Techniques for applying, calibrating, and controlling nerve fiber stimulation

• US 20050197675A1
• Filed: 02/18/2005
• Published: 09/08/2005
• Est. Priority Date: 08/31/2001
• Status: Active Grant

• Current Assignee: Medtronic Incorporated (Medtronic Plc)
• Original Assignee: BioControl Medical (B.C.M) Ltd.
• Inventors: Ezra, Omry B., Cohen, Ehud, Ayal, Shai, David, Tamir B.
• Granted Patent: US 7,634,317 B2
• Time in Patent Office: Days
• US Class Current: 607/9
• CPC Class Codes: A61B 5/024 Detecting, measuring or recording pulse rate or heart rate A61B5/0205, A61B5/021 take precedence
• CPC Class Codes: A61B 5/4029 for evaluating the peripheral nervous systems A61B5/24 takes precedence
• CPC Class Codes: A61B 5/4041 Evaluating nerves condition
• CPC Class Codes: A61B 5/412 Detecting or monitoring sepsis
• CPC Class Codes: A61B 5/7217 of noise originating from a therapeutic or surgical apparatus, e.g. from a pacemaker
• CPC Class Codes: A61N 1/0551 Spinal or peripheral nerve electrodes
• CPC Class Codes: A61N 1/0556 Cuff electrodes
• CPC Class Codes: A61N 1/36114 Cardiac control, e.g. by vagal stimulation stimulating the heart A61N1/362
• CPC Class Codes: A61N 1/3621 for treating or preventing abnormally high heart rate
• CPC Class Codes: A61N 1/3627 for treating a mechanical deficiency of the heart, e.g. congestive heart failure or cardiomyopathy

Abstract

Apparatus is provided including an electrode device, adapted to be coupled to a site of a subject; and a control unit, adapted to drive the electrode device to apply a current to the site intermittently during alternating “on” and “off”periods, each of the “on” periods having an “on” duration equal to between 1 and 10 seconds, and each of the “off” periods having an “off”duration equal to at least 50% of the “on” duration. Other embodiments are also described.

Claims

1-164. -164. (canceled)

165. Apparatus comprising:

an electrode device, adapted to be coupled to a site of a subject selected from the list consisting of;

a vagus nerve of the subject, an epicardial fat pad of the subject, a pulmonary vein of the subject, a carotid artery of the subject, a carotid sinus of the subject, a coronary sinus of the subject, a vena cava vein of the subject, a right ventricle of the subject, and a jugular vein of the subject; and

a control unit, adapted to;

drive the electrode device to apply to the site a current in respective bursts of pulses in each of a plurality of cardiac cycles of the subject, and

count a number of pulses applied to the site.

166. The apparatus according to claim 165, wherein the control unit is adapted to drive the electrode device to apply the current intermittently during alternating “

on” and

“

off”

periods, each of the “

on”

periods having an “

on”

duration equal to between 1 and 10 seconds, and each of the “

off”

periods having an “

off”

duration equal to at least 50% of the “

on”

duration.

167. The apparatus according to claim 165, wherein the control unit is adapted to configure the current so as to reduce a heart rate of the subject.

168. The apparatus according to claim 165, wherein the control unit is adapted to configure the current so as to increase a heart rate of the subject.

169. The apparatus according to claim 165, wherein the control unit is adapted to configure the current so as to minimize an effect of the applying of the current on a heart rate of the subject.

172. The apparatus according to claim 165, wherein the control unit is adapted to:

count the number of pulses applied to the site during a period of time,

count a number of bursts applied to the site during the period, and

calculate an average number of pulses per burst by dividing the number of pulses counted during the period by the number of bursts counted during the period.

173. The apparatus according to claim 172, wherein the control unit is adapted to modify a parameter responsively to the average number of pulses per burst, the parameter selected from the list consisting of:

a parameter of the current, and a parameter of a feedback algorithm used by the control unit.

176. The apparatus according to claim 165,

comprising a sensing element, adapted to sense heart beats of the subject,

wherein the control unit is adapted to:

count a number of bursts applied to the site during a period of time, and count a number of heart beats sensed during the period.

