EP2106275A2 - Stimulation nerveuse dynamique employant une modulation de fréquence - Google Patents

Stimulation nerveuse dynamique employant une modulation de fréquence

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Publication number
EP2106275A2
EP2106275A2 EP07809483A EP07809483A EP2106275A2 EP 2106275 A2 EP2106275 A2 EP 2106275A2 EP 07809483 A EP07809483 A EP 07809483A EP 07809483 A EP07809483 A EP 07809483A EP 2106275 A2 EP2106275 A2 EP 2106275A2
Authority
EP
European Patent Office
Prior art keywords
stimulation
nerve
intensity
pattern
period
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07809483A
Other languages
German (de)
English (en)
Inventor
John D. Dobak
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Leptos Biomedical Inc
Original Assignee
Leptos Biomedical Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US11/657,877 external-priority patent/US7702386B2/en
Application filed by Leptos Biomedical Inc filed Critical Leptos Biomedical Inc
Publication of EP2106275A2 publication Critical patent/EP2106275A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/36007—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation of urogenital or gastrointestinal organs, e.g. for incontinence control
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
    • A61N1/3606—Implantable neurostimulators for stimulating central or peripheral nerve system adapted for a particular treatment
    • A61N1/36082—Cognitive or psychiatric applications, e.g. dementia or Alzheimer's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor

Definitions

  • the indicators of metabolic syndrome include obesity, and particularly obesity around the waist. A waistline of 40 inches or more for men and 35 inches or more for women would qualify. Another indicator is high blood pressure such as a blood pressure of 130/85 mm Hg or greater. Yet another factor is one or more abnormal cholesterol levels including a high density lipoprotein level (HDL) less than 40 mg/dL for men and under 50 mg/dL for women. A triglyceride level above 150 mg/dL may also be an indicator. Finally, a resistance to insulin is an indicator of metabolic syndrome which may be indicated by a fasting blood glucose level greater than 100 mg/dL.
  • HDL high density lipoprotein level
  • pancreas can not keep up the levels of insulin necessary to maintain proper blood glucose levels by stimulating absorption, and glucose levels continue to increase.
  • Chronic stimulation of insulin-producing cells of the pancreas eventually results in a significant decrease in insulin output, a condition known as Type ⁇ diabetes.
  • onset of metabolic syndrome occurs prior to the onset of Type ⁇ diabetes.
  • the stimulation pattern comprises a frequency, a pulse width, and a current, the frequency is between about 0.1Hz and about 50Hz, the pulse width is between about 100 microseconds and about 1 millisecond, and the current is between about 0.1 mA and about 10 mA.
  • the stimulation pattern comprises an signal-on time and an off time, and the off time is no less than the signal-on time.
  • the stimulation pattern comprises a substantially continuous signal-on time, wherein the signal-on time is comprised of at least one suprathreshold period and at least one subthreshold period. In certain embodiments, the subthreshold period is no less than the suprathreshold period.
  • the suprathreshold period is greater than the subthreshold period.
  • the method further comprises providing a first electrical signal to the splanchnic nerve at a first stimulation intensity during a first portion of a first stimulation period, the stimulation period comprises at least one on-time, the on-time comprises at least one of a suprathreshold period and a subthreshold period; applying a second electrical signal to the splanchnic nerve at a second stimulation intensity during a second portion of the first stimulation period; ceasing or substantially reducing the applying of the second signal during a first no-stimulation period; thereafter, applying a third electrical signal to the splanchnic nerve at a third stimulation intensity during a first portion of a second stimulation period, the stimulation period comprises at least one on-time, the on-time comprises at least one of a suprathreshold period and a subthreshold period; applying a fourth electrical signal to the splanchnic nerve at a fourth stimulation intensity during a second portion of
  • the second stimulation intensity is greater than the first stimulation intensity.
  • fourth stimulation intensity is greater than the third stimulation intensity.
  • the second stimulation intensity is greater than the first stimulation intensity, and the fourth stimulation intensity is greater than the third stimulation intensity.
  • the third stimulation intensity is approximately equal to the first stimulation intensity.
  • the duration of the first no-stimulation period is approximately equal to the duration of the second no-stimulation period.
  • the duration of the first stimulation period is approximately equal to the duration of the second stimulation period.
  • the duration of the first portion of the first stimulation period is approximately equal to the duration of the second portion of the first stimulation period.
  • the duration of the first portion of the second stimulation period is approximately equal to the duration of the second portion of the second stimulation period.
