . a detector of norepinephrine concentration in the subject,

-׳׳ 'll. , :

• an ECG sensor, , . T _{f t} ' .;» ,<׳־.. . . . J < ‘ . , ¹ ;

• arespiration sensor, and/or ,. , ,,, • an impedance cardiography sensor. - -

Alternatively or additionally, die at least one sensed parameter includes an • 1 ״ , ׳ i ׳ * * * *״^s 1 י * ׳ > v ׳. * ׳ ׳ , ^ * * ^v * ׳ indicator of decreased cardiac contractility, an indicator of cardiac output, and/or an indicator of a time derivative of a LVP, and tlie control unit receives the indicator.

In an embodiment, the sensor unit includes ,an electrocardiogram (ECG) monitor, ־; . ’ !־ . ־.־.ί : ׳־ ' . ־ ^ז.-’ ^! - . . ' .-'׳ 7¹*ד״ י’ .^,. .׳ . ' 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. _ ן , .

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 fate 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 2 0 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 2 5 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 die 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 Rwave 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 secondaiy 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.

יי׳ 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 apode, and/or the cathode includes a plurality of discrete primary anodes, 5 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.

10' ' 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 \^;agus nerve, so as to selectively stimulate nerve fibers of the vagus nerve responsive to the positions of the nerve fibers in 15 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

0 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.

0 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 nf 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^י a P-Tvave^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 waver! ׳:

Typically, the termination physiological parameter includes'/difference in time between two features of an ECG signal recorded by the ECG monitor, and thVcbntrol 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 . ,׳.-. ׳ .׳b . .׳^ר .-b 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 ¹control unit is adapted to 10 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. ־ .־“’ . ^!OiJi.־

Alternatively, the termination physiological parameter includes a P-R interval . , , ׳. ..׳ . .' i. - ^l- *A : λ. ~. ״. ־ ־ * between a sensing of a P-'wave of a cardiac cycle of the subject and a sensing of an R. . . XL .' .׳--;'..;־* -I.. .- ./ . :׳:'-. i'> ’i;'4 I 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 tennination 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 20 responsive to the average ofthe P-R intervals.

׳ . ' . .- '^,ft' ' ' ’

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:

b 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 3 0 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 5 following״ so as to treat the condition:

• a lung of the subject, • aheartofthe subj ect, • an immune system of the subject, and/or • an adrenal gland of the subject ¹⁰ There is additionally provided, in accordance with an embodiment of the present invention, apparatus for treating a condition of a subject, innhiding.

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 15 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:

0 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 2 5 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:

. ³ דPPW, ^t0 a vagus.nerve of, the subject, at a stimulation location, a stimulating current which is capable of inducing action potentials in the vagus nerve; sb as to treat the subject; and

... ,.,. .,. ׳ ׳ . .. . , ׳, smc.1׳ ־׳- .

applying to the vagus nerve ata 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 foe vagus ,nerye.

.> , ־“.־־ ־' ־ ”־. ׳יי ־ ־. . \ >׳־ y'. -״“‘’״.״ יייי' ‘ 1 יין. י ** .>^j v: ץf—ί *י ,; י-י f; 1 ז ^:i י:-־. ^: :There is still further provided, in accordance with an embodiment of the present invention, a method for treating a condition of a subject, ihcluding:

applying, to am autonomic nerve of the subject, a^: sfiimtiatitig‘ current which is 10 . capable, of inducing action potentials in a therapeutic direction in a firstiset and a second set of nerve fibers of the. nerve; and c, an inhibiting current which is׳ capable' of inhihiting the ^^dui:ed P?lP^ntials Raveling, in the therapeutic direction in the' secbiid set of nerve fibers, thq nerve fibers in the second set having generally larger diameters than the nerve 15 fibers in the first set.

There is also provided, in accordance with anembodiment of the present invention, a method for treating a condition of a subject, including:

applying; to an׳ autonomic nerve of the־ subject,''af a stimulation location, a stimulating current which is capable of inducing action potential's in the nerve, so as to 20 treat the subject; and . ¹ ,......

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. 'יי

There is forther provided,, in accordance with an^;embodiment of.the present 35 invention^ app^afos for trealfog a, subject, including:, . ..

an electrode (ieyice, 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: .: . .