177. The apparatus according to claim 176, wherein the control unit is adapted to calculate an average number of bursts per heart beat by dividing the number of bursts counted during the period by the number of heart beats counted during the period.

178. The apparatus according to claim 177, wherein the control unit is adapted to modify a parameter responsively to the average number of bursts per heart beat, the parameter selected from the list consisting of:

a parameter of the current, and a parameter of a feedback algorithm used by the control unit.

180. The apparatus according to claim 176, wherein the control unit is adapted to:

count the number of pulses applied to the site during the period, and

calculate an average number of pulses per burst by dividing the number of pulses counted during the period by the number of bursts counted during the period.

181. The apparatus according to claim 165, comprising a sensing element, adapted to sense heart beats of the subject, wherein the control unit is adapted to:

count a number of pulses applied to the site during a period of time, and

count a number of heart beats sensed during the period.

182. The apparatus according to claim 181, wherein the control unit is adapted to:

count a number of bursts applied to the site during the period, and

calculate an average number of pulses per burst by dividing the number of pulses counted during the period by the number of bursts counted during the period.

183. The apparatus according to claim 181, wherein the control unit is adapted to calculate an average number of pulses per heart beat by dividing the number of pulses counted during the period by the number of heart beats counted during the period.

184. The apparatus according to claim 183, wherein the control unit is adapted to modify a parameter of the current responsively to the average number of pulses per heart beat.

185. The apparatus according to claim 165, wherein the site includes the vagus nerve, and wherein the electrode device is adapted to be coupled to the vagus nerve.

186. The apparatus according to claim 185, wherein 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.

187. The apparatus according to claim 185, wherein the control unit is adapted to configure the current to include a stimulating current, which is capable of inducing action potentials in the vagus nerve, and an inhibiting current, which is capable of inhibiting action potentials induced by the stimulating current and traveling in the vagus nerve in an afferent direction toward a brain of the subject.

170-171. -171. (canceled)

174-175. -175. (canceled)

179. (canceled)

188. Apparatus comprising:

an electrode device, adapted to be coupled to a site of a subject selected from the list consisting of;

a vagus nerve of the subject, an epicardial fat pad of the subject, a pulmonary vein of the subject, a carotid artery of the subject, a carotid sinus of the subject, a coronary sinus of the subject, a vena cava vein of the subject, a right ventricle of the subject, and a jugular vein of the subject;

a sensing element, adapted to sense a physiological parameter of the subject; and

a control unit, adapted to;

drive the electrode device to apply a current to the site,

configure a parameter of the current responsively to the sensed physiological parameter,

calculate an average of the current parameter, over a period of time having a duration of at least 1 minute, and

regulate the current parameter such that the average of the current parameter does not exceed a maximum current parameter level regardless of the sensed physiological parameter.

189. The apparatus according to claim 188, wherein the control unit is adapted to regulate the current parameter by modifying a parameter of a feedback algorithm used by the control unit.

190. The apparatus according to claim 188, wherein the control unit is adapted to regulate the current parameter by driving the electrode device to apply the current intermittently during alternating “

on” and

“

off”

periods, each of the “

on”

periods having an “

on”

duration equal to at least 1 second, and each of the “

off”

periods having an “

off”

duration equal to at least 50% of the “

on”

duration.

191-211. -211. (canceled)

212. Apparatus comprising:

an electrode device, adapted to be coupled to a site of a subject selected from the list consisting of;

a vagus nerve of the subject, an epicardial fat pad of the subject, a pulmonary vein of the subject, a carotid artery of the subject, a carotid sinus of the subject, a coronary sinus of the subject, a vena cava vein of the subject, a right ventricle of the subject, and a jugular vein of the subject;

a heart rate sensor, adapted to sense a heart rate of the subject; and

a control unit, adapted to;

drive the electrode device to apply to the site a current, and

configure the current responsively to a comparison of. (a) the sensed heart rate and. (b) a target heart rate that is a function of an average heart rate of the subject.