  • the method comprises applying a first plurality of temporally sequential electrical signals during a first plurality of respective stimulation periods, each of the first plurality of signals having a stimulation intensity that is greater than the stimulation intensity of the preceding signal, each stimulation period comprises at least one on-time, the on-time comprises at least one of a suprathreshold period and a subthreshold period; thereafter, ceasing or substantially reducing electrical stimulation to the splanchnic nerve during a first no-stimulation period; thereafter, applying a second plurality of temporally sequential electrical signals during a second plurality of respective stimulation periods, each of the second plurality of signals having a stimulation intensity that is greater than the stimulation intensity of the preceding signal, each stimulation period comprises at least one on-time, the on-time comprises at least one of a suprathreshold period and a subthreshold period; and thereafter, ceasing or
  • the dyslipidemia comprises elevated triglycerides. In certain embodiments, the dyslipidemia comprises elevated LDL. In certain embodiments, the attendant condition comprises an elevated blood pressure. In certain embodiments, the attendant- condition comprises hyperglycemia. In certain embodiments, the attendant condition comprises hyperinsulinemia. In certain embodiments, the attendant condition comprises insulin resistance.
  • a method to increase lean muscle mass of a patient comprises electrically modulating a sympathetic nerve of a patient in a stimulation pattern effective to increase a lean muscle mass of the patient, wherein the stimulation pattern comprises at least one on-time.
  • the on-time comprises at least one of a suprathreshold period and a subthreshold period.
  • the method further comprises secondly (2) thereafter, electrically simulating the splanchnic nerve for a second time and at a second stimulation intensity during the first stimulation period, the second stimulation intensity being greater than the first stimulation intensity.
  • the method further comprises thirdly (3) thereafter, providing a second period during which electrical stimulation at the splanchnic nerve is less than the first stimulation intensity.
  • the subthreshold period is zero or about zero seconds.
  • the method comprises repeating steps 1-3.
  • a duration of the second period is configured to minimize weight gain or maximize weight loss in the mammal during the period.
  • the method comprises electrically stimulating the splanchnic nerve at least one additional time between the first time and the second time during the first stimulation period.
  • the second stimulation intensity is about 1% to about 10,000% greater than the first stimulation intensity. In certain embodiments, the second stimulation intensity is about 2% to about 1,000% greater than the first stimulation intensity. In certain embodiments, the second stimulation intensity is about 4% to about 500% greater than the first stimulation intensity. In certain embodiments, the second stimulation intensity is about 8% to about 100% greater than the first stimulation intensity. In certain embodiments, the second stimulation intensity is about 10% to about 50% greater than the first stimulation intensity. Ih certain embodiments, the second stimulation intensity is about 15% to about 30% greater than the first stimulation intensity. In certain embodiments, the second stimulation intensity is about 20% greater than the first stimulation intensity. In certain embodiments, the first stimulation intensity is about equal to the threshold for skeletal muscle twitch in the mammal.
  • the mammal is a human.
  • the first time is between about 30 seconds and about 300 days. Ih certain embodiments, the first time is between about one minute and about 100 days. In certain embodiments, the first time is between about five minutes and about 50 days. In certain embodiments, the first time is between about 30 minutes and about 30 days. In certain embodiments, the first time is between about one hour and about seven days. In certain embodiments, the first time is between about four hours and about four days. In certain embodiments, the first time is between about six hours and about 36 hours. Ih certain embodiments, the first time is between about 20 hours and about 28 hours. In certain embodiments, the first time is about 24 hours. In certain embodiments, the second time is between about 30 seconds and about 300 days.
  • the second time is between about one minute and about 100 days. In certain embodiments, the second time is between about five minutes and about 50 days. In certain embodiments, the second time is between about 30 minutes and about 30 days. In certain embodiments, the second time is between about one hour and about seven days. In certain embodiments, the second time is between about four hours and about four days. In certain embodiments, the second time is between about six hours and about 36 hours, hi certain embodiments, the second time is between about 20 hours and about 28 hours. In certain embodiments, the second time is about 24 hours. In certain embodiments, the first time is approximately equal to the second time. In certain embodiments, the second period is between about 30 seconds and about 300 days. In certain embodiments, the second period is between about one minute and about 100 days.
  • the second period is between about five minutes and about 50, days. In certain embodiments, the second period is between about 30 minutes and about 30 days. In certain embodiments, the second period is between about one hour and about 15 days. In certain embodiments, the second period is between about one day and about ten days. In certain embodiments, the second period is between about two days and about seven days. In certain embodiments, the second period is between about three days and about five days. In certain embodiments, the second period is about four days.
  • an implantable pulse generator programmed to modulate electrically a splanchnic nerve in a mammal.
  • the implantable pulse generator comprises providing a first electrical signal to the splanchnic nerve at a first stimulation intensity during a first portion of a first stimulation period, the first stimulation period comprises at least one on-time, the on-time comprises at least one of a suprathreshold period and a subthreshold period, wherein the splanchnic nerve is selected from the group consisting of the greater splanchnic nerve, the lesser splanchnic nerve, and the least splanchnic nerve.