0 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

WO 2004/J 03455 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 largediameter 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 cunent having a cathodic amplitude sufficient to induce action potentials in the medium- and largediameter 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. . . . .: .. . τ

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 5 bradycardia;:; ¹ ' - ׳ -^j” י'. י

In an embodiment, the control unit is adapted to configure the current so as to .reduce the heart rate towards a target heart rate. .׳ '־ ' ׳ ' ^{: !l υ} , ־ .־ .,י־. : .׳ V- ;.v *. '^,י . ־י

For some applications, the normal heart rate includes a normal heart rate of the ,. subject. י Alternatively; the normal heart rate includes a normal heart rate of a typical 10 human. . 1.׳ י: ; ׳ ׳־ ״ס. : י'.:. , -. - ,^: ’

In an embodiment, the control unit is adapted to drive the electrode device to . . - -_r ׳ . : ? ־ ; ; - . ־ > .> J'! ־ apply the current with an amplitude of between about 2 and about 10 milliamps.

• J- ,־׳ ..' ./:.Λ:-;. . ^:' . - LT .י. /!׳ ' י' '־.

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.

~׳ יי - -י׳ ־”- י .־- .י ׳׳־:;>׳ - . .: !; .

. 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 2 0 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 eachof 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

5 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. . . .

0 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 largediameter 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 anodalcurrents, and .. < _?7j ; .. >l. . v 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.

¹.. 7‘. י .;.׳? ׳־.: . . ״:: . ^; “ ¢::7- י' ־. :t_v. ..ך

Tn 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 -.- - - V ‘ 1 i.¹., 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..

&lt; -7- .־.־ ^ril’. ,,. -)7. ._ז/, .. . ., . ;.-׳ .״״ף, '.־. ןך_;.

There is additionally provided, in accordance with an embodiment of the present ^Ύ:1 -.?l.' . ,:ך,,. ך; י ״:»י־,:.

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 '׳׳*' t¹‘'¹-.‘. !.?.:כ, ' ? .: י.׳.־ -׳־:-1; ״. ., ,: < ,J; ., rate signal responsive thereto; and a control unit including an integral feedback controller that has inputs including -^ς . *.-' ¹ .׳ . J ‘ ^l' .’) 1 _ <!. * .־t . . - i . '־;'>« .י , ’ . ’ > 2 0 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.

’ ¹ ׳ .׳ י ’ ־Λ . :. י ^!

In an embodiment, the control unit is adapted to configure the current to include a

5 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

0 stimulating, current and the inhibiting current to the vagus nerve. .

Tn 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 largediameter 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.

-גננ an embodiment; the control unit.is adapted to drive the: ?lectrodg device to apply, the current in intermittent ones of a plurality of cardiac cycles of the subj ect. י

In an embodiment, the apparatus includes an electrode selected from the list non si sting of: ah electrode for pacing the hearty and an electrode for-defibrillating the 5 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 ^om 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 respdnsive to a summation 10־ over time of the difference. : r- ;׳ .׳ ;.׳.׳ . >

Tn an embodiment, the control unit is adapted to set- a level of a stimulation ¹ ׳ 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 15 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.

- . ׳ . ־ .j ׳ .כ .־/ ..' ׳ j . .ן... :׳. .!,j.;::,. '^:

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 20 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

5 suitable value of the leyel is between the two discrete values, the control unit is adapted to ’ ' ' - ' 7 . '׳.A::. .'.'י ..Λ. ' . .: ־ :. :. > .יו .J 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.

Th an embodiment, the control unit is adapted to drive the electrode device to

0 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 5 operation of the apparatus, the number of pulses per burst by no more than one pulse.

Tn 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.

Tn 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 15 the ECG.

Tn 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.

Tn 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,

0 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 25 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.

Tn an embodiment, die control unit is adapted to change the at least one parameter

0 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 tihe 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 charge 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 * ־ י^,־' - * '׳־' . ־ - . V . ’ ^r ’, Jr7 ! ׳'j- ’ . » - '^: ‘ ׳ ‘ &lt; ך . ־ &lt; ' .. ־ f . ין־ ־ decreases.

^ג ‘-.-י '.’י ־'/ ’ .*‘ '׳ '?L. ״G.L. י; ' . . . _ &lt;^י i ך׳’׳׳( , _t ן .- In an embodiment, the control unit is adapted to use a time derivative of an R-R י י ^L ‘ ׳ ' י י ״ - ׳-׳ ׳ w .'U'.mtyc ־ ' v .. .. , *.׳.,; :&lt;j׳ :־,־ן ׳ 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 uni t i s 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.