213. The apparatus according to claim 212, wherein the control unit is adapted to determine the target heart rate in real time.

214. The apparatus according to claim 212, wherein the control unit is configured to determine the average heart rate of the subject responsively to the sensed heart rate of the subject.

221. The apparatus according to claim 212, wherein the control unit is adapted to determine the average heart rate when the subject is at rest.

225. The apparatus according to claim 212, wherein the control unit is adapted to set the target heart rate greater than the average heart rate.

226. The apparatus according to claim 225, wherein the control unit is adapted to set the target heart rate equal to 15% greater than the average heart rate.

227. The apparatus according to claim 212, wherein the site includes the vagus nerve, and wherein the electrode device is adapted to be coupled to the vagus nerve.

228. The apparatus according to claim 227, wherein 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.

229. The apparatus according to claim 227, wherein the control unit is adapted to configure the current to include a stimulating current, which is capable of inducing action potentials in the vagus nerve, and an inhibiting current, which is capable of inhibiting action potentials induced by the stimulating current and traveling in the vagus nerve in an afferent direction toward a brain of the subject.

215-220. -220. (canceled)

222-224. -224. (canceled)

230. Apparatus comprising:

an electrode device, adapted to be coupled to a site of a subject selected from the list consisting of;

a vagus nerve of the subject, an epicardial fat pad of the subject, a pulmonary vein of the subject, a carotid artery of the subject, a carotid sinus of the subject, a coronary sinus of the subject, a vena cava vein of the subject, a right ventricle of the subject, and a jugular vein of the subject; and

a control unit, adapted to;

drive the electrode device to apply to the site a current that changes a heart rate of the subject, and

gradually modify at least one parameter of the current by less than a percentage selected from the list consisting of;

50% of a pre-termination value per heart beat of the subject, and 5% per heart beat of the subject, until the parameter reaches a desired value, during a transitional period selected from the list consisting of;

a commencement of stimulation period, and a termination of stimulation period.

231. The apparatus according to claim 230, wherein the control unit is adapted to gradually modify the parameter during the transitional period, which transitional period includes the commencement of stimulation period and has a duration of at least 24 hours, such that a level of vagal stimulation caused by the current gradually increases.

232. The apparatus according to claim 230, wherein the control unit is adapted to gradually modify the parameter according to a predetermined schedule.

237. The apparatus according to claim 230, wherein the parameter includes an amplitude of the current, and wherein the control unit is adapted to gradually modify the amplitude.

239. The apparatus according to claim 230, wherein the control unit is adapted to drive the electrode device to apply the current in respective bursts of pulses in each of a plurality of cardiac cycles of the subject.

240. The apparatus according to claim 239, wherein the parameter is selected from the list consisting of:

pulses per burst, pulse frequency, and pulse width, and wherein the control unit is adapted to gradually modify the selected parameter.

233-236. -236. (canceled)

238. (canceled)

241-254. -254. (canceled)

255. Apparatus comprising:

an electrode device, adapted to be coupled to a site of a subject;

a heart rate sensor, adapted to sense a heart rate of the subject; and

a control unit, adapted to;

drive the electrode device to apply to the site electrical stimulation in respective bursts in each of a plurality of cardiac cycles of the subject, each of the bursts including one or more pulses,

set at least one primary parameter of the stimulation, using a feedback algorithm that includes as an input thereto the sensed heart rate, and

modify at least one secondary parameter if an average duty cycle of the stimulation crosses a threshold value, the secondary parameter selected from the list consisting of;

a parameter of the stimulation, and a parameter of the feedback algorithm.

256. The apparatus according to claim 255, wherein the site is selected from the list consisting of:

a vagus nerve of the subject, an epicardial fat pad of the subject, a pulmonary vein of the subject, a carotid artery of the subject, a carotid sinus of the subject, a coronary sinus of the subject, a vena cava vein of the subject, a right ventricle of the subject, and a jugular vein of the subject, and wherein the electrode device is adapted to be coupled to the selected site.

