Extremely low duty-cycle activation of the cholinergic anti-inflammatory pathway to treat chronic inflammation

• US 9,211,410 B2
• Filed: 07/21/2014
• Issued: 12/15/2015
• Est. Priority Date: 05/01/2009
• Status: Active Grant

• Current Assignee: Setpoint Medical Corporation
• Original Assignee: Setpoint Medical Corporation
• Inventors: Levine, Jacob A., Faltys, Michael A.
• Primary Examiner(s): GETZOW, SCOTT M
• Application Number:
  US14/336,942
• Publication Number:
  US 20140330349A1
• Time in Patent Office: 512 Days
• US Class Current: 1/1
• CPC Class Codes: A61N 1/36053 adapted for vagal stimulation A61N1/36114 takes precedence
• CPC Class Codes: A61N 1/36139 with automatic adjustment
• CPC Class Codes: A61N 1/36167 Timing, e.g. stimulation onset
• CPC Class Codes: A61N 1/36175 Pulse width or duty cycle
• CPC Class Codes: A61N 1/37205 Microstimulators, e.g. implantable through a cannula

Abstract

Described herein are systems and methods for applying extremely low duty-cycle stimulation sufficient to treat chronic inflammation with progressively longer delays (off periods) from an initial stimulation. In particular, described herein are supra-threshold pulses of electrical stimulation sufficient to result in a long-lasting (e.g., >48 hours) inhibition of pro-inflammatory cytokines and/or effects of chronic inflammation; the delay between initial doses (which may be single-pulse doses) may be extended for subsequent doses, potentially dramatically enhancing battery and device longevity.

Claims

1. A system for treating chronic inflammation in a subject, the system comprising:

an implantable microstimulator configured to apply a low duty-cycle stimulation to a vagus nerve; and

a controller adapted to set a dose regimen of progressively delayed supra-threshold stimulus pulses for the microstimulator, wherein the dose regimen comprises a first dose comprising a supra-threshold stimulus pulse followed by a first off-period of at least about 48 hours, a second dose comprising a supra-threshold stimulation pulse followed by a second off-period that is longer than the first off-period, and a series of sequential doses each comprising a supra-threshold stimulation pulse followed by an off-period that is longer than the second off-period, wherein the supra-threshold stimulus pulses are configured to reduce a level of inflammation in the subject.

2. The system of claim 1, wherein the first off-period is at least about 72 hours and the second off period is at least about 7 days.

3. The system of claim 1, wherein the first dose comprises a single supra-threshold stimulus pulse.

4. The system of claim 1, wherein the first does comprises a single burst of supra-threshold stimulus pulses.

5. The system of claim 1, wherein the first off-period is at least about 7 days and the second off period is at least about 10 days.

6. The system of claim 1, wherein the off-periods of the sequential doses are each at least about two weeks.

7. The system of claim 1, wherein the off-periods of the sequential doses are ramped up to a predetermined length of time.

8. The system of claim 1, further comprising an analyte detector configured to measure a level of an inflammatory analyte in the subject'"'"'s blood or bodily fluids.

9. The system of claim 1, wherein the controller is configured to adjust the second dose and subsequent doses based on the level of an inflammatory response in the subject.

10. The method of claim 1, wherein the controller is configured to adjust the second dose and subsequent doses based on the level of an inflammatory response analyte.

11. The system of claim 1, wherein the controller is configured to adjust the second off period based on the level of an inflammatory response in the subject.

12. The system of claim 1, wherein the controller is configured to adjust the second off period based on the level of the based on the level of an inflammatory analyte.

13. The system of claim 1, wherein the microstimulator comprises a sensing electrode configured to monitor vagus nerve activity.

14. The system of claim 1, wherein the microstimulator comprises a sensing electrode configured to monitor vagus nerve activity and further comprising a processor configured to process the monitored vagus nerve activity to determine a level of an inflammatory response.

15. A method of treating chronic inflammation in a subject by progressively increasing the off-times between stimulation, the method comprising:

applying a single supra-threshold stimulus from a microstimulator to a vagus nerve, wherein the delivery of the stimulus is followed by a first off-time of at least about 48 hours during which an inflammatory response is suppressed; and

applying subsequent supra-threshold stimuli, wherein each subsequent stimulus is followed by an off-time of longer than the first off-time.

16. The method of claim 15, wherein applying the single supra-threshold stimulus comprises applying a single burst of pulses.

17. The method of claim 15, wherein the first off-time is at least about 72 hours.

18. The method of claim 15, wherein the first off-time is at least about 7 days.

19. The method of claim 15, wherein the subsequent off-times are at least about two weeks.

20. The method of claim 15, wherein the subsequent off-times are ramped up from the first off-time to a longer predetermined length of time.

21. The method of claim 15, further comprising:

determining the level of an inflammatory response; and

adjusting the off-times following the subsequent supra-threshold stimuli based on the level of the inflammatory response.

22. The method of claim 15, further comprising determining the level of an inflammatory response by monitoring vagus nerve activity and adjusting the off-times following the subsequent supra-threshold stimuli based on the level of inflammation.

23. The method of claim 15, further comprising determining the level of an inflammatory response analyte in the subject'"'"'s blood or bodily fluids and adjusting the off-times following the subsequent supra-threshold stimuli based on the level of analyte.

24. A method of treating chronic inflammation in a subject by progressively increasing the off-times between stimulation, the method comprising:

applying, from an implanted microstimulator to a vagus nerve, a first dose comprising a supra-threshold stimulus, followed by a first off-time of at least about 48 hours, wherein the application of the first dose reduces the level of an inflammatory response in the subject;

applying a second dose comprising a supra-threshold stimulus, followed by a second off-time that is longer than the first off-time; and

applying subsequent doses comprising supra-threshold stimuli, wherein each does is followed by an off-time that is longer than the second off-time.