  • the implantable pulse generator further comprises providing a second electrical signal to the splanchnic nerve at a second stimulation intensity during a second portion of a first stimulation period.
  • the implantable pulse generator further comprises ceasing or substantially reducing the providing of the second signal during a first no-stimulation period.
  • the implantable pulse generator further comprises thereafter providing a third electrical signal to the splanchnic nerve at a third stimulation intensity during a first portion of a second stimulation period, the second stimulation period comprises at least one on-time, the on-time comprises at least one of a suprathreshold period and a subthreshold period.
  • the implantable pulse generator further comprises providing a fourth electrical signal to the splanchnic nerve at a fourth stimulation intensity during a second portion of a second stimulation period.
  • the implantable pulse generator further comprises ceasing or substantially reducing the providing of the fourth signal during a second no-stimulation period.
  • the implantable pulse generator is configured such that the second stimulation intensity is greater than the first stimulation intensity, and the fourth stimulation intensity is greater than the third stimulation intensity.
  • an implantable pulse generator programmed to modulate electrically a splanchnic nerve in a mammal.
  • the implantable pulse generator comprises firstly (1) electrically stimulating the splanchnic nerve for a first time and at a first stimulation intensity during a stimulation period, the stimulation period comprises at least one on-time, the on-time comprises at least one of a suprathreshold period and a subthreshold period, wherein the splanchnic nerve is selected from the group consisting of the greater splanchnic nerve, the lesser splanchnic nerve, and the least splanchnic nerve.
  • the implantable pulse generator further comprises secondly (2) thereafter, electrically simulating the splanchnic nerve for a second time and at a second stimulation intensity during the first stimulation period, the second stimulation intensity being greater than the first stimulation intensity.
  • the implantable pulse generator further comprises thirdly (3) thereafter, providing a second period during which electrical stimulation at the splanchnic nerve is absent or substantially less than the second stimulation intensity.
  • a tissue modulation device for treating at least one of obesity, metabolic syndrome, and Type II diabetes in a patient.
  • the device comprises a storage module having computer-readable instructions for delivering an electrical stimulation pattern to a splanchnic nerve of the patient, wherein the stimulation pattern comprises at least one on-time.
  • the on-time comprises at least one of a suprathreshold period and a subthreshold period.
  • the splanchnic nerve is selected from the group consisting of the greater splanchnic nerve, the lesser splanchnic nerve, and the least splanchnic nerve.
  • the pattern is effective to ameliorate at least one attendant condition of obesity, metabolic syndrome, and Type ⁇ diabetes in the patient.
  • the attendant condition comprises at least one of dyslipidemia, hypertension, hyperinsulinemia, hyperglycemia, and insulin resistance.
  • a tissue modulation device comprising a storage module having computer-readable instructions for delivering an electrical stimulation pattern to a splanchnic nerve, wherein the stimulation pattern comprises at least one on-time.
  • the on-time comprises at least one of a suprathreshold period and a subthreshold period.
  • the splanchnic nerve is selected from the group consisting of the greater splanchnic nerve, the lesser splanchnic nerve, and the least splanchnic nerve.
  • the pattern is effective to result in an increase in the patient's lean muscle mass.
  • the device comprises an energy delivery module that is electrically coupled to the storage module, wherein the energy delivery module is configured to deliver electrical energy to the splanchnic nerve of the patient according to the instructions.
  • a tissue modulation device comprises means for storing computer-readable instructions for delivering an electrical stimulation pattern to a splanchnic nerve of the patient, wherein the stimulation pattern comprises at least one on-time.
  • the on-time comprises at least one of a suprathreshold period and a subthreshold period.
  • the splanchnic nerve is selected from the group consisting of the greater splanchnic nerve, the lesser splanchnic nerve, and the least splanchnic nerve.
  • the pattern is effective to result in an increase in the patient's lean muscle mass.
  • a method to reduce a concentration of serum triglycerides in a patient comprises electrically modulating a sympathetic nerve of a patient in a stimulation pattern, wherein the stimulation pattern comprises at least one on-time.
  • the on-time comprises at least one of a suprathreshold period and a subthreshold period.
  • the pattern is effective to reduce the concentration of serum triglycerides in the patient.
  • a splanchnic nerve comprises the sympathetic nerve, wherein the splanchnic nerve is selected from the group consisting of the greater splanchnic nerve, the lesser splanchnic nerve, and the least splanchnic nerve.
  • a tissue modulation device for treating hypertension in a patient.