257. The apparatus according to claim 256, wherein the secondary parameter includes the primary parameter, and wherein the control unit is adapted to modify the at least one primary parameter if the average duty cycle crosses the threshold value.

258. The apparatus according to claim 256, wherein the secondary parameter includes a target heart rate, and wherein the control unit is adapted to modify the target heart rate if the average duty cycle of the stimulation crosses the threshold value.

259. The apparatus according to claim 256, wherein the secondary parameter includes an integral slope of the feedback algorithm, and wherein the control unit is adapted to modify the integral slope if the average duty cycle of the stimulation crosses the threshold value.

260. The apparatus according to claim 256, wherein the secondary parameter includes an amplitude of the current, and wherein the control unit is adapted to modify the amplitude if the average duty cycle of the stimulation crosses the threshold value.

263. The apparatus according to claim 256, wherein the site includes the vagus nerve, and wherein the electrode device is adapted to be coupled to the vagus nerve.

264. The apparatus according to claim 263, wherein 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.

265. The apparatus according to claim 263, wherein the control unit is adapted to configure the current to include a stimulating current, which is capable of inducing action potentials in the vagus nerve, and an inhibiting current, which is capable of inhibiting action potentials induced by the stimulating current and traveling in the vagus nerve in an afferent direction toward a brain of the subject.

261-262. -262. (canceled)

266. Apparatus comprising:

an electrode device, adapted to be coupled to a site of a subject;

a heart rate sensor, adapted to sense a heart rate of the subject; and

a control unit, adapted to;

drive the electrode device to apply to the site, intermittently during alternating “

on” and

“

off”

periods, electrical stimulation capable of lowering the heart rate, the stimulation having a duty cycle expressed as a number of stimulations per heart beat, and each of the “

on”

periods having an “

on”

duration equal to at least 1 second, and each of the “

off”

periods having an “

off”

duration equal to at least 50% of the “

on”

duration,

responsively to the sensed heart rate, set at least one parameter of the stimulation, and

determine a magnitude of a heart-rate-lowering effect of the stimulation by comparing an aspect of each “

on”

period to an aspect of each “

off”

period.

267. The apparatus according to claim 266, wherein the site is selected from the list consisting of:

a vagus nerve of the subject, an epicardial fat pad of the subject, a pulmonary vein of the subject, a carotid artery of the subject, a carotid sinus of the subject, a coronary sinus of the subject, a vena cava vein of the subject, a right ventricle of the subject, and a jugular vein of the subject, and wherein the electrode device is adapted to be coupled to the selected site.

268. The apparatus according to claim 267, wherein the control unit is adapted to determine a presence of the heart-rate-lowering effect.

269. The apparatus according to claim 267, wherein the aspect of each “

on”

period includes a duration of each “

on”

period, and the aspect of each “

off”

period includes a duration of each “

off”

period, and wherein the control unit is adapted to determine the magnitude by comparing. (a) a ratio of the duration of each “

on”

period to the duration of each “

off”

period, to. (b) the duty cycle of the stimulation.

270-301. -301. (canceled)

302. A method comprising:

applying to a site of a subject a current in respective bursts in each of a plurality of cardiac cycles of the subject, each of the bursts including two or more pulses, the site selected from the list consisting of;

a vagus nerve of the subject, an epicardial fat pad of the subject, a pulmonary vein of the subject, a carotid artery of the subject, a carotid sinus of the subject, a coronary sinus of the subject, a vena cava vein of the subject, a right ventricle of the subject, and a jugular vein of the subject; and

counting a number of pulses applied to the site.

303. The method according to claim 302, wherein applying the current comprises applying the current intermittently during alternating “

on” and

“

off”

periods, each of the “

on”

periods having an “

on”

duration equal to between 1 and 10 seconds, and each of the “

off”

periods having an “

off”

duration equal to at least 50% of the “

on”

duration.

304. The method according to claim 302, wherein applying the current comprises configuring the current so as to reduce a heart rate of the subject.