₁₅ in an embodiment; the־ control unit is adapted to cycle between on. periods,.

‘ during which the control unit drives the electrode device tc apply the current, and off' ־ periods; during which the control unit withholds diving the electrode device. For some applications, the control unit is adapted, to determine a desired levql of stimulation applied by the electrode device, and to configure the cycling between the on and off periods

0 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

5 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

0 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, hi an p-mbodimont, 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 in 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.

Tn 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 10 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. . י־ ׳:. _ ..r.. . ,

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! ’־. . < . ; . . :,. _ς. > , ., י an anode, adapted to be disposed at an anodal site of the vagus nerve, and to apply 2 0 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-

5 diameter fibers, but generally insufficient to induce action potentials in the small-diameter fibers, and . . , י 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.

0 - 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,

PCT/IL2004/00044(» 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 cunent, 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 cunent having a cathodic amplitude sufficient to induce action potentials in the medium- and largediameter fibers, but generally insufficient to induce action potentials in the small-diameter fibers, and τ . 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 5 י’^-. י. increase the variability of the heart rate above a target heart rate variability; .: .. ,. .־ ־. יי־ ’’ ’י ' ׳ : ‘ - , * ’ r י , ־ י'׳ 1’ י _χ . . . .׳ ן :

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. - .' ׳ ־ י .־'־ ׳' .י־ ^;

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 ־ ’? X. . ’. ז ~Γ ₄ .;ן -.'! . 'tit .: * . .’״..!:־־ »Ϊ .־,-.י-.״.

in intermittent ones of a plurality of caa-diac cycles of the subject.

In an embodiment, the apparatus includes an electrode selected from the list 15 ' 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 deyicefo 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

0 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 25 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 . ׳ י*:. ’,.].><

0 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 ofthe 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 additiorially 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 ofthe 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

-. י configuring the current to increase a variability of the heart rate.

׳ ’״'׳ 1 . .־.־‘ .זי י. . . ’ ’ . '־' _t . .:ר׳י־י־

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 &lt; t / . . ’ ¹ . ' ^f, .,. ., .״ ־ _l , j, .* ן ׳־ ¹' ץ ׳; י ; ן י ί ׳ * 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. .׳״;!. . ׳׳.&lt; ׳;

Tn 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 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 ofthe subject, so as to treat the subject. . . . . . υ-.,.

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.

0 ׳ 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 ofthe 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 farther 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.

Tn 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 cunent by more than 10% below a baseline thereof.

Tn 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.

. WO 2004/103455

-,- , For'some applications, the control unit is adapted to.driy^~the.,.electrode device during exertion by the subject; Alternatively, the control unit is adapted to withhold drivino the electrode device when the subject is not experiencing exertion.. _

For some applications, the control'unit is adapted'to' configure; the current to 5 rediice 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 tile 'current to reduce a heart rate variability :of the' subject having a characteristic frequency between about 0.04 and about 0.15 Hz; ¹ ''¹ ׳־

For some applications, the control unit is adapted to drive the electrode device to 10 apply the current with‘an amplitude of between about 2 and about 10 milliamps.:

.a . -.rs./: ׳. y. , ; , ,,/-: '.:.:;r

For some applications, the control unit is adapted to drive the electrode device to apply die current in intermittent ones of a plurality of cardiac cycles of the subject. For ri-.'-’ ?1 : Η; .-.-'׳η. < י': ׳' ^ז;- י. ,. L>i ('?. ',;,-.!ז ,, . ;., ;. I ,. .- ,.-, some applications, the control unit is adapted to dnve 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 ./'.'.? : ״״;I' ii> ׳.:

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, 1' ,. 1 ׳: :־־. ־:״.::־ >ה -. ־׳.::/. i.;. ij«., i. .-.,> .^;ז־.’־ ״ /,.-, .־;*.

the control unit is adapted to withhold driving the electrode device when the subject is sleeping.

0 For some applications, the control unit is adapted to drive the electrode device to

- ' '.־: f “ i‘ . ־.י. , ־ '־. . &lt; ,, . .*t.; ןד ־דד, , ך _י 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 cunent in a manner that reduces the heart rate variability by at least 5 0%.

Tn an embodiment, the control unit is adapted to drive the electrode device to . . ־. - - . ־ _K . . , I 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

0 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.

Tn 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.