  • the device comprises means for storing computer-readable instructions for electrically modulating a splanchnic nerve of a patient in a stimulation pattern, wherein the stimulation pattern comprises at least one on-time.
  • the on-time comprises at least one of a suprathreshold period and a subthreshold period.
  • the splanchnic nerve is selected from the group consisting of the greater splanchnic nerve, the lesser splanchnic nerve, and the least splanchnic nerve.
  • the pattern is effective to lower a blood pressure in the patient.
  • a tissue modulation device for treating at least one of obesity, metabolic syndrome, and Type H diabetes in a patient.
  • the device comprises means for storing computer-readable instructions for delivering an electrical stimulation pattern to a splanchnic nerve of the patient, wherein the stimulation pattern comprises at least one on-time.
  • the on-time comprises at least one of a suprathreshold period and a subthreshold period.
  • the splanchnic nerve is selected from the group consisting of the greater splanchnic nerve, the lesser splanchnic nerve, and the least splanchnic nerve.
  • the pattern is effective to ameliorate at least one attendant condition of obesity, metabolic syndrome, and Type II diabetes in the patient, without causing significant net weight loss.
  • the attendant condition comprises at least one of dyslipidemia, hypertension, hyperinsulinemia, hyperglycemia, and insulin resistance.
  • the stimulation pattern is effective to result in an increase in the. patient's lean muscle mass.
  • the device is configured to deliver the electrical signal in response to a physiological parameter.
  • the physiological parameter is at least one of eating, a blood glucose level, a blood insulin level, a blood cholesterol level, a blood HDL level, a blood LDL level, a ghrelin level, a leptin level, a catecholamine level, an adipokine level, and an arterial pressure.
  • the device further comprises a sensor configured to measure the physiological parameter, and wherein the device is configured to deliver the electrical signal in response to a signal received from the sensor.
  • the sensor is positionable within the body of the mammal.
  • the device is configured to be implanted in a human patient.
  • the device is configured to deliver the electrical signal in response to a command from the patient.
  • the stimulation intensity pattern comprises: stimulating at a first intensity during at least a portion of a first interval; stimulating at a second intensity during at least a portion of a second interval. In some embodiments, the stimulation intensity pattern is repeated at least once in a 24 hour period.
  • the first intensity is about 2.5 mA to about 5 mA.
  • the second intensity is about 0 mA to about 1.0 mA.
  • the first intensity is about 3.5 mA, and the second intensity is about 0.5 mA.
  • the stimulation frequency pattern comprises at least one change in frequency.
  • the at least one change in frequency occurs at a constant rate.
  • the at least one change in frequency occurs by at least one increment.
  • the at least one increment is about 1 Hz to about 20 Hz. In some embodiments, the at least one increment is about 2 Hz to about 10 Hz.
  • the stimulation frequency pattern comprises: applying the electrical signal at a first stimulation frequency during a first portion of the stimulation frequency pattern; applying the electrical signal at a second stimulation frequency during a second portion of the stimulation frequency pattern; applying the electrical signal at a third stimulation frequency during a third portion of the stimulation frequency pattern.
  • the first stimulation frequency is about 10 Hz
  • the second stimulation frequency is about 20 Hz
  • the third stimulation frequency is about 30 Hz.
  • the method further comprises applying the electrical signal at a fourth stimulation frequency during a fourth portion of the stimulation frequency pattern.
  • the fourth frequency is about 40 Hz.
  • the stimulation frequency pattern is repeated at least once in a 24 hour period.
  • FIG. 2 is a diagrammatic view of a sympathetic nervous system anatomy.
  • FIG. 7 shows a more detailed view of a portion of the exemplary stimulation pattern of FIG. 6.
  • FIG. 11 shows the weight (as a seven-day rolling average) and the current amplitude for canine subject '202 over the course of its 28-day, ramp-cycling therapy.
  • FIG. 12 shows the food intake (as a seven-day rolling average) and the current amplitude for canine subject '202 over the course of its 28-day, ramp-cycling therapy.
  • FIG. 15 shows the food intake (as a seven-day rolling average) and the current amplitude for canine subject '554 over the course of its 28-day, ramp-cycling therapy.
  • FIG. 22 shows the food intake (as a seven-day rolling average) and the current amplitude for canine subject '202, in which both the maximum stimulation intensity, and the level to which the stimulation intensity is decreased, are variable parameters.
  • FIG. 23 shows the percent change (relative to day one) in weight and food intake for canine subject '202 over the course its ramp-cycling therapy in which both the maximum stimulation intensity, and the level to which the stimulation intensity is decreased, are variable parameters.
  • FIG. 27 is a graphical representation showing change in body fat as a percentage of total body mass for two sets of test subjects and a control set as determined by DEXA scanning.