305. The method according to claim 302, wherein applying the current comprises configuring the current so as to increase a heart rate of the subject.

306. The method according to claim 302, wherein applying the current comprises configuring the current so as to minimize an effect of the applying of the current on a heart rate of the subject.

307. The method according to claim 302, wherein counting the number of pulses applied to the site comprises counting the number of pulses applied to the site during a period of time, and comprising:

counting a number of bursts applied to the site during the period; and

calculating an average number of pulses per burst by dividing the number of pulses counted during the period by the number of bursts counted during the period.

309. The method according to claim 302, comprising:

sensing heart beats of the subject;

counting a number of bursts applied to the site during a period of time; and

counting a number of heart beats sensed during the period.

310. The method according to claim 309, comprising calculating an average number of bursts per heart beat by dividing the number of bursts counted during the period by the number of heart beats counted during the period.

311. The method according to claim 310, wherein applying the current comprises modifying a parameter responsively to the average number of bursts per heart beat, the parameter selected from the list consisting of:

a parameter of the current, and a parameter of a feedback algorithm used to apply the current.

313. The method according to claim 309, comprising:

counting the number of pulses applied to the site during the period; and

calculating an average number of pulses per burst by dividing the number of pulses counted during the period by the number of bursts counted during the period.

314. The method according to claim 302, comprising:

sensing heart beats of the subject;

counting a number of pulses applied to the site during a period of time; and

counting a number of heart beats sensed during the period.

315. The method according to claim 314, comprising:

counting a number of bursts applied to the site during the period; and

calculating an average number of pulses per burst by dividing the number of pulses counted during the period by the number of bursts counted during the period.

316. The method according to claim 314, comprising calculating an average number of pulses per heart beat by dividing the number of pulses counted during the period by the number of heart beats counted during the period.

317. The method according to claim 302, wherein the site includes the vagus nerve, and wherein applying the current comprises applying the current to the vagus nerve.

308. (canceled)

312. (canceled)

318. A method comprising:

sensing a physiological parameter of a subject;

applying a current to a site of the subject selected from the list consisting of;

a vagus nerve of the subject, an epicardial fat pad of the subject, a pulmonary vein of the subject, a carotid artery of the subject, a carotid sinus of the subject, a coronary sinus of the subject, a vena cava vein of the subject, a right ventricle of the subject, and a jugular vein of the subject;

configuring a parameter of the current responsively to the sensed physiological parameter;

calculating an average of the current parameter, over a period of time having a duration of at least 1 minute; and

regulating the current parameter such that the average of the current parameter does not exceed a maximum current parameter level regardless of the sensed physiological parameter.

319. The method according to claim 318, wherein regulating the current parameter comprises modifying a parameter of a feedback algorithm used to apply the current.

320. The method according to claim 318, wherein applying the current comprises applying the current intermittently during alternating “

on” and

“

off”

periods, each of the “

on”

periods having an “

on”

duration equal to at least 1 second, and each of the “

off”

periods having an “

off”

duration equal to at least 50% of the “

on”

duration.

321-339. -339. (canceled)

340. A method comprising:

sensing a heart rate of a subject;

applying a current to a site of the subject selected from the list consisting of;

a vagus nerve of the subject, an epicardial fat pad of the subject, a pulmonary vein of the subject, a carotid artery of the subject, a carotid sinus of the subject, a coronary sinus of the subject, a vena cava vein of the subject, a right ventricle of the subject, and a jugular vein of the subject; and

configuring the current responsively to a comparison of. (a) the sensed heart rate and (b) a target heart rate that is a function of an average heart rate of the subject.

341. The method according to claim 340, wherein configuring the current comprises determining the target heart rate in real time.

342. The method according to claim 340, wherein configuring the current comprises determining the average heart rate of the subject responsively to the sensed heart rate of the subject.

346. The method according to claim 340, wherein configuring the current comprises setting the target heart rate greater than the average heart rate.

347. The method according to claim 340, wherein the site includes the vagus nerve, and wherein applying the current comprises applying the current to the vagus nerve.