Tn an embodiment, the control unit is adapted to configure the current to reduce a heart rate of the subject.

WO 20((4/103455 ־ ⁷ ' ׳ 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 tfie heart rate of the subject toward the target heart rate. For some applications, the target heart rate includes a target formal heart rate within a range of normal heart rates of the *subject, and the control unit is adapted to configure the current sb as to־ reduce the heart rate ׳of the subject toward the target normal heart rate? - : ^J - .J _L0 !η an embodiment, the control unit is adapted to'׳ configure the¹'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% sp as to treat the heart;failure. ^For some applications, the condition includes an occurrence of 15 arrhythmia of the subject, and the control unit.is ad.apted .to. cp^gurethe^curcpnt.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 reducejheheart_L1ate variability so as to treat the atrial fibrillation.,״״ ...,...; ,,

0 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 tire drawings, in which.

2₅ 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 3 0 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, 5 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 ofthe 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 20 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-

5 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

0 electrode device responsive thereto.

י ' 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 10 ־־־ external to control unit 20, and, optionally, external to .the patients 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 hear( 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 '־ ⁵י י י '^f י .י' . ^ד.’ ’־'־ י-I . . * ' 7’ j. '1 'ז ’:j .־^τ .V \. . ־ ,' י ־. X’ λ. . 1 ⁸¹\ ’י׳ .J \ / ‘ί f ’ • control loop executed by control unit 20, in order to increase the heart rate when the heart . ,־:. ,/ך .״/'־;;.ό. >-!ד -π?, .ה! . 1 ר^;־ -,;׳ז!;.

rate for any reason is too low.

.z..;.:Fig. 2A is. a simplified cross-sectional illustration of a generally-cylindrical 20 ' electrode device .40 applied to vagus nerve 36, in accordance, with an embodimentof 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 (44a, 44b, herein: efferent anode set 44), placed between cathode 46 and the edge of

5 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 ‘ - ¹ . . :זז;,:;-, , : , ... . ,. ,.. I;. ,I,.;

(45a, 45b, herein: afferent anode set 45), placed between cathode 46 and the edge of

0 electrode device 40 closer to brain 34. Afferent anode set 45 applies a positive current י! - \ ., י :./.j ־'׳ י.:..'. .‘/'‘'־נ “ (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 incluces a stronger blockade¹ of the’ cathodic stimulation.! .

Reference is now made to Fig. 2B, which is a simplified dross-sectional illustration of a generally-cylindncal 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 7/י _י .־ , ץ; .* . .>.*. : ; ׳; . -- .־.. - ' ־ . . ׳ י .־יי U יי. .^?, ?י r׳ electrodes. Such additional recesses accommodate swelling of vagus nerve 24 without increasing the contact area .between the. vagus nerve and the electrodes. For some *׳' . ־.. < ׳ ־ ־ ' י *' .*־־.Λ. .: . '.!,.’I /?‘-^,.I‘ 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 ־ ' ׳...־. '&lt; . יי ‘-^ג'- : J; - ,.:- /.½ .

, device 40. . , . . ...:.&lt;.

₁₅ in an embodiment. of the present invention,, efferent anode set ,44 comprises a plurality of anodes 44, typically two anodes 44a and 44b, spaced approximately ,0.$ 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 44a 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 44b). When such techniques are not used, the virtual cathode effect generally hinders blocking of smallerdiameter fibers, as described below, because a relatively large anodal current is generally necessary to block such fibers.

_:,-,- Anode 44a 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 44b. For applications, in which the blocking current through anode 44b is expected to vary substantially, efferent anode set 44 typically comprises a plurality of virtual-cathodeinhibiting anodes 44a, one or more of which is activated at any time based on the

. .י.;׳;'! .:. י . : ’ ' ־ . .' ‘ '

0 expected magnitude and location of the virtual cathode effect.

' Likewise, afferent anode set 45 typically comprises a plurality of anodes 45, typically two anodes 45a and 45b, 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 US Patent Application 10/205,474 to Gross et al., 5 filed July 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 US Patent Application 10/205,475 to Gross et al., filed July 24, 2002, 10 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 US Provisional Patent Application 60/383,157 to Ayal et al., filed May 23, 15 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 2 0 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.