  • FIG. 27A illustrates graphical data showing percentage change in total cholesterol, FJDL cholesterol and LDL cholesterol from baseline for canine test subjects.
  • FIG. 28 shows a ramp-cycling technique where the maximum stimulation intensity is also a parameter that is varied over the course of multiple stimulation time periods.
  • FIG. 36 is a graphical representation of an embodiment of an electrical signal waveform.
  • FIG. 41 is a diagrammatic view of an exemplary catheter-type lead and electrode assembly.
  • electrically activating a splanchnic nerve of a patient using a stimulation pattern may ameliorate or eliminate an attendant conditions of obesity, metabolic syndrome, and/or Type II diabetes in a patient.
  • attendant conditions such as dyslipidemia, hypertension, hyperinsulinemia, hyperglycemia, and insulin resistance may be affected.
  • the stimulation pattern may ameliorate or eliminate an attendant condition of obesity, metabolic syndrome, and/or Type H diabetes without producing a significant net loss in total body weight.
  • lean muscle mass increases in a proportion approximately equal to or greater than an amount of fat mass that is lost.
  • FIG. 27 is a graphical representation showing change in body fat as a percentage of total body mass including mean value plus standard deviation for two sets of test subjects and a control set as determined by DEXA scanning. Growth trends showed a sharp decline in body mass during stimulation ramping, and after a 1 month transition period, sustained reduction in weight gain relative to Control group animals. When stimulation was initially terminated, another sharp decline in food intake and body mass was observed, followed by a gradual return to baseline after 3 weeks.
  • the stimulation intensity is initially set to a value approximately equal to the muscle twitch threshold.
  • the stimulation intensity is then increased at regular intervals until the chosen maximum stimulation intensity is achieved, which may fall in a range of about 8 times to about 10 times the muscle twitch threshold.
  • the stimulation intensity is increased in regular increments and at regular intervals.
  • the stimulation intensity is increased by about 10% to about 20% of the value of the previous stimulation intensity until the desired maximum stimulation intensity is attained. Once the desired maximum stimulation intensity is attained, the stimulation intensity is reduced in a single step to the muscle twitch threshold.
  • this pattern of increasing the stimulation intensity to about 8 times to about 10 times the muscle twitch threshold and reducing the stimulation intensity back down to about the muscle twitch threshold is repeated for a period of about 1 week to about 4 months. Following that period of about 1 week to about 4 months, the pattern is changed such that the maximum stimulation intensity for the next week to several months is set to about 2 times to about 4 times the muscle twitch threshold, rather than about 8 times to about 10 times the muscle twitch threshold.
  • the first cycle is re-instituted whereby the maximum peak intensity is set again to about 8 times to about 10 times the muscle twitch threshold for about 1 week to about 4 months.
  • a schematic diagram of this embodiment is shown in FIG. 28. The overarching pattern of changes to the maximum stimulation intensity may then be repeated regularly or in a random pattern.
  • some embodiments of treating a patient by modulation of at least a portion of a sympathetic nervous system of a patient may include activating a splanchnic nerve of the patient with a first electrical signal during an activation interval and inhibiting nerve transmission of the splanchnic nerve of the patient with a second electrical signal during an inhibition interval.
  • the activation and inhibition may be carried out at different times relative to each other.
  • the modulation includes a plurality of activation intervals and a plurality of inhibition intervals. Each activation interval is alternated with an inhibition interval in order to reduce tolerance to the modulation by the sympathetic nervous system of the patient.
  • Tolerance to the modulation may include habituation, compensation, tachyphylaxis as well as other mechanisms.
  • the length of the activation intervals may be substantially equal to the length of the inhibition intervals. Ih certain embodiments, the length of the activation intervals may be greater than the length of the inhibition intervals. For example, in some embodiments, the length of the activation intervals is about 1.5 times to about 10 times greater than the length of the inhibition intervals.
  • Such embodiments of stimulation patterns may be used to treat metabolic syndrome, obesity, or any of the attendant or contributing conditions of metabolic syndrome.
  • the stimulation frequency and/or the duty cycle may operate to optimize the activation of a given subset of fibers.
  • the stimulation frequency is about 20 Hz to about 30 Hz
  • the stimulation duty cycle is set to about 30% to about 50%.
  • the changes in the stimulation duty cycle may be accomplished by fixing the signal on-time to a certain duration (e.g. about 15 seconds to about 60 seconds), and the signal-off time may be varied from about 15 seconds to about 5 minutes.
  • the fixed signal on-time would be a suprathreshold period, as described above. This maybe accomplished randomly or through a preset pattern such as 50%, 33%, 25%, 20%, 10% that repeats upward and/or downward indefinitely.