343-345. -345. (canceled)

348. A method comprising:

applying to a site of a subject a current that changes a heart rate of the subject, the site selected from the list consisting of;

a vagus nerve of the subject, an epicardial fat pad of the subject, a pulmonary vein of the subject, a carotid artery of the subject, a carotid sinus of the subject, a coronary sinus of the subject, a vena cava vein of the subject, a right ventricle of the subject, and a jugular vein of the subject; and

gradually modifying at least one parameter of the current by less than a percentage selected from the list consisting of;

50% of a pre-termination value per heart beat of the subject, and 5% per heart beat of the subject, until the parameter reaches a desired value, during a transitional period selected from the list consisting of;

a commencement of stimulation period, and a termination of stimulation period.

349. The method according to claim 348, wherein gradually modifying the parameter comprises gradually modifying the parameter during the transitional period, which transitional period includes the commencement of stimulation period and has a duration of at least 24 hours, such that a level of vagal stimulation caused by the current gradually increases.

351. The method according to claim 348, wherein applying the current comprises applying the current in respective bursts of pulses in each of a plurality of cardiac cycles of the subject.

352. The method according to claim 351, wherein the parameter is selected from the list consisting of:

pulses per burst, pulse frequency, and pulse width, and wherein gradually modifying the parameter comprises gradually modifying the selected parameter.

350. (canceled)

353. (canceled)

354. A method comprising:

sensing a heart rate of a subject;

applying to a site of the subject a current in respective bursts in each of a plurality of cardiac cycles of the subject, each of the bursts including one or more pulses;

setting a number of pulses in each of the bursts, using a feedback algorithm that includes as an input thereto the sensed heart rate; and

modifying at least one parameter if an average number of pulses per burst crosses a threshold value, the parameter selected from the list consisting of;

a parameter of the current, and a parameter of the feedback algorithm.

355. The method according to claim 354, wherein the site is selected from the list consisting of:

a vagus nerve of the subject, an epicardial fat pad of the subject, a pulmonary vein of the subject, a carotid artery of the subject, a carotid sinus of the subject, a coronary sinus of the subject, a vena cava vein of the subject, a right ventricle of the subject, and a jugular vein of the subject, and wherein applying the current comprises applying the current to the selected site.

356. The method according to claim 355, wherein the parameter of the feedback algorithm includes a target heart rate, and wherein modifying the at least one parameter comprises modifying the target heart rate if the average number of pulses per burst crosses the threshold value.

357. The method according to claim 355, wherein the parameter of the feedback algorithm includes a reaction speed parameter governing the feedback algorithm, and wherein modifying the at least one parameter comprises modifying the reaction speed parameter if the average number of pulses per burst crosses the threshold value.

358. The method according to claim 355, wherein the parameter of the current includes an amplitude of the current, and wherein modifying the at least one parameter comprises modifying the amplitude if the average number of pulses per burst crosses the threshold value.

363. The method according to claim 355, wherein the site includes the vagus nerve, and wherein applying the current comprises applying the current to the vagus nerve.

359-362. -362. (canceled)

364. A method comprising:

sensing a heart rate of a subject;

applying to a site of the subject electrical stimulation in respective bursts in each of a plurality of cardiac cycles of the subject, each of the bursts including one or more pulses;

setting at least one primary parameter of the stimulation, using a feedback algorithm that includes as an input thereto the sensed heart rate; and

modifying at least one secondary parameter if an average duty cycle of the stimulation crosses a threshold value, the secondary parameter selected from the list consisting of;

a parameter of the stimulation, and a parameter of the feedback algorithm.

365. The method according to claim 364, wherein the site is selected from the list consisting of:

a vagus nerve of the subject, an epicardial fat pad of the subject, a pulmonary vein of the subject, a carotid artery of the subject, a carotid sinus of the subject, a coronary sinus of the subject, a vena cava vein of the subject, a right ventricle of the subject, and a jugular vein of the subject, and wherein applying the electrical stimulation comprises applying the electrical stimulation to the selected site.