5 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 144a and 144b and a cathode 146 typically comprise point electrodes (typically 2 to 100), fixed inside an insulating cuff 148 and arranged ground vagus nerve 36 so as to selectively stimulate nerve fibers according to

0 their positions inside the nerve. Jri 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 50 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 .144a, comprise a ring electrode, as described with reference . ׳.'׳'־. . .־׳'? ־־ . » - r - ' 4.. F z. t 1׳ j.' ‘\ ’ . to Fig. •20, such that electrode device. 140. comprises both ring electrode(s) apd point electrodes (configuration not shown). Additionally, electrode ffevice; 4;0 > optionally comprises an afferent anode set (positioned like anodes 45a and^ 45b in Fig. 2A), the anodes of which comprise point electrodes and/or ring electrodes. ~ , ^!< Alternatively, ordinary, noh-cuff electrodes are used, such as when the .electrodes 10 are placed on the epicardial fat pads instead of on the vagus nerve. in'iu:׳׳... .״ ־' *־ .. i־_s a^’conceptuai illustration of thd 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 actiori'potentials towards heart 30, control' unit '20 doves electrode'device 40 to' selectively recruit nerve fibers 15 beginning with smaUer-diameter fibers and to progressively recruit larger-diameter fibers ־ as the desired stimulation level increases. This smaller-tp-larger diameter recruitment '־ hrder mimics the body's natural order of recruitment. .1 . .. ־־..:.־ λ.υ׳<,.ι

Typically, in order to' achieve this recruitment order, the control unirstimulates ’myeiinated fibers essentially of all diameters using cathodic current from'cathode 46, 2 0 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 25 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 3 0 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 44a is shown generating less current 51 than anode pole 44b in order to minimize the virtual cathode effect in the direction ofthe 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 5 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 10 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, 15 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 20 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 45b is shown generating, less cun-ent .than anode 45a in order to minimize the virtual cathode

5 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

0 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 52 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 5 necessarily, embodiments using approximately 5 ,mA of cathodic current have toe 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 combmation with electrode distances from toe axis of toe 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.

’ t .'׳

T־n an embodiment of toe present invention, toe cathodic current is applied by cathode 46 with an amplitude sufficient to induce action potentials in large- and mediumdiameter fibers 50, 52, and 54 (e.g., A- and B-fibers), b'ut insufficient to “induce action potentials in small-diameter fibers 56 (e.g., C-fibers). Simultaneously, ah anodal current 15 is applied by anode 44b in order to inhibit action potentials induced by toe cathodic current in the large-diameter fibers (e.g., A-fibers). This combination of cathodic and anodal current generally results in toe stimulation of medium-diameter fibers (e.g., Bfibers) only. At toe same time, a portion of toe afferent action'potentials induced by toe cathodic current are blocked by anode 45a, as described above.:׳ Alternatively, toe afferent 2 0 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 toe 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 25 combination with, techniques, described hereinabove for achieving generally uniform stimulation of toe vagus nerve. Such generally uniform stimulation enables toe use of a '’ ‘ י ’.?. .7 ׳- ־. j יי־'.'. ’ ._ ׳ cathodic current sufficiently weak to avoid stimulation of C-fibers near toe surface of toe nerve, while still sufficiently strong to stimulate B-fibers, including B-fibers situated more deeply in toe nerve, i.e., near the center of toe nerve. For some applications, when 3 0 employing such techniques for achieving generally uniform stimulation' of the vagus nerve, toe amplitude of toe cathodic current applied by cathode 46 ’may be between about 3 and about 10 milliamps, and toe amplitude of toe anodal current applied by anode 44b 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.)

Tn 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.

{Π (1'tG'; ‘יי >.

• 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 nertain 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, whi.cl| 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 . . sensitivityh׳:-.-.־s :.; .,. -.: .-T ״׳.־ /.«״. ־׳:/’.$./

LO The parameters and behaviors included in_uthis; 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.

Tn 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. Jhe heart rate of the 15 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.