  • the on- time may comprise both suprathreshold and subthreshold periods. In certain embodiments, the suprathreshold period would be longer than the subthreshold period.
  • the duty cycle is “longer” or “shorter,” depending on the length of the subthreshold period. This reflects the use of the term duty cycle to mean the total period for one suprathreshold/subthreshold period cycle. If there is any ambiguity, one of ordinary skill in the art will understand from the context or the units provided whether the quantity being referred to is the total time, or the ratio of the suprathreshold period to the sum of the suprathreshold period plus the subthreshold period, the definition primarily used herein.
  • norepinephrine and epinephrine are approximately 25 pg/mL and 300 pg/mL, respectively, as shown in FIG. 30. Detectable physiologic changes such as increased heart rate occur at norepinephrine levels of approximately 1,500 pg/mL and epinephrine levels of approximately 50 pg/mL. Venous blood levels of norepinephrine may reach as high 2,000 pg/mL during heavy exercise, and levels of epinephrine can reach as high as 400 to 600 pg/mL during heavy exercise.
  • Splanchnic nerve stimulation has been shown to eliminate or substantially reduce ghrelin surges or spikes.
  • WAT white adipose tissue
  • TNF- ⁇ tumor necrosis factor a.
  • adiponectin adipokine
  • metabolic syndrome may be treated by reducing insulin resistance in a patient by stimulation of at least one sympathetic nerve in order to stimulate secretion or increased secretion of anti-inflammatory hormones such as IL-6.
  • the modulation or stimulation of the sympathetic nerves may be carried out by any of the devices or methods discussed herein.
  • a level of catecholamine or other level may be measured by any suitable variety of methods or otherwise sensed by sensor.
  • the level of catecholamine may then be communicated to a processor of a pulse generator which may compare the measured or sensed level to a predetermined target level and select treatment energy parameters or patterns which are configured to adjust the level to the target level.
  • Such an arrangement may be controlled by a feedback loop or the like.
  • Signals may be sent to four electrodes, timed such that when the efferent activation pair created a bi-directional action potential, the blocking pair would be active as the afferent potential traveled up the nerve.
  • the blocking pair can be activated continuously during the treatment period.
  • a tripolar electrode may also be used to get activation of a select fiber size bilaterally or to get unilateral activation.
  • a tripolar electrode with the cathode flanked proximally and distally by anodes may be used. Unidirectional activation may be achieved by moving the cathode closer to the proximal electrode and delivering differential current ratios to the anodes.
  • the various circuitry components of the IPG 28 may be housed in an epoxy-titanium shell 38.
  • the IPG shell 38 is generally disc shaped and may have an outer transverse dimension of about 3 cm to about 15 cm and a thickness of about 3 mm to about 15 mm.
  • a wireless system may be employed by having an electrode that inductively couples to an external radiofrequency field.
  • a wireless system may be used to avoid problems such as lead fracture and migration, found in wire-based systems. It would also simplify the implant procedure, by allowing simple injection of the wireless electrode in proximity to the splanchnic nerve, and avoiding the need for lead anchoring, tunneling, and subcutaneous pulse generator implantation.
  • a wireless electrode embodiment 54 may contain a coil/capacitor element 56 that may receive a radiofrequency signal.
  • the radiofrequency signal may be generated by a device that would create an electromagnetic field sufficient to power the electrode. It may also provide for the transmission of information configured to set the desired stimulation parameters such as frequency, pulse width, current amplitude, signal on/off time and the like.
  • Embodiments of the radiofrequency signal generator can be worn externally or implanted subcutaneously.
  • Embodiments of the electrode may also have metallic elements for electrically coupling to the tissue or splanchnic nerve. The metallic elements can be made of platinum or platinum iridium.
  • the wireless electrode may have a battery that would be charged by an radiofrequency field that would then provide stimulation during intervals without an radiofrequency field.
  • a larger energy field may be created in order to couple electrically the electrode on the lead with the remote external portion of the IPG, and the generation of this larger energy field may result in activation of the nerve even in the absence of close proximity between the single lead electrode and the nerve.
  • This allows successful nerve stimulation with the single electrode placed in "general proximity" to the nerve, meaning that there may be significantly greater separation between the electrode and the nerve than the "close proximity” used for bipolar stimulation.
  • the magnitude of the allowable separation between the electrode and the nerve will necessarily depend upon the actual magnitude of the energy field that the operator generates with the lead electrode in order to couple with the remote electrode.
  • Proximity to the splanchnic nerve by the introducer can be sensed by providing energy pulses to the introducer electrically to activate the nerve while monitoring for a rise in MAP or muscle twitching. All but the tip of the introducer can be electrically isolated so as to focus the energy delivered to the tip of the introducer. The lower the current amplitude used to cause a rise in the MAP or muscle twitch, the closer the introducer tip would be to the nerve.