366. The method according to claim 365, wherein the secondary parameter includes the primary parameter, and wherein modifying the at least one secondary parameter comprises modifying the at least one primary parameter if the average duty cycle crosses the threshold value.

367. The method according to claim 365, wherein the secondary parameter includes a target heart rate, and wherein modifying the at least one secondary parameter comprises modifying the target heart rate if the average duty cycle of the stimulation crosses the threshold value.

368. The method according to claim 365, wherein the secondary parameter includes a reaction speed parameter governing the feedback algorithm, and wherein modifying the at least one secondary parameter comprises modifying the reaction speed parameter if the average duty cycle of the stimulation crosses the threshold value.

369. The method according to claim 365, wherein the secondary parameter includes an amplitude of the current, and wherein modifying the at least one secondary parameter comprises modifying the amplitude if the average duty cycle of the stimulation crosses the threshold value.

372. The method according to claim 365, wherein the site includes the vagus nerve, and wherein applying the stimulation comprises applying the stimulation to the vagus nerve.

370-371. -371. (canceled)

373. A method comprising:

sensing a heart rate of a subject;

applying to a site of the subject intermittently during alternating “

on” and

“

off”

periods, electrical stimulation capable of lowering the heart rate, the stimulation having a duty cycle expressed as a number of stimulations per heart beat, and each of the “

on”

periods having an “

on”

duration equal to at least 1 second, and each of the “

off”

periods having an “

off”

duration equal to at least 50% of the “

on”

duration;

responsively to the sensed heart rate, setting at least one parameter of the stimulation; and

determining a magnitude of a heart-rate-lowering effect of the stimulation by comparing an aspect of each “

on”

period to an aspect of each “

off”

period.

374. The method according to claim 373, wherein the site is selected from the list consisting of:

a vagus nerve of the subject, an epicardial fat pad of the subject, a pulmonary vein of the subject, a carotid artery of the subject, a carotid sinus of the subject, a coronary sinus of the subject, a vena cava vein of the subject, a right ventricle of the subject, and a jugular vein of the subject, and wherein applying the electrical stimulation comprises applying the electrical stimulation to the selected site.

375. The method according to claim 374, wherein determining the magnitude of the heart-rate-lowering effect comprises determining a presence of the heart-rate-lowering effect.

376. The method according to claim 374, wherein the aspect of each “

on”

period includes a duration of each “

on”

period, and the aspect of each “

off”

period includes a duration of each “

off”

period, and wherein determining the magnitude comprises comparing. (a) a ratio of the duration of each “

on”

period to the duration of each “

off”

period, to. (b) the duty cycle of the stimulation.

377-383. -383. (canceled)

384. A method comprising:

applying a current to a site of a subject selected from the list consisting of;

a vagus nerve of the subject, an epicardial fat pad of the subject, a pulmonary vein of the subject, a carotid artery of the subject, a carotid sinus of the subject, a coronary sinus of the subject, a vena cava vein of the subject, a right ventricle of the subject, and a jugular vein of the subject;

sensing a first physiological parameter of the subject;

configuring a parameter of the current responsively to the first physiological parameter;

while the subject is exercising, sensing a second physiological parameter of the subject at a plurality of different exercise levels of exertion of the subject; and

determining a tolerance of the subject to the application of the current by analyzing the second physiological parameter at the plurality of different exercise levels.

385. The method according to claim 384, wherein applying the current comprises:

applying the current during a plurality of time periods; and

configuring at least one parameter of the current to have a different value during each of the time periods,

wherein sensing the second physiological parameter comprises sensing the second physiological parameter during the plurality of time periods.

386. The method according to claim 384, comprising configuring the current responsively to determining the tolerance.

387. The method according to claim 384, wherein a first one of the different exercise levels of exertion includes a resting level of exertion, and wherein sensing the second physiological parameter comprises sensing the second physiological parameter at the first exercise level.