.:?v ה׳;‘

0 For example, such parameters may include the amplitude of the applied current. Alternatively or additionally, in an embodiment of the present invention, the stimulation ------ן- ' ._ς . . .י., - - . _r . . . .

is applied in a series of pulses that are synchronized or are not synchronized with “⁶cardiac 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. “ ^!v

0 . 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 0-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 ofthe 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 ofthe subject (e.g., detected using an accelerometer), the average heart rate ofthe 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- P^U1^SPS

*. 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 maybe 56 ,5 ,5.,5 ,5.,6 ,5-,5. ,5 ״,. ., in order tp achieve an effective PPT of 5.2.

q . in an embodiment of the present invention,, control unit 20 uses. a_; slow-reacting heart rate regulation algorithm to modify heart-rate-cqntrolhng 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 ipcrease .from a target heart rate of 60 beats per minute (BPM) to 100 BPM over a period of only a 15 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 20 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 25 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 3 0 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 oh 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 5 feedback is updated, periodically by inputting the current, heartrate. _£ 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 algorithni adds the square of each R-R'interval, 10 thus taking into account the non-uhifonnity of the update interval, e.g., in order to properly analyze feedback' stability using ־ standard tools and methods developed for ־ canonical feedback; * . . .:, ! ;?.λ ;&lt; . . , ז!;. ;;a !!!

' ף T, , ; י [ל. ־'־ / -if{ , ’ , . . - י ,. . . - ,. , , . ‘ __r Γ, f .

In an embodiment of the present invention, control unit 20 implements a detection blanking period, during which the control unit does hot detect heart beats; - In' some 15 instances, such non-detection may reduce false detections of heart beats’? One or both of the following techniques are typically implemented: !. ; ; ; ,7' • 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

0 . detections,,. .For example, the . expected maximal heart rate may be 200

BPM, resulting in a minimal detection interval of 3 QQ milliseconds. After , detection of a beat, the control unit disregards:any signal^ indicative of a beat during the next 300 milliseconds., • Stimulation blanking. During application of a stimulation burst, and for an 25 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

0 '. 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.

Tn 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.

Tn an embodiment of the present invention, control unit 20 implements an integral feedback controller, which can most generally be described by:

K = Kj*jedt . in which K represents the strength ofthe feedback, Kj is a coefficient, and Je 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.

Tn 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 / 2TimeC0eff

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.

־ Ihe 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 ‘ * ’.-. '-'’.י ' ., ., ; . . > י’ . <_x ..'? ύ '.*יד. י <

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 ofthe -־ u .. ׳. - > v .. .. .. .. .׳. :...?־j .;. ..5 ־? >. ו.׳ ׳!״י. ׳.:.. י;

example. . , _t . , ... ....

<td rowspan="2">_v .י , ״. _t .1.,,. -.-. .,., ;</td><td colspan="4"> . Heart Beat Number</td>

<td>- ;׳׳</td><td> 2 . -י a . ־: j</td><td> ,,.I..</td><td> .;A,.</td>

<td> Heart rate (BPM)</td><td> 100</td><td> 98</td><td> 96</td><td>_{; ;j}W²</td>

<td> R-R interval (ms), , _f</td><td> 600 , ־-זו./י /,r.v.,</td><td>⁶¹⁰</td><td> 620</td><td> 590</td>

<td rowspan="2"> R-R.(l/128 sec) . _ז</td><td rowspan="2"> .,: - 76 ¹.A:. &lt; . ״</td><td rowspan="2"> 78</td><td> 79</td><td> 75</td>

<td></td><td></td>

<td> e (l/128sec) . .,, ..</td><td> ..,., ⁵²</td><td> ,. ⁵°</td><td>⁴⁹</td><td>⁵³ ן i ♦» ר י •</td>

<td> Limited e - . . . . ״ ־ .־ ’ ז</td><td> r-r.³?.</td><td>³²</td><td> 32</td><td> 32 j ר;.</td>

<td> Error ? .'־/.?,. _v;. .־ .* .־ l . n ־ . . . ‘ . . ד־</td><td> 2432</td><td> 2496 I.-..</td><td> 2528</td><td> 2400</td>

<td> Integral ' י i.. ׳.־ ’־ ;־ ל-., \. ־'</td><td> 2432 ץ. - r—!. -».ל</td><td> ’ ’4928</td><td> ' 7456</td><td> 9856 ^״ '</td>

<td> , PPT... _ג .41 -. 1 ' - &gt; » . i. -u *. *i ^ז *' ׳</td><td> 0 \ ן n •4*'.</td><td> 1</td><td> 1</td><td> .. .. ₂</td>

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 10 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 15 . 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 2 0 in one ofthe following modes: . . - 61 • 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

0 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

0 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, jn 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 and 76 showing the timing of the application of a burst of stimulation ]raises 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 10 ^; target heart rate; determined as described above. Precise graded slowing of th^ 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 »־:׳.T?lr>c1cing;.־as !described herein, is typically applied .during, each cardiac cycle in burst of 15.: pulses 74, typically containing between about 1 and about 20 pulsps^each^of^about^l - 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 vagusnerve. Additionally, the

- ״.-number. of pulses, and/or: their duration is sometimes.,varied in order to facilitate 20 achievement of precise graded slowing of the heart beat.