  • the introducer tip serves as the cathode for stimulation.
  • a stimulation endoscope can be placed into the stomach of the patient for electrical stimulation of the stomach.
  • the evoked potentials created in the stomach may be sensed in the splanchnic nerve by the introducer.
  • the introducer can sense evoked potentials created by electrically activating peripheral sensory nerves.
  • evoked potentials can be created in the lower intercostal nerves or upper abdominal nerves and sensed in the splanchnic.
  • a catheter type lead electrode assembly would be inserted through the introducer and adjacent to the nerve.
  • a wireless, radiofrequency battery charged, electrode may be advanced through the introducer to reside alongside the nerve. In either case, stimulating the nerve and monitoring for a rise in MAP or muscle twitch can be used to confirm electrode placement.
  • stimulation electrodes may be placed along the sympathetic chain ganglia from approximately vertebra T4 to TI l. This implantation may be accomplished in a similar percutaneous manner as discussed above. This may create a more general activation of the sympathetic nervous system, though it would include activation of the neurons that comprise the splanchnic nerves.
  • the lead/electrode assembly may be placed intra- abdominally on the portion of the splanchnic nerve that resides retroperitoneally on the abdominal aorta just prior to synapsing in the celiac ganglia. Access to the nerve in this region can be accomplished laparoscopically, using typical laparoscopic techniques, or via open laparotomy.
  • a cuff electrode may be used to encircle the nerve unilaterally or bilaterally.
  • the lead can be anchored to the eras of the diaphragm.
  • a cuff or patch electrode can also be attached to the celiac ganglia unilaterally or bilaterally. Similar activation of the splanchnic branches of the sympathetic nervous system would occur as implanting the lead electrode assembly in the thoracic region.
  • the apparatus for nerve stimulation may be shielded or otherwise made compatible with magnetic resonance imaging (MRT) devices, such that the apparatus is less susceptible to current induction and its resultant heat effects and potential malfunction of electronics in the apparatus, and movement of the apparatus due to Lorentz forces.
  • MRT magnetic resonance imaging
  • This type of magnetic shielding may be accomplished by, for example, using materials for the IPG or other generator embodiments and/or electrode that are nanomagnetic or utilize carbon composite coatings.
  • Such techniques are described in U.S. Patent Nos. 6,506,972 and 6,673,999, and U.S. Patent Application No. 2002/0183796, published December 5, 2002; U.S. Patent Application No. 2003/0195570, published October 16, 2003; and U.S. Patent Application No. 2002/0147470, published October 10, 2002. The entireties of all of these references are hereby incorporated by reference.
  • the stimulation intensity and/or stimulation frequency may be changed to preset values, or they may be changed to randomly generated values, m this regard, it can be advantageous to provide a programmable EPG such that "fine-tuning" of the stimulation parameter can be varied during the course of a treatment regime in order to optimize the dynamic and frequency modulation of the neural stimulation thus achieving either a desired or a maximal rate of weight loss. Li some cases it may be desirable to lose weight at a certain rate that is less than the maximum rate of loss possible for a particular patient. Such regime would be possible with embodiments as disclosed herein.
  • the vagus nerve relays signals related to stomach distension.
  • This mechanical information is another source of information regarding fullness during feeding.
  • the frequency of impulses carried from the stomach by the vagus is directly correlated with the degree of distension.
  • stimulating afferent vagal neurons at high frequency will mimic a distended stomach.
  • By stimulating at this frequency an artificial sense of fullness results which leads to reduced feeding, and again weight loss.
  • Results from a study of five canine test subjects in which the nervous system was electrically stimulated over a period of about 30 days using an electrical signal configured according to embodiments of the present disclosure are shown in FIGS. 44 46.
  • Each test subject was given an electrical stimulus having a stimulation intensity pattern, where the nerve was stimulated at a first stimulation intensity for at least a portion of a first interval, and then at a second stimulation intensity for at least a portion of a second interval, and where the stimulation intensity pattern is repeated.
  • the first stimulation intensity was about 3.5 mA and the second stimulation intensity was about 0.5 mA.
  • the electrical signal was configured to include a frequency pattern, such that the nerve was stimulated first at 10 Hz, then at 20 Hz, then at 30 Hz, and then the frequency was returned to 10 Hz. This pattern was repeated once a day for the 30-day duration of the experiment.
  • the group receiving frequency modulated treatment showed decreases in fat and lean mass, while these values for these two parameters increased in the dynamically stimulated control group. Moreover, the treatment group receiving a frequency modulated stimulus showed a decrease in total mass, in contrast to the dynamically stimulated control group, which experienced an increase in total mass. Finally, the frequency modulated treatment group showed a very slight increase in percent body fat while the dynamically stimulated control group displayed a significantly greater increase in percent body fat.