388. The method according to claim 384, wherein a first one of the different exercise levels of exertion includes a recovery from exercise level of exertion, and wherein sensing the second physiological parameter comprises sensing the second physiological parameter at the first exercise level.

389. The method according to claim 384, comprising adjusting the parameter of the current so as to achieve a heart rate of the subject at which the heart is maximally effective.

390. The method according to claim 384, wherein the site includes the vagus nerve, and wherein applying the current comprises applying the current to the vagus nerve.

391. The method according to claim 384, wherein the first physiological parameter includes a heart rate of the subject, and wherein configuring the parameter of the current comprises configuring the parameter of the current responsively to the heart rate of the subject.

392. The method according to claim 391, wherein configuring the parameter comprises increasing a strength of the current responsively to an increase in the heart rate.

393. A method comprising:

applying a current to a site of a subject selected from the list consisting of;

a vagus nerve of the subject, an epicardial fat pad of the subject, a pulmonary vein of the subject, a carotid artery of the subject, a carotid sinus of the subject, a coronary sinus of the subject, a vena cava vein of the subject, a right ventricle of the subject, and a jugular vein of the subject;

while the subject is exercising, sensing, at a plurality of different exercise levels of exertion of the subject, a physiological parameter of the subject indicative of an effectiveness of a heart of the subject; and

responsively to the physiological parameter, configuring a parameter of the current to change a heart rate of the subject to a rate at which the effectiveness increases.

394. The method according to claim 393, wherein applying the current comprises:

applying the current during a plurality of time periods; and

configuring the parameter of the current to have a different value during each of the time periods.

395. The method according to claim 393, wherein the site includes the vagus nerve, and wherein applying the current comprises applying the current to the vagus nerve.

396. A method comprising:

during a calibration period of time that includes a plurality of different naturally-occurring heart rates of a subject, intermittently applying a calibration current to a site of the subject during a plurality of alternating “

on” and

“

off”

periods, each of the “

on”

periods having an “

on”

duration equal to at least 1 second, and each of the “

off”

periods having an “

off”

duration equal to at least 50% of the “

on”

duration,

the site selected from the list consisting of;

a vagus nerve of the subject, an epicardial fat pad of the subject, a pulmonary vein of the subject, a carotid artery of the subject, a carotid sinus of the subject, a coronary sinus of the subject, a vena cava vein of the subject, a right ventricle of the subject, and a jugular vein of the subject;

sensing a heart rate of the subject during the calibration period; and

for each of two or more of the “

on”

periods, plotting a point on a graph, a first coordinate of the point indicative of an “

on”

average heart rate of the subject during the “

on”

period, and a second coordinate of the point indicative of an “

off”

average heart rate during at least one of;

the “

off”

period immediately preceding the “

on”

period, and the “

off”

period immediately following the “

on”

period.

397. The method according to claim 396, wherein applying the calibration current comprises subjecting the subject to an exercise test during at least a portion of the calibration period.

398. The method according to claim 396, wherein plotting the point comprises expressing the “

on” and

“

off”

average heart rates as R-R intervals.

399. The method according to claim 398, wherein the first and second coordinates are y- and x-coordinates of the point, respectively, and comprising interpreting that the point lies above a line defined by x=y as an indication that the “

on”

average heart rate is less than the “

off”

average heart rate for the point.

400. The method according to claim 396, wherein applying the calibration current comprises:

subjecting the subject to an exercise test during at least a first portion of the calibration period;

instructing the subject to relax during at least a second portion of the calibration period; and

instructing the subject to rest during at least a third portion of the calibration period.

401. The method according to claim 396, wherein each of the “

on”

periods has a duration of between 45 and 75 seconds, and wherein each of the “

off”

periods has a duration of between 90 and 150 seconds.

402. The method according to claim 396, wherein the calibration period includes at least 200 “

on”

periods and at least 200 “

off”

periods.

403. The method according to claim 396, wherein the calibration period has a duration of at least 24 hours.

404. The method according to claim 396, wherein the site includes the vagus nerve, and wherein applying the calibration current comprises applying the current to the vagus nerve.