^; 7 . In an embodiment of the present invention (e.g., ,when the heart rate regulation . - algorithm described hereinabove is not implemented), to apply the . clpsed-loop system, : the target heart rate is expressed as a ventricular R-R interval (shown as the interval between Rj. and R₂- in Fig. 5)., The actual R-R. interval is measured in. real time and 25 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 30 is modified accordingly. .ד:.,. .־.,.

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 5 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 10 applied for treating a subject suffering from heart failure. In heart failure, hyperactivation 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 hefirt rest time (accelerated 15 heart rate), and cause direct tbxic damage to myocardial muscles through oxygen free radicals ־ and DNA damage. Artificial^1! 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

0 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 MN 25 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

0 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.

Tn 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 64 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 above5 cited article * by Feliciano L et aE): ־ For some ׳ applications, the- vagal^ז stimulation techniques described herein are used to improve coronary blood flow iii 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 . .--־.’.־. .v' ' . ., . . • 4. ..י . . .>,. :>^r'.’ >־C V.¹‘׳ . . effect of acetylcholine administration. , .

10. .י ?>.:־ 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

-^r’. 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,. th^ control unit does not 20 . synchronize the stimulation with the cardiac cycle. For example, the stimiilation 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 , nf pulses that are synchronized with the cardiac cycle of the subject, such as described hereinabove with reference to Fig. 5...

' ' \ ' '. ^: .-'' '.' 1' ..־ - ./ . u. ־. τ .,?!;י

,. 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: . .. , - . ,1. ,.

0 . 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 ofthe 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 10 not reducing the average heart rate ofthe 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 ofthe subject. Such stimulation typically does not substantially 15 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. Tho magnitude ofthe change in average heart rate as well as the percentage of time during

0 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. 25 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

0 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 5 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 10 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 י is typically configured to reduce low-frequency heart.rate variability, , and ,to. adjust the level of stimulation applied based on the circadian and ״ .־׳-. ’-.,.*.- ־r. :. . -. c.-. ; : j.ב⁴ י...*^,.׳. ׳.*. j .

. ., . 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 ,. ׳ . reduc^hKirtj^tejVariabih.ty at .all frequencies. . % !, _ה ׳'׳.' Maximizing' the mechanical efficiency of; the . heart, by maintaining relatively constant ventricular filling times and pressures. For example, 20' ’ this therapeutic effect may be beneficial for subjects suffering from, atrial • ׳ fibrillation, in which fluctuations in heart filling times and pressure reduce ^; cardiac efficiency. ‘ ־ .._1־ ; ' ' ׳ . >

• Eliminating the normal cardiac response to changes in the breathing cycle ' '־.’. , ( t ־ .f ־ , ' י' - . i . - «-־-.. .. ־. ־...־' .. It (i.e., respiratory sinus arrhythmia). Although generally beneficial in young

5 and efficient hearts, respiratory sinus arrhythmia may be harmful tb 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. ־..ג,״ . / ־ ..־ .־

0 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 67

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 5 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 15 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

0 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 nonstimulation periods increased to approximately 95 beats per minute (approximately baseline value). Thus, these experimental results demonstrate that the application of vagal 25 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

0 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 יי־ «-׳: .’. ״.--. :. ־ ״י - י <־ ׳. ' ־ י ׳ ' ־ ״־ -V.^r: . ΊΧΌ ί stimulation to one or more of the following: lhe lacrimal nerve, the salivary nerve, the vagus nerve, the pelvic splanchnic nerve, or one or more sympathetic or parasympathetic ־-־ ־׳£ .- ג ־ ־־ .; ; . ־ .i. , . -.ז. .,- - . .--, ₎ .׳. > .-\. ־.ז. ׳ *'.

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 vhat has been particularly shown and described hereinabove. Rather, the scope of the present invention includes both combinations and subcombihations of the various י' features described, hereinabove, as well as variations and-modifications thereof that are ' ״ not in the prior aft, which would occur to :persons skilled in the art upon reading the foregoing description. -A?-'כ ׳..:״ ׳ «.-׳ ׳-'׳.¹‘־.;t..״