  • frequency changes can be discrete, while in some embodiments, frequency changes continuously according to the pattern configuration dictated by the device programming, or in response to input from sensors that measure physiological parameters.
  • a number of frequency patterns are possible, of which FIGS. 47 A-C provides some examples.
  • each succeeding cycle be identical to those that precede it.
  • the time taken to change from one frequency to the next, the time spent at a particular frequency, and the actual stimulation frequencies can be varied from one iteration of the cycle to the next.
  • a cycle may be divided into equal time intervals where the time spent at each frequency is substantially the same.
  • the time period spent at one frequency may be different from the time period at one or more of the other frequencies.
  • the time taken to change from one frequency to the next in the cycle can be the same or different.
  • the cycle can be repeated once per day, or the cycle can be repeated more or less often.
  • the pattern of frequency changes and stimulation intensity interval changes may be repeated indefinitely.
  • the frequency change pattern may also be repeated during constant stimulation at a static stimulation intensity.
  • the frequency pattern may occur several times daily (for instance, in the morning, afternoon, and evening).
  • the overall simulation pattern will comprise a "layering" of several factors including duration, voltage, current, and frequency of the stimulus.
  • the IPG could be programmed to be self-homeostatic, using sensor measurements of physiological parameters as triggers to alter the ramp-cycling and/or frequency modulation parameters. Again this will enhance the rate of weight loss or aid in maintaining a target weight once that has been achieved.

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  • Measurement And Recording Of Electrical Phenomena And Electrical Characteristics Of The Living Body (AREA)

Abstract

L'invention concerne un appareil et des procédés pour moduler électriquement un nerf chez un mammifère. Un signal électrique qui comprend un dessin d'intensité de signal et un dessin de fréquence de signal est transmis à un nerf. La combinaison du dessin d'intensité de signal et du dessin de fréquence de signal permet d'aboutir à une perte de poids, une perte de graisse et/ou un gain de masse maigre, chez un mammifère. Dans certains modes de réalisation, le nerf est modulé en réponse à un paramètre physiologique. Dans certains modes de réalisation, le paramètre physiologique est mesuré par un capteur.
EP07809483A 2006-06-09 2007-06-11 Stimulation nerveuse dynamique employant une modulation de fréquence Withdrawn EP2106275A2 (fr)

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US80441506P 2006-06-09 2006-06-09
US11/657,877 US7702386B2 (en) 2002-03-22 2007-01-24 Nerve stimulation for treatment of obesity, metabolic syndrome, and Type 2 diabetes
PCT/US2007/013780 WO2007146287A2 (fr) 2006-06-09 2007-06-11 Stimulation nerveuse dynamique employant une modulation de fréquence

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US7689276B2 (en) 2002-09-13 2010-03-30 Leptos Biomedical, Inc. Dynamic nerve stimulation for treatment of disorders
US7239912B2 (en) 2002-03-22 2007-07-03 Leptos Biomedical, Inc. Electric modulation of sympathetic nervous system
US7702386B2 (en) 2002-03-22 2010-04-20 Leptos Biomedical, Inc. Nerve stimulation for treatment of obesity, metabolic syndrome, and Type 2 diabetes
US7689277B2 (en) 2002-03-22 2010-03-30 Leptos Biomedical, Inc. Neural stimulation for treatment of metabolic syndrome and type 2 diabetes
WO2010011969A1 (fr) 2008-07-24 2010-01-28 Boston Scientific Neuromodulation Corporation Système et procédé pour éviter, inverser, et gérer l'adaptation neurologique à une stimulation électrique
US8321030B2 (en) 2009-04-20 2012-11-27 Advanced Neuromodulation Systems, Inc. Esophageal activity modulated obesity therapy
US8788048B2 (en) * 2010-11-11 2014-07-22 Spr Therapeutics, Llc Systems and methods for the treatment of pain through neural fiber stimulation
US9119832B2 (en) 2014-02-05 2015-09-01 The Regents Of The University Of California Methods of treating mild brain injury

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US5188104A (en) * 1991-02-01 1993-02-23 Cyberonics, Inc. Treatment of eating disorders by nerve stimulation
US5458626A (en) * 1993-12-27 1995-10-17 Krause; Horst E. Method of electrical nerve stimulation for acceleration of tissue healing
US6542776B1 (en) * 1999-04-14 2003-04-01 Transneuronix Inc. Gastric stimulator apparatus and method for installing

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Title
See references of WO2007146287A2 *

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